HANDBOOK OF ORGANOPALLADIUM CHEMISTRY FOR ORGANIC SYNTHESIS Volume 1
HANDBOOK OF ORGANOPALLADIUM CHEMISTRY FOR ORGANIC SYNTHESIS Volume 1
Edited by
Ei-ichi Negishi Purdue University West Lafayette, Indiana
A. de Meijere, Associate Editor Editorial Board
J. E. Bäckvall S. Cacchi T. Hayashi Y. Ito M. Kosugi S. I. Murahashi K. Oshima Y. Yamamato
A John Wiley & Sons, Inc., Publication
This book is printed on acid-free paper. Copyright © 2002 by John Wiley & Sons, Inc., New York. All rights reserved. Published simultaneously in Canada. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except as permitted under Sections 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4744. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, (212) 850-6011, fax (212) 850-6008, E-mail:
[email protected]. For ordering and customer service, call 1-800-CALL-WILEY. Library of Congress Cataloging-in-Publication Data is available. ISBN 0-471-31506-0
Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1
CONTENTS PREFACE
xix
CONTRIBUTORS
xxv
ABBREVIATIONS
xxxiii
VOLUME 1 I INTRODUCTION AND BACKGROUND I.1 Historical Background of Organopalladium Chemistry
3
Ei-ichi Negishi
I.2 Fundamental Properties of Palladium and Patterns of the Reactions of Palladium and Its Complexes
17
Ei-ichi Negishi
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION, IN SITU GENERATION, AND SOME PHYSICAL AND CHEMICAL PROPERTIES II.1 Background for Part II
39
Ei-ichi Negishi
II.2 Pd(0) and Pd(II) Compounds without Carbon–Palladium Bonds II.2.1 Metallic Palladium and Its Mixtures
41 41
Ei-ichi Negishi
II.2.2 Palladium Complexes Containing Halogen and Oxygen Ligands
43
Ei-ichi Negishi
II.2.3 Pd(0) and Pd(II) Complexes Containing Phosphorus and Other Group 15 Atom Ligands
47
Dani¯ele Choueiry and Ei-ichi Negishi
II.2.4 Pd(0) and Pd(II) Complexes Containing Sulfur and Selenium Ligands
67
Kunio Hiroi
II.2.5 Hydridopalladium Complexes
81
King Kuok (Mimi)Hii v
vi
CONTENTS
II.2.6 Palladium Complexes Containing Metal Ligands
91
Koichiro Oshima
II.2.7 Chiral Pd(0) and Pd(II) Complexes
103
Masamichi Ogasawara and Tamio Hayashi
II.3 Organopalladium Compounds Containing Pd(0) and Pd(II) II.3.1 General Discussion of the Methods of Synthesis and in-Situ Generation of Organopalladium Compounds
127 127
Ei-ichi Negishi
II.3.2 Stoichiometric Synthesis and Some Notable Properties of Organopalladium Compounds of Pd(0) and Pd(II)
147
Dani¯ele Choueiry
II.4 Palladium Complexes Containing Pd(I), Pd(III), or Pd(IV)
189
Allan J. Canty
III PALLADIUM-CATALYZED REACTIONS INVOLVING REDUCTIVE ELIMINATION III.1 Background for Part III
215
Ei-ichi Negishi
III.2 Palladium-Catalyzed Carbon–Carbon Cross-Coupling
229
III.2.1 Overview of the Negishi Protocol with Zn, Al, Zr, and Related Metals
229
Ei-ichi Negishi
III.2.2 Overview of the Suzuki Protocol with B
249
Akira Suzuki
III.2.3 Overview of the Stille Protocol with Sn
263
Masanori Kosugi and Keigo Fugami
III.2.4 Overview of Other Palladium-Catalyzed Cross-Coupling Protocols
285
Tamejiro Hiyama and Eiji Shirakawa
III.2.5 Palladium-Catalyzed Aryl–Aryl Coupling
311
Luigi Anastasia and Ei-ichi Negishi
III.2.6 Palladium-Catalyzed Alkenyl–Aryl, Aryl–Alkenyl, and Alkenyl–Alkenyl Coupling Reactions
335
Shouquan Huo and Ei-ichi Negishi
III.2.7 Heteroaromatics via Palladium-Catalyzed Cross-Coupling Kjell Undheim
409
CONTENTS
III.2.8 Palladium-Catalyzed Alkynylation III.2.8.1 Sonogashira Alkyne Synthesis
vii
493 493
Kenkichi Sonogashira
III.2.8.2 Palladium-Catalyzed Alkynylation with Alkynylmetals and Alkynyl Electrophiles
531
Ei-ichi Negishi and Carding Xu
III.2.9
Palladium-Catalyzed Cross-Coupling between Allyl, Benzyl, or Propargyl Groups and Unsaturated Groups
551
Ei-ichi Negishi and Fang Liu
III.2.10 Palladium-Catalyzed Cross-Coupling between Allyl-, Benzyl-, or Propargylmetals and Allyl, Benzyl, or Propargyl Electrophiles
591
Ei-ichi Negishi and Baiqiao Liao
III.2.11 Palladium-Catalyzed Cross-Coupling Involving Alkylmetals or Alkyl Electrophiles III.2.11.1 Palladium-Catalyzed Cross-Coupling Involving Saturated Alkylmetals
597 597
Ei-ichi Negishi and Sebastien Gagneur
III.2.11.2 Reactions between Homoallyl-, Homopropargyl-, or Homobenzylmetals and Alkenyl or Aryl Electrophiles
619
Ei-ichi Negishi and Fanxing Zeng
III.2.12 Palladium-Catalyzed Cross-Coupling Involving -Hetero-Substituted Organic Electrophiles III.2.12.1 Palladium-Catalyzed Cross-Coupling with Acyl Halides and Related Electrophiles
635 635
Takumichi Sugihara
III.2.12.2 Palladium-Catalyzed Cross-Coupling with Other -Hetero-Substituted Organic Electrophiles
649
Takumichi Sugihara
III.2.13 Palladium-Catalyzed Cross-Coupling Involving -Hetero-Substituted Organometals III.2.13.1 Palladium-Catalyzed Cross-Coupling Involving Metal Cyanides
657 657
Kentaro Takagi
III.2.13.2 Other -Hetero-Substituted Organometals in Palladium-Catalyzed Cross-Coupling
673
Fen-Tair Luo
III.2.14 Palladium-Catalyzed Cross-Coupling Involving -Hetero-Substituted Compounds
693
viii
CONTENTS
III.2.14.1 Palladium-Catalyzed -Substitution Reactions of Enolates and Related Derivatives Other than the Tsuji–Trost Allylation Reaction
693
Ei-ichi Negishi
III.2.14.2 Palladium-Catalyzed Cross-Coupling Involving -Hetero-Substituted Compounds Other than Enolates
721
Ei-ichi Negishi and Asaf Alimardanov
III.2.15 Palladium-Catalyzed Conjugate Substitution
767
Ei-ichi Negishi and Yves Dumond
III.2.16 Palladium-Catalyzed Asymmetric Cross-Coupling
791
Tamio Hayashi
III.2.17 Synthesis of Conjugated Oligomers and Polymers via Palladium-Catalyzed Cross-Coupling III.2.17.1 Synthesis of Conjugated Oligomers for Applications in Biological and Medicinal Areas
807 807
Bruce H. Lipshutz
III.2.17.2 Synthesis of Conjugated Polymers for Materials Science
825
A. Dieter Schlüter and Zhishan Bo
III.2.18 Synthesis of Natural Products via Palladium-Catalyzed Cross-Coupling
863
Ze Tan and Ei-ichi Negishi
III.2.19 Structural and Mechanistic Aspects of PalladiumCatalyzed Cross-Coupling
943
Christian Amatore and Anny Jutand
III.2.20 Palladium-Catalyzed Homocoupling of Organic Electrophiles or Organometals
973
Martin Kotora and Tamotsu Takahashi
III.3 Palladium-Catalyzed Carbon–Hydrogen and Carbon– Heteroatom Coupling III.3.1 Palladium-Catalyzed Hydrogenolysis
995 995
Anthony O. King and Robert D. Larsen
III.3.2 Palladium-Catalyzed Amination of Aryl Halides and Related Reactions
1051
John F. Hartwig
III.3.3 Palladium-Catalyzed Synthesis of Aryl Ethers and Related Compounds Containing S and Se
1097
John F. Hartwig
III.3.4 Palladium-Catalyzed Carbon–Metal Bond Formation via Reductive Elimination Akira Hosomi and Katsukiyo Miura
1107
CONTENTS
ix
IV PALLADIUM-CATALYZED REACTIONS INVOLVING CARBOPALLADATION IV.1 Background for Part IV
1123
Stefan Bräse and Armin de Meijere
IV.2 The Heck Reaction (Alkene Substitution via Carbopalladation– Dehydropalladation) and Related Carbopalladation Reactions IV.2.1 Intermolecular Heck Reaction IV.2.1.1 Scope, Mechanism, and Other Fundamental Aspects of the Intermolecular Heck Reaction
1133 1133 1133
Mats Larhed and Anders Hallberg
IV.2.1.2 Double and Multiple Heck Reactions
1179
Stefan Bräse and Armin de Meijere
IV.2.1.3 Palladium-Catalyzed Coupling Reactions for Industrial Fine Chemicals Syntheses
1209
Matthias Beller and Alexander Zapf
IV.2.2 Intramolecular Heck Reaction IV.2.2.1 Synthesis of Carbocycles
1223
Stefan Bräse and Armin de Meijere
IV.2.2.2 Synthesis of Heterocycles
1255
Gerald Dyker
IV.2.3 Asymmetric Heck Reactions
1283
Masakatsu Shibasaki and Futoshi Miyazaki
IV.2.4 Carbopalladation of Alkenes not Accompanied by Dehydropalladation
1317
Sergei I. Kozhushkov and Armin de Meijere
IV.2.5 Carbopalladation of Alkynes Followed by Trapping with Nucleophilic Reagents
1335
Sandro Cacchi and Giancarlo Fabrizi
IV.2.6 Carbopalladation of Alkynes Followed by Trapping with Electrophiles
1361
Vladimir Gevorgyan and Yoshinori Yamamoto
IV.3 Palladium-Catalyzed Tandem and Cascade Carbopalladation of Alkynes and 1,1-Disubstituted Alkenes IV.3.1 Palladium-Catalyzed Cascade Carbopalladation: Termination with Alkenes, Arenes, and Related -Bond Systems
1369
1369
Stefan Bräse and Armin de Meijere
IV.3.2 Palladium-Catalyzed Cascade Carbopalladation: Termination by Nucleophilic Reagents Stefan Bräse and Armin de Meijere
1405
x
CONTENTS
IV.3.3 Palladium-Catalyzed Tandem and Cascade Carbopalladation of Alkynes and 1,1-Disubstituted Alkenes Terminated by Carbonylative Reactions
1431
Ei-ichi Negishi and Christophe Copéret
IV.4
Allylpalladation and Related Reactions of Alkenes, Alkynes, Dienes, and Other -Compounds
1449
Takashi Takahashi and Takayuki Doi
IV.5
Alkynyl Substitution via Alkynylpalladation–Reductive Elimination
1463
Vladimir Gevorgyan
IV.6
Arene Substitution via Addition–Elimination
1471
IV.6.1 Arene Analogs of the Heck Reaction
1471
Keisuke Suzuki and Ken Ohmori
IV.6.2 Arene Substitution Involving Temporary Incorporation and Removal of Carbon Tethers via Carbopalladation and Decarbopalladation
1479
Marta Catellani
IV.7
Carbopalladation of Allenes
1491
Shengming Ma
IV.8
Synthesis of Natural Products via Carbopalladation
1523
James T. Link
IV.9
Cyclopropanation and Other Reactions of Palladium-Carbene (and Carbyne) Complexes
1561
Oliver Reiser
IV.10 Carbopalladation via Palladacyclopropanes and Palladacyclopropenes IV.10.1 Palladium-Catalyzed Oligomerization and Polymerization of Dienes and Related Compounds
1579 1579
James M. Takacs
IV.10.2 Palladium-Catalyzed Benzannulation Reactions of Conjugated Enynes and Diynes
1635
Shinichi Saito and Yoshinori Yamamoto
IV.10.3 Other Reactions Involving Palladacyclopropanes and Palladacyclopropenes
1647
Armin de Meijere and Oliver Reiser
IV.11 Palladium-Catalyzed Carbozincation Paul Knochel
1651
CONTENTS
xi
VOLUME 2 V PALLADIUM-CATALYZED REACTIONS INVOLVING NUCLEOPHILIC ATTACK ON LIGANDS V.1 Background for Part V
1663
Ei-ichi Negishi
V.2 Palladium-Catalyzed Nucleophilic Substitution Involving Allylpalladium, Propargylpalladium, and Related Derivatives V.2.1 The Tsuji–Trost Reaction and Related Carbon–Carbon Bond Formation Reactions V.2.1.1 Overview of the Palladium-Catalyzed Carbon– Carbon Bond Formation via -Allylpalladium and Propargylpalladium Intermediates
1669 1669
1669
Jiro Tsuji
V.2.1.2 Synthetic Scope of the Tsuji-Trost Reaction with Allylic Halides, Carboxylates, Ethers, and Related Oxygen Nucleophiles as Starting Compounds
1689
Lara Acemoglu and Jonathan M. J. Williams
V.2.1.3 Palladium-Catalyzed Allylation with Allyl Carbonates
1707
Marcial Moreno-Mañas and Roser Pleixats
V.2.1.4 Palladium-Catalyzed Allylation and Related Substitution Reactions of Enolates and Related Derivatives of “Ordinary” Ketones, Aldehydes, and Other Carbonyl Compounds
1769
Ei-ichi Negishi and Show-Yee Liou
V.2.1.5 Palladium-Catalyzed Substitution Reactions of Alkenyl Epoxides
1795
Christine Courillon, Serge Thorimbert, and Max Malacrìa
V.2.1.6 Palladium-Catalyzed Substitution Reactions of Sulfur and Other Heavier Group 16 Atom-Containing Allylic Derivatives
1811
Kunio Hiroi
V.2.1.7 Palladium-Catalyzed Substitution Reactions of Nitrogen and Other Group 15 Atom-Containing Allylic Derivatives
1817
Shun-Ichi Murahashi and Yasushi Imada
V.2.1.8 Palladium-Catalyzed Substitution Reactions with Propargyl and Related Electrophiles Tadakatsu Mandai
1827
xii
CONTENTS
V.2.1.9 Palladium-Catalyzed Reactions of Soft Carbon Nucleophiles with Dienes, Vinylcyclopropanes, and Related Compounds
1833
Hiroyuki Nakamura and Yoshinori Yamamoto
V.2.2 Palladium-Catalyzed Allylic, Propargylic, and Allenic Substitution with Nitrogen, Oxygen, and Other Groups 15–17 Heteroatom Nucleophiles V.2.2.1 Palladium-Catalyzed Substitution Reactions of Allylic, Propargylic, and Related Electrophiles with Heteroatom Nucleophiles
1845
1845
Tadakatsu Mandai
V.2.2.2 C—O and C—N Bond Formation Involving Conjugated Dienes and Allylpalladium Intermediates
1859
Pher G. Andersson and Jan-E. Bäckvall
V.2.2.3 Use of Alkenes as Precursors to -Allylpalladium Derivatives in Allylic Substitution with O, N and Other Heteroatom Nucleophiles
1875
Björn Åkermark and Krister Zetterberg
V.2.3 Palladium-Catalyzed Allylic, Propargylic, and Allenic Substitution with Hydrogen and Metal Nucleophiles V.2.3.1 Palladium-Catalyzed Hydrogenolysis of Allyl and Related Derivatives
1887 1887
Katsuhiko Inomata and Hideki Kinoshita
V.2.3.2 Palladium-Catalyzed Deprotection of Allyl-Based Protecting Groups
1901
Mark Lipton
V.2.3.3 Palladium-Catalyzed Allylic and Related Silylation and Other Metallations
1913
Yasushi Tsuji
V.2.3.4 Palladium-Catalyzed Reactions of Allyl and Related Derivatives with Organoelectrophiles
1917
Yoshinao Tamaru
V.2.4 Palladium-Catalyzed Asymmetric Allylation and Related Reactions
1945
Lara Acemoglu and Jonathan M. J. Williams
V.2.5 Other Reactions of Allylpalladium and Related Derivatives V.2.5.1 Elimination of Allylpalladium and Related Derivatives
1981 1981
Isao Shimizu
V.2.5.2 Cycloaddition Reactions of Allylpalladium and Related Derivatives Sensuke Ogoshi
1995
CONTENTS
V.2.5.3 Rearrangements of Allylpalladium and Related Derivatives
xiii
2011
Pavel Kocˇovsk´y and Ivo Star´y
V.2.6 Synthesis of Natural Products and Biologically Active Compounds via Allylpalladium and Related Derivatives
2027
Véronique Michelet, Jean-Pierre Genêt, and Monique Savignac
V.3 Palladium-Catalyzed Reactions Involving Nucleophilic Attack on -Ligands of Palladium–Alkene, Palladium–Alkyne, and Related Derivatives V.3.1 The Wacker Oxidation and Related Intermolecular Reactions Involving Oxygen and Other Group 16 Atom Nucleophiles V.3.1.1 The Wacker Oxidation and Related Asymmetric Syntheses
2119 2119 2119
Patrick M. Henry
V.3.1.2 Other Intermolecular Oxypalladation– Dehydropalladation Reactions
2141
Takahiro Hosokawa and Shun-Ichi Murahashi
V.3.1.3 Intermolecular Oxypalladation not Accompanied by Dehydropalladation
2161
Takahiro Hosokawa and Shun-Ichi Murahashi
V.3.2 Intramolecular Oxypalladation and Related Reactions Involving Other Group 16 Atom Nucleophiles V.3.2.1 Oxypalladation–Dehydropalladation Tandem and Related Reactions
2169 2169
Takahiro Hosokawa and Shun-Ichi Murahashi
V.3.2.2 Oxypalladation–Reductive Elimination Domino Reactions with Organopalladium and Hydridopalladium Derivatives
2193
Sandro Cacchi and Antonio Arcadi
V.3.3 Aminopalladation and Related Reactions Involving Other Group 15 Atom Nucleophiles
2211
V.3.3.1 Aminopalladation–Dehydropalladation and Related Reactions
2211
Takahiro Hosokawa
V.3.3.2 Aminopalladation–Reductive Elimination Domino Reactions with Organopalladium Derivatives
2227
Sandro Cacchi and Fabio Marinelli
V.3.4 Palladium-Catalyzed Reactions Involving Attack on Palladium–Alkene, Palladium–Alkyne, and Related -Complexes by Carbon Nucleophiles Geneviève Balme, Didier Bouyssi, and Nuno Monteiro
2245
xiv
CONTENTS
V.3.5 Palladium-Catalyzed Reactions via Halopalladation of -Compounds
2267
Xiyan Lu
V.3.6 Synthesis of Natural Products via Nucleophilic Attack on -Ligands of Palladium–Alkene, Palladium–Alkyne, and Related -Complexes
2289
Caiding Xu and Ei-ichi Negishi
VI PALLADIUM-CATALYZED CARBONYLATION AND OTHER RELATED REACTIONS INVOLVING MIGRATORY INSERTION VI.1 Background for Part VI
2309
Ei-ichi Negishi
VI.2 Migratory Insertion Reactions of Alkyl-, Aryl-, Alkenyl-, and Alkynylpalladium Derivatives Involving Carbon Monoxide and Related Derivatives VI.2.1 Reactions of Acylpalladium Derivatives with Oxygen, Nitrogen, and Other Group 15, 16, and 17 Atom Nucleophiles VI.2.1.1 Intermolecular Processes VI.2.1.1.1 Palladium-Catalyzed Carbonylation of Aryl and Vinylic Halides
2313
2313 2313 2313
Miwako Mori
VI.2.1.1.2 Palladium-Catalyzed Hydrocarboxylation and Related Carbonylation Reactions of -Bonded Compounds
2333
Bassam El Ali and Howard Alper
VI.2.1.2 Intramolecular Cyclization Processes via Palladium-Catalyzed Carbonylative Lactonization and Lactamization
2351
Vittorio Farina and Magnus Eriksson
VI.2.1.3 Tandem and Cascade Processes Terminated by Carbonylative Esterification, Amidation, and Related Reactions
2377
Hans-Günther Schmalz and Oliver Geis
VI.2.1.4 Palladium-Catalyzed Double Carbonylation Reactions
2399
Yong-Shou Lin and Akio Yamamoto
VI.2.2 Reactions of Acylpalladium Derivatives with Organometals and Related Carbon Nucleophiles Yoshinao Tamaru and Masanari Kimura
2425
CONTENTS
VI.2.3 Reactions of Acylpalladium Derivatives with Enolates and Related Amphiphilic Reagents
xv
2455
Ei-ichi Negishi and Hidefumi Makabe
VI.2.4 Synthesis of Aldehydes via Hydrogenolysis of Acylpalladium Derivatives
2473
Robert D. Larsen and Anthony O. King
VI.3 Migratory Insertion Reactions of Allyl, Propargyl, and Allenylpalladium Derivatives Involving Carbon Monoxide and Related Derivatives
2505
Tadakatsu Mandai
VI.4 Acylpalladation and Related Addition Reactions VI.4.1 Intramolecular Acylpalladation VI.4.1.1 Intramolecular Acylpalladation Reactions with Alkenes, Alkynes, and Related Unsaturated Compounds
2519 2519
2519
Christophe Copéret and Ei-ichi Negishi
VI.4.1.2 Intramolecular Acylpalladation with Arenes
2553
Youichi Ishii and Masanobu Hidai
VI.4.2 Polymeric Acylpalladation
2559
Giambattista Consiglio
VI.4.3 Other Intermolecular Acylpalladation
2577
Christophe Copéret
VI.4.4 Carbonylation of Alkenes and Alkynes Initiated by RXCO—Pd and RXCOO—Pd Bonds (X = N or O Group) VI.4.4.1 Carbonylation Processes Not Involving CO Incorporation into a Ring
2593 2593
Gian Paolo Chiusoli and Mirco Costa
VI.4.4.2 Cyclocarbonylation
2623
Bartolo Gabriele and Giuseppe Salerno
VI.5 Other Reactions of Acylpalladium Derivatives VI.5.1 Palladium-Catalyzed Decarbonylation of Acyl Halides and Aldehydes
2643 2643
Jiro Tsuji
VI.5.2 Formation and Reactions of Ketenes Generated via Acylpalladium Derivatives
2655
Hiroshi Okumoto
VI.6 Synthesis of Natural Products via Palladium-Catalyzed Carbonylation Miwako Mori
2663
xvi
CONTENTS
VI.7 Palladium-Catalyzed Carbonylative Oxidation VI.7.1 Palladium-Catalyzed Carbonylative Oxidation of Arenes, Alkanes, and Other Hydrocarbons
2683 2683
Yuzo Fujiwara and Chengguo Jia
VI.7.2 Palladium-Catalyzed Carbonylative Oxidation Other than Those Involving Migratory Insertion
2691
Shin-ichiro Uchiumi and Kikuo Ataka
VI.8 Synthesis of Oligomeric and Polymeric Materials via PalladiumCatalyzed Successive Migratory Insertion of Isonitriles
2705
Yoshihiko Ito and Michinori Suginome
VII CATALYTIC HYDROGENATION AND OTHER PALLADIUMCATALYZED REACTIONS VIA HYDROPALLADATION, METALLOPALLADATION, AND OTHER RELATED SYN ADDITION REACTIONS WITHOUT CARBON–CARBON BOND FORMATION OR CLEAVAGE VII.1 Background for Part VII
2715
Ei-ichi Negishi
VII.2 Palladium-Catalyzed Hydrogenation VII.2.1 Palladium-Catalyzed Heterogeneous Hydrogenation
2719 2719
Anthony O. King, Robert D. Larsen, and Ei-ichi Negishi
VII.2.2 Palladium-Catalyzed Homogeneous Hydrogenation VII.2.2.1 Palladium-Catalyzed Homogeneous Hydrogenation with Dihydrogen and Related Hydrogen Transfer Reactions
2753
2753
Anthony O. King
VII.2.2.2 Palladium-Catalyzed Hydrogenation Equivalents
2759
Fumie Sato
VII.2.3 Palladium-Catalyzed 1,4-Reduction (Conjugate Reduction)
2767
Ariel Haskel and Ehud Keinan
VII.3 Palladium-Catalyzed Isomerization of Alkenes, Alkynes, and Related Compounds without Skeletal Rearrangements
2783
Ei-ichi Negishi
VII.4 Palladium-Catalyzed Hydrometallation Hidefumi Makabe and Ei-ichi Negishi
2789
CONTENTS
VII.5 Metallopalladation
xvii
2825
Koichiro Oshima
VII.6 Palladium-Catalyzed Syn-Addition Reactions of X—Pd Bonds (X Group 15, 16, and 17 Elements)
2841
Akiya Ogawa
VIII PALLADIUM-CATALYZED OXIDATION REACTIONS THAT HAVE NOT BEEN DISCUSSED IN EARLIER PARTS VIII.1 Background for Part VIII
2853
Ei-ichi Negishi
VIII.2 Oxidation via Reductive Elimination of Pd(II) and Pd(IV) Complexes VIII.2.1 Homodimerization of Hydrocarbons via Palladium-Promoted C—H Activation
2859 2859
Yuzo Fujiwara and Chengguo Jia
VIII.2.2 Palladium-Promoted Alkene-Arene Coupling via C—H Activation
2863
Yuzo Fujiwara
VIII.3 Palladium-Catalyzed or -Promoted Oxidation via 1,2- or 1,4-Elimination VIII.3.1 Oxidation of Silyl Enol Ethers and Related Enol Derivatives to ,-Unsaturated Enones and Other Carbonyl Compounds
2873
2873
Yoshihiko Ito and Michinori Suginome
VIII.3.2 Oxidation of Amines, Alcohols, and Related Compounds
2881
Shun-Ichi Murahashi and Naruyoshi Komiya
VIII.3.3 Other Palladium-Catalyzed or -Promoted Oxidation Reactions via 1,2- or 1,4-Elimination
2895
Yuzo Fujiwara and Ei-ichi Negishi
VIII.4 Other Miscellaneous Palladium-Catalyzed or -Promoted Oxidation Reactions
2905
Ei-ichi Negishi
IX REARRANGEMENT AND OTHER MISCELLANEOUS REACTIONS CATALYZED BY PALLADIUM IX.1 Background for Part IX Ei-ichi Negishi
2915
xviii
CONTENTS
IX.2 Rearrangement Reactions Catalyzed by Palladium IX.2.1 Palladium-Catalyzed Carbon Skeletal Rearrangements IX.2.1.1 Cope, Claisen, and Other [3,3] Rearrangements
2919 2919 2919
Hiroyuki Nakamura and Yoshinori Yamamoto
IX.2.1.2 Palladium-Catalyzed Carbon Skeletal Rearrangements Other than [3, 3] Rearrangements
2935
Ei-ichi Negishi
IX.2.2 Palladium-Catalyzed Rearrangements of Oxygen Functions
2939
Masaaki Suzuki, Takamitsu Hosoya, and Ryoji Noyori
X TECHNOLOGICAL DEVELOPMENTS IN ORGANOPALLADIUM CHEMISTRY X.1 Aqueous Palladium Catalysis
2957
Irina P. Beletskaya and Andrei V. Cheprakov
X.2 Palladium Catalysts Immobilized on Polymeric Supports
3007
Tony Y. Zhang
X.3 Organopalladium Reactions in Combinatorial Chemistry
3031
Stefan Bräse, Johannes Köbberling, and Nils Griebenow
R REFERENCES R.1 General Guidelines on References Pertaining to Palladium and Organopalladium Chemistry
3129
Ei-ichi Negishi
R.2 Books (Monographs)
3137
Ei-ichi Negishi
R.3 Reviews and Accounts (as of September 1999)
3139
Ei-ichi Negishi and Fang Liu
SUBJECT INDEX
3173
PREFACE Organic compounds mostly consist of just ten to a dozen non-metallic elements including C, H, N, P, O, S, and halogens. This may be one of the main reasons why chemists, until relatively recently, tended to rely heavily on those reactions involving only non-metallic elements. Many of them including the Diels-Alder reaction, the Claisen and Cope rearrangements continue to be important. Even so, their combined synthetic scope has been rather limited. Regardless of how one defines metallic elements, more than three quarters of the elements may be considered to be metals. It is therefore not surprising that some of them, mostly main group metals such as Li, Na, K, and Mg, have been used as reagents or components of reagents for many decades primarily for generating carbanionic and other anionic species. Some other main group metals, such as Al and B, have also been used for many years primarily as components of Lewis acid catalysts in the Friedel-Crafts and other acid-catalyzed reactions. The significance of metal’s ability to readily provide lowlying empty orbitals has become gradually but widely recognized and led to the development of a modern synthetic methodology involving B, Al, and other predominantly Lewis-acidic main group metals. Some d-block transition metals (transition metals hereafter) including Ni, Pd, Pt, Rh, Ru, and so on have long been used as catalysts or catalyst components for hydrogenation and other reductions, while some others, such as Cr and Mn, have been used in stoichiometric oxidation reactions. Even some transition metal-catalyzed C!C bond-forming reactions, such as Roelen’s oxo process was discovered as early as 1938. However, it was not until the 1950s that the full synthetic potential of transition metals began to be recognized. The discovery and development of the Ziegler-Natta polymerization indicated the ability of some early transition metals, such as Ti and Zr, to serve as superior catalysts for C!C bond formation. Development of the Dewar-Chatt-Duncanson synergistic bonding scheme provided a theoretical foundation for the “carbenoidal” characteristic of transition metals, as discussed in Sect. II.3.1. The discovery of ferrocene in 1951 and the subsequent clarification of its structure triggered systematic investigations that have made available a wide range of metallocene and related transition metal complexes for reagents and catalysts. In the area of organopalladium chemistry, it is widely agreed that invention of the Wacker oxidation in 1959 may have marked the beginning of the modern Pdcatalyzed organic synthesis (Sect. I.1). Over the last thirty to forty years, compounds containing roughly ten to a dozen transition metals have been shown to serve as versatile and useful catalysts in organic synthesis. Today, they collectively represent the third major class of catalysts, enzymes and non-transition metal acids and bases being the other two. Of various factors, the following two appear to be critically responsible for rendering them superior catalysts and catalyst components. One is their ability to provide readily and simultaneously both filled nonbonding and low-lying empty orbitals. Together, they provide effective frontier orbitals, namely HOMO and LUMO, for concerted and synergistic interactions leading to xix
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low energy-barrier transformations. The other is their ability to undergo simultaneously and reversibly both oxidation and reduction under one set of reaction conditions. Then, why Pd? This is a very interesting but rather difficult question. Nonetheless, an attempt to answer this question is made in Sect. I.2, and the generalization summarized in Table 2 of Sect. I.2 is further supported by the experimental results presented throughout this Handbook. In short, Pd simultaneously displays wide-ranging reactivity and high stereo-, regio-, and chemo-selectivities. Its complexes are, in many respects, highly reactive. And yet, they are stable enough to be used as recyclable reagents and intermediates in catalytic processes. These mysteriously favorable characteristics appear to be reserved for just a few late second-row transition metals including Pd, Rh, and Ru that offer a combination of (i) moderately large atomic size and (ii) relatively high electronegativity, both of which render these elements very “soft”, in addition to (iii) ready and simultaneous availability of both filled nonbonding and empty valence-shell orbitals and (iv) ready and reversible availability of two oxidation states separated by two elections mentioned above. The general lack of serious toxicity problems and ease of handling, which may not require rigorous exclusion of air and moisture in many cases are two additional factors associated with them. The versatility of Pd is very well indicated by the contents of this Handbook listing nearly 150 authored sections spread over ten parts. This Handbook cannot and does not list all examples of the organopalladium reactions. However, efforts have been made to consider all conceivable Pd-catalyzed organic transformations and discuss all known ones, even though it was necessary to omit about ten topics for various unfortunate reasons. Part I discusses the historical background of organopalladium chemistry (Sect. I.1) as well as the fundamental properties and patterns of the reactions of Pd and its complexes (Sect. I.2). In Part II, generation and preparation of Pd complexes are discussed. These discussions are rather brief, as the main focus of this Handbook is placed on Pd-catalyzed organic transformations. In some of the previously published books on organopalladium chemistry, topics are classified according to the organic starting compounds. This may be a useful and readily manageable classification from the organometallic viewpoint. However, it is envisioned that the prospective readers and users of this Handbook are mostly synthetic organic chemists who are primarily interested in knowing how the organic compounds of their interest might be best prepared by using Pd complexes as catalysts. This perspective, however, does not readily lend itself to an attractive and satisfactory means of classifying the organopalladium chemistry. For both synthetic organic chemists and those who wish to learn more about the organopalladium chemistry from a more organometallic perspective, it appears best to classify the organopalladium chemistry according to some basic patterns of organometallic transformations representing the starting compound ! product relationships. As discussed in Sect. I.2, formation of carbon!carbon and/or carbon!heteroatom bonds through the use of organotransition metals can be mostly achieved via the following four processes: (i) reductive elimination, (ii) carbometallation, (iii) nucleophilic or electrophilic attack on ligands, and (iv) migratory insertion. As a versatile transition metal, Pd has been shown to participate in them all. Thus, in Part III, the Pd-catalyzed cross-coupling including the carbon-carbon crosscoupling represented by the Negishi, Stille, and Suzuki protocols as well as the Sonogashira alkynylation (Sect. III.2) and the more recently developed carbon-heteroatom coupling reactions (Sect. III.3) are presented. In most of these reactions, reductive
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elimination is believed to be a critical step. This is followed by Part IV in which a systematic discussion of carbopalladation represented by the Heck reaction (Sect. IV.2) is presented. The scope of carbopalladation, however, extends far beyond that of the Heck reaction, and these other topics are discussed in Sects. IV.3–IV.11. There are two major topics that pertain to nucleophilic attack on ligands of organopalladium complexes discussed in Part V. One is the Tsuji-Trost reaction. This and related reactions of allylpalladium derivatives are discussed in Sect. V.2. The other is the Wacker oxidation. This and related reactions involving Pd -complexes are discussed in Sect. V.3. In Part VI, carbonylation and other migratory insertion reactions of organopalladium compounds are discussed. In Parts III–VI, the significance of applications of the abovementioned reactions to the synthesis of natural products (Sects. III.2.17.1, III.2.18, IV.8, V.2.6, V.3.6, and VI.6) and polymers of material chemical interest (Sects. III.2.17.2, VI.4.2, and VI.8) are recognized and discussed in the sections shown in parentheses. Aside from the systematic classification mentioned above, the synthetic significance of Pd-catalyzed reduction and oxidation is abundantly clear. Some of those reduction and oxidation reactions that are not discussed in Parts III–VI are therefore discussed in Parts VII and VIII, respectively. It should be noted, however, that many of the reactions discussed in Parts III–VI also leads to oxidation or reduction of organic compounds. Despite the high propensity to undergo concerted reactions, organopalladium derivatives can also serve as sources of carbocationic species as indicated in Part V. In some cases, this can lead to skeletal rearrangements similar to the pinacol-pinacolone rearrangement. Other more concerted rearrangements are also observable, as discussed in Part IX. These reactions add extra dimensions to the diverse chemistry of organaopalladium compounds. Lastly, some significant technological developments including aqueous palladium catalysis (Sect. X.1), immobilized Pd catalysts (Sect. X.2) and combinatorial organopalladium chemistry (Sect. X.3) are making organopalladium chemistry even more important and useful in organic synthesis. Looking back, it all started when one of my senior colleagues, Professor H. Feuer, repeatedly visited my office several years ago to persuade me to write a book for VCH and later Wiley. Despite my initial firm determination not to write any book, a notion of preparing this Handbook on a topic that has occupied a significant part of my own research career grew in my mind, and I was finally persuaded by him and Dr. Barbara Goldman of Wiley. My life-long mentor and a 1979 Nobel Prize winner, Professor H. C. Brown, has directly and indirectly influenced and encouraged me throughout my career, including this Handbook writing. I wish to dedicate my own contributions to these two senior colleagues at Purdue. I should also like to acknowledge that, through the generosity of Professor and Mrs. Brown, the Herbert C. Brown Distinguished Professorship was established in 1999, of which I have been the very fortunate inaugural appointee. This has had many favorable influences on my involvement in this Handbook preparation. In this and other connections, I am very thankful to my colleagues in the Chemistry Department, especially Dean H. A. Morrison and former Head R. A. Walton. The actual overall and detailed layout of the Handbook was finalized during my twomonth stay in Göttingen, Germany, as an Alexandar von Humboldt Senior Researcher Awardee during the summer of 1998. My German host and Associate Editor of the Handbook, Professor A. de Meijere has not only enthusiastically supported my plan but also heavily contributed to the Handbook both as an author and as a member of the editorial board. I am also deeply indebted to the other eight editorial board members,
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namely Professors J. E. Bäckvall, S. Cacchi, T. Hayashi, Y. Ito, M. Kosugi, S. I. Murahashi, K. Oshima, and Y. Yamamoto. They all have contributed one or more sections and sacrificed their extremely precious time in the editorial phase. In fact, the ten editorial board members have authored and coauthored nearly one half of all sections. It is nonetheless unmistakably clear that this Handbook is a joint production by a community or group of 141 chemists and that the great majority of writing and drawing works have actually been performed by the 131 contributors whom I sincerely thank on behalf of the editorial board including myself. Without their massive contributions and cooperation, it would have been absolutely impossible to publish a book of this magnitude. It is my particular pleasure to note that no less than 21 current and former associates of my own research group have made their massive contributions and enthusiastically supported my activities. They are, in the order of appearance, D. Choueiry, L. Anastasia, S. Huo, C. Xu, F. Liu, B. Liao, S. Gagneur, F. Zeng, T. Sugihara, K. Takagi, F. T. Luo, A. Alimardanov, Y. Dumond, Z. Tan, M. Kotora, T(amotsu) Takahashi, A. O. King, C. Coperet, S. Ma, S. Y. Liou, and H. Makabe. While I must refrain from mentioning the names of the other 110 contributors, most of them are indeed my long-time colleagues and friends, to whom I deeply thank for their collaborations and contributions. I have also greatly appreciated and enjoyed collaborations with my new colleagues, some of whom I have not yet met. Many of my other esteemed colleagues were too busy to participate in the project. Some of them nevertheless made valuable suggestions that have been very useful in the planning stage. Typing and a significant part of drawing of our own manuscripts and, more importantly, a seemingly infinite number of correspondences as well as a myriad of other Handbook-related jobs have been handled by Ms. M. Coree (through 2000) and Ms. Lynda Faiola (since 2001). The preparation of this extensive Handbook would not have been possible without their dedicated work for which I am deeply thankful. Many direct and indirect assistances made by my wife, Sumire, and other members of my family are also thankfully acknowledged. Last but not least, I thank editorial staff members of Wiley, including compositors and freelancers, especially Dr. Barbara Goldman in the initial phase, Dr. Darla Henderson, Amy Romano, and Christine Punzo for their interest, encouragement, and collaboration in this project. One of the undesirable and yet inevitable consequences of this kind of publication requiring a few years of preparation time is that the book is outdated by at least a few years at the time of publication. There are at least two approaches to cope with this problem. One is to keep publishing as frequently as possible quick and hopefully up-to-date collections of reviews. This approach, however, is not conducive to a systematic, thorough, and penetrating discussion of the chosen topic. Each publication is outdated in due course and forgotten. The other is to publish once a systematic, comprehensive, and well-organized collection of authoritative and penetrating reviews and use it as the foundation for future periodical updating activities. I intend to use this Handbook in this manner. The part and section numbers have therefore been assigned with future updating in mind. They will indeed be retained and used in our future updating. Thus, it is my plan to continue surveying and classifying the Pd-related publications by abstracting them with the use of a computerized abstract form and assigning one to a few pertinent section numbers to each. The classified abstracts may then be published periodically in the conventional book form and/or electronically. Hopefully, these updates will, in turn, continuously revive and reinforce the value of the original Handbook. With the classified updated information, some
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seriously outdated sections may be revised and published as supplementary volumes at appropriate times. In this regard, I have already received oral consents from more than a dozen colleagues, and I am currently seeking a dozen or so additional collaborators. Ei-ichi Negishi Herbert C. Brown Distinguished Professor of Chemistry Purdue University, West Lafayette, Indiana
CONTRIBUTORS LARA ACEMOGLU, School of Chemistry, University of Bath, Bath, BA2 7AY United Kingdom. BJÖRN ÅKERMARK, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden. ASAF ALIMARDANOV, Chemical Process Research, DSM Pharmaceuticals, 5900 NW Greenville Boulevard, Greenville, North Carolina 27834, USA. HOWARD ALPER, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, K1N 9B4, Canada. CHRISTIAN AMATORE, Departement de Chimie, École Normale Superieure, UMR CNRS 8640, 24 Rue Lhomond 75231 Paris, Cedex 05, France. LUIGI ANASTASIA, Herbert C. Brown Laboratories of Chemistry, Purdue University, West Lafayette, Indiana 47907-1393, USA. PHER G. ANDERSSON, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE 106 91 Stockholm, Sweden. ANTONIO ARCADI, Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta di Scienze, Universita de L’Aquila Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy. KIKUO ATAKA, UBE Industries, Ltd., UBE Research Institute, 1978-5 Kogushi, Ube, Yamaguchi, 755-8633 Japan. JAN-E. BÄCKVALL, Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden. GENEVIÈVE BALME, Laboratoire de Chimie Organique 1, UMR 5622 du CNRS, Universite Claude Bernard Lyon 1, Bâtiment 308, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cédex, France. IRINA P. BELETSKAYA, Laboratory of Elementoorganic Compounds, Department of Chemistry, Moscow State University, Moscow, 119899, Russia. MATTHIAS BELLER, Institut für Organische Katalyseforschung an der Universität Rostock e.V., Buchbinderstr 5-6, Rostock, Germany 18055. ZHISHAN BO, Freie Universität Berlin, Institut für Organische Chemie, Takustr. 3, D-14195 Berlin, Germany. DIDIER BOUYSSI, Laboratoire de Chimie Organique 1, U.M.R. 5622 du CNRS, Universite Claude Bernard Lyon 1, Bâtiment 308, 43 Bd du 11 Novembre 1918, 69622 Villeurbanne Cédex, France. xxv
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STEFAN BRÄSE, Kekule-Institut für Organische Chemie und Biochemie der Rheinischen, Friedrich-Wilhelms-Universitat Bonn, Gerhard-Domagk-Strasse 1, D-53121 Bonn, Germany. SANDRO CACCHI, Dipartimento di Studi di Chimica e Tecnologia, delle Sostanze Biologicamente Attive, Universita degli Studi “La Sapienza,” P. le A. Moro, 5, I-00185 Rome, Italy. ALLAN J. CANTY, School of Chemistry, University of Tasmania, Hobart and Launceston, Tasmania, Australia. 7001. MARTA CATELLANI, Dipartimento di Chimica Organica e Industriale, Università degli Studi di Parma, Parco Area delle Scienze, 17/A, 43100 Parma, Italy. ANDREI V. CHEPRAKOV, Laboratory of Elementoorganic Compounds, Department of Chemistry, Moscow State University, 119899 Moscow, Russia. GIAN PAOLO CHIUSOLI, Dipartimento di Chimica Organica e Industriale, Università Degli Studi di Parma, Parco Area delle Scienze 17/A, I-43100 Parma, Italy. DANIÈLE CHOUEIRY, Lilly Development Centre SA, Parc Scientifique de Louvainla-Neuve, Rue Granbonpré 11, B-1348 Mont-Saint-Guibert, Belgium. GIAMBATTISTA CONSIGLIO, Laboratorium für Technische Chemie, ETH-Zentrum Universitätstrasse 6, CH-8092 Zürich, Switzerland. CHRISTOPHE COPÉRET, Laboratoire de Chimie, Organometallique de Surface, UMR 9986 CNRS-ESCPE Lyon, Bât. F308, 43 Bd du 11 Novembre 1918, F-69616 Villeurbanne, France. MIRCO COSTA, Dipartimento di Chimica Organica e Industriale, Università Degli Studi di Parma, Parco Area delle Scienze 17/A, I-43100 Parma, Italy. CHRISTINE COURILLON, Universite Pierre et Marie Curie (Paris VI), Laboratoire de Chimie Organique de Synthèse, Case 229, T.44, 2ET, 4 Place Jussieu, 75252 Paris, Cedex 05, France. ARMIN DE MEIJERE, Institut für Organische Chemie, Georg-August-Universität, Tammanstrasse 2, D-37077 Göttingen, Germany. TAKAYUKI DOI, Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo, 152-8552, Japan. YVES DUMOND, Roche Vitamins Ltd. VFCR Department, Bldg. 214, Room 0.62, CH4070 Basel, Switzerland. GERALD DYKER, Facbereich 6, der Universität-GH Duisburg, Lotharstrasse 1, 47048 Duisburg, Germany. BASSAM EL ALI, Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia. MAGNUS ERIKSSON, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road Ridgefield, Connecticut 06877-0368, USA. GIANCARLO FABRIZI, Dipartimento di Studi di Chimica e Tecnologia, delle Sostanze Biologicamente Attive, Universita degli Studi “La Sapienza,” P. leA. Moro, 5, Rome, Italy.
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VITTORIO FARINA, Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368, USA. KEIGO FUGAMI, Department of Chemistry, Faculty of Engineering, Gunma University, 1-5-1 Tenjin-cho, Kiryu, Gunma, 376-8515, Japan. YUZO FUJIWARA,
2-28-22 Tajima, Jyonanku, Fukuoka 814-0113, Japan.
BARTOLO GABRIELE, Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy. SEBASTIEN GAGNEUR, BASF Aktiengesellschaft, Functional Materials, ZDF/O-J 550, 67056 Ludwigshafen, Germany. OLIVER GEIS, Institut für Organische Chemie, Universitat zu Koeln, Greisnstraße 4, D-50939 Koeln, Germany. JEAN-PIERRE GENÊT, Ecole Nationale Superieure de Chimie de Paris, Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR C.N.R.S. 7573, 11, rue Pierre et Marie Curie, 75231, Paris, Cedex 05, France. VLADIMIR GEVORGYAN, Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois, 60607-7061, USA. NILS GRIEBENOW, Zentrale Forschung/Wirkstofforschung, Gebäude Q18, D-51368 Leverkusen, Germany. ANDERS HALLBERG, Department of Organic Pharmaceutical Chemistry, BMC, Uppsala University, SE-751 23 Uppsala, Sweden. JOHN F. HARTWIG, Department of Chemistry, Yale University, 350 Edwards, New Haven, Connecticut 06520-8107, USA. ARIEL HASKEL, Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. TAMIO HAYASHI, Department of Chemistry, Faculty of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan. PATRICK M. HENRY, Department of Chemistry, Loyola University of Chicago, 6525 North Sheridan Road, Chicago, Illinois, 60626, USA. MASANOBU HIDAI, Department of Materials Science and Technology, Faculty of Industrial Science and Technology, Science University of Tokyo, 2641 Yamazaki, Noda, Chiba, 278-8510, Japan. KING KUOK (MIMI) HII, King’s College London, Chemistry Department, Strand WC2R 2LS London, United Kingdom. KUNIO HIROI, Department of Synthetic Organic Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan. TAMEJIRO HIYAMA, Division of Material Chemistry, Graduate School of Engineering, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan. TAKAHIRO HOSOKAWA, Department of Environmental Systems Engineering, Kochi University of Technology, Tosayamada, Kochi, 782-8502, Japan.
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CONTRIBUTORS
AKIRA HOSOMI, Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8571, Japan. TAKAMITSU HOSOYA, Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu, 501-1193, Japan. SHOUQUAN HUO, Herbert C. Brown Laboratories of Chemistry, Purdue University, West Lafayette, Indiana, 47907-1393, USA. YASUSHI IMADA, Department of Chemistry, Graduate School of Engineering Science, Osaka University, Machikaneyama 1-3, Toyonaka, Osaka, 560-8531, Japan. KATSUHIKO INOMATA, Department of Chemistry, Faculty of Science, Kanazawa University, Kakuma, Kanazawa Ishikawa, 920-1192, Japan. YOUICHI ISHII, Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan. YOSHIHIKO ITO, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan. CHENGGUO JIA, Department of Chemistry, University of Waterloo 200 University Ave., W. Waterloo, ON N2L 3G1, Canada. ANNY JUTAND, Departement de Chimie, École Normale Superieure, 24 Rue Lhomond 75231 Paris, Cedex 05, France. EHUD KEINAN, Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd. MB20, La Jolla, California, 92037, USA. MASANARI KIMURA, Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, Nagasaki, Japan. ANTHONY O. KING, Process Research Dept., Merck & Co., Inc., West Scott Ave. RY800-C262 Rahway, New Jersey, 07065, USA. HIDEKI KINOSHITA, Laboratory of Organic Chemistry, Department of Chemical Science, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa Ishikawa, 920-1192, Japan. PAUL KNOCHEL, Institut für Organische Chemie, Ludwig-Maximilians-Universität, Butenandstrr. 5-13, D-81377 München, Germany. JOHANNES KÖBBERLING, Institut für Organische Chemie, RWTH Aachen, ProfessorPirlet-Strafe 1, D-52074 Aachen, Germany. PAVEL KOCˇ OVSKY´, Department of Chemistry, University of Glasgow, Glasgow, G12 8QQ, United Kingdom. NARUYOSHI KOMIYA, Department of Chemistry, Graduate School of Engineering Science, Osaka University, Machikaneyama 1-3, Toyonaka, Osaka, 560-8531, Japan. MASANORI KOSUGI, Department of Chemistry, Gunma University, Kiryu, Gunma, 376-8515, Japan. MARTIN KOTORA, Department of Organic and Nuclear Chemistry, Faculty of Science, Charles University, Hlavova 8, 12840 Praha 2 Czech Republic.
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SERGEI I. KOZHUSHKOV, Institut für Organische Chemie, der Georg-August-Universität, Tammanstrasse 2 D-37077 Göttingen, Germany. MATS LARHED, Department of Organic Pharmaceutical Chemistry, Uppsala University, SE-751 23 Uppsala, Sweden. ROBERT D. LARSEN, Dept. of Process Research, 126 E. Lincoln Ave, Merck & Co., Inc., Rahway, New Jersey, 07065, USA. BAIQIAO LIAO, USA.
c/o Mr. Xiao Mu Zheng 6969 Richfield Dr. Reynoldsburg, Ohio, 43068,
YONG-SHOU LIN, Materials R&D, E-One Moli Energy (Canada) Ltd., 20,000 Stewart Crescent, Maple Ridge, British Columbia, Canada. V2X 9E7. JAMES T. LINK, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois, 600646098, USA. SHOW-YEE LIOU, Chemical Abstracts Service, 2540 Olentangy River Rd., Columbus, Ohio, 43210, USA. BRUCE H. LIPSHUTZ, Department of Chemistry, University of California, Santa Barbara, California, 93106, USA. MARK A. LIPTON, Herbert C. Brown Laboratories of Chemistry, Purdue University, West Lafayette, Indiana, 47907-1393, USA. FANG LIU,
795 Brunsdorph Rd. Fairlawn, Ohio 44333 USA.
XIYAN LU, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, China. FEN-TAIR LUO, Institute of Chemistry, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, Taiwan. 11529. SHENGMING MA, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai, 200032, Peoples Republic of China. HIDEFUMI MAKABE, Department of Bioscience and Biotechnology, Shinshu University, 8304 Minamiminowa Kamiina, Nagano, 399-4598, Japan. MAX MALACRÌA, Universite Pierre et Marie Curie (Paris VI), Laboratoire de Chimie Organique de Synthèse, 75252 Paris, Cedex 05, France. TADAKATSU MANDAI, Department of Chemistry and Bioscience, Kurashiki University of Science and the Arts, 2640 Nishinoura, Tsurajima, Kurashiki, 712-8505, Japan. FABIO MARINELLI, Dipartimento di Chimica Ingegneria Chimica e Materiali della Facolta di Scienze, Universita de L’Aquila, Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy. VÉRONIQUE MICHELET, École Nationale Superieure de Chimie de Paris, Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR C.N.R.S. 7573, 11, rue Pierre et Marie Curie, 75231 Paris, Cedex 05, France. KATSUKIYO MIURA, Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Ibaraki, 305-8571, Japan.
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FUTOSHI MIYAZAKI, Elsai Co., Ltd., 1–3, Tokodai 5-chome, Tsukubashi, Ibaraki, 300-2635 Japan. NUNO MONTEIRO, Laboratoire de Chimie Organique 1, Universite Claude Bernard Lyon 1, 69622, Villeurbanne Cédex, France. MARCIAL MORENO-MAÑAS, Department of Chemistry, Universitat Autònoma de Barcelona, Edifici C, 08193 Cerdanyola (Barcelona), Spain. MIWAKO MORI, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan. SHUN-ICHI MURAHASHI, Department of Applied Chemistry, Okayama University of Science, Ridai-cho 1-1 Okayama, 700-0005, Japan. HIROYUKI NAKAMURA, Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan. EI-ICHI NEGISHI, Herbert C. Brown Laboratories of Chemistry, Purdue University, West Lafayette, Indiana, 47907-1393, USA. RYOJI NOYORI, Department of Chemistry, Faculty of Science, Nagoya University, Chikusa, Nagoya, 464, Japan. MASAMICHI OGASAWARA, Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan. AKIYA OGAWA, Department of Chemistry, Faculty of Science, Nara Women’s University, Kitauoyanishi-machi, Nara, 630-8506, Japan. SENSUKE OGOSHI, Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka, 565-0871, Japan. KEN OHMORI, Department of Chemistry, Tokyo Institute of Technology, 2-12-1, O-okayama, Meguro-ku, Tokyo, 152-8551, Japan. HIROSHI OKUMOTO, Department of Chemistry and Bioscience, Kurashiki University of Science and the Arts, 2640 Nishinoura Tsurajima, Kurashiki, 712-8505, Japan. KOICHIRO OSHIMA, Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Sakyo, Kyoto, 606-8501 Japan. ROSER PLEIXATS, Department of Chemistry, Universitat Autònoma de Barcelona, Edifici C, 08193 Cerdanyola (Barcelona), Spain. OLIVER REISER, Universität Regensburg, Institut für Organische Chemie, Universitätsstr. 31, 93053 Regensburg, Germany. SHINICHI SAITO, Organometallic Chemistry Lab, The Institute of Physical and Chemical Research (RIKEN), Wako, Saitama, 351-0198, Japan. GIUSEPPE SALERNO, Dipartimento di Chimica, Università della Calabria, 87030 Arcavacata di Rende, Cosenza, Italy. FUMIE SATO, Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
CONTRIBUTORS
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MONIQUE SAVIGNAC, École Nationale Superieure de Chimie de Paris, Laboratoire de Synthèse Sélective Organique et Produits Naturels, UMR C.N.R.S. 7573, 11 rue Pierre et Marie Curie, 75231 Paris, Cedex 05, France. A. DIETER SCHLÜTER, Freie Universität Berlin, Institut für Chemie/Organische Chemie, Takustrasse 3, D-14195 Berlin, Germany. HANS-GÜNTHER SCHMALZ, Institute of Organic Chemistry, University zu Koeln, Greinstrasse 4, D-50939 Koeln, Germany. MASAKATSU SHIBASAKI, Faculty of Pharmaceutical Science, University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-003, Japan. ISAO SHIMIZU, Department of Applied Chemistry, School of Science & Engineering, Waseda University, Okuba 3-4-1, Shinjuku, Tokyo, 169-8555, Japan. EIJI SHIRAKAWA, Graduate School of Materials Science, Japan Advanced Institute of Science and Technology, Asahidai, Tatsunokuchi, Ishikawa, 923-1292, Japan. KENKICHI SONOGASHIRA, Department of Applied Science and Chemistry, Faculty of Engineering, Fukui University of Technology, 3-6-1, Gakuen, Fukui, 910-8505, Japan. ´, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of IVO STARY the Czech Republic, Flemingovo 2, 16610 Prague 6, Czech Republic. TAKUMICHI SUGIHARA, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho Tokushima, 770-8514, Japan. MICHINORI SUGINOME, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan. AKIRA SUZUKI, Department of Chemical Technology, Kurashiki University of Science and the Arts, Kurashiki, 712-8505, Japan. KEISUKE SUZUKI, Department of Chemistry, Tokyo Institute of Technology, O-okayama, Meguro-ku, Tokyo, Japan. MASAAKI SUZUKI, Department of Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu, 501-1193, Japan. JAMES M. TAKACS, Department of Chemistry-841 HAH, University of Nebraska-Lincoln, Lincoln, Nebraska, 68588-0304, USA. KENTARO TAKAGI, Department of Chemistry, Faculty of Science, Okayama University, Tsushima-naka, Okayama, 700-8530, Japan. TAKASHI TAKAHASHI, Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro, Tokyo, 152-8552, Japan. TAMOTSU TAKAHASHI, Catalysis Research Center, Hokkaido University, Sapporo, 060, Japan. YOSHINAO TAMARU, Department of Applied Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo, Nagasaki, 852-8521, Japan.
xxxii
CONTRIBUTORS
ZE TAN, Herbert C. Brown Laboratories of Chemistry, Purdue University, West Lafayette, Indiana, 47907-1393, USA. SERGE THORIMBERT, Universite Pierre et Marie Curie (Paris VI), Laboratoire de Chimie Organique de Synthese, Case 229, T. 44 2éme ET., 04 Place Jussieu, 75252 Paris, Cedex 05, France. JIRO TSUJI, Professor Emeritus of Tokyo Institute of Technology, Tsu 602-128 Kamakura, 248-0032, Japan. YASUSHI TSUJI, Catalysis Research Center, Hokkaido University, Sapporo, 060-0811, Japan. SHIN-ICHIRO UCHIUMI, Corporate Research and Development, UBE Industries, Ltd., 1978-5 Kogushi, Ube, Yamaguchi, 755-8633, Japan. KJELL UNDHEIM, Department of Chemistry, University of Oslo, Blindern, 0315 Oslo, Norway. JONATHAN M. J. WILLIAMS, School of Chemistry, University of Bath, Bath, BA2 7AY, United Kingdom. CAIDING XU, Affymax Research Institute, 4001 Miranda Ave. Palo Alto, California 94304, USA. AKIO YAMAMOTO, Advanced Research Institute for Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo, 169-8555, Japan. YOSHINORI YAMAMOTO, Department of Chemistry, Graduate School of Science, Tohoku University, Sendai, 980-8578, Japan. ALEXANDER ZAPF, Institut für Organische Katalyseforschung an der Universität Rostock E.V. (IfOK), Buchbinderstr. 5-6, D-18055 Rostock, Germany. FANXING ZENG, Herbert C. Brown Laboratories of Chemistry, Purdue University, West Lafayette, Indiana, 47907-1393, USA. KRISTER ZETTERBERG, School of Chemistry and Chemical Engineering, Royal Institute of Technology, Teknikringen 56, S-100 44 Stockholm, Sweden. TONY Y. ZHANG, Lilly Research Laboratories DC 4813, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
ABBREVIATIONS
Ac, Acetyl acac, Acetylacetonate AIBN, Azobis(isobutyronitrile) AMPHOS, 2,2–Bis(diphenylarsino)–1,1 binaphthyl Ar, aryl 9-BBN, 9–Borabicylo[3.3.1.]nonane BHT, 2,6-Di-tert-butyl-4-methylphenol BINAP, (2R, 3S), 2,2-Bis-(diphenylphosphino)-1,1-binapthyl BINAPO, 2-Diphenylphosphino-1,1-binaphthalenyl-2-ol BINAS, 2,2–Bis(diphenylarsino)–1,1 binaphthyl BIPHEMP, 2,2-Bis(diphenylphosphino)6,6-dimethylbiphenyl Bipy(BPY), Bipyridine Bn, Benzyl Bz, Benzoyl BNPPA, Binaphthyl–2,2– dyl hydrogenphosphate BPPFA, N–Dimethyl–1–[1,2– bis(diphenylphosphino)ferrocenyl] ethylamine BPPFOH, (R)––[(S)–1,2– Bis(dipnenylphosphino)ferrocenyl] ethyl alcohol BPPM, 1–t–Butoxycarbonyl–4–diphenylphosphino–2–(diphenylphosphinomethyl) azolidine BSA, Bistrimethylsilyl acetamide, N, O–Bis(trimethylsilyl)acetamide BTMC, Benzyltrimethylammonium carbonate Bu, Butyl c-, CycloCAN, Ceric ammonium nitrate
Cbz, Carbobenzyloxy CHIRAPHOS, (R,R)- or (S,S)- 2,3Bis(diphenylphosphino)butane COD, Cyclooctadiene Cp, Cyclopentadienyl CSA, Camphosulfonic acid Cy, Cyclohexyl DABCO, 1,4-Diazobicyclo[2.2.2]octane DBA(often shown as dba), Dibenzalacetone DBN, 1,5-Diazabicyclo[4.3.0] non-5-ene DBPF, 1–Bis–di–t–butylphosphinoferrocene DBU, 1,8-Diazabicyclo[5.4.0] undec-7-ene DCC, 1,3-Dicyclohexylcarbodiimide DCD model, Dewar–Chatt–Duncanson model DCE, Dichloroethane DDQ, 2,3-Dichloro-5,6-dicyano-1, 4benzoquinone DEA, Diethylamine DEAD, Diethylazodicarboxylate Dec, Decyl DFT, Density functional theory DIBAH, Diisobutylaluminum hydride DIBAL-H DIBAH (sometimes shown as DIBAL) DIEA, Diisopropylethylamine DIOP, (4R,5R)–trans–4,5– Bis[(diphenylphosphino)methyl]– 2;2–dimethyl–1,3–dioxolane, Diphos, See DPE. DMA, N,N–Dimethylacetamide DMAD, Dimethyl acetylenedicarboxylate DMAP, 4-Dimethylaminopyridine DME, Dimethoxyethane DMF, Dimethylformamide DMI, 1,3–Dimethyl–2–imidazolidinone, N,N–Dimethyl–2–imidazolidinone xxxiii
xxxiv
ABBREVIATIONS
DMSO, Dimethylsulfoxide DP, Degrees of polymerization DPEphos, Bis(o-diphenylphosphinophenyl) ether DPEPY, 2–(2–Diphenylphosphinoethyl)pyridine DPMEPY, 2–(Diphenylphosphonomethyl)pyridine DPPB (dppb), 1,4–bis(Diphenylphosphino)butane DPPE (dppe), 1,2-Bis(diphenylphosphino)ethane DPPF (dppf), Bis-(diphenylphosphino)ferrocene DPPP (dppp), 1,3–Bis-(diphenylphosphino)propane EDA, Ethylenediamine EL, Electroluminescence Et, Ethyl EWG, Electron–withdrawing group FBS, Fluorous biphasic system FOS, Formal oxidation state GPC, Gel permeation chromatography Hex, Hexyl HIV, Human immunodeficiency virus HMDS, Hexamethyldisilazane HMPA, Hexamethylphosphoramide HOMO, Highest occupied molecular orbital ICPs, Integrated chemical processes i-, Iso- i-Pr or iPr, Isopropyl L, Ligand LAH, Lithium aluminum hydride, LiAlH4 LDA, Lithium diisopropylamide LED, Light–emitting diodes LUMO, Lowest unoccupied molecular orbital MCPBA, m-Chloroperoxybenzoic acid MCR, Multicomponent reactions Me, Methyl MEM, -Methoxyethoxymethyl Mes, Mesityl Ms, Mesyl, Methanesulfonyl MOM, Methoxymethyl MOP ligands, 2-(Diphenylphosphino)-2 -methoxy-1,1-binaphthyl n-, Normal Naph, Naphthyl
NBS, N-Bromosuccinimide NCS, N-Chlorosuccinimide NDMBA, N,N–Dimethylbarbituric acid NIS, N-Iodosuccinimide NIT, Nitronyl nitroxide NMM, N–methylmorpholine NMP, N–Methylpyrrolidone NMR, Nuclear magnetic resonance NOE, Nuclear Overhauser effect. NORPHOS, 2,3Bis(diphenylphosphino)bicyclo[2.2.1] hept-5-ene Oct, Octyl PAA, Polyacrylamide PCC, Pyridinium chlorochromate PDC, Pyridinium dichromate PEG, Polyethylene glycol Pent, Pentyl PFS, Pentafluorostyrene PG, Prostaglandin Ph, Phenyl PHANEPHOS, 4,12-Bis(diphenylphosphino)[2.2]paracyclophane Phen, 1, 10-Phenanthroline PHOPHOS, 2,2–Bis(diphenylarsino)–1,1binaphthyl PL, Photoluminescence PMHS, Polymethylhydrosiloxane PMP, 1, 2, 6–Pentamethylpiperidine PPA, Polyphosphoric acid PPE, Poly(phenylene ethinylene) PPP, Poly(para-phenylene) Pr, n-Propyl Py, Pyridine PROPHOS, 1,2Bis(diphenylphosphino)propane PTA, 1,3,5–Triaza–7–phosphaadamantane PTC, Phase–transfer catalyst PTSA, p-Toluenesulfonic acid R, An organic group RAMP, R-()-Amino-2(methoxymethyl)pyrrolidine Rf, Perfluoroalkyl Red-Al, Na[AlH2(MeOCH2CH2O)2] SAMP, S-( )-Amino-2(methoxymethyl)pyrrolidine Sec; s, Secondary s-Bu, sBu, sec-Bu, Secondary butyl.
ABBREVIATIONS
SEM, 2-(Trimethylsilyl)ethoxymethyl (S)-(R)-BPPFA, Ferrocenylbisphosphine (S)-(R)-PPFA, Ferrocenylmonophosphine tert, t, Tertiary TADDOL ,,,-tetraaryl-4,5dimethoxy-1,3-dioxolane TASF, Tris-(Diethylamino)sulfonium difluorotrimethyl silicate TBAF, Tetrabutylammonium fluoride TBDMS, tert–Butyldimethylsilyl TBS TBDMS t-Bu, tBu, tert-Bu, Tertiary butyl TCPP, Tris(p–chlorophenyl)phosphine TDMPP, Tris(2,6–dimethoxyphenyl) phosphine TEBA, Triethylbenzylammonium chloride Terpy, Terpyridine Tf, Trifluoromethanesulfonyl, triflyl TFA, Trifluoroacetic acid TFP, Tris(2–furyl)phosphine
xxxv
THF, Tetrahydrofuran THP, Tetrahydropyran(yl) TIBAH, Triisobutylaluminum TMDHS, Tetramethyldihydrosiloxane TMEDA, Tetramethylethylenediamine TMM, Trimethylenemethane TMM-Pd, Trimethylenemethane palladium TMOF, Trimethyl orthoformate TMS, Trimethylsilyl TMU, N,N,N,N–Tetramethylurea TOF, Turnover frequency Tol, Tolyl Tol-BINAP, 2,2-Bis(di-p-tolylphosphino)1,1-binaphthyl TON, Turnover number TPPTS, Triphenylphosphane m– trisulfonate sodium salt Tr, Trityl Ts, Tosyl, p-Toluenesulfonyl WGS, Water gas shift reaction
PART I Introduction and Background
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
Historical
I.1
Historical Background of Organopalladium Chemistry EI-ICHI NEGISHI
This Handbook is all about the use of palladium (Pd) mostly as a component of catalysts for organic synthesis. Today, it is widely recognized that Pd has very significantly changed and improved the art of organic synthesis over the last three decades. It seems reasonable to state that Pd already is one of the most versatile, useful, and hence significant metals in organic synthesis along with Li, Mg, B, Cu and a few others and that its significance is still sharply rising. Over 1000 research publications dealt with the use of Pd mostly in organic synthesis in 1998 alone. One question this author has frequently encountered is: Why is Pd so versatile and useful? This is indeed a good question, which is not so easy to answer, but some attempts will be made later in Sect. I.2. In this section, however, let us look back and try to become acquainted with some of the notable events in the history of organopalladium chemistry with emphasis on the use of Pd in organic synthesis. In 1912 V. Grignard and P. Sabatier shared, for the first time, a Nobel Prize in chemistry.[1] It is striking to note that the significance of both Grignard’s mostly stoichiometric main group organometallic chemistry and Sabatier’s catalytic transition metal chemistry were correctly recognized in a largely prophetic manner by the Royal Swedish Academy of Sciences almost a century ago. It is also striking that the developments of both areas up to that point were rather slow, circuitous, and evolutionary in many ways. The discovery and development of Grignard reagents spanned roughly half a century after Frankland’s discovery of Et2Zn as the first well-recognized main group organometallic compounds in 1849.[2] It took a few to several decades before organomagnesium chemistry, developed mainly by Barbier,[3] supplanted that of organozincs. Subsequent studies by Grignard led to the discovery and development of the Grignard reagents.[4] The significance and synthetic utility of the Grignard reagents have only increased with time. Along with organolithiums developed later,[5] they continue representing one of the most important classes of organometallic compounds. The development of organopalladium chemistry for organic synthesis has been even more sluggish than that of the organometallic chemistry of Mg and Li. It has been reported[6] that Wollaston in London discovered and isolated Pd in 1803 and named it after the asteroid Pallas, which was discovered a year before. Although an ethylene
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
3
4
I INTRODUCTION AND BACKGROUND
complex of Pt, commonly known as Zeise’s salt, was reported as early as 1827,[7] little was known a bout either organopalladiums or the use of Pd in organic synthesis during the 19th century. Sabatier’s systematic investigation of catalytic hydrogenation[8],[9] about a century ago was instrumental in laying the foundation for the widespread use of catalytic hydrogenation in both academia and industry. However, he clearly stated in his Nobel lecture[9] that catalytic hydrogenation of acetylene with H2 over Pt black producing ethylene and/or ethane had been reported by von Wilde in 1874.[10] Moreover, if his Nobel Lecture is an accurate indication, he used mostly Ni along with Pt, Co, Cu, and Ag but perhaps not Pd. As cited by von Wilde, the earliest work on the reduction with H2 over transition metals appears to be that conceived and suggested by Kolbe[11] and performed under his guidance and reported by Saytzeff [12] on the reduction of benzophenone and related carbonyl compounds with H2 over Pd. By 1912, however, the use of Pd in catalytic reduction including that of alkenes and alkynes had been reported by various chemists including Paal and Amberger[13] and Wieland,[14] and the autoclave technology permitting high-pressure catalytic hydrogenation had been introduced by Ipatieff.[15] As clearly established later, organopalladiums serve as intermediates in these reactions. In this Handbook, catalytic hydrogenation and related addition reactions are discussed mainly in Part VII, with other related reactions being discussed in several other sections including II.2.1, II.2.5, III.3.1, and VI.2.4. As important as these earlier developments of Pd-catalyzed hydrogenation and related reduction reactions were in the area of organic synthesis, they nevertheless represented an isolated, largely technological, and practical discipline and had remained so until recently. Neither Roelen’s development[16] of the “oxo” process in the 1930s nor the wide-scope investigations of organotransition metal chemistry led by Reppe[17] during World War II made Pd an important transition metal for organic synthesis, even though Pd may have shown some catalytic activities in these investigations. Invention of the Wacker process[18] in 1959 and its subsequent development represent one of the most important milestones in the history of organopalladium chemistry. Although not widely known, the stoichiometric conversion of ethylene to acetaldehyde by the action of PdCl2 under aqueous conditions, which was accompanied by precipitation of Pd black, was reported as early as 1894.[19] Aside from the historical intricacy, however, the catalytic hydrogenation and the Wacker oxidation firmly established that Pd and its compounds can serve as catalysts for both reduction and oxidation. At its core, the Wacker process involves a stoichiometric oxypalladation – dehydropalladation tandem (Scheme 1), and the development of a catalytic process required an exquisitely engineered two-stage oxidation involving O2 and CuCl2,[18] (Scheme 2), as detailed in Sect. V.3. More recent results have clearly indicated that the scope of the Wacker oxidation can be and has indeed been expanded far beyond the initial oxidation of ethylene and 1-alkenes to give aldehydes and ketones. Thus, related aminopalladation, halopalladation, and other addition reactions of heteroatomPd bonds have been developed. Furthermore, these addition reactions can provide organopalladium intermediates that can be used further for the formation of additional bonds including C — C bonds (Sect. V.3). In the meantime, many other types of oxidation reactions catalyzed by Pd have also been discovered and developed. These other Pd-catalyzed oxidation reactions are discussed in Part VIII. For some practical reasons, however, a few additional oxidation reactions involving C — C bond formation are discussed in earlier sections, such as Sects. III.2.20, VI.4.4, and VI.7.
I.I HISTORICAL BACKGROUND OF ORGANOPALLADIUM CHEMISTRY
OH2
PdCl2, H2O
H2C CH2
5
OH
oxypalladation
H2C CH2 + HX
H2C CH2
XPd
X2Pd Scheme 1 H2C CH2
+
Pd(II)Cl2 +
H2O
ClPdCH2CH2OH
ClPdCH2CH2OH Pd(0) 2 Cu(I)Cl
+
+
2 HCl
2 Cu(II)Cl2 +
H2C CH2
1 2
O2
+
1 2
cat.
HCl
CH3CHO
+
Pd(II)Cl2
+ 2 Cu(I)Cl
2 Cu(II)Cl2 + O2
+
Pd(0)
+
HCl
H2O
CH3CHO
cat. = PdCl 2, CuCl2 Scheme 2
Mechanistic consideration of the Wacker reaction, which is thought to involve nucleophilic attach of ethylene complexed with Pd by H2O, led to the discovery of a carbon–carbon bond-forming reaction of 1,5-cyclooctadiene – Pd -complex with ethyl malonate in the presence of Na2CO3 by Tsuji et al. in 1965[20] (Scheme 3). Researchers[21] admit that an analogy between the organopalladium derivatives in Scheme 3 and -allylpalladium complexes was drawn and exploited in the discovery of the reaction of -allylpalladium with malonate also in 1965 (Scheme 4). It is noteworthy that this reaction remained only stoichiometric in Pd for several years. Once its catalytic version[21],[22] was developed, however, this reaction has been extensively developed by Tsuji,[23] Trost,[24] and many others, as detailed in Sect. V.2. Today, it is widely referred to as the Tsuji– Trost reaction, and it represents one of the most widely investigated areas of the organopalladium chemistry (Scheme 4). The birth of the Heck reaction, another important Pd-catalyzed C — C bond-forming reaction, was not straightforward either. In 1968, Heck[25] reported the reaction of organometals containing Hg, Sn, and Pb with alkenes in the presence of one equivalent of a Pd(II) complex leading to substitution of an alkenyl hydrogen with a carbon group of the organometallic reagent, typically an organomercury (Scheme 5). Here again, however, history has been skewed by frequent and unfortunate omission of a closely related stoichiometric reaction by Moritani and Fujiwara[26] reported in 1967 and shown at the bottom of Scheme 5. Unfortunately, both of these stoichiometric reactions were as such not very attractive from the synthetic viewpoint. It was not until three to four years later that Mizoroki et al.[27] and Heck and Nolley[27a] reported what is now generally referred to as the Heck reaction, sometimes called the Mizoroki– Heck reaction (Scheme 5). As detailed in Part IV, this reaction has been shown to proceed via addition of C — Pd bond to alkenes (i.e., carbopalladation), followed by dehydropalladation (Scheme 6). The use of the term ‘‘Heck reaction’’ should be limited to those processes that involve this carbopalladation – dehydropalladation sequence, be they stoichiometric or catalytic. It is
6
I INTRODUCTION AND BACKGROUND CHE2
Na2CO3
+ CH2E2
E = CO2Et
Pd Cl
Pd
Cl
Cl
2
CE2
E
NaH intramolecular nucleophilic substitution with malonate
E Pd(0) Pd Cl CHE2
CHE2
CHE2
NaH intermolecular nucleophilic substitution with malonate
CHE2
Pd(0)
Pd Cl Scheme 3 Original stoichiometric version 1 2
Cl Pd
)
DMSO
+ NaCH(COOEt)2
CH(COOEt)2 + Pd + NaCl
2
Catalytic version of the Tsuji−Trost reaction X
−Nu
Pd(0)Ln 2e oxid.
Pd(II)LnX
2e red.
Nu + Pd(0)Ln + X−
Scheme 4 Stoichiometric Heck reaction ArHgX + H2C CHR + Pd(II)X2
ArCH CHR + HgX2 + Pd(0) + HX
Catalytic Heck reaction ArX +
H2C CHR
cat. Pd(0)Ln
ArCH CHR + HX
Stoichiometric Moritani−Fujiwara reaction ArH +
H2C CHR + Pd(II)X2
ArCH CHR + Pd(0) + 2 HX Scheme 5 H Pd(II)X
ArPd(II)X + HC C
ArC C Scheme 6
ArC C
+ Pd(0) + HX
I.I HISTORICAL BACKGROUND OF ORGANOPALLADIUM CHEMISTRY
7
important to do so because the scope of carbopalladation itself is considerably broader than that of the Heck reaction, as can readily be seen in Part IV. For example, Blomquist and Maitlis[28] earlier investigated Pd-catalyzed cyclic oligomerization reactions of alkynes proceeding via a series of carbopalladation, which do not fall within the definition of the Heck reaction. The full synthetic scope and utility of those reactions that involve carbopalladation including the Heck reaction became apparent only in the 1980s through extensive investigations by a number of workers, as detailed in Part IV. The scope of carbopalladation may conceptually be further expanded so as to include addition reactions of palladium–carbene complexes as well as palladacyclopropanes, palladacyclopropenes, and higher palladacycles. These reactions are also discussed in Part IV (i.e., Sects. IV.9 and IV.10). It is generally agreed that Roelen’s discovery of the hydroformylation reaction[16] was the birth of the transition metal-catalyzed carbonylation. Initially, Co catalysts were most extensively used, but the Rh-based processes have since been developed as a superior methods. Although Pd may have been tested along with several other metals, such as Fe, Ru, and Ni, it has never been shown to be very useful in the hydroformylation reaction, sometimes called the “oxo” process. A publication in 1963 by Tsuji et al.[29] on a related but clearly different reaction of alkenes with CO and alcohols in the presence of a Pd catalyst producing esters was one of the earliest, if not the earliest, reports describing a successful and potentially useful Pd-catalyzed carbonylation reaction. This was soon followed by the discovery of another Pd-catalyzed carbonylation reaction of allylic electrophiles with CO and alcohols[30] (Scheme 7). R
+ CO + R1OH
R
cat. PdLn [29]
R
X
+ CO + R1OH
COOR1 cat. PdLn [30]
R
COOR1
Scheme 7
By 1974 the latter reaction had been generalized, and a wide variety of organic halides and other related electrophiles including alkenyl and aryl halides had been used, most notably by Heck and co-workers.[31] Also developed in his study was a related carbonylation reaction for the synthesis of amides.[32] Use of organometals and metal hydrides in place of alcohols and amines most notably by Steffy and Stille[33] further expanded the scope of Pd-catalyzed carbonylation. Yet another important development in the area of Pd-catalyzed carbonylation is the development of acylpalladation and related carbonyl – Pd bond addition reactions. Acylpalladation may be defined as a process of acyl – Pd bond addition to alkenes and alkynes. Clearly, it is a kind of carbopalladation reaction. For practical reasons, however, it is discussed in Part VI together with other carbonylation reactions mentioned above. Tsuji and Hosaka[34] reported in 1965 what appears to be the first example of the perfectly alternating alkene – CO copolymerization (Scheme 8). Independently, Brewis and Hughes[35] reported also in 1965 a Pd-catalyzed cyclic carbonylation of dienes with CO and methanol (Scheme 9). Although the exact mechanism of the initiation is unclear, these reactions
8
I INTRODUCTION AND BACKGROUND
must involve acylpalladation for crucial C — C bond formation. As promising as they were, they remained a couple of isolated studies until about 1980. O +
CO
C
cat. PdLn
n
Scheme 8 O +
MeOH
CO (10 atm) cat. PdLn
COOMe
150 °C
50% Scheme 9
The potential for industrial use of the perfectly alternating alkene–CO copolymers recognized primarily by Shell[36] triggered intensive investigations throughout the world, as detailed in Sect. VI.4.2. Independently and concurrently, a systematic investigation of the cyclic acylpalladation was initiated by Negishi and co-workers[37]–[40] using -alkene-substituted organic halides. This has led to the discovery and development of several different carbonylation reactions involving CO and -compounds, as discussed in Sects. VI.4.1 and VI.4.3. Cross-coupling between organometals and organic electrophiles, such as organic halides, is not only one of the most straightforward methods but also the potentially most general method for the formation of carbon–carbon bonds (Scheme 10). Even so, the development of cross-coupling in general and of the Pd-catalyzed version in particular has been surprisingly sluggish. In fact, Pd-catalyzed cross-coupling was one of the last to be developed among the several fundamentally different patterns of C — C bond formation that are widely observable with Pd, as discussed further in Sect. I.2. R1M
+
R 2X
R1
R2
+
MX
Scheme 10
Before the 1960s, the scope of cross-coupling as defined above was largely limited to those involving Mg and Li. In general, organometals containing these metals undergo synthetically useful cross-coupling only with certain relatively unhindered alkyl halides, such as those containing methyl, primary alkyl, allyl, and benzyl. Unsaturated organic halides containing Csp2— X and Csp — X bonds do not generally undergo cross-coupling with organolithiums and Grignard reagents. Even their reactions with alkyl halides are subject to various side reactions, such as and eliminations, halogen-metal exchange leading to the formation of homocoupled products, and so on, in addition to their competitive reactions with other electrophilic functional groups present in the reactants. Although there were some exceptions, such as alkylation of alkynylmetals containing Li and Mg, direct cross-coupling was, in the main, something to be avoided and substituted with more reliable but more circuitous enolate-based methods. Introduction and development of organocopper-based methods in the 1960s[41] solved many of the difficulties mentioned above. Nonetheless, a number of other problems remained unsolved.
I.I HISTORICAL BACKGROUND OF ORGANOPALLADIUM CHEMISTRY
9
In 1972, Tamao et al.[42] as well as Corriu and Masse[43] reported independently that the reaction of Grignard reagents with alkenyl or aryl halides could be catalyzed by Ni complexes, especially Ni– phosphine complexes. A related study of the stoichiometric carbon –carbon coupling reaction of diorganylnickel derivatives by Yamamoto et al.[44] is also noteworthy. Although many other transition metal-catalyzed reactions of Grignard reagents with organic halides without the use of phosphines were known, these so-called Kharasch-type reactions,[45] with the exception of the Cu-catalyzed versions,[46]–[48] were not well suited for cross-coupling due to various complications including cross-homo scrambling. The discovery of Pd-catalyzed cross-coupling was more subtle and evolutionary. Formation of C — C bonds via reductive elimination of diorganylpalladium – phosphine complexes was reported in the early 1970s,[49] but no catalytic procedure was developed. During the 1975 –1976 period, several groups of workers including Cassar,[50] Murahashi et al.[51] Baba and Negishi,[52] Fauvarque and Jutand,[53] and Sekiya and Ishikawa[54] reported seemingly independently some Pd-catalyzed cross-coupling reactions. The alkyne version of the Heck reaction by Dieck and Heck[55] and its variant involving the use of Cu(I) salts developed by Sonogashira et al.[56] were also reported during the same period. In most of these studies, however, one or two papers were published in a rather fragmentary manner, but the systematic studies by Negishi and coworkers [52,[57]–[63] during the 1976 –1978 period clearly pointed to the current vision and scope and thus established the foundation for the current broad-spectrum Pd-catalyzed cross-coupling. As detailed in Sect. III.1, the studies during this period generated many notable findings, such as (i) generality with respect to the metal countercations including Zn,[57]–[59],[62] B,[62],[63] Al,[52],[61] Sn,[62] and Zr[60],[61] in addition to Mg[51]; (ii) development of both hydrometallation–cross-coupling[52] and carbometallation–crosscoupling[61] tandem procedures with Al and Zr demonstrating some distinct advantages of Pd over Ni; (iii) development of protocols using metals of intermediate electronegativity including Zn, Al, and Zr for superior reactivity and chemoselectivity; and (iv) demonstration of double metal catalysis involving Pd and added metal compounds, especially ZnCl2 and ZnBr2.[61] During this period, related Pd-catalyzed cross-coupling reactions of organotins with aryl[64] and acyl halides[65] were reported by Kosugi and coworkers. These first-generation studies were followed by extensive second-generation studies of the Pd-catalyzed cross-coupling involving various metals, most notably Zn,[66] B,[67] and Sn[68] over the past two decades. Today, Pd-catalyzed cross-coupling involving metals of intermediate electronegativity, mostly Zn, Al, and Zr, is often referred to as the Negishi coupling.[66] No other metals appear to have exhibited a higher reactivity than Zn. However, higher chemoselectivity associated with more electronegative meals, especially B[67] and Sn,[68] and their other advantages have been recognized and exploited. Intramolecular cross-coupling of -haloorganometals containing B[69] and Sn[70] as well as the carbopalladation–cross-coupling tandem and cascade reactions of organotins[71] are but a few representative examples demonstrating their potential advantages. Coupled with their stability in water, Pd-catalyzed cross-coupling reactions involving B and Sn have become widely used, as discussed in detail in Part III. The B protocol is commonly known as the Suzuki reaction, and that involving Sn is often called the Stille reaction. Their first papers on Pd-catalyzed cross-coupling with organoborons and organotins were reported in 1979[72] and 1978,[73] respectively. Here again, however, earlier contributions by other workers including the first Pd-catalyzed organoboron cross-coupling reaction by Negishi[62],[63] and seminal contributions with Sn by Kosugi et al.[64],[65] as well as extensive studies with Sn
10
I INTRODUCTION AND BACKGROUND
by Beletskaya[74] should not be overlooked. Extensive developmental studies of the Murahashi Pd-catalyzed cross-coupling with Grignard reagents[51],[75] by several workers including Negishi et al.,[57],[76],[76a] Linstrumelle and co-workers,[77]–[79] and Hayashi et al.[80],[81] initiated in the late 1970s are also noteworthy. Today, the Negishi, Suzuki, and Stille reactions represent the three most widely used protocols along with the Sonogashira reaction[82] specializing in the synthesis of alkynes. These reactions are discussed mostly in Part III along with the recently developed Si-based cross-coupling (Sect. III.2.4) as well as related Pd-catalyzed hydrogenolysis and carbon – heteroatom bond formation reactions (Sect. III.3). Aside from various types of isomerization, rearrangements, and other miscellaneous organopalladium reactions discussed in Part IX, most of the fundamental and widely observable patterns of organopalladium reactions had probably been discovered by 1980. However, this was about the time when developments of those reactions discovered earlier as well as their applications, especially in the areas of natural products synthesis and the synthesis of polymers and other compounds of materials chemical interest, began becoming intensive. In recognition of their significance, applications of organopalladium chemistry to the natural products synthesis are highlighted in Sects. III.2.17.1, III.2.18, IV.8, V.2.6, V.3.6, and VI.6, while those applications to the synthesis of polymers and other compounds of materials chemical interest are discussed in Sects. III.2.17.2 and VI.8. Development of enantioselective procedures for those reactions discovered earlier also began in the 1980s. Four of the most notable investigations along this line are (i) development of enantioselective cross-coupling by Hayashi et al.[83] (Sect. III.2.16), (ii) development of the enantioselective Heck reaction by Overman[84] and Shibasaki[85] (Sect. IV.2.3), (iii) development of highly enantioselective procedures for Pd-catalyzed allylation by Trost and Van Vranken[86] (Sect. V.2.4), and (iv) development of enantioselective copolymerization of alkenes and CO by several workers[87]–[90] (Sect. VI.4.2). Yet another important aspect of fundamental significance is the “living” and “cascading” nature of some of the organopalladium reactions, especially carbopalladation and migratory insertion. The discovery of “cascading” organopalladium reactions can be traced back to pioneering findings in the 1960s represented by Maitlis’ cyclooligomerization of alkynes[28],[91] that was shown to proceed by a series of carbopalladation (Scheme 11) and Tsuji’s alternating copolymerization of norbornadiene and CO[34] (Scheme 8).
R RC CR
PdCl2
R Cl
R PdCl RC CR
R
2 RC CR
R
PdCl Cl
R R
R PdCl2
R
R
R Scheme 11
R
R R
R
R
R R
I.I HISTORICAL BACKGROUND OF ORGANOPALLADIUM CHEMISTRY
11
As such, these reactions may be suited for the synthesis of symmetrically structured oligomers and polymers. In fact, the latter reaction[36] has been intensively investigated in the 1980s and 1990s primarily for its commercial application (Sect. VI.4.2). However, these reactions are not readily adaptable to the selective synthesis of unsymmetrically structured natural products and other molecules of biological and medicinal interest. The feasibility of cascading carbopalladation within the context of the selective synthesis of unsymmetrical molecules was more or less simultaneously demonstrated by Abelman and Overman,[92] Trost and co-workers,[93],[94] and Negishi and co-workers[95]–[97] only about a decade ago. A related investigation of the cyclic allylpalladation –acylpalladation mainly by Oppolzer[98]–[100] is also noteworthy. Some prototypical and maximally “cascading” examples of cyclic carbopalladation are shown in Scheme 12. These examples have triggered interest in exploiting the “living” and “cascading” possibilities that organopalladium chemistry offers even for the synthesis of unsymmetrical molecules. Some chemists including this author use the term “tandem” process for twostage cascades, especially in cases where two different kinds of processes are involved, while others have used the term “domino” in place of “cascade.” Usage of these relatively nonscientific but amusing and attractive terms is largely a matter of personal preference, but it is nonetheless important to be familiar with their definitions. In reality, some of the most useful reactions may involve just two- or three-stage “tandem” and “cascade” (or “domino”) processes. Nonetheless, the full and widespread recognition of the “living” Spiro-mode cascade PdLn, base
I
[92]
MeO
OMe PdLn [94]
PhO2S
PhO2S SO2Ph
SO2Ph
86%
Linear-fused-mode cascade I
PdLn, base [92]
Zipper-mode cascade
I E
SiMe3
PdLn, base [95]
SiMe3
E
E
E Scheme 12 (Continued)
12
I INTRODUCTION AND BACKGROUND
E
E
PdLn, base
E
I
E
[96]
76% OH
O R CO, base
E
PdLn
E
I
[97]
O R
E E 66%
E = COOMe or COOEt Dumbbell-mode cascade SiMe3 I
SiMe3 PdLn, base [95]
Scheme 12 (Continued)
characteristics of carbopalladation and migratory insertion has transformed the mostly unidimensional organopalladium chemistry dealing with just one organopalladium reaction at a time into a multidimensional one, thereby significantly expanding its synthetic usefulness. Many “cascading” organopalladium reactions are discussed in Part IV, and additional discussions may be found in various sections including Sects. V.3.2.2, V.3.3.2, V.3.4, V.3.5, VI.2.1.3, VI.4.1, and VI.4.3. As further investigations and developments at all fronts of organopalladium chemistry have been continued and intensified, some other largely technological aspects of organopalladium chemistry have also become important. They include such matters as (i) immobilization of Pd catalysts through the use of polymer-bound Pd-complexes and polymer support materials (Sect. X.2), (ii) development of aqueous organopalladium chemistry for various purposes (Sect. X.1), (iii) applications of organopalladium chemistry within the context of combinatorial chemistry (Sect. X.3), and (iv) minimization of unsafe and/or toxic materials such as pyrophoric metals, toxic metals, and toxic ligands, such as As and even P compounds, and (v) use of more economical reagents, for example, organic chlorides in place of iodides and bromides. These dynamic activities incorporate not just fundamental chemical matters but also practical engineering and technological issues that are particularly important in industry. They are clearly adding new dimensions to organopalladium chemistry that cut across the entire field.
REFERENCES [1] [2]
L. K. James, Ed., Nobel Laureates in Chemistry, 1901 – 1992, American Chemical Society, Washington, DC, 1993, 798 pp. E. Frankland, Liebigs Ann. Chem., 1849, 71, 171.
I.I HISTORICAL BACKGROUND OF ORGANOPALLADIUM CHEMISTRY
13
[3]
C. Blomberg and F. A. Hartog, Synthesis, 1977, 18, and references therein.
[4]
V. Grignard, Compt. Rend., 1900, 130, 1322.
[5]
M. Schlosser, in Organometallics in Synthesis, M. Schlosser, Ed., Wiley, Chichester 1994, 1 – 166. Organoalkali Reagents.
[6]
S. E. Livingstone, Comp. Inorg. Chem., 1973, 3, 1163 – 1189, 1274 – 1329.
[7]
W. C. Zeise, Pogg. Ann., 1831, 21, 497. (Its original Latin version was published in 1827.)
[8]
P. Sabatier and J. B. Senderens, Compt. Rend., 1897, 124, 1358.
[9] [10]
P. Sabatier, in Nobel Lectures: Chemistry, 1901 – 1921, Elsevier, Amsterdam, 1966, 221. M. P. von Wilde, Chem. Ber., 1874, 7, 352.
[11]
H. Kolbe, J. Prakt. Chem. [N.F.], 1871, 4, 418.
[12]
M. Saytzeff, J. Prakt. Chem. [N.F.], 1873, 6, 128.
[13]
C. Paal and C. Amberger, Chem. Ber., 1905, 38, 1406.
[14]
H. Wieland, Chem. Ber., 1912, 45, 484.
[15]
W. Ipatieff, Chem. Ber., 1907, 40, 1270.
[16]
O. Roelen, German Patent, 1938, Nos. 849, 548.
[17]
J. W. Reppe, Acetylene Chemistry (P. B. Report –18852-s), C. A. Meyer & Co., New York, 1949, 209 pp.
[18]
(a) J. Smidt, W. Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Ruttinger, and H. Kojer, Angew. Chem., 1959, 71, 176. (b) J. Smidt, W. Hafner, R. Jira, R. Sieber, J. Sedlemeier, and J. Sabel, Angew. Chem. Int. Ed. Engl., 1962, 1, 80.
[19]
F. C. Phillips, Am. Chem. J., 1894, 16, 255.
[20]
J. Tsuji, H. Takahashi, and M. Morikawa, J. Am. Chem. Soc., 1965, 87, 3275.
[21]
J. Tsuji, H. Takahashi, and M. Morikawa, Tetrahedron Lett., 1965, 4387.
[22]
G. Hata, K. Takahashi, and A. Miyake, Chem. Commun., 1970, 1392.
[22a] K. Alkins, W. E. Walker, and R. M. Manyik, Tetrahedron Lett., 1970, 3821. [23]
J. Tsuji, Chem. Met. Carbon Bond, 1985, 3, 163 – 199.
[24]
B. M. Trost, Acc. Chem. Res., 1980, 13, 385 – 393.
[25]
R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5518.
[26]
I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 1119.
[27]
T. Mizoroki, K. Mori, and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581; 1973, 46, 1505.
[27a] R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320. [28]
A. T. Blomquist and P. M. Maitlis, J. Am. Chem. Soc., 1962, 84, 2329.
[29]
J. Tsuji, M. Morikama, and J. Kiji, Tetrahedron Lett., 1963, 1437.
[30]
J. Tsuji, J. Kiji, S. Imamura, and M. Morikawa, J. Am. Chem. Soc., 1964, 86, 4350.
[31]
A. Schoenburg, J. Bartoletti, and R. F. Heck, J. Org. Chem., 1974, 39, 3318.
[32]
A. Schoenberg and R. F. Heck, J. Org. Chem., 1974, 39, 3327.
[33]
F. K. Steffy and J. K. Stille, J. Am. Chem. Soc., 1983, 105, 7173.
[34]
J. Tsuji and S. Hosaka, Polym. Lett., 1965, 3, 703.
[35]
S. Brewis and P. R. Hughes, J. Chem. Soc. Chem. Commun., 1965, 489; 1966, 6.
[36]
E. Drent and P. H. M. Budzelaar, Chem. Rev., 1996, 96, 663– 681.
[37]
E. Negishi and J. A. Miller, J. Am. Chem. Soc., 1983, 105, 6761.
14 [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75]
I INTRODUCTION AND BACKGROUND J. M. Tour and E. Negishi, J. Am. Chem. Soc., 1985, 107, 8289. E. Negishi and J. M. Tour, Tetrahedron Lett., 1986, 27, 4869. E. Negishi, G. Wu, and J. M. Tour, Tetrahedron Lett., 1988, 29, 6745. G. H. Posner, Org. React., 1975, 22, 253. K. Tamao, K. Sumitani, and M. Kumada, J. Am. Chem. Soc., 1972, 94, 4374. R. J. P. Corriu and J. P. Masse, J. Chem. Soc. Chem. Commun., 1972, 144. T. Yamamoto, A. Yamamoto, and S. Ikeda, J. Am. Chem. Soc., 1971, 93, 3350. M. S. Kharasch and O. Reinmuth, in Grignard Reactions of Nonmetallic Substances, Prentice-Hall, New York, 1954, Chap. 16, 1146 – 1132. M. Tamura and J. Kochi, Synthesis, 1971, 303. T. Sato, T. Kawara, M. Kawashima, and T. Fujisawa, Chem. Lett., 1980, 571. B. H. Lipshutz, in Organometallics in Synthesis, M. Schlosser, Ed., Wiley, New York, 1994, 283 – 382. G. W. Parshall, J. Am. Chem. Soc., 1974, 86, 2360. L. Cassar, J. Organomet. Chem., 1975, 93, 253. M. Yamamura, I. Moritani, and S. I. Murahashi, J. Organomet. Chem., 1975, 91, C39. S. Baba and E. Negishi, J. Am. Chem. Soc., 1976, 98, 6729. J. F. Fauvarque and A. Jutand, Bull. Soc. Chim. Fr., 1976, 765. A. Sekiya and N. Ishikawa, J. Organomet. Chem., 1976, 118, 349. H. A. Dieck and R. F. Heck, J. Organomet. Chem., 1975, 93, 259. K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 1975, 4467. E. Negishi, A. O. King, and N. Okukado, J. Org. Chem., 1977, 42, 1821. A. O. King, N. Okukado, and E. Negishi, J. Chem. Soc. Chem. Commun., 1977, 683. A. O. King, E. Negishi, F. J. Villani, Jr., and A. Silveira, Jr., J. Org. Chem., 1978, 43, 358. N. Okukado, D. E. Van Horn, W. L. Klima, and E. Negishi, Tetrahedron Lett., 1978, 1027. E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, and B. I. Spiegel, J. Am. Chem. Soc., 1978, 100, 2254. E. Negishi, in Aspects of Mechanism and Organometallic Chemistry, J. H. Brewster, Ed., Plenum Press, New York, 1978, 285 – 317. E. Negishi, Acc. Chem. Res., 1982, 15, 340 – 348. M. Kosugi, K. Sasazawa, Y. Shimizu, and T. Migita, Chem. Lett., 1977, 301. M. Kosugi, Y. Shimizu, and T. Migita, Chem. Lett., 1977, 1423. E. Negishi and F. Liu, in Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., VCH, Weinheim, 1998, 1 – 47. N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457 – 2483. V. Farina, V. Krishnamurthy, and W. J. Scott, Org. React., 1997, 50, 1 – 652. N. Miyaura, H. Suginome, and A. Suzuki, Tetrahedron Lett., 1984, 25, 761. A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem., 1991, 56, 2883. E. Negishi, Y. Noda, F. Lamaty, and E. J. Vawter, Tetrahedron Lett., 1990, 31, 4393. N. Miyaura, K. Yamada, and A. Suzuki, Tetrahedron Lett., 1979, 3437. D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1978, 100, 3636. I. P. Beletskaya, J. Organomet. Chem., 1983, 250, 551 – 564. S. I. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, and K. Kondo, J. Org. Chem., 1979, 44, 2408.
I.I HISTORICAL BACKGROUND OF ORGANOPALLADIUM CHEMISTRY
[76] [76a] [77] [78] [79] [80] [81] [82]
15
E. Negishi, L. F. Valente, and M. Kobayashi, J. Am. Chem. Soc., 1980, 102, 3298. E. Negishi, F. T. Luo, and C. L. Rand, Tetrahedron Lett., 1982, 23, 27. H. P. Dang, and G. Linstrumelle, Tetrahedron Lett., 1978, 191. C. Huynh and G. Linstrumelle, Tetrahedron Lett., 1979, 1073. T. Jeffery-Luong and G. Linstrumelle, Tetrahedron Lett., 1980, 21, 5019. T. Hayashi, M. Konishi, and M. Kumada, Tetrahedron Lett., 1979, 21, 1871. T. Hayashi, K. Kabeta, I. Hamachi, and M. Kumada, Tetrahedron Lett., 1983, 24, 2865. K. Sonogashira, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 203 – 229. [83] T. Hayashi, S. Niizuma, T. Kamikawa, N. Suzuki, and Y. Uozumi, J. Am. Chem. Soc., 1995, 117, 9101. [84] L. E. Overman, Pure Appl. Chem., 1994, 66, 1423 – 1430. [85] M. Shibasaki, Adv. Metal-Org. Chem., 1996, 5, 119– 151. [86] B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395 – 422. [87] M. Brookhart, M. Wagner, G. G. A. Balavoine, and H. A. Haddou, J. Am. Chem. Soc., 1994, 116, 3641. [88] Z. Jiang, S. E. Adams, and A. Sen, Macromolecules, 1994, 27, 4436. [89] S. Bronco, G. Consiglio, R. Hutter, A. Batistini, and U. W. Suter, Macromolecules, 1994, 27, 4436. [90] K. Nozaki, N. Sato, and H. Takaya, J. Am. Chem. Soc., 1995, 117, 9911. [91] P. M. Maitlis, Acc. Chem. Res., 1976, 9, 93– 96. [92] M. M. Abelman and L. E. Overman, J. Am. Chem. Soc., 1988, 110, 2328. [93] B. M. Trost and D. C. Lee, J. Am. Chem. Soc., 1988, 110, 7255. [94] B. M. Trost and Y. Shi, J. Am. Chem. Soc., 1991, 113, 701. [95] Y. Zhang and E. Negishi, J. Am. Chem. Soc., 1989, 111, 3454. [96] Y. Zhang, G. Wu, G. Agnel, and E. Negishi, J. Am. Chem. Soc., 1990, 112, 8590. [97] T. Sugihara, C. Copéret, Z. Owczarczyk, L. S. Harring, and E. Negishi, J. Am. Chem. Soc., 1994, 116, 7923. [98] W. Oppolzer, T. H. Keller, M. Bedoya-Zurita, and C. Stone, Tetrahedron Lett., 1989, 30, 5883. [99] K. Yamamoto, M. Terakado, K. Murai, M. Miyazawa, J. Tsuji, K. Takahashi, and K. Mikami, Chem. Lett., 1989, 955. [100] W. Oppolzer, Pure Appl. Chem., 1990, 62, 1941.
I.2
Fundamental Properties of Palladium and Patterns of the Reactions of Palladium and Its Complexes EI-ICHI NEGISHI
A. FUNDAMENTAL PROPERTIES OF Pd Palladium (Pd) is the 46th atom in the periodic table with an average atomic weight of 106.4, and it consists of six isotopes. As mentioned earlier, it was named after the asteroid Pallas.[1] This name (i.e., Pallas in Latin or Palladium in Greek) was in turn derived from that of the mythological goddess of wisdom or learning, and palladium also means any object considered essential to the safety of a community, according to English dictionaries. Some of the notable properties of Pd are summarized in Table 1. Attempts are made below to probe the origins of the versatility, selectivity, and overall synthetic usefulness of Pd in organic synthesis in terms of some of its fundamental properties shown in Table 1. First, as the 46th atom in the periodic table, Pd is a second row transition metal of moderately large atomic size, which is, of course, larger than Ni but smaller than Pt. This size factor appears to significantly contribute to a number of its chemical properties, such as moderate stability of its compounds and their controlled but wide-ranging reactivity leading to both versatility and certain kinds of selectivity features associated with it. Second, Pd strongly favors the 0 and 2 oxidation states. Although other oxidation states, such as 1, 3, and 4, may prove to be significant in the future, they are currently rather rare (Sect. II.4). The facts presented above may, at least in part, stem from the size factor discussed previously. Thus, larger Pt tends to form Pd(IV) d6 octahedral complexes more readily than Pd, while smaller Ni is more prone to produce Ni(I) species via one-electron processes than Pd. This might possibly make Ni an even more versatile metal than Pd. In a sense, it is perhaps true. However, reactivity and instability are like the two faces of a coin, and they come together. Thus, the low tendency of Pd to undergo one-electron or radical processes appears to be responsible for making many organopalladium reactions selective possibly through avoidance and minimization of unwanted side reactions. There are also a number of indications that, in Ni-catalyzed reactions, the products are generally more prone to product-consuming side reactions than the corresponding Pd-catalyzed reactions. In those reactions that are catalyzed by both Pd and Ni, the Pd-catalyzed reactions tend to be cleaner and more chemo- and
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
17
18
I INTRODUCTION AND BACKGROUND
TABLE 1. Some Fundamental Properties of Pd Property Atomic number Atomic weight Isotopes and relative abundance a
Value and/or Description
Magnetic property
46 106.4 102 104 Pd 0.8% Pd 105 106 Pd 22.6% Pd 108 110 Pd 26.7% Pd 105 Pd has I 53 , but it is of very low sensitivity.
Electronic configuration
1s22s22p63s23p64s24p64d10 = [Kr]4d10
Common oxidation states and coordination numbers
Oxidation State 0 2 4 (rare)
Electronegativityb Occurrence in the lithospherec
Electronic Configuration 10
d d8 d6
9.3% 27.1% 13.5%
Geometry Tetrahedral Square planar Octahedral
2.2 (Pauling), 1.57 (Sanderson) 0.015 ppm Some data for comparison: C (180 ppm), Ni (99 ppm), Pt (0.01 ppm), Ru and Rh (0.001 ppm each)
a
Handbook of Chemistry and Physics, 42nd ed., C. D. Hodgman, R. C. Weast, and S. M. Selby, Eds., The Chemical Rubber Publishing Co., Cleveland, 1960, p. 470. b (i) L. Pauling, The Nature of the Chemical Bond, 3rd ed., Cornell University Press, Ithaca, NY, 1960, p. 93. (ii) R. T. Sanderson, Inorganic Chemistry, Van Nostrand-Reinhold, New York, 1967, p. 72. c W. S. Fyfe, Geochemistry, Oxford University Press, 1974.
stereoselective than the corresponding Ni-catalyzed reactions. On the other hand, organoplatinum derivatives appear to be often too stable to be synthetically useful. The crude generalization made above with the Ni triad appears to be applicable also to some other triads, such as the Ti triad. Third, as the second member of the group 10 Ni triad, Pd is a representative late transition metal, which tends to form d10 and d8 complexes of relatively low oxidation states (i.e., 0 or 2). Both high d-electron counts and low oxidation states as well as the moderately large size among those atoms that are commonly encountered in organic synthesis render Pd rather “soft.” Coupled with the ready formation of coordinatively unsaturated species of 16 or even less electrons providing one or more empty coordination sites, Pd can indeed provide simultaneously at least one each of empty and filled nonbonding orbitals. Valence-shell empty orbitals provide Lewis acidic or electrophilic sites, one of which would serve as the LUMO (i.e., lowest unoccupied molecular orbital), while filled nonbonding orbitals provide Lewis basic or nucleophilic sites, one of which would act as the HOMO (i.e., highest occupied molecular orbital). It can therefore be easily understood why Pd can readily participate in a variety of concerted reactions of relatively low activation energies. Indeed, the great majority of the Pd-catalyzed reactions appear to be concerted processes where orbital symmetry and alignment are critically important. Some of the selectivity features, especially stereoselectivity, observed with them may readily be attributable to this nature.
I.2 FUNDAMENTAL PROPERTIES OF PALLADIUM
19
One significant consequence of the high propensity for concerted processes is the high general affinity of Pd for nonpolar -compounds, such as alkynes, alkenes, and even arenes. It can also readily form bonds with nonbonding electron donors (n-electron donors or n-donors, hereafter), such as amines, imines, nitriles, phosphines, phosphites, and various other N, P, S, and even O containing donors. Carbon monoxide and isoelectronic isonitriles are representative examples of C-centered n-electron donors. Some of these - and n-electron donors rank among the most reactive functional groups toward Pd, and their presence in appropriate locations in the reactants is often critically important in observing various reactions of other functional groups, such as halides and carbonyl derivatives, as well. Fourth, Pd is relatively electronegative, its Pauling and Sanderson electronegativity values being 2.2 and 1.57, respectively. Consequently, C—Pd bonds are relatively nonpolar, and they display rather low reactivity toward those polar groups that are very reactive toward Grignard reagents and organolithiums including various carbonyl compounds, such as ketones, esters, amides, and even aldehydes, as well as nitro compounds, and singlebonded polar electrophiles, such as alkyl halides and epoxides lacking proximal - or n-donors. Acyl halides represent one notable exception, and their high reactivity toward Pd must stem from the simultaneous presence of a carbonyl and a carbon – halogen bond sharing one common C atom. As mentioned earlier, nitriles, representative triply bonded polar carbon electrophiles, do react readily as n-electron donors, but organopalladium derivatives do not readily add to the C#N triple bond. Even though there is hardly any generally applicable reactivity scale in chemistry, Scheme 1 might give a useful, if somewhat vague and limited, guideline, which must be used judiciously. Functional groups reactive toward Pd X
> −
Ar
X
C C X > − RCOX > C C X
> ArX >> [alkyl
− X]
X
Notes: 1. Alkyl halides lacking proximal π- or n-donor groups are relatively inert but included for comparison. 2. The X groups and approximate reactivity order are: I > OTf > Br > Cl > OZ > NZ2, CZ3, etc., where Z is any atom or group attached to O, N, and C. Functional groups relatively unreactive toward Pd 1 2 1 2 [RCOX] >> RCHO > R1COR2 > − R COOR , R CONR2 Notes: 1. Acyl halides are very reactive, but included for comparison. 2. Other relatively inert groups, such as NO 2 and C#N, may not be readily placed on the scale.
Scheme 1
20
I INTRODUCTION AND BACKGROUND
Despite some ambiguities and complications, it is clear that the reactivity trend observed with Pd and its compounds is largely opposite to that observed with the Grignard reagents and other “hard” and polar organometals. Thus, organopalladium chemistry has nicely complemented the traditional organometallic chemistry mostly involving Mg and Li. This is also one of the main reasons why organopalladium reactions are very loosely termed “very chemoselective,” which usually means that those electrophilic functional groups that are reactive toward polar organometals are tolerated. It should, however, be clearly noted that “chemoselectivity,” unlike stereoselectivity, is a rather vague and subjective term that heavily depends on one’s viewpoint, reaction conditions, presence or absence of other functional groups, and so on. Fifth, although the relative inertness of carbonyl compounds excluding acyl halides was emphasized above, most everything in chemistry is relative, and organopalladium chemistry is no exception. Thus, in the absence of faster reaction paths, Pd and its complexes may react with aldehydes via C—H activation to give acylpalladium derivatives and subsequent decarbonylation (Sect. VI.5.1), while ketones may be reduced to alcohols and even to hydrocarbons, as discussed in Sect. VII.2.3.1, although the presence of proximal - or n-donors may be critical in such reactions. Another important group of compounds that are relatively unreactive under mild conditions but can react with Pd and its complexes under more forcing or favorable conditions are H donors including aldehydes mentioned above and H2 widely used in Pdcatalyzed hydrogenation (Sect. VII.2). In fact, Pd and its complexes can react, under a variety of different conditions, with almost any H-containing compounds, and this versatility may, in most cases, be attributable to the ability of Pd to provide simultaneously one or more empty and filled nonbonding orbitals. Those reactions that involve Pd(0) complexes may be interpreted in terms of concerted oxidative addition. In these reactions, the so-called acidity of the H compounds may play some roles, but it may not be the dominant factor. Thus, H donors that are reactive toward Pd include (i) H2, (ii) hydrogen halides, (e.g., HCl) and other mineral acids, (iii) carboxylic acids, alcohols, and other OH-containing compounds, (iv) amines, and (v) a wide variety of C—H compounds including aldehydes mentioned above and formic acid derivatives, alkynes, alkenes, arenes, and other proximally activated C—H compounds, such as carbonyl compounds containing hydrogens, cyclopentadiene, and even unactivated alkanes, such as CH4. Metal hydrides, be they electrophilic, neutral, or nucleophilic, also are generally reactive toward Pd complexes. The conventional wisdom regarding the relationship between the reactivity of H compounds and their acidity expressed in pKa must be significantly modified. While this author never suggests that one stop being analytical, logical, and rational, liberation of one’s thinking from some old dogmas is always critically needed in science. For example, it would be absurd to use strong acids as H sources for generating metal hydrides containing “hard” and highly electropositive metals, such as Li and Mg, but it is perfectly acceptable for generation of palladium hydrides. While the definitions of and distinction between proton and hydride or, for that matter, neutral hydrogen are unmistakably clear, one must not forget that hydrogen is hydrogen regardless of whether it is viewed as proton, neutral hydrogen, or hydride in any given H-containing compounds. Perhaps, one only needs to recall that anionotropic 1,2-hydride shift may be initiated by protonation of alkenes. It is clear from the foregoing discussion that the reactivity of Pd and its complexes can be modified over a very wide range, as needed. Of course, this statement may apply to almost any class of reagents and compounds, but it does appear that Pd and some
I.2 FUNDAMENTAL PROPERTIES OF PALLADIUM
21
other transition metals, especially late transition metals, possess a remarkable ability to elevate or lower their reactivity toward a given substrate according to given reaction conditions, which leads to many different consequences ranging from a facile reaction to no reaction. Although not very clear, one can speculate that this may once again stem from their size and the availability of many interaction sites that may be filled or emptied, as needed. In any case, it is reasonable to state that Pd is very versatile and yet its reactions can be very selective. These two features are not mutually exclusive. For example, alkyl halides, even iodides, may be totally inert to Pd, as in a highly chemoselective transformation shown in Scheme 2[2] (Sect. III.2.11.2). And yet, in the absence of faster and more favorable reactions, alkyl halides, such as neopentyl iodide, can undergo Pd-catalyzed reactions.
I
I+
ClZn
SiMe3
cat. PdLn
I
SiMe3
Scheme 2
It is indeed advisable not to consider any compounds to be inert to Pd and its complexes. Tertiary amines, such as Et3N, are often used mainly to neutralize some acids generated as by-products. However, amines can react with Pd complexes to undergo oxidation, as discussed in Sect. VIII.3.2. So, unless the desired reaction is much faster than this oxidation reaction, there can be some undesirable consequences. Many solvents, such as HOAc, are also reactive with Pd complexes. In some cases, such reactions have been shown to be essential to observing favorable results[3] (Sect. IV.4). Even a small amount of adventicious impurities, such as H2O, can significantly alter the courses of organopalladium reactions,[4] as discussed in Sect. VI.4.3, even though many other organopalladium reactions can be satisfactorily carried out in water, where the molar ratio of water to substrate may exceed 100. Sixth, Pd is rare and expensive. Therefore, all efforts must be made to use Pd as a catalyst or a catalyst component. In the majority of Pd-catalyzed reactions, some interconversions between Pd(0) and Pd(II) species must occur. Two crucial requirements in this respect are (i) that such Pd(0) – Pd(II) interconversions be kinetically facile and (ii) that they occur in either direction under one set of reaction conditions. As a late d-block transition metal that can readily provide at least one empty valence-shell orbital, Pd very well fulfills both of these two requirements. To further illustrate this point, consider S, for example. Many S compounds are known to be readily oxidized or reduced. However, concurrent oxidation and reduction of S compounds may not be readily observed in one pot under a single set of reaction conditions. Some other important features associated with catalysts in redox reactions are that two and only two oxidation states separated by two elections be readily available and that the catalyst must not undergo other serious side reactions, especially those that would destroy the catalysts. So, the well-known fact presented earlier that Pd very strongly favors the 0 and 2 oxidation states appears to be serving as a very favorable factor rather than a limitation. Finally, Pd appears to be relatively nontoxic, although there may never be completely nontoxic substances. Despite its relative lack of toxicity, all efforts should be made to avoid product contamination with Pd, and some potential toxicity that might be associated
22
I INTRODUCTION AND BACKGROUND
TABLE 2. Relationships between Some Fundamental Properties of Pd and Chemical Consequences Fundamental Properties of Pd
Consequences
• Moderately large size
• Moderate stability of organopalladiums (Ni Pd Pt)
• Strong preference for the 0 and 2 oxidation states separated by a relatively narrow energy gap
• Relatively rare one-electron or radical processes (e.g., relative to Ni) • Ready and reversible two-electron oxidation and reduction (Q catalysis)
• Late transition metal favoring d10 Pd(0) and d 8 Pd(II) configurations Q (i) soft, (ii) ready availability of Pd complexes containing both empty and filled nonbonding orbitals (LUMO and HOMO)
• High propensity for concerted processes • High affinity toward soft - and n-donors • Selective and yet very resourceful reactivity permitting reactions with almost any type of compounds
• Relatively electronegative
• Relatively unreactive toward polar functional groups • High chemoselectivity • Largely complementary with the chemistry of Grignard reagents and organolithiums
with Pd-containing derivatives either introduced as reagents or generated in their reactions must always be anticipated and carefully examined, as needed. The foregoing discussions may be summarized as shown in Table 2. B. GENERAL PATTERNS OF THE REACTIONS OF Pd AND Pd COMPLEXES Synthesis of any organic compounds via organopalladium complexes must involve generation of C—Pd bonds and their cleavage. Additionally, interconversion of organopalladium intermediates occurs between the generation and cleavage of C—Pd bonds in most cases. Furthermore, if such reactions are to be catalytic in Pd, active Pd catalysts must be regenerated via cleavage of C—Pd bonds under these reaction conditions. So, most of the Pd-catalyzed organic synthetic reaction may be represented schematically by Scheme 3. In a relatively small number of cases, the organopalladium interconversion process may be omitted.
Starting organic compounds
C Pd bond formation
C Pd bond cleavage
Organopalladium interconversion R2PdLn
R1PdLn Pd catalyst Scheme 3
Organic product
I.2 FUNDAMENTAL PROPERTIES OF PALLADIUM
23
Although a large number of reactions for each of the three crucial processes — that is, formation and cleavage of C—Pd bonds as well as organopalladium interconversion — are known, the great majority, probably more than 80–90%, of the currently known processes may be classified into approximately 20 general patterns summarized in Table 3. It is important to note that these are reaction patterns rather than mechanisms. They merely indicate starting material–product relationships without implying detailed mechanisms. In fact, detailed well-established mechanisms are not known in many cases. And yet, it is these reaction patterns that are most useful and hence important in the use of organopalladium chemistry for organic synthesis. The following discussion is intended to provide reasonable understanding of many of the known organopalladium reactions and some predictive power for the discovery and development of many additional organopalladium reactions in the future. It should also be mentioned here that, in Table 3, some rare processes and examples are deliberately omitted for the sake of simplicity and clarity. For example, Pd(IV) as well as Pd(I) and Pd(III) species are omitted from consideration, even though the significance of various processes involving Pd(IV) species is expected to increase in the future. For oxidative addition, only the mononuclear 1,1-oxidative addition process is shown, but this may be well justified, as the others are still of negligible importance from the organic synthetic viewpoint. For each pattern, exceptions to and deviations from the summary may be found. However, the main goal of this table is not complete accuracy but an aid to the development of some useful framework for rational thinking with predictive power. Due allowance must be made for some exceptions and deviations, and such cases must be handled accordingly. Some additional comments pertaining to Table 3 are also in order. Although -complexation and oxidative complexation as well as -decomplexation and reductive decomplexation are listed separately, distinction within each pair is essentially a semantic matter. It is desirable to list them separately, since some numbers, such as FOS (change in formal oxidation state) and Coord. No. (change in coordination number) are different. It may also be argued that, unless the formation of Pd(IV) species is considered to be likely, the reaction of -compounds (XY) with Pd(II) complexes may not be viewed as oxidative complexation. In general, however, either of the two options may be chosen, as deemed appropriate. As indicated in the footnote f of Table 3, various addition processes of Pd species involving alkenes and alkynes may involve the formation of -complexes as discrete species, while others may not. For this reason, the terms used in this Handbook for addition processes, such as hydropalladations, include both complexation and addition. Patterns 11 through 19 are formally the reversals of the corresponding patterns 1 through 9. It should be remembered that they merely are patterns without mechanistic implications. So, each corresponding pair (e.g., 1 and 11) may or may not be the microscopic reversal of each other. Nucleophilic or electrophilic attack on ligands cannot readily be represented by one generic equation. In organopalladium chemistry, electrophilic attack still appears to be relatively insignificant, and most of the known processes involve nucleophilic attack. Two representative examples of nucleophilic attack on ligands are shown in Scheme 4. Finally, there are some other miscellaneous processes that may not be readily represented by any of those listed in Table 3, which should be supplemented, as needed. As such, all of the processes shown in Table 3 are stoichiometric in Pd. As stated earlier, they must be combined and sequenced appropriately to come up with Pd-catalyzed reactions. One critical requirement is that all of the Pd complexes in the catalytic cycle must be regenerated in the same forms and structures. In the redox process-containing
24 TABLE 3. Fundamental and General Patterns of Chemical Processes of Pd and Pd Complexes a General Pattern
FOS b of Starting Compound
FOS b
Pd(0) or Pd(II)
0
Pd(0) or Pd(II)
Formation of C—Pd Bond
Cleavage of C—Pd Bond
Interconversion of RPdLn
1
Applicable
Possible
0
1 (or 2)d
Applicable
Possible
Pd(0) e
2
2
Applicable
Possible
Pd(0) e
2
2
Applicable
Possible
Pd(II)
0
0
Possibleg
Coord. No.c
Mostly C—Pd Bond Formation 1. -Complexation X + PdLn
X
PdLn
2. -Complexation X Y
X
+ PdLn
Y
PdLn
3. Oxidative Complexation X Y
X
+ PdLn
Y
PdLn
4. Oxidative Addition X
Y + PdLn
XYPdLn
5. Hydropalladation f C
C
+ HPdLn
H
C
C
PdLn
Pd(II)
0
0
Possibleg
Pd(II)
0
0
Possibleg
Pd(II)
0
Applicable
Applicable
Pd(II)
0
0
Pd(II) or Pd(0)i
0 or 2i
0 or 2i
Applicable
Applicable
Applicable
0
1
Applicable
Possible
6. Metallopalladation f C
C
M
+ MPdLn
C
C
PdLn
7. Heteropalladation f,h C
C
X
+ XPdLn
C
C
PdLn
8. Migratory Deinsertion X
Y
PdLn
Y
PdLn X
Both Formation and Cleavage of C—Pd Bonds 9. Carbopalladation f C
C
+ RPdLn
R
C
C
PdLn
10. Transmetallation X1PdLn1 + X2PdLn2
X2PdLn1
+
X1PdLn2
Mostly C — Pd Bond Cleavage 11. -Decomplexation X
PdLn
Pd(II) or Pd(0)
X + PdLn
25
(Continued )
26 TABLE 3. (Continued ) FOS b of Starting Compound
FOS b
Pd(II) or Pd(0)
0
13. Reductive Decomplexation X + PdLn PdLn Y Y
Pd(II) j
14. Reductive Elimination
General Pattern 12. -Decomplexation X
PdLn
Y
Y
C
C
C
C
PdLn
C
C
C
C
Applicable
Possible
2
2
Applicable
Possible
Pd(II) j
2
2
Applicable
Possible
Pd(II)
0
0
Possible
Pd(II)
0
0
Possible
Pd(II)
0
0
Possible
+ HPdLn
PdLn
C
C
+ MPdLn
17. Deheteropalladation X
1(or 2 )d
Y + PdLn
16. Demetallopalladation M
Interconversion of RPdLn
+ PdLn
15. Dehydropalladation H
Cleavage of C—Pd Bond
X
X
XYPdLn
Formation of C—Pd Bond
Coord. No.c
PdLn
C
C
+ XPdLn
18. Migratory Insertion Y
X
PdLn
Y
Pd(II)
0
1
Applicable
Applicable
Pd(II)
0
0
Pd(II) or Pd(0)
2 or 0
2 or 1
Possible
Possible
PdLn
X Both Formation and Cleavage of C — Pd Bonds 19. Decarbopalladation R
C
C
PdLn
C
C
+ RPdLn
Other Processes 20. Nucleophilic or Electrophilic
Attack on Ligands (see text) X, Y Atoms and groups containing H, C, heteroatoms, and metals. Ln Ligands. or Signs mean that the indicated process either occurs or does not occur, respectively. Term “applicable” means that the indicated process occurs if X and/or Y are C groups, while term “possible” means that the indicated process can occur with varying degrees of probabilities in cases where Ln contains C groups. b Backdonation is not considered in determining FOS. FOS Change in FOS. c Coord. No.Change in coordination number. d In Some cases, 2-ligands may be considered to occupy two coordination sites. e In some cases, Pd(II) complexes may undergo this process to form Pd(IV) complexes. f The process involves both -complexation and addition. g Possible but relatively rare. h Heteropalladation Addition of heteroatom — Pd bonds to -bonds. i Some transmetallation processes, such as Pd(0) 2 CuCl2 : Pd(II)Cl2 2 CuCl, are redox processes. j This process involving Pd(IV) species is possible. a
27
28
I INTRODUCTION AND BACKGROUND
PdLnX
+ M+C−H(COOMe)2
CH(COOR)2 + PdLn + MX [5]
O R1
C PdLn
O +
R1
HOR2 [6]
C OR2
+ PdLn + HX
Scheme 4
catalytic cycles, oxidation must be precisely counterbalanced by reduction. In cases where this requirement cannot be met with the reagents present in the desired reactions, some external oxidizing or reducing agents must be introduced. It should also be noted that some Pd-catalyzed reactions, especially those using Pd(II) catalysts, may not involve redox processes. In Table 3, patterns 1 through 10 as well as 19 represent the processes for the formation of C—Pd bonds, and one of them may be chosen to come up with a desired catalytic cycle represented by Scheme 3. These processes are discussed in detail in Sect. II.3. Similarly, patterns 9 through 20 provide a menu for C—Pd bond cleavage processes that can be used in Scheme 3. Interconversion of organopalladium intermediates can be accomplished by essentially all of the processes listed in Table 3. However, (i) carbometallation and (ii) decarbometallation, (iii) migratory insertion and (iv) migratory deinsertion, as well as (v) transmetallation represent several most frequently encountered interconversion processes. Further discussions of these processes are presented throughout this Handbook. Even without mechanistic information, one can begin to rationalize and, perhaps more importantly, predict various catalytic organopalladium reactions in consultation with Table 3 and Scheme 3. For example, the following four reactions shown in Scheme 5 are representative of the four most important types of Pd-catalyzed C—C bond formation processes discussed in detail in Parts III – VI. It is useful to note that only four patterns in Table 3, that is, (i) carbopalladation, (ii) reductive elimination, (iii) migratory insertion, and (iv) nucleophilic (or electrophilic) attack on ligands, can achieve C—C bond formation. This summary can also be appropriately modified for the formation of other types of bonds, such as C—H, C—M, C—X, and X—X bonds, where M is a metal and X is a heteroatom. Although the catalytic cycles shown in Scheme 5 do contain some mechanistic implications, they remain as rationalizations and, in some cases, predictions of Pd-catalyzed reactions rather than mechanisms until further scrutinized and experimentally supported. Even so, they are of considerable value from the viewpoints of rational interpretations and predictions. So, readers are well advised to become thoroughly familiar with the basic knowledge presented in this section and skillful in using such knowledge.
C. SOME USEFUL PRINCIPLES AND GENERALIZATIONS PERTAINING TO Pd-CATALYZED REACTIONS All Pd-catalyzed organic synthetic reactions discussed in this Handbook consist of a series of stoichiometric processes. However, good understanding of individual stoichiometric
I.2 FUNDAMENTAL PROPERTIES OF PALLADIUM
29
Pd-catalyzed cross-coupling (Part III) R1X
Pd(0)Ln
R2M
R1Pd(II)LnX
Formation of C Pd bond
R1R2Pd(II)Ln
Pd(0)Ln + R1R2
Interconversion of RPdLn
−
Cleavage of C Pd bond
−
Recycling Pd(0)Ln
Heck reaction (Part IV) HC C
R1X
R1Pd(II)LnX
Pd(0)Ln Formation of C Pd bond
R1C C H Pd(II)LnX Cleavage of C Pd bond
Interconversion of RPdLn
−
−
HPd(II)LnX + R1C C
Pd(0)Ln + HX Recycling Pd(0)Ln
Tsuji−Trost reaction (Part V) X
Pd(II)LnX
Pd(0)Ln
MCH(COOMe)2
Pd(0)Ln +
CH(COOMe)2
Cleavage of C Pd bond
Formation of C Pd bond
−
−
Recycling Pd(0)Ln
Carbonylative esterification of organic halides (Part VI)
Pd(0)Ln
R1X
R1Pd(II)LnX
Formation of C Pd bond
−
CO
R1COPd(II)LnX
Interconversion of RPdLn
Recycling Pd(0)Ln Scheme 5
HOR2
Pd(0)Ln+R1COOR2+HX
Cleavage of C Pd bond
−
30
I INTRODUCTION AND BACKGROUND
processes alone is insufficient for understanding the overall catalytic processes. The following principles and generalizations are presented to fill this gap. C.i. “Zero Sum” Principle with Respect to the Oxidation State of Pd It has already been repeatedly mentioned that any Pd catalysts and Pd-containing intermediates in a catalytic cycle itself must be regenerated in the reaction vessel under one set of reaction conditions without any additional external manipulations. This requires that the sum of FOS (i.e., change in formal oxidation state) for the entire catalytic cycle be zero. This is but one of many “zero sum” principles governing various aspects of chemical processes. Although no additional discussion of this principle per se will be presented, it is nonetheless useful to become familiar with various different kinds of reagents and reactions that can reduce Pd(II) species to Pd(0) species or undergo reverse oxidations for devising catalytic cycles satisfying this “zero sum” principle. Although not discussed here, similar considerations should be made in cases where Pd(II) L Pd(IV) redox processes are involved. It has often been loosely stated that a wide variety of reactions involving the reactants, ligands, and/or solvents present in a given reaction mixture would reduce Pd(II) species and that deliberate reduction of Pd(II) species by externally added reducing agents is unnecessary in most cases. In fact, this statement is true. If so, what actually reduces Pd(II) species and how? Inspection of Table 3 indicates that only reductive elimination, reductive decomplexation, and some processes involving nucleophilic attack on ligands can reduce Pd(II) species. A systematic discussion of reduction of Pd(II) species with organic compounds is presented in Sect. VII.1. from the viewpoint of oxidation of organic compounds. After all, two-electron reduction of Pd must be precisely offset by two-electron oxidation. Below, several widely observable process of two-electron reduction of Pd are presented primarily to provide a reasonable notion of how Pd(II) species added as precatalysts might be transformed into catalysts that appear in catalytic cycles themselves. Any externally added Pd compounds that must be converted to Pd catalysts are usually called “precatalysts,” while any other Pd compounds that lie outside catalytic cycles but are interconvertible with Pdcontaining intermediates are normally termed “resting states” or “resting forms.” Their schematic relationships are shown in Scheme 6. Pd-containing intermediate
Pd precatalyst
Pd catalyst
means the indicated process may or may not occur
Pd-containing resting state
Pd-containing intermediate
Pd-containing intermediate
Note: There may be more or less steps in a catalytic cycle. Scheme 6
Pd-containing resting state
Pd-containing resting state
I.2 FUNDAMENTAL PROPERTIES OF PALLADIUM
31
1. Organometals, enolates, and metal hydrides used throughout this Handbook, especially in cross-coupling and related reactions (Part III) and the Tsuji–Trost reaction (Part V), can, in general, readily reduce Pd(II) complexes via transmetallation-reductive elimination, as shown in Scheme 7.
2 RM
R2Pd(II)Ln
X2Pd(II)Ln
Pd(0)Ln
+ RR
Pd(0)Ln
+ HX
Pd(0)Ln
+ H2
red. elim.
transmetal. HM
H(X)Pd(II)Ln red. elim.
transmetal. HM
transmetal
H2Pd(II)Ln
red. elim.
Scheme 7
2. Alkenes, alkynes, and -compounds including even arenes can reduce Pd(II) species to Pd(0) species. Recall that reduction of PdCl2 with ethylene and water is a crucial part of the Wacker oxidation of ethylene[7] (Scheme 2 of Sect. I.1). Many other related processes of this type are discussed in Sect. V.3. 3. Various n-electron donors, such as phosphines, amines, and ethers, used as reagents, ligands, and solvents can reduce Pd(II) species typically via -complexation–dehydropalladation – reductive elimination. A few such reactions of phosphines and amines are discussed in Sect. II.2.3. and many additional examples are discussed in Part VIII. 4. Various H donors in addition to those already discussed above can reduce Pd(II) species via formation and reductive elimination of H(X)Pd(II)Ln. One typical example[8] is shown in Scheme 8, and various other reactions of this class are discussed throughout this Handbook.
X2Pd(II)Ln
HCOOH
H Pd(II)LnX C O O
HPd
H(X)Pd(II)Ln red. + CO2
Pd(0)Ln
+ HX
elim.
Scheme 8
5. Although -organyl substituents, such as -alkenyl and -aryl, on Pd are relatively resistant to nucleophilic attack, many others, such as allyl, propargyl, acyl, and related COcontaining substituents, are readily attacked by various nucleophiles. So, a combination of any compounds that can generate -bonded (or ,-bonded) organopalladium species and suitable nucleophiles can be used to reduce Pd. A few such examples have already been presented in Scheme 5 in Sect. I.2, and many additional examples may be found throughout this Handbook, especially in Sect. V.2 and Parts VI and VIII.
32
I INTRODUCTION AND BACKGROUND
In summary, the discussions presented in the items 1–5 above amply support the widely accepted notion that Pd(II) species added as precatalysts can be reduced to Pd(0) catalysts by various compounds present in the reaction mixtures without resorting to externally added reducing agents. Although the majority of Pd-catalyzed reactions are initiated by Pd(0) catalysts, which then undergo a series of Pd(0) L Pd(II) redox processes, there are many other Pdcatalyzed reactions that are initiated by Pd(II) complexes. Some such reactions are nonredox processes that do not involve Pd(0) species, as exemplified by a Pd(II)-catalyzed hydrogen transfer hydroalumination[9] discussed in detail in Sect. VII.4.1; most of the Pd(II)-initiated reactions do involve reduction of Pd(II) species to Pd(0) species, as in the Wacker oxidation (Scheme 2 in Sect. I.1 and Sect. V.3.1). In many of these reactions, the Pd(0) species thus generated must be externally oxidized to regenerate the original Pd(II) catalysts. In addition to O2 and CuCl2 used in the Wacker oxidation, quinones (e.g., DDQ), peroxides (e.g., t-BuOOH) halogens, and halo-derivatives including organic halides have been used, as discussed in various sections, in particular Sect. V.3. C.ii. Some Rules Concerning Formal Oxidation State and Electron Counting As the term itself implies, “formal oxidation state” is a formalism with which the oxidation state of an atom or species in question is expressed in a round number and often somewhat arbitrarily. Thus, for example, the formal oxidation state (FOS) of Pd in a complex obtained by -complexation of an alkene with Pd(0) species is considered to be 0, whereas the same Pd atom in the same complex may be assigned an FOS of 2, if the process of formation is regarded as oxidative complexation and if the product is viewed as a palladacyclopropane, as indicated in Table 3. This sort of seeming ambiguity is not a concern, at least in the great majority of cases, as long as this formalism is dealt with in an internally consistent and logically sound manner. After all, most of the practical and synthetic matters in chemistry are dealt with in terms of formalism. The FOS of any atom or group may be determined by merely considering the bond polarity of all bonds to the atom or group in consideration. In this Handbook the following somewhat arbitrary relative order of electronegativity is assumed (Scheme 9). As mentioned above, the arbitrariness has no serious consequences, although reasonable assignments of relative electronegativity values are desirable.
Electropositive metals (e.g., Li and Mg)
98% Z)
[23]
COOH
O
Ph H PdLn
H
3% BnPdCl(PPh3)2 THF, reflux
C CR
[24]
NHBu O
R
R
NBu
NBu
O
O Ar
ArC CCOOCH2CH
CHAr
cat. Cl2Pd(PhCN)2 LiCl, CuCl2
Ar
[25]
Cl
Cl Pd O O
Ar
Ar
PdCl
Ar
Ar
CuCl2
O
Cl
Cl
O
Cl O
O Scheme 15 (Continued )
Even in the cases of alkenes, cyclic heteropalladation involving geometrically defined alkenes can provide clear stereochemical information as in Scheme 16.[26] In intermolecular heteropalladation of simple alkenes, clarification of the stereochemistry is somewhat more difficult and involved. Thus, for example, the anti-stereochemistry of aminopalladation to alkenes was established by running a pair of reactions using both (E)- and (Z)-2-butenes and comparing the NMR spectra of the products,[27] as summarized in Scheme 17.
H
CO, MeOH cat. PdX2
R
O H
Me
COOMe R
+ R
O
H
O
Me 70:30
CO, MeOH H PdX PdX2 R
O H
Me
R
O
H
Scheme 16
Me
COOMe
II.3.1 GENERAL DISCUSSION OF THE METHODS OF SYNTHESIS
11.95 H Me Cl
Me
Me
HNMe2
Pd H Cl
H
NMe2
ClPd H
Me
Me
and H
141
15.94 H
Me
Cl Pd NMe2
14.11 and 18.71 Me H Cl
Me
HNMe2
H
Pd H Cl
Me NMe2 ClPd H
Me
H
Me
H
Me
Cl Pd NMe2
Scheme 17
Although the results shown in Schemes 15–17 amply demonstrate the predominance of the anti-addition in heteropalladation, various factors can readily render the synheteropalladation reactions more favorable than the corresponding anti-addition processes. Such syn-addition processes may well be concerted as in the cases of hydropalladation and carbopalladation. As a representative example, norbornene has been converted to syn-7-norbornenol,[28] which can readily be explained in terms of synoxypalladation–rearrangement–elimination, as shown in Scheme 18. Diaryl disulfides and diselenides undergo Pd-catalyzed syn-addition of S—S and Se—Se bonds, which may be most readily explained in terms of (i) oxidative addition of S—S and Se—Se bonds, (ii) syn-heteropalladation, and (iii) reductive elimination[29] (Scheme 19).
OH
NaOAc, cat. PdCl 2 CuCl2, HOAc
NaOAc PdCl2
OAc
Pd
OAc Cl
Cl Scheme 18
PhSSPh cat. Pd(PPh3)4
R
H C C
PhS RC CH
PhSeSePh cat. Pd(PPh3)4
Scheme 19
SPh
R
H C C
PhSe
(91%)
SePh
(82%)
142
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
E. MIGRATORY INSERTION AND MIGRATORY DEINSERTION Migratory insertion (pattern 18) and migratory deinsertion (pattern 8) represent some of the most fundamental processes for bond formation and cleavage. These processes are often called 1,2-shifts. Many organic processes, such as Wagner – Meerwein rearrangement, pinocol – pinacolone rearrangement, Beckmann rearrangement, and Bayer – Villiger reaction, are considered to be 1,2-shift processes.[30] The great majority of these reactions appear to contain concerted processes as key elements regardless of whether they are polar or nonpolar, and 1,2-shift processes proceeding by radical mechanisms appear to be very rare. Concerted 1,2-shift processes generally proceed with retention of configuration of the migratory group (Y). They may involve (i) a coordinatively unsaturated migration terminus (i.e., B in Eq. 1), (ii) a coordinatively saturated migration terminus undergoing inversion (i.e., B in Eq. 2), or (iii) double migratory insertion leading to transposition of X and Y as in Eq. 3 (Scheme 20). Y
Y A
A B
+
Y
B−
(1)
Y A+
A B
B + X−
(2)
X Y
Y
A B
(3)
A B
X
X Scheme 20
1,2-Migration of a carbon group from Pd to an adjacent atom (i.e., migratory insertion) (pattern 18) involves cleavage of a C—Pd bond. On the other hand, its microscopic reversal (i.e., migratory deinsertion) (pattern 8) generates a C—Pd bond. As is true with many concerted processes, migratory insertion processes are often readily reversible even under mild reaction conditions. Typically, acylpalladium species can readily undergo migratory deinsertion to give decarbonylated organopalladium species (Scheme 21), despite the fact that a number of acylpalladium complexes have been isolated and identified (Sect. II.3.2). This can be a useful preparative method in cases where RX does not readily undergo oxidative addition, even though the number of examples demonstrating this synthetic option is still very low.[31]
RCOX
PdLn oxid. add.
RCOPdLnX
mig. deinsert.
R
Pd(CO)LnX
Scheme 21
Another potentially useful but not yet widely employed class of electrophiles are sulfonyl chlorides and other halides that can also undergo oxidative addition – migratory deinsertion[32] (Scheme 22).
II.3.1 GENERAL DISCUSSION OF THE METHODS OF SYNTHESIS
RSO2X
PdLn oxid. add.
RSO2PdLnX
mig. deinsert.
143
RPdLnX + SO2
Scheme 22
Despite these interesting and promising possibilities, the current scope of the in situ generation of organopalladium derivatives via migratory deinsertion is still rather limited. Although no 1,2-migratory insertion is involved, aryldiazonium salts have been used to generate organopalladium derivatives via extrusion of a small molecule (i.e., N2)[33] (Scheme 23).
N2+BF4−
Me N2
Me
COOEt cat. Pd(Dba)2, NaOAc
COOEt Me
[33]
94%
PdLn
Pd+LnBF4−
Pd+LnBF4− COOEt
COOEt
Me Scheme 23
F. TRANSMETALLATION Transmetallation represents a class of single bond metathesis reactions in which two organometallic compounds, mostly of two different metals, exchange ligands, as shown in Scheme 24. As indicated in Scheme 24, transmetallation is significantly promoted by the presence of a metal empty orbital. In cases where both metals M1 and M2 are coordinatively unsaturated, transmetallation is kinetically quite facile, and the eventual equilibrium is thermodynamically dictated. As a rule of thumb, the major driving force is provided by the formation of a bond between the more electropositive metal and the more electronegative ligand. Thus, organometals containing those metals that are more electropositive than Pd including K, Na, Li, Mg, Zn, Al, and Zn undergo facile transmetallation with Pd complexes containing relatively electronegative ligands, as extensively discussed in Part III. One must, however, recall the Curtin – Hammett principle[14] discussed in Sect. I.2. Thus, thermodynamically unfavorable transmetallation processes may be involved in many Pdcatalyzed reactions provided that the overall process is thermodynamically favorable. Thus, organometals containing relatively electronegative metals, such as organoboranes, organostannanes, and even organosilanes, have participated in Pd-catalyzed reactions (e.g., cross-coupling), which are thought to proceed via transmetallation, as amply discussed in Part III. Bases have played important roles in the reactions of organoboranes, suggesting that at least, in some cases, coordinately saturated organoborates might act as reactive species in putative transmetallation processes. In fact, preformed alkynylborates were employed in the initial phase of the Pd-catalyzed cross-coupling of organoboron compounds.[34] In this and many other cases of Pd-catalyzed cross-coupling reactions of
144
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
LnM1
X1 + X2 M2Ln
LnM1
X2 +
LnPd
X +
LnPd
R
R MLn
+
X1 M2Ln
(1)
X MLn (2)
R R MLn =
LnPd
LnPd
MLn
X X R LnPd
X +
R MLn
LnPd
MLn X
(3)
R LnPd
R
+ [MLn]
LnPd
MLn
LnPd
R + XMLn
X X Scheme 24
organoboron, organotin, and organosilicon compounds, nucleophilic organometals may be coordinatively saturated, and their transmetallation processes may not be readily accommodated by the mechanism shown in Eq. 2 of Scheme 24. In such cases, a two-stage transmetallation process involving just one empty valence orbital shown in Eq. 3 of Scheme 24 may be operative. Irrespective of mechanistic details, transmetallation involving Pd complexes has been one of the most general methods for generating -bonded organopalladiums along with oxidative addition and several nonredox addition reactions, as discussed throughout this Handbook, especially in Part III. As might be expected from the concerted mechanisms shown in Scheme 24, transmetallation proceeds with retention of configuration of the R and X groups.
REFERENCES [1] C. A. Tolman, Chem. Rev., 1977, 77, 313. [2] J. P. Collman, L. S. Hegedus, J. R. Norton, and R. G. Finke, Principles and Applications of Organotransition Metal Chemistry, 2nd ed., University Science Books, Mill Valley, CA, 1987, 989 pp. [3] M. J. S. Dewar, Bull. Soc. Chim. Fr., 1951, C71. See also M. J. S. Dewar and G. P. Ford, J. Am. Chem. Soc., 1979, 101, 783. [4] J. Chatt and L. A. Duncanson, J. Chem. Soc., 1953, 2939. [5] A. de Meijere, Angew. Chem. Int. Ed. Engl., 1979, 18, 809. [6] J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic Synthesis, Wiley, New York, 1995, 560 pp. [7] P. Fitton and J. F. Meckeon, Chem. Commun., 1968, 4. [8] E. Negishi, S. Chatterjee, and H. Matsushita, Tetrahedron Lett., 1981, 22, 3737. [9] B. M. Trost and P. E. Strege, J. Am. Chem. Soc., 1977, 99, 1649.
II.3.1 GENERAL DISCUSSION OF THE METHODS OF SYNTHESIS
[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34]
145
J. K. Stille and K. S. Y. Lau, Acc. Chem. Res., 1977, 10, 434 – 442. P. Fitton and E. A. Rick, J. Organomet. Chem., 1971, 28, 287. M. Beller, W. A. Moradi, M. Eckert, and H. Neumann, Tetrahedron Lett., 1999, 40, 4523. J. F. Hartwig and F. Paul, J. Am. Chem. Soc., 1995, 117, 5373. D. Y. Curtin, Rec. Chem. Prog., 1954, 15, 111. N. A. Cortese, C. B. Ziegler, Jr., B. J. Hrnjez, and R. F. Heck, J. Org. Chem., 1978, 43, 2952. Z. Owczarczyk, F. Lamaty, E. J. Vawter, and E. Negishi, J. Am. Chem. Soc., 1992, 114, 10091. R. F. Heck, Org. React., 1982, 27, 345 – 390. S. Ma and E. Negishi, J. Am. Chem. Soc., 1995, 117, 6345. N. Chatani, N. Amishiro, and S. Murai, J. Am. Chem. Soc., 1991, 113, 7778. N. Chatani and T. Hanafusa, Chem. Commun., 1985, 838. C. Lambert, K. Utimoto, and H. Nozaki, Tetrahedron Lett., 1984, 25, 5323. A. Arcadi, A. Burini, S. Cacchi, M. Delmastro, F. Marinelli, and B. R. Pietroni, J. Org. Chem., 1992, 57, 976. M. Kotora and E. Negishi, Synthesis, 1997, 121. H. Sashida and A. Kawamukai, Synthesis, 1999, 1145. S. Ma and X. Lu, J. Org. Chem., 1993, 58, 1245. M. F. Semmelhack and C. Bodurow, J. Am. Chem. Soc., 1984, 106, 1496. B. Åkermark and K. Zetterberg, J. Am. Chem. Soc., 1984, 106, 5560. W. C. Baird, Jr., J. Org. Chem., 1966, 31, 2411. H. Kuniyasu, A. Ogawa, S. Miyazaki, I. Ryu, N. Kambe, and N. Sonada, J. Am. Chem. Soc., 1992, 114, 9796. J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992, 1495 pp. H. V. Blaser and A. Spencer, J. Organomet. Chem., 1982, 233, 267; 1982, 240, 209; 1984, 265, 323. M. Miura, H. Hashimoto, K. Itoh, and M. Nomura, Tetrahedron Lett., 1989, 30, 975. K. Kikukawa, K. Nagira, F. Wada, and T. Matsuda, Tetrahedron, 1981, 37, 31. E. Negishi, in Aspects of Mechanism and Organometallic Chemistry, J. H. Brewster, Ed., Plenum Press, New York, 1978, 285 – 317.
Csp3-Pd, Csp2-Pd, Csp-Pd
II.3.2 Stoichiometric Synthesis and Some Notable Properties of Organopalladium Compounds of Pd(0) and Pd(II) DANIÈLE CHOUEIRY
A. INTRODUCTION As discussed in Sect. I.2, palladium complexes of general formula PdLn can react according to well-defined reaction patterns that lead to organopalladium complexes through C — Pd bond formation. These general patterns were largely discussed in Sect. II.3.1. While these principles are most often used to generate in situ organopalladium species, under catalytic conditions, they have also been applied to the preparation of discrete organopalladium entities in a stoichiometric way. Isolation of organopalladium complexes is important not only in the preparation of organopalladium catalysts, but also for mechanistic investigations. Indeed, it is through the understanding of both their reactivity and the rules governing their formation that the discovery of new catalytic reactions via organopalladium complexes can be significantly facilitated. Palladium forms complexes with a variety of carbon ligands. The carbon ligand may be neutral or charged, and sp3, sp2, or sp hybridized. Pd complexes of neutral carbon ligands, such as CO and alkenes, are typically generated by complexation reactions, while oxidative addition, hydro-, carbo-, and heteropalladation reactions, and transmetallation provide major routes to the organopalladium complexes containg a C — Pd bond. The reactivity of organopalladium complexes is also indicated by the general patterns (Sect. II.3.1). While some of these patterns, such as carbometallation and migratory insertion, result in new organopalladium species, some others, such as reductive elimination or nucleophilic attack on ligands, result in the destruction of organopalladium species.
B. PALLADIUM COMPLEXES CONTAINING NEUTRAL CARBON LIGANDS ONLY Palladium forms complexes with a variety of neutral carbon ligands. While some of them, such as CO and isonitriles, bind to palladium in a - or -fashion, others, such as alkenes, dienes, and alkynes, form -complexes.
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
147
148
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
B.i. - and -Carbon Ligands: Carbonyl and Isonitrile Complexes The chemistry of palladium – carbonyl complexes has experienced extensive recent developments due to an increased interest in the role of palladium in surface catalysis especially in automobile exhaust catalysts. Palladium – carbonyl complexes are nevertheless still relatively rare, which is probably due to their relative instability in comparision with that of Ni complexes. The homoleptic Pd(CO)4 only exists at low temperatures (80 K) in noble gas or CO matrices, in sharp contrast with isoleptic Ni(CO)4, which is stable at ambient temperature. Table 1 compiles some of the known and representative carbonyl complexes of palladium. In cases of dinuclear Pd – carbonyl complexes, the carbonyl ligand can be linear [i.e., Pd(-CO)] or bridging [i.e., Pd2(-CO)]. Actually, the great majority of dinuclear Pd carbonyls have carbonyl-bridged structures. However, most of these complexes are Pd(I) complexes and will not be covered in this section. An exception is the Pd(II) complex, Pd2(CO)2Cl4, in which the CO ligands are terminal. Palladium – carbonyl complexes are typically formed from PdX2 (X Cl, Br, or I) and CO. For example, Pd2(CO)2Cl4 is obtained by high-pressure carbonylation of PdCl2. Similarly, the anionic M[Pd(CO)X3] are obtained from carbonylation of PdX2 or M2(Pd2X6). While the iodide is relatively unstable, the chloride and bromide could be characterized by X-ray crystallography.[4] Alternatively, CO can displace a variety of ligands from palladium and Pd – CO complexes have been prepared from Pd – nitrile and even Pd – phosphine complexes. For instance, Pd(CO)2Cl2 has been obtained via ligand displacement of Cl2Pd(PhCN)2 with CO. In cases of Pd(0) complexes, the starting materials can be either Pd(0) species, such as Pd(PPh3)4, or Pd(II) species, such as Cl2Pd(PPh3)2. In the latter cases, the use of added reducing agents may be desirable or necessary, as in the preparation of Pd(CO)(PPh3)3 (Scheme 1).[10] Alternatively, this same complex can be obtained from Pd(PPh3)4 and CO TABLE 1. Palladium–Carbonyl Complexes Carbon Number a
Pd – Carbonyl Complex
Comments
M[Pd(CO)Cl3] M[Pd(CO)Br3] M[Pd(CO)I3] M[Pd(CO)Cl(SnCl3)2] Pd(CO)2Cl2 Pd(CO)4 [Pd(CO)(PEt3)2Cl]X Pd[CO)3(PPh3) Pd(CO)(PPh3)3
M Et2H2N, Bu4N M K, Bu4N M Bu4N; readily loses CO M Et4N
References for Preparation
MONOMERS
1
2 4 13 21 55 DIMERS
1
OC Cl OC Br
a
Pd Pd
Cl Cl Br Br
Pd Pd
Only by matrix isolation X BF4; readily loses CO Only under CO pressure
[1],[2] [1],[3] [4] [5] [6] [7] [8] [9] [10],[11]
Cl CO
[2]
Br
[4]
CO
Number of C atoms in a monomer unit.
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
149
(Scheme 1).[11] Palladium – carbonyl complexes can themselves be the source of other carbonyl complexes. For example, (Et2H2N)[Pd(CO)Cl3] can be obtained from Pd2Cl4(CO)2 and Et2H2NCl.[2] NaBH4, PPh3
Pd(PPh3)2Cl2 + CO
Pd(PPh3)4
Pd(CO)(PPh3)3
[10]
+ CO
Pd(CO)(PPh3)3
[11]
Scheme 1
The most interesting feature of the reactivity of Pd – CO complexes is their migratory insertion reaction that takes place in cases where the Pd – CO complex simultaneously contains an additional C — Pd bond. This migratory insertion of CO leads to the formation of acyl – Pd complexes. Indeed, Pd(0) complexes of CO, such as Pd(CO)(PPh3)3, can react with methyl iodide, allyl chloride, and vinyl chloride, to give the corresponding acyl – Pd complexes (Scheme 2).[10] This transformation can be explained in terms of an oxidative addition – migratory insertion sequence (Scheme 2). Acyl – Pd complexes will be discussed in greater detail in Sect. C.ii.
O PPh3
MeI
Pd(CO)(PPh3)3
Me
C Pd
I
PPh3 oxidative addition
PPh3 Me
Pd
migratory insertion
CO I
Me
PPh3
Pd
I
PPh3 Scheme 2
This reaction profile, also called carbonylation, governs the reactivity of Pd – carbonyl complexes. Anionic M[Pd(CO)I3], for instance, catalyzes the reductive carbonylation of esters.[12] On the other hand, Pd(CO)(PPh3)3 was reported to catalyze the carboxymethylation of organic halides[13] and the cyclocarbonylation of cinnamyl halides.[14] However, the Pd – CO complexes are most often generated in situ from preformed alkyl – palladium complexes and CO under stoichiometric[15] or catalytic conditions, for example, in the copolymerization of alkenes and CO.[16] Decarbonylation reactions also involve the intermediacy of Pd – CO complexes. In this case, migratory deinsertion (Sect. II.3.1), that is, the microscopic reversal of the migratory insertion, takes place. Closely related to the palladium – carbonyl complexes are the palladium – isonitrile complexes. Isonitriles are better -donors than the isoelectronic CO and are consequently better ligands for Pd than CO. Their Pd complexes are indeed more stable than the corresponding CO complexes. Isonitrile – palladium complexes are usually prepared from PdX2 (X Cl, Br, I), or their derivatives, for example, Na2PdCl4, and Cl2Pd(CH3CN)2, via ligand exchange. Occasionally, organopalladium complexes such as (5-C5H5)
150
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 2. Palladium–Isonitrile Complexes Carbon Number 8 10
14
References for Preparation
Pd – Isonitrile Complex
Comments
Pd[(CNMe)4]X2 Pd(CNBu-t)2 Pd(CNBu-t)2Cl2 Pd(CNBu-t)2I2 Pd(CNBu-t)2O2
X BF4, PF6
Pd CN
[17],[18] [19] [20] [19] [19]
cis trans X Cl, I; cis
X2
[21]
2
(3-C3H5)Pd (Sect. C.i) serve as precursors to Pd – isonitrile complexes, for example, Pd(CNR)2. Finally, Pd – isonitrile complexes can also serve as precursors to other Pd – isonitrile complexes. An example is provided by the preparation of Pd(CNBu-t)2O2 from Pd(CNBu-t)2. Table 2 lists some representative Pd – isonitrile complexes. Like Pd – CO complexes, Pd – isonitrile complexes can undergo oxidative addition into carbon – halide bonds, and then subsequent migratory insertion, as exemplified in Scheme 3.[22] Another interesting reaction of Pd( I I ) – isonitrile complexes is that with protic compounds to produce palladium – carbene complexes (Scheme 4).[23]
Bu-t
Bu-t
N
N
C Pd(CNBu-t)2 + MeI
Me Pd I
1 2
Me
C t-Bu
N
N
C
Pd
C
I I
Pd
C
N
Bu-t
C Me N Bu-t
Bu-t Scheme 3
R NH LnPd=C=NR + HY
LnPd Y
HY = OR′, NR′R′′ Scheme 4
B.ii. 2-,4-Carbon Ligands (-Complexes): Alkenes, Dienes, and Alkynes Complexes Many examples of Pd – alkene, Pd – diene, and Pd – alkyne complexes are known for both Pd(0) and Pd(II) oxidation states. Representative examples are given in Tables 3, 4, and 5.
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
151
TABLE 3. Palladium–Monoene -Complexes Carbon Number a
Pd – Monoene Complex
Comments
M[Pd(H2CRCH2)Cl3] Pd(H2CRCH2)2Cl2 Pd(H2CRCH2)3
M Bu4N; unstable at r.t.b Stable under C2H4 Stable under C2H4
References for Preparation
MONOMERS
2 4 6 21
[24] [25] [26] [26]
Pd
3
Cy
c
Cy P Pd
30
Stable at 0 C
[27]
Air-sensitive Air-sensitive
[28] [28]
Air-stable
[29]
Unstable
[30] [31]
P Cy
38
Cy
Pd(H2CRCH2)(PPh3)2 Pd(H2CRCH2)(PCy3)2 O
40
Pd
O (PPh3)2 O
Pd(dba)3d Pd(2-C60)(PPh3)2
51 96 DIMERS
2
4 Cl
Cl
Cl
Cl
Pd
Cl
Cl Cl
Ph
8 Cl
Pd
a
d
dba
Ph
Ph
[32],[33]
[34]
Cl Cl
Pd
Pd
Cl Cl
Number of C atoms in a monomer unit. r.t. room temperature. c Cy Cyclohexyl. O b
trans
cis
Pd
Cl
Pd
Cl
Pd
Cl
Pd
Cl
6
Cl
Pd
Cl
[32]
Cl
Pd
[32]
Cl
[32] Ph
152
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 4. Palladium–Diene and Palladium–Polyene -Complexes Carbon Number
Pd Complex
Comments
References for Preparation
DIENE COMPLEXES
6
PdCl2
7
PdX2
8
[35]
X Cl, Br X Cl, Br, I; commercially available for X Cl
a
PdX2
PdCl2 b
16
Pd
34 51
Pd(dba)2d Pd2(dba)3d
56
Pd
[36]
[37],[38]
Air-sensitive
[39]
Stable below r.t.c
[26] [40] [41]
Ph
Ph
Ph
Ph
[42] 2
POLYENE COMPLEXES
60
Pd(C60)
[43]
a
Pd(1,5-cyclooctadiene)Cl2 or Pd(1,5-cod)Cl2. Pd(1,5-cod)2. c r.t. room temperature. O b
d
dba Ph
Ph
Alkene complexes of Pd(0) can be obtained from either Pd(0) or Pd(II) precursors. For example, Pd(H2C"CH2)3 (Table 3) is obtained by the condensation of Pd atoms with ethylene, or via ligand displacement from Pd(1,5-cod)2 (Table 4),[26] which, in turn, is obtained by the reduction of Pd(1,5-cod)Cl2 in the presence of 1,5-cyclooctadiene.[26] Likewise, mixed alkene/phosphine Pd(0) complexes, for example, Pd(alkene)(PR3)2, can be obtained either by the reduction of a Pd(II) species, such as Pd(acac)2 or Pd(OAc)2, in the presence of the desired alkene and phosphine,[28] or by the reaction of Pd(PR3)4 with the desired alkene.[29] Dienes and polyenes can also serve as ligands in such complexes. In these cases, however, they act as monoenes, for example, Pd(2-1,3butadiene)(Cy2PC2H4PCy2) and Pd(2-C60)(PPh3)2, and are consequently classified in Table 3. Alkene complexes of Pd(0) are usually less stable than their Ni or Pt analogs, but electron-withdrawing groups in alkenes stabilize the resulting complexes, for example, Pd(maleic anhydride)(PPh3)2.[29] Alkynes containing electron-withdrawing groups behave
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
153
TABLE 5. Palladium–Alkyne -Complexes Carbon Number a
References for Preparation
Pd Complex
MONOMERS
20 32 40 42
Pd(CF3C#CCF3)(PPhMe2)2 Pd(MeOOCC#CCOOMe) (Cy2PCH2CH2PCy2) Pd(CF3C#CCF3) (PPh3)2 Pd(PhC#CPh)2 (C6F5)2 Pd(MeOOCC#CCOOMe) (PPh3)2
[44] [27] [44] [45] [44]
[Pd(t-BuC#CBu-t)Cl2]2
[46]
DIMERS
10 a
Number of C atoms in a monomer unit.
similarly to form relatively stable mixed alkyne/phosphine – Pd complexes and are prepared in manners similar to those of their alkenes analogs (Table 5). Some of the synthetically important Pd – alkene -complexes include Pd(dba)2 and Pd2(dba)3, which are stable to air and commercially available. The ease of displacement of the dba ligands by a variety of ligands including phosphines is at the origin of their extensive use as Pd(0) precursors, for both stoichiometric preparation (Scheme 5)[43] and in situ generation of Pd(0) species.[47],[48] The role of dba in the reactions of Pd(0) complexes in situ generated from Pd(dba)2 and phosphines has been thoroughly investigated in the past few years.[49] 1 2
Pd2(dba)3
+
Pd(C60)
C60 Scheme 5
It is worth noting that Pd(dba)2 and Pd2(dba)3 are structurally closely related complexes in which the dba act as 4 ligands (Scheme 6). Recrystallization of Pd(dba)2, which actually is better represented by [Pd2(dba)3](dba), from chloroform, benzene, or toluene leads to [Pd2(dba)3](solvent).[41] On the other hand, Pd(dba)3 is obtained by the addition of an excess of dba to Pd(dba)2. In this case, dba acts as an 2 ligand (Scheme 6).[30] Ph
O
Ph
Ph
Ph O
O
Ph Pd2(dba)3
Pd
Pd
Ph
O
Ph
Pd Ph
Ph Ph
Pd(dba)3 O
Ph O
Ph Scheme 6
154
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
It should be noted that Pd(dba)2 and Pd2(dba)3 have also proved to be useful as “ligandless” catalysts, that is, without added P-, As-, or N-containing ligands, in Pdcatalyzed processes, such as the Suzuki coupling.[50],[51] This is an important development considering the toxicity of the frequently used phosphine or arsine ligands. Recently, an interesting Pd(0) – triolefin complex of a phosphine-free 15-membered macrocyclic ligand (Scheme 7) has been prepared and proved useful as a recoverable catalyst in crosscoupling reactions.[52]
SO2Ar N
Pd ArO2S
N
N
SO2Ar
Scheme 7
Pd(II) complexes are electrophilic species, and they readily coordinate alkenes, dienes, and alkynes. These complexes are typically prepared from PdCl2 and its derivatives, for example, Li2PdCl4 and Na2PdCl4, or Cl2Pd(PhCN)2, and the corresponding -carbon ligand. This reaction leads to monomeric Pd complexes in the case of dienes (Table 4), while the use of alkenes and alkynes leads to the formation of dimeric species (Tables 3 and 5). The reaction of Cl2Pd(PhCN)2 with ethylene, for instance, leads to the formation of [Pd(CH2"CH2)Cl2]2, which can be converted into Pd(CH2"CH2)2Cl2 only under a high pressure of ethylene.[25] Alternatively, [Pd(alkene)Cl2]2 can react with another alkene or an alkyne to generate a new Pd – alkene or Pd – alkyne complex via ligand exchange. As Pd(PhC#CPh)2(C6F5)2 is a rare example of stable bisacetylene Pd(II) complexes, it is listed in Table 5 despite the presence of two uninegative C6F5 groups. As in the cases of carbonyl complexes, anionic complexes of alkenes, for example, (Bu4N)[Pd(CH2"CH2)Cl3], have been generated by the reaction of the corresponding alkene with (Bu4N)2Pd2Cl6.[24] From the structural viewpoint, it is interesting to note that alkene and diene complexes of Pd(II), such as [Pd(CH2"CH2)Cl2]2 (1) and Pd(1,5-cod)Cl2 (2), have, for steric reasons, the double bond C — C axis perpendicular to the Pd square plane (Scheme 8).[53] In some cases, however, one alkene can be constrained to lie in the coordination plane of Pd, as exemplified by 3.[54]
Cl Cl Pd Pd Cl Cl 1
Cl Pd Cl 2 Scheme 8
Cl Pd Cl 3
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
155
One of the most remarkable features associated with the Pd – ( C — C) complexes is the high reactivity of the -ligands toward nucleophiles rather than electrophiles. Whereas alkenes, dienes, and alkynes generally react readily with electrophiles, those coordinated with Pd(II) species react with nucleophiles, such as water, alkoxides, alcohols, amines, and carbon nucleophiles, such as malonic ester anions and Grignard reagents. These nucleophilic attacks induce the transformation of Pd – ( C — C) complexes into new palladium complexes containing a C — Pd bond, resulting in an overall hetero- or carbopalladation process. Butylamine, for instance, reacts with [Pd(CH2"CH2)Cl2]2 to give MeCH"NBu-n by the nucleophilic attack of the amine on the Pd-coordinated ethylene followed by syn -elimination and 1,3-hydrogen shift (Scheme 9).[55] On the other hand, the reaction of sodium methoxide with Pd(1,5-cod)Cl2 leads to a new Pd(alkene)(alkyl) complex (Scheme 10).[37]
Cl
H
Cl Pd
Pd Cl
NHBu-n
n-BuNH2
Cl
NHBu-n β-elimination
H PdLn
LnPd H
hydropalladation
Me
β-elimination
N Bu-n
LnPd
−HPdLn
H MeC NBu-n
H
Scheme 9 OMe Cl Pd
NaOMe
Cl
1 2
Pd
Cl
2
Scheme 10
These nucleophilic attacks proceed in an intermolecular fashion and give the anti or exo addition products. This has been clearly demonstrated in the reaction of Pd(1,5cod)Cl2 with sodium methoxide,[37] which has yielded a complex analyzed by NMR spectroscopy.[56] On the contrary, syn or endo addition takes place when Grignard reagents are used. In these cases, transmetallation leading to the formation of a C — Pd bond takes place first (Scheme 11).[57] As a result, the nucleophile is delivered intramolecularly in a syn or endo fashion, via a carbopalladation reaction (Scheme 11).[57] Ph Cl
Cl Pd
LnPd
Cl
Ph
Ph β-elimination
RMgBr
Pd Cl
Ph
−HPdLn
LnPd R
Ph
Scheme 11
R
R
156
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
Alkene – Pd, diene – Pd, or alkyne – Pd complexes can be useful catalysts or catalyst precursors for many organic transformations. In addition to the widely used Pd–dba complexes (vide supra), other Pd–alkene complexes have shown some interesting catalytic activity. For instance, Pd(1,5-cod)Cl2, which is commercially available, catalyzes the selective protection of primary alcohols as acetals under neutral condtions.[58] Another example is Pd(maleic anhydride)(PPh3)2, which has been used as a catalyst in the reaction of allene with diolefins,[59] amines,[60] or active hydrogen compounds.[60] Besides its high stability, its high solubility in organic solvents makes this -complex a convenient catalyst. A catalytic quantity of Pd(CH2"CH2)(PPh3)2 was found to induce the alkylation of (Z)-3-acetoxy5-carbomethoxy-1-cyclohexene with dimethylmalonate,[61] leading to a more extensive stereochemical scrambling than Pd(PPh3)4 in a process in which a high phosphine/Pd ratio seems important. Finally, [Pd(CH2"CH2)Cl2]2 and [Pd(cyclohexene)Cl2]2 were found to be as good as Cl2Pd(PhCN)2 and PdCl2 in the catalytic isomerization of olefins, indicating that all of these catalyst precursors are converted to a common Pd – olefin intermediate that must serve as the actual catalyst.[62] Indeed, Pd – alkene, Pd – diene, or Pd – alkyne -complexes have often been assumed to be the actual catalysts in several Pd-catalyzed transformations, and the stoichiometric preparation and isolation of some of them provide a strong support for their intermediacy. An example of a process involving the likely intermediacy of an alkene – Pd complex is provided by the Cl2Pd(MeCN)2-catalyzed transformation of oallylanilines to indoles (Scheme 12).[63]
cat. Cl2Pd(MeCN)2 O
NH2
N H
O LiCl
Scheme 12
Another well-known example is the Wacker process known to proceed via a hydroxypalladation mechanism (Sect. V.3).[64] The stereochemistry of the hydroxypalladation of alkenes was actually assessed by studying the reaction of the preformed [Pd(CD2"CD2)Cl2]2 with water under carbonylative conditions and was found to proceed in an anti fashion (Scheme 13).[65] D D Cl
H
Cl Pd
Pd Cl
D
H
D
2 H 2O
Cl D
CO
O O
D 2 H2O
DH HO
O
Cl Pd HD
DH
CO 2
Cl Pd
HO Scheme 13
HD
2
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
157
A recent application of the Pd(II)-induced activation of double or triple bonds toward nucleophilic attack is the development of an interesting one-pot synthesis of substituted tetrahydrofurans and pyrrolidines.[66]–[68] The ease with which nucleophiles add to alkenes and alkynes coordinated to Pd(II) combined with the tendency of Pd to form -allyl complexes accounts for the limited number of Pd(II) – alkene, Pd(II) – diene, or Pd(II) – alkyne complexes. Indeed, as detailed in the next section, depending on the conditions or their structural features, alkenes, dienes, and alkynes often lead to the formation of -allylpalladium complexes instead of 2 or 4 -complexes. This is particularly true in the case of alkenes bearing hydrogens to the double bond, 1,3-dienes, such as 1,3-butadiene, and alkynes of low steric hindrance. In marked contrast, Pd(1,5-hexadiene)Cl2 is obtained from the reaction of Cl2Pd(PhCN)2 with allyl chloride.[35]
C. Pd COMPLEXES CONTAINING ANIONIC CARBON LIGANDS The majority of known organopalladium complexes contain anionic carbon groups, such as alkyl, benzyl, aryl, alkenyl, and alkynyl groups. Acylpalladium complexes also belong to this category. These organyl ligands form bonds with Pd. With allyl and cyclopentadienyl groups, Pd in most cases is simultaneously linked to an anionic carbon group through a bond and to one or two allylic C"C bonds through -complexation. In such cases, 3-allylpalladium and 5-cyclopentadienylpalladium complexes are formed rather than the corresponding 1-allyl- or cyclopentadienylpalladium complexes. C.i. - and -Bonded Complexes of Palladium: -Allyl and Cyclopentadienyl Complexes A large variety of -allylpalladium complexes have been isolated. Some representative examples of such complexes are shown in Table 6. A large number of allylic compounds, such as allyl halides, allyl alcohols, allyl acetates, allyl trifluoroacetates, and also allyl Grignard reagents, react with palladium salts, such as PdCl2 or Na2PdCl4, to give -allylpalladium complexes. The reaction of Na2PdCl4 with allyl chloride in MeOH in the presence of CO leads to the formation of the dimeric complex Pd2(3-C3H5)2(-Cl)2.[84] The role of CO in this reaction is to ensure the reduction of the Pd(II) species into a Pd(0) species (see Sect. II.2.3) necessary for the oxidative addition into the C — Cl bond (Scheme 14). In contrast, allylmagnesium chloride reacts with Pd(II)Cl2 to produce homoleptic Pd(3-C3H5)2 via transmetallation (Scheme 14). It is interesting to note that this latter type of complexes exist in solution as a mixture of the cis and trans isomers, while the trans isomer is favored in the solid state (Scheme 15).[96] These reactions can be applied to the formation of substituted 3-allylpalladium complexes. Once Pd2(3-C3H5)2(-Cl)2 and Pd(3-C3H5)2 are prepared, they can be transformed into a variety of other allylpalladium species, as exemplified in Scheme 16. Alternative direct synthetic routes starting from Pd(0) or Pd(II) species have also been utilized (Scheme 17). Cationic allylpalladium complexes represented by [(3-C3H5)PdL2]X can be generated by the reaction of the dimeric Pd2(3-C3H5)2(-X)2, where X is Cl or Br, with salts of noncoordinating anions, for example, NaBPh4 or AgBF4, in the presence of ligands such as
158
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 6. Allylpalladium Complexes Carbon Number a
Pd Complex
Comments
References for Preparation
MONOMERS
3
PdX2
6
Pd
X Cl, Br
Ph4P
[70]
8
Pd
9
[69]
Pd PMe3
Readily decomposes in solution
[71]
Unstable above 0 C
[72]
Br
[73]
Pd PEt3
Air-sensitive; decomposes in solution above 25 C
11 Me3P
12
Pd
Pd
[74],[75]
Air-sensitive; decomposes above 20 C
[76]
X Br, BF4
[77]
b
N
13
Pd
X N
15
PEt3 X
Pd PEt3 X
21
Pd
X Br, BPh4
[78],[79]
X Br, AcO
[80],[81]
PCy3 Cl
[82]
Pd PPh3 DIMERS
X
3
Pd
Pd X
X Cl, Br, I, OAc; commercially available for X = Cl
[83]–[88]
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
159
TABLE 6. (Continued ) Carbon Number a
Pd Complex
Comments X
4
Pd
Pd
X Cl, Br, I
[84],[87] [89] –[91]
Pd
X Cl, Br
[92]–[94]
X X
7
Pd
References for Preparation
X
Ph Cl 9
Pd
Pd
[90],[95]
Cl Ph a b
Number of carbons in a monomer unit. [(3-C3H5)Pd(bipy)]X.
phosphines[79] or bidentate amines, for example, bipy. Alternatively, this class of complexes can be obtained by the oxidative addition of allylic derivatives in the presence of an excess of ligand or chelating ligands. An interesting example is the preparation of [(3C3H5)Pd(bipy)]Br from allyl bromide and Me2Pd(bipy), demonstrating that dialkylpalladium species, which can be converted to Pd(0) species via reductive elimination (vide infra), can also be used to generate -allyl complexes.[77] With smaller amounts of ligands neutral (3-C3H5)Pd(L)X are obtained. It should be noted, however, that while the treatment of allyl acetate with Pd(PCy3)2 does provide the expected (3-C3H5)Pd(PCy3)OAc complex, the use of Pd – PPh3 complexes, for example, Pd (PPh3)4, does not lead to the desired 3allyl(acetato)palladium complexes.[80],[81] This latter result is in agreement with a recent study, which provided evidence for the reversibility of the formation of -allylpalladium complexes from the oxidative addition of Pd(0) – PPh3 complexes into allyl acetate.[97] Some of these allylpalladium complexes, Pd2(3-C3H5)2(-Cl)2 in particular, are important not only as precursors to a large variety of allylpalladium complexes, but also as Pd(0) sources in a variety of Pd-catalyzed processes.[98] It is actually commercially available. It is worth noting that in essentially all of the examples listed in Table 6 the isolated species correspond to the 3--allylpalladium complexes. The structure of Pd2(3C3H5)2(-Cl)2 has been determined by X-ray crystallography,[99],[100] which has confirmed that the allyl group is bonded in an 3-mode occupying two coordination sites at an angle of about 110° relative to the plane of the Pd2Cl2 unit. It is indeed quite rare to isolate the -allylpalladium complexes, as they are usually less stable than the corresponding -allyl derivatives. Mixed /-allyl complexes could nonetheless be isolated by adding phosphines to bis(-allyl)palladium complexes.[72],[74],[75] It is important to keep in mind, however, that the two species can in principle interconvert in a dynamic equilibrium. This dynamic equilibrium has been clearly established for species such as (3-allyl)PdX(PR3) in which interconversion between syn and anti substituents is rationalized by invoking the intermediacy of 1-allyl species.[96]
160
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
X
Pd(0)
X
1 2
PdX
Pd
Pd X
PdCl2
MgCl
2
Pd
−2 MgCl2
Pd
Scheme 14
Pd
Pd
trans
cis Scheme 15
NaI or AgOAc
X Pd
[85],[87]
KCl/PPh4Cl
X = I, OAc
PdCl2− PPh4+
[69]
Cl Pd
Pd X
Pd Cl
Cl
2 PPh3
Pd
[82]
PPh3
4 PEt3 NaBPh4
+ PEt3 Pd PEt3
[79]
PMe3
BPh4−
Pd PMe3
Pd PMe3 2
Me3P Pd Scheme 16
Alkenes can also react with Pd(II) salts to give -allylpalladium complexes. One key requirement is that the alkene has one or more hydrogens to the double bond that can be abstracted to give a -allyl complex. Heat[89],[90] or the presence of a base (Scheme 18),[101] such as sodium carbonate or sodium acetate, favors the transformation of the initially formed 2-alkene complex into the -allyl species.
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
X
X
Pd black
Pd
[88]
Br PEt3 + PEt3 Pd PEt3
Br [78] 3
Pd(dba)2
X = Br, I
Pd
potassium slurry [73]
Pd(PEt3)3
Pd X
Br
Br2Pd(PEt3)2
161
Br−
Pd
[76]
Scheme 17 n-C3H7 Cl Pd Cl
Cl Pd
Cl
Na2CO3 100%
Cl n-C3H7
Pd
Pd
C3H7-n + HCl
Cl
C3H7-n Scheme 18
The use of highly electrophilic Pd(OCOCF3)2 has proved to be useful in cases where alkenes are less reactive. 2-Alkenes usually form the more substituted -allylpalladium complexes. When an electron-withdrawing group, such as a keto or a carboxyl group, is present at an allylic position, -allylpalladium formation is favored, and its regiochemistry is well defined.[102] Allenes, 1,3-dienes, cyclopropanes, cyclopropenes, and even acetylenes can also serve as the starting materials for -allylpalladium complexes. Some representative examples are given in Scheme 19. It is interesting to note that while sterically hindered t-BuC#CBu-t displaces the two ethylene ligands from [Pd(CH2"CH2)Cl2]2 to give the corresponding alkyne – Pd complex (Sect. B.ii, Table 5), sterically less hindered PhC#CBu-t reacts with the same Pd complex to generate a -allylpalladium species (Scheme 19).[46] The reactions of -allylpalladium complexes are dominated by the nucleophilic attack on the -allyl ligand. A well-known example is the stoichiometric version of the Tsuji– Trost reaction (Scheme 20).[111] Another interesting reaction of -allylpalladium species is their reaction with carbon monoxide. -Allylpalladium chloride, for instance, reacts with CO in EtOH to give carbonylation products (Scheme 21).[112] -Allylpalladium species are implied in many organic transformations catalyzed by Pd species. A notable example is provided by the oligomerization and telomerization of 1,3butadiene in which the intermediacy of -allylpalladium species was clearly established when the -allylpalladium intermediates of dimerized or trimerized 1,3-butadiene were actually prepared and isolated (Scheme 22).[74]–[76] Recent studies have shown that allylpalladium complexes can also react as nucleophiles. Bis(-allyl)palladium, for instance, was found to be a key intermediate in the Pd-catalyzed allylation of aldehydes and imines by allylstannane.[113] This complex has
162
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
Allenes [103]−[106] Cl Cl
Pd Cl Cl obtained in nonpolar solvents
PdCl2
Pd
H2C C CH2
+
Cl
Cl Pd Cl
Pd
Cl obtained in polar solvents Nu
1,3-Dienes[107]−[109] PdCl2
Cl
Nu = Cl, OR, OAc
+
Pd
Pd Cl
Cyclopropanes [110]
Nu Cl Cl(CH2)2
[Pd(CH2 CH2)Cl2]2 +
Pd
Pd
(CH2)2Cl
Cl Bu-t
Alkynes[46] [Pd(CH2 CH2)Cl2]2 + Ph C C Bu-t
Ph
Cl Cl Pd Pd Cl Cl Bu-t
Scheme 19
Cl
1 2
Pd
NaCH(COOEt)2
Pd
CH(COOEt)2 + Pd(0) + HCl
Cl Scheme 20
1 2
Cl Pd
CO, EtOH
Pd
COOEt
Cl Scheme 21
Pd
Pd(dba)2
PR3 2
3
Pd
Pd Scheme 22
R3P Pd
Ph
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
163
also been found to react as an amphiphilic allylating agent, that is, a reagent that can simultaneously act as a nucleophile and an electrophile, in the Pd-catalyzed double allylation of activated olefins by allylstannane.[114] Like allylic electrophiles, propargylic halides or acetates oxidatively add to Pd(0) derivatives, such as Pd(PPh3)4. In this case, however, either 1-propargylpalladium or allenylpalladium complexes are obtained depending on the size of the C3 substituent. These complexes display some interesting reactivity.[115] A recent report clearly demonstrates the possibility of 3 bonding in the case of propargyl chloride having a bulky group at C3, when the propargylpalladium species is generated from Pd2(dba)3 in the presence of 1 equiv of PPh3 per Pd atom. If a second equivalent of PPh3 is added, however, the 1-propargylpalladium is formed.[116] Closely related to the -allylpalladium complexes are the cyclopentadienylpalladium complexes. Although Cp2Pd, where Cp is 5-C5H5, remains unknown, several monocyclopentadienyl – Pd complexes have been prepared and characterized. Some representative examples of such complexes are summarized in Table 7. With the exception of CpPdNO, a Pd(0) species prepared from Pd(Cl)NO and TlCp, all of the Cp – Pd complexes shown in Table 7 are Pd(II) complexes. Cyclopentadienylpalladium complexes are generally obtained by the reaction of appropriate Pd complexes with MCp, where M is Na or Tl. Complexes of the CpPd(L)X type, with X Cl, Br, or I, and L PR3, are obtained by the reaction of TlCp or NaCp with dimeric complexes Pd2X4L2 or Pd2X2L2(-OAc)2.[119],[127] These complexes of the general formula CpPd(L)X can in turn react with another ligand L , where L can be PR3, CO, or C2H4, to give [CpPdLL ]X complexes. When X is not a halogen but ClO4 or PF6 , AgClO4 or KPF6, respectively, is required. In special cases where L L PEt3 or olefin, an alternative synthesis of complexes of the general formula [CpPdL2]X is possible from X2PdL2 and TlCp or FeCpBr(CO)2. This is the case with [CpPd(PEt3)2]Br,[119] [CpPd(1,5-cod)](FeBr4),[120] and [CpPd(4-C4Ph4)](FeBr4).[120] One such example is shown in Scheme 23. When Pd2X2L2(-OAc)2 is treated with 2 equiv of TlCp per Pd instead of one, (5Cp)(1-Cp)PdL is obtained.[123] These complexes exhibit a fluxional behavior in solution, that is, / (or 1/5) exchange of the two Cp ligands.[123] This is rather interesting, since NMR studies on a variety of Cp – Pd complexes have shown that the Cp ligand is bound symmetrically with no fluxional behavior.[130] Other types of cyclopentadienylpalladium complexes have been generated by similar approaches. One such example is CpPd(3-C3H5), which is prepared from Pd2(3C3H5)2(-Cl)2 (Scheme 24).[118] Pd complexes containing substituted cyclopentadienyl ligands, such as C5Me5 and C5Ph5, have also been prepared using various methods discussed above. Cyclopentadienylpalladium complexes have not yet been shown to be very useful in organic synthesis. This may be due to the fact that the Cp ligand is very labile. It is indeed easily cleaved under a variety of conditions, as exemplified in Scheme 25.[130] One interesting feature of the Cp – Pd complexes is that they are intensely colored. This characteristic could potentially be interesting, as it provides a direct and straightforward way of monitoring their formation or disappearance. C.ii. -Bonded Complexes: Alkyl, Benzyl, Aryl, Alkenyl, Alkynyl, and Acyl Complexes As mentioned previously, -bonded organopalladium complexes may contain carbon groups, such as alkyl, benzyl, aryl, alkenyl, alkynyl, and acyl groups. Representative
164
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 7. Cyclopentadienylpalladium Complexes Carbon Number
Pd Complex
Comments
References for Preparation
5
PdNO
[117]
8
Pd
[118]
11
Pd(PEt3)X
13
Pd
16
X Cl, Br, I X BF4, FeBr4
X
Pd
[119]
[120]–[122]
[123]
PEt3
17
Pd(PEt3)2 X
X Br
23
Pd(PPh3)X
X Cl, Br
[119],[124]
X ClO4; polentially explosive
[125],[126]
X ClO4; potentially explosive
[125],[126]
24
Pd
CO X
PPh3 25
Pd
X
PPh3
28
[119]
[127]
Pd(PPh3)Cl
[123]
Pd PPh3 Ph
Ph P
31
Pd
X PF6 OTf ’
X P
Ph
33
[128],[129]
Ph Ph
Ph
Ph
Ph
X
Pd
X FeBr4, Br; air-stable
[120]
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
Ph
Ph
Ph
Ph
Br2Pd
2 FeCpBr(CO)2
+ Pd
Ph
Ph
Ph
Ph
165
FeBr4−
Scheme 23
Cl Pd
Pd
CpLi
Pd
+
LiCl
Cl Scheme 24
Cl
HCl
Pd
Pd
+ C5H6
Cl Pd PPh3
Pd(PPh3)4
Scheme 25
examples of alkyl- and benzylpalladium complexes are listed in Table 8. Aryl-, alkenyl-, and alkynylpalladium complexes are exemplified in Table 9, and acylpalladium complexes in Table 10. In cases where palladium is bonded to chelating ligands, such species may be considered as palladacycles. Those palladacycles containing at least one C — Pd bond in the ring are shown in Table 11. Finally, some polymeric carbon – Pd complexes containing Pd in their backbones are given in Table 12. C.ii.a. Alkyl-, Benzyl-, Aryl-, Alkenyl-, and Alkynylpalladium Complexes. Alkyl- and benzylpalladium complexes (Table 8) can be obtained by a variety of synthetic methods. Oxidative addition of Pd(0) species into carbon – halogen bonds leading to monoalkylor benzylpalladium complexes of the type “RPdX,” where X is a halogen atom, is certainly one of the most general methods for the synthesis of -bonded organopalladiums. Pd(0) complexes, such as Pd2(dba)3 and Pd(PPh3)4, have been used for this purpose. Metallic palladium generated by metal vapor technique has also been used in the cases of perfluorinated alkyls, such as CF3I and CF3CF2I.[15] Although this method is not widely applicable and is low-yielding, it has been used to generate remarkably stable CF3(CF2)7PdBr (vide infra) from the corresponding bromide.[133] Most often, however, monoalkyl- or benzylpalladium complexes are isolated as complexes of a variety of stabilizing phosphorus or nitrogen ligands and are usually prepared either from a Pd(0) complex of the desired ligand or from Pd2(dba)3 in the presence of the desired ligand (Scheme 26). Pd(0) complexes can also be generated in situ from Pd(II) species in the presence of an appropriate reducing agent (see Sect. II.2.3). Unless bidentate ligands are involved, the oxidative addition generally leads to the formation of trans-palladium complexes. Pd(II) complexes can also serve as precursors to monoalkylpalladium complexes via transmetallation if 1 equiv of an organometallic reagent per Pd complex is used. A large
166
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 8. Alkylpalladium and Benzylpalladium Complexes Carbon Number a
Pd Complex
Comments
MePdI(PMe3)2 CF3(CF2)7PdBr MePdCl(1,5-cod) b [MePd(PMe3)3]X MePdX(bipy) c MePdI(CNBu-t)2 MePdX(PEt3)2 CF3PdBr(PEt3)2 PhCH2PdCl(PMe3)2 CF3PdI(Ph2PCH2CH2PPh2) d MePdX(PPh3)2 CF3PdI(PPh3)2 PhCH2PdX(PPh3)2
trans
References for Preparation
Monorganyl Complexes MONOMERS
7 8 9 10 11 13
27 37 43
X BPh4 X Cl, Br, I trans X Cl, Br, I; trans trans trans X Cl, Br, I; trans trans X Cl, Br; trans
[131],[132] [133] [134] [131],[132] [135],[136] [22] [78],[137]–[139] [15],[140] [141] [142] [143]–[145] [142] [144]–[146]
DIMERS
3 19
Cl
Me Pd Ph3P
25
X Cl, Br, I
(MePdX.SMe2)2 PPh3 Pd
Cl Pd
Ph3P
[134],[148]
Me
Cl
PhCH2
[147]
PPh3 Pd
Cl
[149]
CH2Ph
Diorganyl Complexes MONOMERS
S
8
Me2Pd
S
[150]
S
10 12 14
22 24
Me2Pd(Me2NCH2CH2NMe2) e Me2Pd(Me2PCH2CH2PMe2) f Me2Pd(PMe3)2 cis and trans Me2Pd(1,5-cod)b Et2Pd(PMe3)2 trans Me2Pd(bipy) c Me2Pd(phen) g Et2Pd(bipy) c Me2Pd(PEt3)2 cis and trans PdMe(PPh3)
PdMe(PPh3)
[151] [151] [152],[153] [137],[154] [153] [135],[137] [135] [155] [137],[153] [156] [157]
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
167
TABLE 8. (Continued) Carbon Number a 28 38 46 a
Pd Complex
Comments
Me2Pd(Ph2PCH2CH2PPh2) Me2Pd(PPh2Me)2 Me2Pd(PPh3)2 (neo-pentyl)2Pd(PPh3)2
cis and trans cis and trans cis
b
Number of carbons in a monomer unit. 1,5-cod 1,5-cyclooctadiene.
c
bipy
N
References for Preparation [137] [158] [137],[158] [159]
N
d
CF3PdI(dppe). e Me2Pd(tmeda). f Me2Pd(dmpe). g
phen N
N
number of organometallic reagents RM, where M can be Li, Mg, Zn, Cd, Al, Sn, Cu, and so on, can be involved in such transmetallation reactions. This approach generally leads to the formation of the trans isomers. Those RM reagents that contain highly electropositive metals (e.g., Li and Mg) tend to introduce two or more R groups into Pd complexes. So, it is often desirable or even necessary to choose more electronegative metals, as in the synthesis of MePdCl(1,5-cod) by the reaction of Cl2Pd(1,5-cod) with Me4Sn.[134] Some of these alkyl- or benzylpalladium derivatives exist as dimers. One interesting group of dimeric alkylpalladium complexes are (MePdX SMe2)2, prepared by the reaction of X2Pd(SMe2)2, where X Cl, Br, or I, with 1 equiv of MeLi.[147] The labile SMe2 ligand can be displaced by a variety of ligands, such as bipy, providing another synthetic route to complexes of the type MePdXL2 (Scheme 27).[135],[136] Nearly all alkylpalladium complexes that have been isolated are those that do not contain -hydrogens. This is because those containing -hydrogens undergo rapid elimination to give alkenes and HPdX. This process involving syn -elimination is a crucial step in the Pd-catalyzed Heck reaction.[160],[161] Perfluoroalkylpalladium halides are by far more stable than the corresponding ordinary alkylpalladium halides. For example, CF3CF2PdI is stable at room temperature.[15] Dialkylpalladium complexes are typically obtained by the reaction of Pd(II) species with alkylmetal reagents. While the cis isomers are obtained by the treatment of X2PdL2 (X Cl or Br) with alkyllithium or -magnesium reagents (Scheme 28),[137] the reaction of Pd(acac)2 with AlR2(OEt) or Al2R3(OEt)3, in the presence of the desired ligand, is a well-established route to trans-R2PdL2.[153] Alternatively, trans dialkylpalladium complexes can be obtained by the reaction of preformed trans-RPdXL2 with an organometallic reagent (Scheme 28).[158] The stepwise approach shown in Scheme 28 provides a convenient route to diorganylpalladium complexes containing two different carbon groups, such as (5-C5H5)PdMe(PPh3), formed by the reaction of MeMgBr with (5-C5H5)PdBr(PPh3).[157] It should be noted,
168
24
12
6
DIMERS AND POLYMERS
43 44
28 40 42
14 18
12
MONOMERS
Monorganyl Complexes
Carbon Number a
Ph3P
C6F5
M2
Pd
C6F5
C6F5
X
X
Pd
Pd
X
X Pd
C6F5
PPh3
M2[(C6X5)PdBr2]2 [(C6F5)PdX] n
C6F5
C6F5
(CH2 RCH)PdBr(PPh2Me)2 (Ph2CRCH)PdBr(PPh2Me)2 PhPdX(PPh3)2 (C6F5)PdCl(PPh3)2 p-NO2(C6H4)PdI(PPh3)2 [(C6F5)Pd(CO)(PPh3)2]X (PhCHRCH)PdBr(PPh3)2 (PhC#C)PdCl(PPh3)2
PhPdI(Me2NCH2CH2NMe2) b PhPdI(PMe3)2 (C6F5)PdCl(1,5-cod) c PhPdX(PEt3)2
Pd Complex
TABLE 9. Aryl-, Alkenyl-, and Alkynylpalladium Complexes
X Cl, Br, I
X Cl, Br; M Bu4N
X F, Cl; M Bu4N X Cl, Br
trans X ClO4 trans; E and Z isomers trans
trans trans X Cl, Br, I; trans
X Cl, Br, I; trans
trans
Comments
[171],[178]
[177]
[175] [15],[176]
[163] [131],[132] [164] [73],[137], [143,[165] [166] [166] [143],[167]–[170] [171] [169] [172] [173] [174]
References for Preparation
169
K2Pd(C#CH)4 (HC#C)2Pd(PMe3)2 (C6X5)2Pd(CO)2 (C6X5)2Pd(THF)2 d (C6F5)2Pd(1,5-cod) c (C6F5)2Pd(bipy)e Li2Pd(C#CBu-t)4 Ph2Pd(PEt3)2 M2Pd(C6F5)4 (t-BuCHRCH)2Pd(PEt3)2 Ph[Me(CH2)5CHRCH](PEt3)2 (HC#C)2Pd(dppe) f K2Pd(C#CPh)4 (MeC#C)2Pd(dppe) f (PhC#C)2Pd(dppe) f (C6F5)2Pd(PPh3)2 (PhC#C)2Pd(PPh3)2
f
e
b
N N dppe Ph2PCH2CH2PPh2.
bipy
Number of carbons in a monomer unit. PhPdI(tmeda). c 1,5-cod 1,5-cyclooctadiene. d THF Tetrahydrofuran.
a
42 48 52
26 30 32
22 24
8 10 14 20
MONOMERS
Bis-, Tris-, and Tetrakisorganyl Complexes
cis/trans mixture trans
trans M K, Bu4N trans; E isomer trans; E isomer
trans X F, Cl; cis X F, Cl; cis
[179] [180],[181] [182] [182] [183],[184] [185] [186] [137],[187] [177],[188] [187] [187] [179] [179] [179] [179] [178] [189],[190]
170
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 10. Acylpalladium and -Functionalized Organylpalladium Complexes Carbon Number a
Pd Complex
Comments
References for Preparation
Monoacyl Complexes MONOMERS
8 11 14
MeCOPdI(PMe3)2 [MeCOPd(PMe3)3]BPh4 [PhCOPd(PMe3)2(CO)]BF4 PhCH2COPdCl(PMe3)2 MeCOPdCl(PEt3)2 [PhCOPd(PMe3)3]BPh4 MeCOPdX(PPh3)2 MeOOCPdCl(PPh3)2 MeSCH2PdCl(PPh3)2 NCCH2PdCl(PPh3)2 PhCOPdX(PPh3)2 PhCH2COPdBr(PPh3)2 PhCOCOPdCl(PPh3)2
16 38
43 44
trans trans; stable under CO trans trans X Cl, I; trans trans trans trans X Cl, Br, I; trans trans trans
[131],[132] [131],[132] [203] [141] [134],[138] [131],[132] [169],[204] [205] [206] [207] [169],[208],[209] [169],[208] [210]
DIMERS
8 25
[MeCOPdCl(PEt3)]2 [PhCOPdI(PPh3)]2
[138] [211]
Bis-, Tris-, and Tetrakisacyl Complexes MONOMERS 14 20 40
(MeOOC)2Pd(bipy) b [(MeOOC)2CH]2Pd(bipy) b (MeOOC)2Pd(PPh3)2
a
Number of carbons in a monomers unit.
b
bipy
N
trans
[212] [213] [214]
N
however, that the reaction of preformed PhCH2PdX(PPh3)2, where X Cl or Br, with Me4Sn or MeMgBr does not give the expected (PhCH2)MePd(PPh3)2 but leads, instead, to the formation of MePdX(PPh3)2 via carbon-for-carbon transmetallation.[144] Under catalytic conditions, however, the desired transmetallation does take place.[144],[145] Along with the previously mentioned -elimination reaction, dialkylpalladium complexes can undergo reductive elimination. Here again, perfluorination tends to inhibit the process. Evidently, the -donating ability of the carbon group seems to promote reductive elimination. Additional requirements must be met for reductive elimination to take place, the most crucial one being the cis arrangement of the two alkyl groups.[158] This condition is necessary but not sufficient. Thermal decomposition of Et2Pd(bipy), for instance, gives ethene and ethane via -elimination but no butane, despite the favorable cis arrangement of the two ethyl groups. In the presence of methyl acrylate, however, butane is obtained in high yields.[155] The effect of methyl acrylate is explained in terms of complexation of the 16-electron Et2Pd(bipy), which plugs the available empty orbital necessary for
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
171
TABLE 11. Palladacycles Containing One or Two Ring C —Pd -Bonds Carbon Number a
Pd Complex
Comments
References for Preparation
THREE-MEMBERED RINGS
20 MeS S
37
[206]
PdCl(PPh3) Pd(PPh3)2
[218]
Pd(PPh3)2
[219]
O S S Se
Pd(PPh3)2
[220]
Se FOUR-MEMBERED RINGS
t-Bu
24
Bu-t
[221]
P PdCl(PBu-t3)
41
[159]
Pd(PPh3)2
FIVE-MEMBERED RINGS
5
Cl
N Pd
N
Cl
N
9
[222]
Pd Cl
Pd
Pd
10
Pd(Me2NCH2CH2NMe2)
N
Commercially available
[223]
(CH2)4Pd(tmeda)
[224]
N
Cl
Cl Pd
[225]
Pd Cl
N
(Continued )
172
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
TABLE 11. (Continued) Carbon Number a
Pd Complex
N
Comments
References for Preparation
Cl
11
[226]
Pd
Pd Cl
N
Ph N
12
Cl
N
Pd
[227]
Pd Cl
N
N
Ph NMe2 PdX
X Cl, Br, I
[228]
NMe2
14
[224]
Pd(bipy) b Ph N
17
21–22
22
23
N
[229]
Pd
P(Bu-t)2 PdX P(Bu-t)2
X Cl, H, Me
Pd(bipy) b
R R P Pd
[230],[231]
[232]
X Pd X
P R R
X OAc; R o-tolyl; commercially available
[233]
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
173
TABLE 11. (Continued ) Carbon Number a
Pd Complex
Comments
PPh2 PdCl PPh2
32
40
[234]
[224]
Pd(PPh3)2
a
Number of carbons in a monomer unit.
b
bipy
N
References for Preparation
N
-elimination. The nature of the ligand can also affect the course of the thermal decomposition of dialkylpalladium complexes. In cross-coupling reactions, for instance, chelating ligands have been found to favor the desired reductive elimination.[162] Aryl-, alkenyl-, and alkynylpalladium complexes (Table 9) are generated in manners similar to the preparation of alkyl- and benzylpalladium derivatives. However, oxidative addition is much more widely applicable and satisfactory than in the preparation of alkylpalladium derivatives, since aryl, alkenyl, and alkynyl halides are not only much more reactive toward Pd(0) complexes than their alkyl counterparts but are also uncomplicated by -elimination. While oxidative addition appears to be the method of choice for preparing trans monoorganylpalladium complexes containing an aryl, alkenyl, or alkynyl group, transmetallation with an organometal containing Li, Na, Mg, Zn, Hg, or Sn provides a general route to diorganylpalladium complexes. For the preparation of alkynyl – Pd complexes, alkynylcopper reagents generated in situ from terminal alkynes have been used.[180],[181] The trans diorganylpalladium derivatives are usually obtained unless a bidentate ligand is used.
TABLE 12. Polymers Containing Palladium in the Polymer Backbones Carbon Number a
References for Preparation
Pd Complex PBu3
28
Pd C C C C
[241] n
PBu3
PBu3 34
Pd C= =C PBu3
a
Number of carbons in a monomer unit.
[242]
C= =C n
174
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
MeI
Pd(PPh3)4
MePdI(PPh3)2
−2 PPh3 [143] 2 MeI/2 bipy
Pd2(dba)3
2 MePdI(bipy)
−3 dba [135]
Scheme 26
1 2
bipy
(MePdI.SMe2)2
MePdI(bipy)
[136]
Scheme 27
Me Me Pd L L
2 MeLi
Cl2PdL2
PdL4
L Me Pd L
MeI
MeLi
I
L Me Pd Me L
Scheme 28
Oxidative addition requires either the use or the in situ generation of a Pd(0) complex. Metal vapor techniques, for instance, have allowed the preparation of nonligated polymeric aryl – Pd complexes, (C6F5PdX)n, where X Cl or Br.[15] The higher thermal stability of the perfluoroorganylpalladium complexes as compared with their ordinary organopalladium derivatives[191] is once again clearly indicated (vide infra). Although a wide variety of leaving groups including I, Br, Cl, and various oxy groups have been employed in oxidative addition, it completely fails to work with organic fluorides. Recently, however, MePdF(PPh3)2 and PhPdF(PPh3)2 have been obtained by sonication of the corresponding iodide in the presence of AgF.[192] Monoarylpalladium complexes have also been prepared by transmetallation. For example, PhPdCl(PEt3)2 and PhPdBr(PEt3)2 have been prepared by the reaction of Ph2Hg and PhMgBr with Cl2Pd(PEt3)2 and Br2Pd(PEt3)2, respectively.[137],[165] On the other hand, dimeric [(C6F5)PdCl(PPh3)2]2 has been obtained from Cl2Pd(PPh3)2 and TlBr(C6F5)2 (Scheme 29).[171]
Cl2Pd(PPh3)2
BrTl(C6F5)2 [171]
1 2
C6F5 Ph3P
Cl Pd
Pd Cl
Scheme 29
PPh3 C6F5
+ PPh3 + TlBr + C6F5Cl
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
175
Redistribution reactions between two palladium complexes have also proved useful for the generation of monoarylpalladium species. For example, C6F5PdCl(1,5-cod) is obtained from (C6F5)2Pd(THF)2, Cl2Pd(PhCN)2, and 1,5-cyclooctadiene (Scheme 30).[164] (C6F5)2Pd(THF)2 + Cl2Pd(PhCN)2
C6F5 [164]
Cl Pd
PhCN
Cl
1,5-cod
NCPh Pd C6F5
2 (C6F5)PdCl(1,5-cod)
Scheme 30
Transmetallation of preformed RPdXL2, such as PhPdI(PEt3)2, allows the formation of trans diorganylpalladium complexes having two different organic groups, such as Ph[(E)Me(CH2)5CH"CH]Pd(PEt3)2 or Ph(Me)Pd(PEt3)2.[187] This process is a crucial step in the Pd-catalyzed cross-coupling reactions. Although most of the diorganylpalladium complexes of nonchelating ligands are trans, some synthetic routes to cis diorganylpalladium complexes, such as cis-(C6F5)2Pd(THF)2 and cis-(C6F5)2Pd(CO)2, exist. While cis-(C6F5)2Pd(THF)2 can be obtained from (Bu4N)2[(C6F5)2PdCl]2, cis-(C6F5)2Pd(CO)2 is obtained from the corresponding THF complex via displacement of THF.[184] The starting (Bu4N)2[(C6F5)2PdCl]2 is in turn obtained from (Bu4N)2(Pd2Cl6) and (C6F5)MgBr.[177] It is interesting to note that homoleptic tetraaryl- and tetraalkynylpalladium “ate” complexes have been obtained by the reaction of K2PdCl4 or Cl2Pd(PPh3)2 with aryl- or alkynyllithium reagents.[186],[188] These tetraorganopalladate complexes do not readily undergo reductive elimination, providing a mechanistic interpretation of the inhibitory action of highly electropositive metals, such as Li, in some Pd-catalyzed coupling reactions.[186] Also interesting is the preparation of cationic palladium complexes, such as [MePd (PMe3)2]X[132] and [(C6F5)Pd(CO)(PPh3)]X,[172] considering the fact that cationic palladium complexes are believed to be the actual catalytic species in several Pd-catalyzed processes, an example of which being the copolymerization of alkenes and CO.[16] The reactivity of the C — Pd bond is very diverse. In addition to the previously discussed -elimination and reductive elimination, alkyl – , benzyl – , aryl – , alkenyl – , and alkynyl – Pd complexes can undergo syn addition of the C — Pd bond across the C — C bond of alkenes and alkynes, that is, carbopalladation. This reaction can generate alkyl – or alkenyl – Pd complexes and is occasionally used as a preparative method, as exemplified in Scheme 31.[164] Closely related is the hydropalladation of alkenes and alkynes. However, these processes are mostly observed under catalytic conditions.[193] Cl Cl Pd
1 2
Pd C6F5
C6F5
2
Scheme 31
A wide variety of nucleophiles, such as KCN,[194] amines,[195] alkoxides,[195],[196] or sulfides,[197] can react with monoarylpalladium complexes, to give RCN, RNR 2, ROR , or RSR . In these processes, the formation of a C —Nu bond is thought to occur via reductive
176
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
elimination of a RPdNu intermediate. As in the C — C bond-forming reductive elimination, judicious choice of ligands is crucial in favoring the desired process over the competing side reactions, such as -H elimination.[198] Although less effective and hence rarely used, C — Pd bonds can also be cleaved with electrophiles, such as HCl or Br2, to give RH or RBr.[199] It is worth noting that alkyl- and arylpalladium complexes containing aryl phosphines can undergo alkyl – aryl and aryl – aryl exchange between Pd and P, which can proceed via phosphine dissociation followed by oxidative addition.[200] – [202] C.ii.b. Acylpalladium Complexes. Among the reaction paths that C — Pd bonds can undergo, CO insertion (Scheme 32) is of great importance in many catalytic processes. This reaction has been used to generate a number of acyl – Pd complexes (Table 10).
R PdLnX + O R C X
+
CO
O R C PdLnX
PdLn
R′OH
O R C OR′
R′NH2
O R C NHR′
Scheme 32
Carbon monoxide can easily insert itself into various C — Pd bonds containing alkyl, benzyl, aryl, alkenyl, alkynyl, and others. The resulting acyl — Pd bond is less prone to insert CO, which explains why products of double carbonylation are rare even under catalytic conditions. Acyl – Pd complexes are also accessible via oxidative addition of Pd(0) into acyl halides (Scheme 32).[131],[132],[209],[210] In fact, the generation of PhCOCOPdCl(PPh3)2 from PhCOCOCl and Pd(PPh3)4 has been claimed.[210] Most of the Pd-catalyzed double carbonylation reactions (Sect. VI.2.1.4) involve reductive elimination of bis(acyl)palladium derivatives,[215] as exemplified by an efficient synthesis of pyridylglyoxylic amides and esters.[216] As a rule, acylpalladium derivatives of the type RCOCOPdLn are prone to facile decarbonylation and hence too unstable to serve as synthetically useful intermediates.[210] Acylpalladium derivatives undergo a wide variety of reactions including solvolysis shown in Scheme 32.[216] These and other reactions of acylpalladium derivatives are discussed mainly in Parts VI and VIII. Related alkoxycarbonyl – Pd complexes of the type (ROOC)PdClL2 or (ROOC)2PdL2 are typically generated from Cl2PdL2, CO, and LiOR. Attack by alkoxy anions on the coordinated CO can explain the process. However, insertion of CO into the Pd —OR bond is a possible alternative. In fact, NMR spectroscopy has provided some evidence for the formation of (MeO)2Pd(bipy) during the preparation of (MeOOC)2Pd(bipy).[212] Also related to the acyl – Pd complexes are the iminoacyl – Pd complexes and the complexes containing a heteroatom in the position, for example, MeSCH2PdCl(PPh3)2. While the iminoacyl complexes are obtained similarly to their acyl analogs by insertion of isonitriles into the C — Pd bond,[22] the -heterofunctional complexes are obtained in manners similar to the synthesis of alkyl – Pd complexes via oxidative addition or transmetallation. One notable difference between insertion of CO and that of isonitriles is that the latter can lead to multiple insertion.[217] Other CO-containing organopalladium derivatives in which the CO group is not directly bonded to Pd are also known and implicated as transient intermediates (Part VI). Some such compounds have also been prepared as discrete species, as exemplified by
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
177
[(COOMe)2CH2]2Pd(bipy) generated by the reaction of (COOMe)2CH2Na with Cl2Pd(bipy).[213] C.ii.c. Palladacycles. Various reactions discussed in this section can also take place intramolecularly to produce palladacycles containing one or two ring C — Pd bonds (Table 11). Palladacycles of various ring sizes have been generated and isolated. Even so, the great majority of palladacycles are five-membered. As in the other cases, oxidative addition and transmetallation are two main routes to palladacycles. Some representative examples follow. Oxidative addition of Pd into the C — Cl bond of MeSCH2Cl in the presence of 1 equiv of PPh3 gives a three-membered palladacycle.[206] In the presence of 2 equiv or more of PPh3 an acyclic species is formed (Scheme 33).[206] The reaction of Cl2Pd(PPh3)2 with Li(CH2)4Li produces (CH2)4Pd(PPh3)2.[224]
S
Cl
S
Cl
Pd(PPh3)4
S
1. Pd 2. PPh3
S
PdCl(PPh3)2 PdCl(PPh3)
Scheme 33
Palladacycles can, however, be generated by other reactions as well. For instance, threemembered palladacycles have been obtained by complexation of Pd(0) species with heteroatom containing -compounds such as COS, CS2, and CSe2. As -complexation can alternatively be viewed as an oxidative complexation (Sect. II.3.1), these palladium complexes can be viewed either as 2 complexes or as three-membered palladacycles (Table 11). One widely observable reaction for the preparation of five-membered palladacycles is intramolecular C — H activation assisted by a donor atom, termed cyclopalladation or orthopalladation. Notably, the reaction of PdCl2 or M2PdCl4 (M Li or Na) with functionalized arenes, such as N,N-dimethylbenzylamine or azobenzene, gives the corresponding five-membered palladacycles as the trans chlorine-bridged dimers in most cases (Scheme 34). A competitive experiment has shown that the former substrate is a better ligand for Pd than the latter.[223] Furthermore, only tertiary benzylamines were found to be capable of participating in these reactions.[223] In the cases of the primary and secondary benzylamines, their interaction with Pd can lead to tighter amine – Pd complexes that are not sufficiently reactive for C — H activation. 2-Phenylpyridine and P,P-disubstitutedbenzylphosphines can also participate in cyclometallation reactions leading to five-membered palladacycles, as shown in Table 11. Oxygen and sulfur analogs have also been used. Halogen-bridged dimeric palladacycles can serve as precursors to monomeric derivatives that can readily be obtained by treating the dimers with various reagents, such as phosphines and organometals (Scheme 35). Benzylic C — H activation can also occur readily to give five-membered palladacycles containing Pd — Csp3 bonds (Scheme 36). Five-membered palladacycles containing Pd — Csp3 bonds may also be prepared via transmetallation (Scheme 36). Palladacycles containing C — Pd -bonds can exhibit similar reactivity patterns as usual C — Pd containing complexes, but chelation usually confers enhanced levels of stability to palladacycles. One representative class of reactions that palladacycles undergo is
178
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
N
1 2
Cl
N
Li 2PdCl4
Pd
N
Ph
Ph N
Pd Cl
[223]
N 1 2
N
Na2PdCl4
N
Cl Pd
Pd Cl
[227]
N
N
Ph Scheme 34
Ph N
1 2
Ph
N
Cl Pd Cl
N
TlCp
Pd N
N
N Pd
[229]
Ph Scheme 35
N
1 2
N
Li 2PdCl4
PR2
1 2
Pd(OAc)2
Cl2Pd(PhCN)2 [222]
N
R R P X Pd Pd X P R R
R = o-tolyl
SnBu3
Pd Cl
[233]
N
Cl Pd
[225]
X = OAc
Cl
N Pd
Pd Cl
N
Scheme 36
ring expansion via carbopalladation, which, in turn, generates new palladacycles (Scheme 37).[235],[236] Double insertion has also been observed (Scheme 37).[236] Conversion of TCPC, which is generated as a tetramer, into monomeric TCPC(L2) can be achieved by its complexation with a variety of ligands.[237],[238] Palladacycles have also proved to be useful as catalysts for several organic transformations. For instance, TCPC derivatives have been widely used for enyne metatheses and
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
2 MeO2C
CO2Me
MeO2C
Pd(dba)2
N
Cl Pd
CO2Me
Cl
Pd
Ph [236]
N
carbometallation
MeO2C
4 Ph
Pd
TCPC
MeO2C
MeO2C oxidative complexation
CO2Me Pd
[235]
179
2
N
Cl Ph Pd Ph
Ph
Ph
Scheme 37
cyclization reactions,[64] and commercially available trans-di(-acetato)bis[o-(dio-tolylphosphine)benzyl]dipalladium has been found to be an efficient catalyst for the Heck olefination[233] and the Suzuki coupling[239] of chloro- and bromoarenes. Similarly, an orthopalladated triarylphosphite complex obtained by the cyclometallation of tris(2,4di-t-butylphenyl)phosphite with PdCl2 was recently found to be an active catalyst for the synthesis of biaryls derivatives by the Suzuki reaction.[240] C.ii.d. Polymers Containing C—Pd Bonds in the Polymer Backbone. Some examples of polymers containing C — Pd bonds in their backbones are known, as indicated in Table 12. These polymers are synthesized in ways similar to the preparation of alkynylpalladium complexes from Pd(II) species and alkynylmetals, such as alkynyltins and alkynylcoppers (Scheme 38).[241] Concentrated solutions of these polymers have been found to form lyotropic liquid crystals.[241],[243]
Cl
P(Bu-t)3 Pd Cl P(Bu-t)3
+
Me3Sn
SnMe3 P(Bu-t)3 Pd P(Bu-t)3
n
Scheme 38
D. CONCLUSION 1. Various methods of generation of organopalladium derivatives discussed in Sects. I.2 and II.3.1 are also applicable to the syntheses of discrete organopalladium compounds that can be isolated and identified. In most of the catalytic reactions, their formation is assumed, and their stoichiometric preparation discussed in this section lends strong support for such assumptions. So the stoichiometric preparation of
180
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
organopalladium compounds provides the foundation for structural and mechanistic investigations of organopalladium chemistry. 2. A statement of caution is in order. In the stoichiometric synthesis of organopalladium complexes, the formation of organopalladium complexes themeselves must be thermodynamically favorable. On the other hand, their formation need not be thermodynamically favorable in their catalytic reactions, since the only two critical requirements in catalytic processes are that the overall stoichiometric transformation be thermodynamically favorable and that each and every catalytic microstep be kinetically favorable. Thus, so long as the kinetic requirement is met, even thermodynamically unfavorable catalytic microsteps, be they oxidative addition, transmetallation, or reductive elimination, can be segments of catalytic processes. Oxidative addition of allyl acetates with Pd(PPh3)4 in the Tsuji – Trost reaction and some transmetallation processes in the Pdcatalyzed cross-coupling are likely to be thermodynamically unfavorable. This significant difference indicated in a generalized manner in Scheme 39 should always be kept in mind. For example, the oxidative addition step in a catalytic reaction may be represented by the SM : I1 process, which is indicated as a thermodynamically unfavorable step.
In = Intermediate mixtures
I2 I1 Energy
I3 Starting compounds (SM) Product mixture (P) Reaction Coordinate Scheme 39
3. Organopalladium compounds prepared as discussed in this section can also serve as catalysts or catalyst precursors. Further investigations along this line will undoubtedly broaden the scope and applicability of the Pd catalysis in organic synthesis.
REFERENCES [1] J. Browning, P. L. Goggin, R. J. Goodfellow, M. G. Norton, A. J. M. Rattray, B. F. Taylor, and J. Mink, J. Chem. Soc. Dalton Trans., 1977, 2061. [2] F. Calderazzo and D. B. Dell’Amico, Inorg. Chem., 1981, 20, 1310. [3] G. G. Kutyukov, A. B. Fasman, V. F. Vozdvizhenskii, and Y. A. Kushnikov, Russ. J. Inorg. Chem., 1968, 13, 809. [4] B. P. Andreini, D. B. Dell’Amico, F. Calderazzo, and M. G. Venturi, J. Organomet. Chem., 1988, 354, 369. [5] J. V. Kingston and G. R. Scollary, J. Chem. Soc.(A), 1971, 3765. [6] T. Yamahara, S. Takamatsu, and K. Hirose, Chem. Abstr., 1974, 80, 120518y.
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42]
181
J. H. Darling and J. S. Ogden, J. Chem. Soc. Dalton Trans., 1973, 1079. H. C. Clark and K. R. Dixon, J. Am. Chem. Soc., 1969, 91, 596. R. Whyman, J. Organomet. Chem., 1973, 63, 467. K. Kudo, M. Hidai, and Y. Uchida, J. Organomet. Chem., 1971, 33, 393. F. Morandini, G. Consiglio, and F. Wenzinger, Helv. Chim. Acta, 1979, 62, 59. J. L. Graff and M. G. Romanelli, J. Chem. Soc. Chem. Commun., 1987, 337. M. Hidai, T. Hikita, Y. Wada, Y. Fujikura, and Y. Uchida, Bull. Chem. Soc. Jpn., 1975, 48, 2075. H. Matsuzaka, Y. Hiroe, M. Iwasaki, Y. Ishii, Y. Koyasu, and M. Hidai, Chem. Lett., 1988, 377. K. J. Klabunde and J. Y. F. Low, J. Am. Chem. Soc., 1974, 96, 7674. E. Drent and P. H. M. Budzelaar, Chem. Rev., 1996, 96, 663. J. S. Miller and A. L. Balch, Inorg. Chem., 1972, 11, 2069. N. Hallinen, V. Besançon, M. Forster, G. Elbaze, Y. Ducommun, and A. E. Merbach, Inorg. Chem., 1991, 30, 1112. S. Otsuka, A. Nakamura, and Y. Tatsuno, J. Am. Chem. Soc., 1969, 91, 6994. D. Perreault, M. Drouin, A. Michel, and P. D. Harvey, Inorg. Chem., 1993, 32, 1903. B. Crociani, T. Boschi, and U. Belluco, Inorg. Chem., 1970, 9, 2021. S. Otsuka, A. Nakamura, and T. Yoshida, J. Am. Chem. Soc., 1969, 91, 7196. K. R. Diwon and A. C. Dixon, Comp. Organomet. Chem., 1995, 9, 193. R. J. Goodfellow, P. L. Goggin, and D. A. Duddell, J. Chem. Soc. (A), 1968, 504. A. D. Ketley, L. P. Fisher, A. J. Berlin, C. R. Morgan, E. H. Gorman, and T. R. Steadman, Inorg. Chem., 1967, 6, 657. M. Green, J. A. K. Howard, J. L. Spencer, and F. G. A. Stone, J. Chem. Soc. Dalton Trans., 1977, 271. R. Benn, P. W. Jolly, T. Joswif, R. Mynott, and K.-P. Schick, Z. Naturforsch. B, 1986, 41, 680. A. Visser, R. Van Der Linde, and R. O. De Jongh, Inorg. Synth., 1977, 16, 127. P. Fitton and J. E. McKeon, Chem. Commun., 1968, 4. M. C. Mazza and C. G. Pierpont, Inorg. Chem., 1973, 12, 2955. V. V. Bashilov, P. V. Petrovskii, V. I. Sokolov, S. V. Lindeman, I. A. Guzey, and Y. T. Struchkov, Organometallics, 1993, 12, 991. M. S. Kharasch, R. C. Seyler, and F. R. Mayo, J. Am. Chem. Soc., 1938, 60, 882. G. F. Pregaglia, F. Conti, B. Minasso, and R. Ugo, J. Organomet. Chem., 1973, 47, 165. J. Chatt and R. G. Wilkins, J. Chem. Soc., 1952, 2622. I. A. Zakharova, G. A. Kukina, T. S. Kuli-Zade, I. I. Moiseev, G. Y. Pek, and M. A. PoraiKoshits, Russ. J. Inorg. Chem., 1966, 11, 1364. R. A. Alexander, N. C. Baenziger, C. Carpenter, and J. R. Doyle, J. Am. Chem. Soc., 1960, 82, 535. J. Chatt, L. M. Vallarino, and L. M. Venanzi, J. Chem. Soc., 1957, 3413. N. Ahmad, E. W. Ainscough, T. A. James, and S. D. Robinson, J. Chem. Soc. Dalton Trans., 1973, 1148. H. P. Fritz and H. Keller, Chem. Ber., 1962, 95, 158. Y. Takahashi, T. Ito, S. Sakai, and Y. Ishii, J. Chem. Soc. Chem. Commun., 1970, 1065. T. Ukai, H. Kawazura, Y. Ishii, J. J. Bonnet, and J. A. Ibers, J. Organomet. Chem., 1974, 65, 253. H. Hoberg and C. Fröhlich, J. Organomet. Chem., 1980, 197, 105.
182
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
[43] H. Nagashima, A. Nakaoka, Y. Saito, M. Kato, T. Kawanishi, and K. Itoh, J. Chem. Soc. Chem. Commun., 1992, 377. [44] E. O. Greaves, C. J. L. Lock, and P. M. Maitlis, Can. J. Chem., 1968, 46, 3879. [45] R. Usón, J. Forniés, M. Tomás, and B. Menjón, J. Organomet. Chem., 1986, 304, C24. [46] T. Hosokawa, I. Moritani, and S. Nishioka, Tetrahedron Lett., 1969, 3833. [47] J. R. Stille, Encycl. Reag. Org. Synth., 1995, 1, 482. [48] J. Tsuji, Encycl. Reag. Org. Synth., 1995, 8, 5431. [49] C. Amatore and A. Jutand, Coord. Chem. Rev., 1998, 180, 511. [50] T. I. Wallow and B. M. Novak, J. Org. Chem., 1994, 59, 5034. [51] M. Moreno-Mañas, F. Pajuelo, and R. Pleixats, J. Org. Chem., 1995, 60, 2396. [52] J. Cortés, M. Moreno-Mañas, and R. Pleixats, Eur. J. Org. Chem., 1999, 239. [53] T. A. Albright, R. Hoffmann, J. C. Thibeault, and D. L. Thorn, J. Am. Chem. Soc., 1979, 101, 3801. [54] G. Wiger, G. Albelo, and M. F. Rettig, J. Chem. Soc. Dalton Trans., 1974, 2242. [55] H. Hirai, H. Sawai, and S. Makishima, Bull. Chem. Soc. Jpn., 1970, 43, 1148. [56] C. B. Anderson and B. J. Burreson, J. Organomet. Chem., 1967, 7, 181. [57] P. M. Maitlis, P. Espinet, and M. J. H. Russell, Comp. Organomet. Chem., 1982, 6, 351. [58] S. Ghosh, Encycl. Reag. Org. Synth., 1995, 3, 1698. [59] D. R. Coulson, J. Org. Chem., 1972, 37, 1253. [60] D. R. Coulson, J. Org. Chem., 1973, 38, 1483. [61] B. M. Trost and T. R. Verhoeven, J. Am. Chem. Soc., 1980, 102, 4730. [62] M. B. Sparke, L. Turner, and A. J. M. Wenham, J. Catal., 1965, 4, 332. [63] L. S. Hegedus, G. F. Allen, J. J. Bozell, and E. L. Waterman, J. Am. Chem. Soc., 1978, 100, 5800. [64] J. Tsuji, Palladium Reagents and Catalysts. Innovations in Organic Synthesis, Wiley, New York, 1995, 560 pp. [65] J. K. Stille and R. Divakaruni, J. Organomet. Chem., 1979, 169, 239. [66] X. Marat, N. Monteiro, and G. Balme, Synlett, 1997, 845. [67] M. Cavicchioli, E. Sixdenier, A. Derrey, D. Bouyssi, and G. Balme, Tetrahedron Lett., 1997, 38, 1763. [68] B. Clique, N. Monteiro, and G. Balme, Tetrahedron Lett., 1999, 40, 1301. [69] R. J. Goodfellow and L. M. Venanzi, J. Chem. Soc. (A), 1966, 784. [70] J. K. Becconsall, B. E. Job, and S. O’Brien, J. Chem. Soc. (A), 1967, 423. [71] B. Henc, P. W. Jolly, R. Salz, G. Wilke, R. Benn, E. G. Hoffmann, R. Mynott, G. Schroth, K. Seevogel, J. C. Sekutowski, and C. Krüger, J. Organomet. Chem., 1980, 191, 425. [72] B. Henc, P. W. Jolly, R. Salz, S. Stobbe, G. Wilke, R. Benn, R. Mynott, K. Seevogel, R. Goddard, and C. Krüger, J. Organomet. Chem., 1980, 191, 449. [73] R. D. Rieke and A. V. Kavaliunas, J. Org. Chem., 1979, 44, 3069. [74] A. Döhring, P. W. Jolly, R. Mynott, K.-P. Schick, and G. Wilke, Z. Naturforsch. B, 1981, 36, 1198. [75] R. Benn, P. W. Jolly, R. Mynott, B. Raspel, G. Schenker, K.-P. Schick, and G. Schroth, Organometallics, 1985, 4, 1945. [76] R. Benn, P. W. Jolly, R. Mynott, and G. Schenker, Organometallics, 1985, 4, 1136. [77] P. K. Byers, A. J. Canty, P. R. Traill, and A. A. Watson, J. Organomet. Chem., 1990, 390, 399.
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
[78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118]
183
R. A. Schunn, Inorg. Chem., 1976, 15, 208. A. J. Deeming, B. F. G. Johnson, and J. Lewis, J. Chem. Soc. Dalton Trans., 1973, 1848. T. Yamamoto, O. Saito, and A. Yamamoto, J. Am. Chem. Soc., 1981, 103, 5600. T. Yamamoto, M. Akimoto, O. Saito, and A. Yamamoto, Organometallics, 1986, 5, 1559. K. C. Ramey and G. L. Statton, J. Am. Chem. Soc., 1966, 88, 4387. J. Smidt and W. Hafner, Angew. Chem., 1959, 71, 284. W. T. Dent and A. J. Wilkinson, J. Chem. Soc., 1964, 1585. S. D. Robinson and B. L. Shaw, J. Organomet. Chem., 1965, 3, 367. M. Sakikabara, Y. Takahashi, S. Sakai, and Y. Ishii, Chem. Commun., 1969, 396. J. Powell and B. L. Shaw, J. Chem. Soc. (A), 1967, 1839. Y. Inoue, J. Yamashita, and H. Hashimoto, Synthesis, 1984, 244. R. Hüttel and M. Bechter, Angew. Chem., 1959, 71, 456. R. Hüttel, J. Kratzer, and M. Bechter, Chem. Ber., 1961, 94, 766. M. S. Lupin, J. Powell, and B. L. Shaw, J. Chem. Soc. (A), 1966, 1410. B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton, and T. J. Dietsche, J. Am. Chem. Soc., 1978, 100, 3407. D. R. Chrisope and P. Beak, J. Am. Chem. Soc., 1986, 108, 334. D. R. Chrisope, P. Beak, and W. H. Saunders, J. Am. Chem. Soc., 1988, 110, 230. M. C. Ashraf, T. G. Burrowes, and W. R. Jackson, Aust. J. Chem., 1976, 29, 2643. P. M. Maitlis, P. Espinet, and M. J. H. Russell, Comp. Organomet. Chem., 1982, 6, 385. C. Amatore, A. Jutand, G. Meyer, and L. Mottier, Chem. Eur. J., 1999, 5, 466. S. A. Godleski, Encycl. Reag. Org. Synth., 1995, 1, 416. A. E. Smith, Acta Crystallogr., 1965, 18, 331. W. E. Oberhansli and L. F. Dahl, J. Organomet. Chem., 1965, 3, 43. A. D. Ketley and J. Braatz, Chem. Commun., 1968, 169. R. Hüttel and H. Schmid, Chem. Ber., 1968, 101, 252. R. G. Schultz, Tetrahedron Lett., 1964, 301. R. G. Schultz, Tetrahedron, 1964, 2809. M. S. Lupin and B. L. Shaw, Tetrahedron Lett., 1964, 883. M. S. Lupin, J. Powell, and B. L. Shaw, J. Chem. Soc. (A), 1966, 1687. S. D. Robinson and B. L. Shaw, J. Chem. Soc., 1964, 5002. M. Donati and F. Conti, Tetrahedron Lett., 1966, 1219. R. M. Rowe and D. A. White, J. Chem. Soc. (A), 1967, 1451. A. D. Ketley and J. A. Braatz, Chem. Commun., 1968, 959. J. Tsuji, H. Takahashi, and M. Morikawa, Tetrahedron Lett., 1965, 4387. J. Tsuji and S. Imamura, Bull. Chem. Soc. Jpn., 1967, 40, 197. H. Nakamura, H. Iwama, and Y. Yamamoto, J. Am. Chem. Soc., 1996, 118, 6641. H. Nakamura, J.-G. Shim, and Y. Yamamoto, J. Am. Chem. Soc., 1997, 119, 8113. J. Tsuji and T. Mandai, Angew. Chem. Int. Ed. Engl., 1995, 34, 2589. K. Tsutsumi, S. Ogoshi, S. Nishiguchi, and H. Kurosawa, J. Am. Chem. Soc., 1998, 120, 1938. V. E. O. Fischer and A. Vogler, Z. Naturforsch. B, 1963, 18, 771. W. R. McClellan, H. H. Hoehn, H. N. Cripps, E. L. Muetterties, and B. W. Howk, J. Am. Chem. Soc., 1961, 83, 1601.
184
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
[119] [120] [121] [122] [123]
R. J. Cross and R. Wardle, J. Chem. Soc. (A), 1971, 2000. P. M. Maitlis, A. Efraty, and M. L. Games, J. Am. Chem. Soc., 1965, 87, 719. B. F. G. Johnson, J. Lewis, and D. A. White, J. Chem. Soc. (A), 1970, 1738. D. A. White, Inorg. Synth., 1972, 13, 55. H. Werner, H.-J. Kraus, U. Schubert, K. Ackermann, and P. Hofmann, J. Organomet. Chem., 1983, 250, 517. M. Onishi, Y. Ohama, K. Hiraki, and H. Shintani, Polyhedron, 1982, 1, 539. T. Majima and H. Kurusawa, J. Organomet. Chem., 1977, 134, C45. H. Kurusawa, T. Majima, and N. Asada, J. Am. Chem. Soc., 1980, 102, 6996. H.-J. Kraus, H. Werner, and C. Krüger, Z. Naturforsch. B, 1983, 38, 733. S. Fallis, L. Rodriguez, G. K. Anderson, and N. P. Rath, Organometallics, 1993, 12, 3851. R. J. Cross, R. W. Hoyle, A. R. Kennedy, L. Manojlovic-Muir, and K. W. Muir, J. Organomet. Chem., 1994, 468, 265. P. M. Maitlis, P. Espinet, and M. J. H. Russell, Comp. Organomet. Chem., 1982, 6, 447. H. Werner and W. Bertleff, J. Chem. Res. (S), 1978, 201. H. Werner and W. Bertleff, J. Chem. Res. (M), 1978, 2720. K. J. Klabunde and R. Campostrini, J. Fluorine Chem., 1989, 42, 93. F. T. Ladipo and G. K. Anderson, Organometallics, 1994, 13, 303. P. K. Byers and A. J. Canty, Organometallics, 1990, 9, 210. P. K. Byers, A. J. Canty, B. W. Skelton, and A. H. White, J. Organomet. Chem., 1990, 393, 299. G. Calvin and G. E. Coates, J. Chem. Soc., 1960, 2008. Y. Hayashi, K. Isobe, Y. Nakamura, and S. Okeya, J. Organomet. Chem., 1986, 310, 127. H. C. Clark, C. R. C. Milne, and N. C. Payne, J. Am. Chem. Soc., 1978, 100, 1164. L. J. Krause and J. A. Morrison, J. Chem. Soc. Chem. Commun., 1981, 1282. D. Milstein, J. Chem. Soc. Chem. Commun., 1986, 817. D. T. Rosevear and F. G. A. Stone, J. Chem. Soc. (A), 1968, 164. P. Fitton, M. P. Johnson, and J. E. McKeon, Chem. Commun., 1968, 6. D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1979, 101, 4981. D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1979, 101, 4992. P. Fitton, J. E. McKeon, and B. C. Ream, Chem. Commun., 1969, 370. P. K. Byers, A. J. Canty, L. M. Engelhardt, and A. H. White, J. Chem. Soc. Dalton Trans., 1986, 1731. A. Singhal and V. K. Jain, J. Chem. Soc. Dalton Trans., 1993, 1515. R. Ros, M. Lenarda, T. Boschi, and R. Roulet, Inorg. Chim. Acta, 1977, 25, 61. M. A. Bennett, A. J. Canty, J. K. Felixberger, L. M. Rendina, C. Sunderland, and A. C. Willis, Inorg. Chem., 1993, 32, 1951. W. de Graaf, J. Boersma, W. J. J. Smeets, A. L. Spek, and G. van Koten, Organometallics, 1989, 8, 2907. R. Tooze, K. W. Chiu, and G. Wilkinson, Polyhedron, 1984, 3, 1025. Y.-J. Kim, K. Osakada, A. Takenada, and A. Yamamoto, J. Am. Chem. Soc., 1990, 112, 1096. M. Rudler-Chauvin and H. Rudler, J. Organomet. Chem., 1977, 134, 115. J. Lau and R. Sustmann, Tetrahedron Lett., 1985, 26, 4907. Y. Hayashi, Y. Nakamura, and K. Isobe, J. Chem. Soc. Chem. Commun., 1988, 403. G. K. Turner and H. Felkin, J. Organomet. Chem., 1976, 121, C29.
[124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157]
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
[158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193]
185
A. Gillie and J. K. Stille, J. Am. Chem., Soc., 1980, 102, 4933. A. Miyashita, M. Ohyoshi, H. Shitara, and H. Nohira, J. Organomet. Chem., 1988, 338, 103. R. F. Heck, Acc. Chem. Res., 1979, 12, 146. A. de Meijere and F. E. Meyer, Angew. Chem. Int. Ed. Engl., 1994, 33, 2379. T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Higuchi, and K. Hirotsu, J. Am. Chem. Soc., 1984, 106, 158. W. de Graaf, J. van Wegen, J. Boersma, A. L. Spek, and G. van Koten, Recl. Trav. Chim. Pays-Bas, 1989, 198, 275. A. C. Albéniz, P. Espinet, Y. Jeannin, M. Philoche-Levisalles, and B. E. Mann, J. Am. Chem. Soc., 1990, 112, 6594. R. J. Cross and R. Wardle, J. Chem. Soc. (A), 1970, 840. T. Son, H. Yanagihara, F. Ozawa, and A. Yamamoto, Bull. Chem. Soc. Jpn., 1988, 61, 1251. D. R. Coulson, Chem. Commun., 1968, 1530. P. Fitton and E. A. Rick, J. Organomet. Chem., 1971, 28, 287. P. E. Garrou and R. F. Heck, J. Am. Chem. Soc., 1976, 98, 4115. E. Negishi, T. Takahashi, S. Baba, D. E. Van Horn, and N. Okukado, J. Am. Chem. Soc., 1987, 109, 2393. R. Usón, P. Royo, J. Forniés, and F. Martinez, J. Organomet. Chem., 1975, 90, 367. R. Uson, J. Fornies, and F. Martinez, J. Organomet. Chem., 1976, 112, 105. M. K. Loar and J. K. Stille, J. Am. Chem. Soc., 1981, 103, 4174. J. Burgess, M. E. Howden, R. D. W. Kemmitt, and N. S. Sridhara, J. Chem. Soc. Dalton Trans., 1978, 1577. R. Usón, J. Forniés, J. A. Nalda, M. J. Lozano, P. Espinet, and A. C. Albéniz, Inorg. Chim. Acta, 1989, 156, 251. K. J. Klabunde, Angew. Chem. Int. Ed. Engl., 1975, 14, 287. R. Usón, J. Forniés, F. Martinez, and M. Tomás, J. Chem. Soc. Dalton Trans., 1980, 888. R. Usón, J. Forniés, and M. P. García, Inorg. Chim. Acta, 1979, 33, 69. R. Nast, H.-P. Müller, and V. Pank, Chem. Ber., 1978, 111, 1627. K. Sonogashira, T. Yatake, V. Tohda, S. Takahashi, and N. Hagihara, J. Chem. Soc. Chem. Commun., 1977, 291. H. Ogawa, T. Joh, S. Takahashi, and K. Sonogashira, J. Chem. Soc. Chem. Commun., 1985, 1220. R. Usón, J. Forniés, M. Tomás, and B. Menjón, Organometallics, 1985, 4, 1912. C. de Haro, G. García, G. Sánchez, and G. López, J. Chem. Res. (S), 1986, 119. C. de Haro, G. García, G. Sánchez, and G. López, J. Chem. Res. (M), 1986, 1128. M. D. Rausch and F. E. Tibbetts, J. Organomet. Chem., 1970, 21, 487. E. Negishi, K. Akiyoshi, and T. Takahashi, J. Chem. Soc. Chem. Commun., 1987, 477. E. Negishi, T. Takahashi, and K. Akiyoshi, J. Organomet. Chem., 1987, 334, 181. G. Lopez, G. Sanchez, G. Garcia, J. Galvez, and J. Ruiz, J. Organomet. Chem., 1987, 321, 273. H. Masai, K. Sonogashira, and N. Hagihara, J. Organomet. Chem., 1971, 26, 271. J. H. Nelson, A. W. Verstuyft, J. D. Kelly, and H. B. Jonassen, Inorg. Chem., 1974, 13, 27. P. M. Treichel and F. G. A. Stone, Adv. Organomet. Chem., 1964, 1, 143. S. L. Fraser, M. Y. Antipin, V. N. Khroustalyov, and V. V. Grushin, J. Am. Chem. Soc., 1997, 119, 4769. E. Negishi, C. Copéret, S. Ma, S.-Y. Liou, and F. Liu, Chem. Rev., 1996, 96, 365.
186
II Pd-COMPOUNDS: STOICHIOMETRIC PREPARATION
[194] R. F. Heck, Palladium Reagents in Organic Synthesis, Academic Press, New York, 1985, 461 pp. [195] J. F. Hartwig, Angew. Chem. Int. Ed. Engl., 1998, 37, 2046. [196] A. Aranyos, D. W. Old, A. Kiyomori, J. P. Wolf, J. P. Sadighi, and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 4369. [197] G. Mann, D. Baranano, J. F. Hartwig, A. L. Rheingold, and I. A. Guzei, J. Am. Chem. Soc., 1998, 120, 9205. [198] J. F. Hartwig, S. Richards, D. Baranano, and F. Paul, J. Am. Chem. Soc., 1996, 118, 3626. [199] A. J. Canty, Comp. Organomet. Chem., 1995, 9, 225. [200] K.-C. Kong and C.-H. Cheng, J. Am. Chem. Soc., 1991, 113, 6313. [201] D. K. David, J. K. Stille, and J. R. Norton, J. Am. Chem. Soc., 1995, 117, 8576. [202] F. E. Goodson, T. I. Wallow, and B. M. Novak, J. Am. Chem. Soc., 1997, 119, 12441. [203] L. Huang, F. Ozawa, K. Osakada, and A. Yamamoto, J. Organomet. Chem., 1990, 383, 587. [204] S. Otsuka, A. Nakamura, T. Yoshida, M. Naruto, and K. Ataka, J. Am. Chem. Soc., 1973, 95, 3180. [205] M. Hidai, M. Kokura, and Y. Uchida, J. Organomet. Chem., 1973, 52, 431. [206] G. Yoshida, H. Kurusawa, and R. Okawara, J. Organomet. Chem., 1976, 113, 85. [207] K. Suzuki and H. Yamamoto, J. Organomet. Chem., 1973, 54, 385. [208] K. Kudo, M. Sato, M. Hidai, and Y. Uchida, Bull. Chem. Soc. Jpn., 1973, 46, 2820. [209] K. Suzuki and M. Nishida, Bull. Chem. Soc. Jpn., 1973, 46, 2887. [210] J.-T. Chen and A. Sen, J. Am. Chem. Soc., 1984, 106, 1506. [211] V. V. Grushin and H. Alper, Organometallics, 1993, 12, 1890. [212] G. D. Smith, B. E. Hanson, J. S. Merola, and F. J. Waller, Organometallics, 1993, 12, 568. [213] G. R. Newkome and V. K. Gupta, Inorg. Chim. Acta, 1982, 65, L165. [214] R. Rivetti and U. Romano, J. Organomet. Chem., 1978, 154, 323. [215] F. Ozawa, H. Soyama, H. Yanagihara, I. Aoyama, H. Takino, K. Izawa, T. Yamamoto, and A. Yamamoto, J. Am. Chem. Soc., 1985, 107, 3235. [216] S. Couve-Bonnaire, J.-F. Carpentier, Y. Castanet, and A. Mortreux, Tetrahedron Lett., 1999, 40, 3717. [217] Y. Yamamoto and H. Yamazaki, Inorg. Chem., 1974, 13, 438. [218] T. R. Gaffney and J. A. Ibers, Inorg. Chem., 1982, 21, 2860. [219] M. C. Baird and G. Wilkinson, J. Chem. Soc. (A), 1967, 865. [220] H. Werner and M. Ebner, J. Organomet. Chem., 1983, 258, C52. [221] R. G. Goel and R. G. Montemayor, Inorg. Chem., 1977, 16, 2183. [222] J. W. Suggs and K. S. Lee, J. Organomet. Chem., 1986, 299, 297. [223] A. C. Cope and E. C. Friedrich, J. Am. Chem. Soc., 1968, 90, 909. [224] P. Diversi, G. Ingrosso, A. Lucherini, and S. Murtas, J. Chem. Soc. Dalton Trans., 1980, 1633. [225] G. E. Hartwell, R. V. Lawrence, and M. J. Smas, Chem. Commun., 1970, 912. [226] C. A. Craig and R. J. Watts, Inorg. Chem., 1989, 28, 309. [227] A. C. Cope and R. W. Siekman, J. Am. Chem. Soc., 1965, 87, 3272. [228] D. M. Grove, G. van Koten, J. N. Louwen, J. G. Noltes, A. L. Spek, and H. J. C. Ubbels, J. Am. Chem. Soc., 1982, 104, 6609. [229] R. F. Heck, J. Am. Chem. Soc., 1968, 90, 313.
II.3.2 STOICHIOMETRIC SYNTHESIS AND SOME NOTABLE PROPERTIES
187
[230] N. A. Al-Salem, H. D. Empsall, R. Markham, B. L. Shaw, and B. Weeks, J. Chem. Soc. Dalton Trans., 1979, 1972. [231] A. L. Seligson and W. C. Trogler, Organometallics, 1993, 12, 738. [232] C. Cornioley-Deuschel and A. von Zelewsky, Inorg. Chem., 1987, 26, 3354. [233] W. A. Herrmann, C. Brossmer, K. Öfele, C.-P. Reisinger, T. Priermeier, M. Beller, and H. Fischer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1844. [234] H. Rimml and L. M. Venanzi, J. Organomet. Chem., 1983, 259, C6. [235] K. Moseley and P. M. Maitlis, J. Chem. Soc. Dalton Trans., 1974, 169. [236] D. W. Evans, G. R. Baker, and G. R. Newkome, Coord. Chem. Rev., 1989, 93, 155. [237] T. Ito, S. Hasegawa, Y. Takahashi, and Y. Ishii, J. Organomet. Chem., 1974, 73, 401. [238] L. D. Brown, K. Itoh, H. Suzuki, and J. A. Ibers, J. Am. Chem. Soc., 1978, 100, 8232. [239] M. Beller, H. Fischer, W. A. Herrmann, K. Öfele, and C. Brossmer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1848. [240] D. A. Albisson, R. B. Bedford, S. E. Lawrence, and P. N. Scully, Chem. Commun., 1998, 2095. [241] N. Hagihara, K. Sonogashira, and S. Takahashi, Adv. Polym. Sci., 1980, 41, 149. [242] M. S. Khan, S. J. Davies, A. K. Kakkar, D. Schwartz, B. Lin, B. F. G. Johnson, and J. Lewis, J. Organomet. Chem., 1992, 424, 87. [243] S. A. Hudson and P. M. Maitlis, Chem. Rev., 1993, 93, 861.
Pd(I)Ln,Pd(III)Ln,Pd(IV)Ln
II.4
Palladium Complexes Containing Pd(I), Pd(III), or Pd(IV) ALLAN J. CANTY
A. INTRODUCTION Although the organometallic chemistry of palladium is dominated by oxidation state 2 for palladium, Pd(0) complexes play a significant role in organic synthesis and there is a rapidly developing field of Pd(IV) chemistry of potential and demonstrated applications in catalysis. In contrast, the odd electron configurations, d9 and d7 for Pd(I) and Pd(III), respectively, have been less successfully developed and indeed elusive for Pd(III). B. Palladium(I) The odd electron configuration for Pd(I), as expected, generally gives rise to Pd—Pd bonding and there is an extensive chemistry of such complexes with -bonding ligands.[1]–[4] Typical structural types are shown as 1–4 in Scheme 1, and complexes with other ligands such as benzene, cyclopentadienyl, and indenyl[2] have been characterized. In view of the important role of allyl ligands in organic synthesis it is of interest to note that Pd(I) complexes of these ligands may be obtained in a similar manner to those of Pd(II) complexes,[5],[6] for example, reaction of allyl acetate with Pd(0) reagents to give both 1 (L PPh3) and Pd(3-C3H5)(O2CMe)(PPh3). Complexes are also formed on reduction of Pd(II) species, for example 1 (X Cl, L PPh3) on reaction of [Pd(-Cl) (3-C3H5)]2 with PPh3 in the presence of sodium methoxide,[7] and 2 (L PPh3) on reaction of Pd(3-C3H5)2 with PPh3 at 0 °C via Pd(3-C3H5)(1-C3H5)(PPh3).[8] Electrochemical studies of both -bonded and Pd—C -bonded species have been reported,[9 ]–[14] with evidence for Pd(I) species, although in these cases the assignment of oxidation state may be regarded as more of a formalism than for 1–4, where there is at least the presence of a Pd—Pd bond to support assignment of oxidation state 1 at the metal center rather than electron transfer at the organic ligands. Typical examples include Pd(5-C5Ph5)(4-diene),[10],[11] and closely related studies of 3,[9] which undergoes a threestep electron transfer process 32 4 3 4 3 4 3. There is one report of the synthesis of 1-hydrocarbylpalladium(I) complexes,[15] for example, 5 is formed by reaction of Al2Me6 with a Pd(I) precursor [PdCl(-dppm)]2 at
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
189
190
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
Ph Ph L
Pd
Pd
L
L
Pd
Pd
Ph
L
Ph Ph Ph Ph Pd Ph Ph
Ph Pd Ph
X
Ph
1
2
3
PPh2
Ph2P L
Pd
Pd
R
L
X
Pd
Pd Ph2P
X
PPh2
4 [4] 5 Scheme 1
78 °C (Scheme 1, R Me; X Me, Cl). Complex 5 (R Me, X Cl) readily undergoes disproportionation to Pd(0) and Pd(II) species, and it is thus intriguing that a wide variety of pentahalogenophenylpalladium(I) complexes are formed in the reverse reaction,[12],[16],[17] for example, the reaction of Pd2(dba)3 CHCl3 with trans-[PdX(C6F5) (1-dppm)]2 to form 5 (R C6F5, X Cl).[16]
C. PALLADIUM(III) Palladium(III) complexes are also expected to exhibit Pd—Pd bonding, but to date there appear to be no examples where this oxidation state or Pd—Pd bonding has been clearly demonstrated in the presence of “innocent” ligands.[12],[18]–[20] For example, electrochemical oxidation of a (1 -phenyl)-2-pyridylmethylpalladium(II) dimer in acetonitrile may form 6 (Scheme 2), although it has not been established whether this contains a Pd—Pd bond.[20] Oxidation of the pincer palladium(II) complex 7 has been shown by EPR spectroscopy to occur at the ligand rather than the metal atom.[19] A series of mononuclear radical species for which assignment of formal oxidation state is problematic have been detected.[18],[19]
2+ Ph H
N N
MeCN L
Pd Cl Cl
Pd
Ph H NCMe
+
ArP
L
Pd Cl
6
7 Scheme 2
PAr
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
191
D. PALLADIUM(IV) D.i. Synthesis and Structure A series of pentafluorophenylpalladium(IV) complexes obtained on chlorine oxidation of Pd(II) substrates was reported in the 1970s.[17],[21],[22] The first hydrocarbylpalladium(IV) complex was isolated by addition of MeI to PdMe2(bpy) in 1986 (Scheme 3),[23],[24] and the field developed rapidly thereafter.[12],[25],[26] All of the PdIV—C -bonded complexes isolated, or detected in solution prior to decomposition, have been obtained via oxidation of organopalladium(II) complexes or, in a limited number of cases, via ligand exchange at Pd(IV) centers.[27],[28] In a recent report the first examples of 5-bonded complexes have been described, obtained by complex reactions involving insertion into Si—Si bonds and Si—C coupling (Scheme 3).[29],[30] There are many reports,[1],[31]–[59] together with some referred to elsewhere in this section, that suggest the occurrence of undetected Pd(IV) species in reactions of Pd(II) complexes. Me Me Me
N N
Pd
+ MeI
Me Me
Pd I 9
8
R R R
R R R
Pd
N N
+
Me2 Me2 Si Si Si
R R
R R Me2Si
Pd
SiMe2
Si
10
11 (R = H, Me) Scheme 3
Examples of the oxidants used to date for the synthesis of PdIV—C -bonded complexes are shown in Schemes 3 and 4 (with the oxidants shown in parantheses). Thus, organic halides oxidize diorganopalladium(II) complexes[23],[24],[60]—[90] to form triorganopalladium(IV) species; halogens form mono- or diorganopalladium(IV) species;[77],[79],[84] dibenzoylperoxide, diphenylsulfide, and diphenyldiselenide oxidize diorganopalladium(II) complexes[91],[92]; and even water will oxidize electron-rich tris(pyrazol-1-yl)borate complexes.[84],[93] There is one report of the oxidation of a monoorganopalladium(II) complex by an alkyl halide,[77] and an earlier reaction for which NMR spectra indicated that an unstable Pd(IV) complex may have been formed.[94] Other examples of isolated or spectroscopically detected complexes are shown in later schemes [diagrams 23 and 26 (Scheme 6), 27, 29, 31, and 32 (Scheme 7), and 40 (RX Br2, Scheme 11)].
192
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
Me Bn
Me Me 2 N Pd N Me2 Br
+ X−
R Me Me
N N N N
Pd N
12
N
Me Me
Pd
S S
S
H
14 13 (from MeI)[75] (from MeI, EtI, BnBr, CH2 CHCH2Br)[24],[60],[69]
(from BnBr)[70]
Me
Me Cl N Pd
O PR2 O PR2 O P Co R2
Me Me
+ I−
Me
Pd
Me H2C
NMe2 Cl
15 (from PdMe2(bpy), MeI,
Pd
N N N N B H2
Cl
N
16 (from Cl2)[77]
17 (from C10H8NBr)[89]
AgL, R = OMe, OEt) [28]
X
R N N N N N N B H
Pd
RX −X −
19 (RX = MeI, EtI, BnBr, CH2 CHCH2I)[82]
Pd
Cl2, Br2, I2;
N N N N B N H N
−X−
N N N N N N B H
Pd
or 2H2O; −OH−, −H2
18
20 (X = Cl, Br, OH) [84] (X2 or H2O as oxidant)
O2CPh Me Me
Pd
N N
EPh (PhCO2)2
Me Me
Pd
N N
O2CPh 21 [91]
Me (PhE)2 E = S, Se Me
Pd
N N
EPh 8
Scheme 4
22 (E = S, Se)[91]
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
193
All Pd(IV) complexes examined crystallographically are octahedrally coordinated,[23],[24],[28],[30],[60],[71],[73],[82],[84],[87],[89],[91] as expected for the d6 configuration, and the diand triorganopalladium(IV) complexes have cis-PdR2[84],[91] and fac-PdR3 configurations,[24],[28],[60],[61],[71],[73],[82],[87],[89] respectively. Both neutral[23],[24],[28],[30],[71],[73],[82],[84],[87],[89],[91] and cationic[24],[60],[84] complexes have been examined crystallographically, including 9, 11, 13 (RX MeI), 15, 17, 20 (X OH), and 22 (X Se). All complexes detected have a bidentate or tridentate ligand, including intramolecular coordination systems such as [C(sp2)NN] (16), [C(sp3)NN],[77] or [C(sp3)N] (17). The polydentates may be either hard or soft donor ligands, for example bidentate nitrogen in phen[24],[62],[64],[67],[71],[73],[74],[76],[78],[88],[91] or TMEDA,[65],[70] or tripodal oxygen (15) or sulfur (14). Examples of compounds containing these ligands are shown in Schemes 3 and 4. Although all complexes contain polydentates, for those complexes containing an additional unidentate ligand there is a wide range of ligands that will support Pd(IV), including halogens (F, Cl, Br, I), pseudohalogens and carboxylates,[27] arenethiolate and areneselenolate,[91],[92] and hydroxo and aqua ligands.[84] Organic groups bonded to Pd(IV) include alkyl, benzyl, allyl, propargyl, allenyl, aryl, and the cyclic systems shown in Scheme 4 and 29 (Scheme 7).[86] Organopalladium(IV) motifs PdAr (16); PdMe2 (21, 22)[79],[91],[92]; PdMe2R (R Me,[23],[24],[28],[60],[61],[63]–[66],[73],[75],[79],[81],[82],[87] Et,[61],[68],[69],[82] Pr,[69] Bn,[61],[64],[69]–[72],[77],[79],[82],[83] [61],[68]–[70],[82] [80],[82],[95] [73] CH2CH"CH2, Ar, ArCOCH2, CH2C#CR and CH"C"CH2,[88] [89] 8-methylquinolinyl); PdMeArR (R Et,[89] Bn[80],[82],[85],[90],[95] including a periphery [89] palladated dendrimer, 8-methylquinolinyl,[89] CH2CH"CH2[82]; Pd(CH2CH2CH2CH2)R (R Me, Et, Bn, allyl, CF3)[82],[86],[96]; the palladacyclic system shown in 27 (Scheme 7) for oxidative addition of methyl, benzyl, and allyl halides[62],[67],[74],[76]; Pd(2-CH2OC6H4C,C)R (R Bn, CH2"CH2)[78]; Pd{C(sp3)NN}Me2[77]; and dibromopallada(IV)cyclopentadienes as in 40[55] (Scheme 11) have been detected. In all cases the formation of additional Pd—C bonds on oxidation of Pd(II) substrates occurs via oxidative addition of methyl, ethyl, propyl, allyl, benzyl, naphthylmethyl, phenacyl, propargyl, or 8-methylquinolinyl halides, or methyl triflate at Pd(II) centers.[65] Arylpalladium(IV) complexes such as 16 and 17 (Scheme 4), 23 (Scheme 6), and 27 (Scheme 7) are obtained on oxidative addition of chlorine or C(sp3)—X (X halogen) bonds to arylpalladium(II) complexes. Detailed kinetic studies of the oxidation of Pd(II) substrates have been reported only for the reactions of PdMe2(L2) (L2 bpy, phen) with MeI [63],[69],[81] and BnBr.[64] The reactions exhibit second order kinetics with activation parameters typical for the classical SN2 mechanism, for example, highly negative values for S‡ consistent with the mechanism shown in Scheme 5. In agreement, solvento-intermediates can be detected in many cases. Thus, for the reaction of Scheme 5, low-temperature NMR studies have shown the intermediacy of [PdMe3(bpy)] in (CD3)2CO (where the cation is assumed to be solvated).[73] Also, the complex PdIMe3(bpy) forms an equilibrium with [PdMe3(bpy)(NCCD3)] in CD3CN [24] and PdMe2(TMEDA) reacts with methyl triflate in CD3CN to form [PdMe3(TMEDA)(NCCD3)].[65] Similar kinetic parameters have been reported by Stille and co-workers for the reaction of cis-PdMe2(PPh2Me)2 with MeI to form trans-PdIMe(PPh2Me)2 and ethane (Scheme 5),[36] except that this reaction is 6000–7000 times slower than the reaction of PdMe2(bpy). In the case of cis-PdMe2(PPh2Me)2, oxidative addition is slow compared with reductive elimination of ethane and hence the Pd(IV) intermediate is not detected spectroscopically. The detection of a cation intermediate for the reaction of PdMe2(bpy)
194
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
I δ− Me δ+ + I−
Me Me Me
Pd
N N
Me Me
Pd
Me
N N
Me Me
Pd
N N
I 9 In acetone at 20 °C: k2 = 3.23 ± 0.08 L mol ∆S‡ = −148 ± 2 J K−1 mol−1 Me Me
Pd
−1 −1
−1
s , Ea = 25.3 ± 0.6 kJ mol ,
slow fast PPh2Me Pd(IV) + MeI PPh2Me ?
Me MePh2P
Pd
PPh2Me + Me Me I
In acetone at 20 °C: k2 = 4.9 × 10−4 L mol−1 s−1, Ea = 68 ± 4 kJ mol−1, ∆S‡ = −85 ± 13 J K−1 mol−1 Scheme 5
(Scheme 5) and the requirement of ligand dissociation in reductive elimination (see Sect. D.ii) imply that the intermediate phosphine complex may be [PdMe3(PPh2Me)2] or [PdMe3(PPh2Me)2(solvent)] rather than PdIMe3(PPh2Me)2. Thus, the development and study of isolable Pd(IV) complexes, in particular of the archetypal reaction of Scheme 3, support the pioneering work of Stille suggesting the formation of transient undetected Pd(IV) species in reactions of alkyl halides or halogens with diorganopalladium(II) complexes containing phosphine donor ligands.[31],[32],[34]–[36] D.ii. Reactivity Organopalladium(IV) complexes are stable toward water and oxygen and toward any excess oxidant used in their synthesis. In almost all reactions of Pd(IV) complexes it appears that loss of a donor group to give a five-coordinate intermediate is required, although the potential involvement of a weak solvent coordination interaction cannot be discounted at present. Solvated cations have been detected by NMR spectroscopy[64],[65],[73] and these species are known to be fluxional when they contain the fac-PdMe3 unit, for example a G‡ of 53 kJ mol1 has been estimated for exchange of axial and equatorial methyl group environments in [PdMe3(TMEDA)(NCCD3)].[65] Silver(I) salts may be employed at low temperature to exchange bromide in PdBrMe2Bn(bpy) to form a series of complexes PdXMe2Bn(bpy) (X F, Cl, I, O2CMe, N3, OCN, SeCN, O2CPh, O2CCF3)[72] and to effect the exchange of both iodide and bpy to form 15 [28] (Scheme 4). Preliminary halide loss is also implicated in alkyl halide exchange reactions of Pd(IV) complexes with Pd(II) [80],[85] and Pt(II) complexes,[64] for which an example is shown in Scheme 6. The reactions are strongly retarded by added halide ion, and kinetic studies of the reaction of PdBrMe2Bn(phen) with PtMe2(phen) reveal second order kinetics and a strong inverse dependence on [Br].[64] Together with the observed selectivity for
195
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
Bn
Bn Me Ph
Pd
N N
Me + Me
Pd
N N
Me Ph
N N
Pd
Me + Me
Br 24
Me Me
25
Pd
N N
26 +
+ Me Me
Pd
N N
Br +Br − Me −Br −
Ph
Pd
N N
Bn
Bn Bn
Bn Pd
N N
Br
23
Me Ph
Pd
N N
−Br − Me +Br−
Ph
Pd
N N
Me Ph
Br
Pd
N N
Scheme 6
exchange, BnI MeI, a mechanism (Scheme 6, where cations may be solvated) directly related to the oxidative addition process (Scheme 5) is anticipated. Methyl group exchange between Pd(II) and Pd(IV) presumably occurs also during reactions of [PdMe2{(pz)3BH}] with halogens or water to form PdIVMe3{(pz)3BH} and “PdIIMe{(pz)3BH}”.[84] These reactions are directly analogous to reactions of the pallada(II)cyclic complex 18 in Scheme 4, except that in the latter cases the product PdIV(CH2CH2CH2CH2)(X){(pz)3BH} (X OH, Cl, Br, I) cannot undergo alkyl group exchange reactions with the reagent nucleophile [PdII(CH2CH2CH2CH2){(pz)3BH}] because of the constrained nature of the palladacycle rings. Kinetic studies of the decomposition of PdIMe3(bpy) reveal first order behavior and a strong inverse dependence on [I], again consistent with preliminary halide loss (Scheme 7).[63],[81] Decomposition of triorganopalladium(IV) complexes occurs almost exclusively via C—C coupling and is generally “clean” in the solid state unless the Pd(IV) complex is exceptionally stable. Studies of the reductive elimination of ethane from PdIMe3(L 2) (L 2 bpy, phen) have enabled the first estimates of Pd—C bond energies to be made (Scheme 7) and the values obtained are 10% less than for the most practically comparable Pt(IV) complexes such as PtIMe3(PMe2Ph)2.[63],[64] A similar decomposition occurs in the solid state for PdBrMe2Bn(L 2) (L 2 bpy, phen), giving predominantly ethane, and in solution the selectivity for ethane is enhanced (100% for bpy; 75% Me—Me and 25% Me—Bn for L2 phen).[64] Reductive elimination generally, but not always, favors coupling Ar—Me Me—Me Me—Bn. Recent reports of decomposition are shown in Scheme 7.[62],[86] Additional examples include PdBrMePhBn(bpy) (23) giving Me—Ph,[80],[85] PdBrMe2Bn(TMEDA) (12) giving Me—Me,[70] and PdIMe2Ph(bpy) giving Me—Me and Me—Ph in 4:1 ratio for which a selectivity in favor of Me—Me rather than Ar—Me coupling is observed.[80] 1-Allylpalladium(IV) complexes decompose to form 3-allylpalladium(II) complexes,[61],[68]–[70],[86],[97] as illustrated in Scheme 7.[86] Pallada(IV)cyclic complexes also undergo C—C bond formation as the first step in decomposition, for example, for the allylpalladium(IV) complex shown in Scheme 7, and for 31 (Scheme 7), where Me—CH2 coupling is followed by decomposition of an undetected pentylpalladium(II) species.[86]
196
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
−I −
PdIMe3(bpy)
+I
[PdMe(bpy)]+ −Me −Me (or solvated) (or solvated)
∆
PdIMe3(bpy)(s)
+I −
[PdMe3(bpy)]+
−
PdIMe(bpy)(s) + Me
−
PdIMe(bpy)
−Me(g)
∆H = −105 ± 2 kJ mol−1; D(Pd Me) ~130 kJ mol−1
Me
Me
Pd
N N
I
N N
Pd
I 28
27
+ Pd
N N
+
+
Pd
+
N N
(+ isomers)
Br 88%
29
9%
3%
30
Me Pd
N N
I
+ (+ isomers) 48%
39%
I
+ 12%
31
EPh Me Me
N N N N N N B H
Pd
E = S: −10 °C E = Se: 0 °C
Me
−Me
32
Scheme 7
+ Me
− EPh
+ EPh2
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
197
Higher stability is favored by ligands that appear to encourage retention of octahedral coordination rather than release of a donor group: ligands that do not create steric congestion at the Pd(IV) center,[24],[27],[66],[69] rigid bidentate ligands,[24],[27],[66],[79] tripod ligands,[24],[28],[60],[61],[69],[75],[82] and the [CN] donor illustrated by 17, which is the only arylpalladium(IV) complex examined crystallographically.[89] Carbon–halogen coupling at Pd(IV) centers occurs to a minor extent for some triorganopalladium(IV) species,[79],[98] and may occur in the decomposition of 31 although other processes for formation of the C–I bond cannot be excluded for this reaction. However, for monoorganopalladium(IV) and diorganopalladium(IV) complexes, carbon– heteroatom coupling appears to be a more prominent process in decomposition. Thus, for diorganopalladium(IV) complexes containing arenethiolate and areneselenolate ligands, C—C coupling is accompanied by C—S and C—Se coupling[92] as illustrated by 32 in Scheme 7. The undetected complex Pd(O2CPh)2Me2(bpy) (21) decomposes in a complex manner involving methyl group exchange to form PdMe3(bpy)(O2CPh), contrary to the early report,[91] Pd(EPh)2Me2(bpy) (22) gives Me—Me and Me—EPh in 1:1 ratio,[91] and 16 forms PdCl2{2-ClC6H4CH2NMeCH2CH2NMe2-N, N } quantitatively.[77]
E. PALLADIUM(I), PALLADIUM(III), AND PALLADIUM(IV) IN ORGANIC SYNTHESIS The chemistry of palladium in organic synthesis is dominated by the 0 and 2 oxidation states, often with catalytic cycles involving two-electron oxidation and reduction steps. Assignment of mechanisms involving other oxidation states in Pd-catalyzed reactions is not straightforward in view of several reactivity characteristics of palladium complexes. These include facile reduction of Pd(II) to Pd(0) by solvents and reagents under mild conditions leading to Pd(0)–Pd(II) cycles, the ability of Pd(II) to facilitate aryl and alkyl group exchange between Pd(II) centers and between Pd(II) and organometal reagents, stabilization of Pd(0) catalytic species at low concentrations by a range of ligand/solvent conditions, catalysis by di- and polynuclear palladium complexes and clusters, and the documentation in other sections in this text of an extraordinary range of catalytic processes that are readily accomplished at Pd(0) and Pd(II) centers. All of these factors favor assignment of oxidation states 2 in mechanisms, and thus the emphasis in this section is placed on consideration of proposals for the involvement of higher oxidation states. Palladium(I) intermediates have been proposed for the telomerization of butadiene with acetic acid yielding acetoxyoctadienes,[5] and in a recent review the involvement of Pd(I) has been suggested for processes in which Pd(II) had been formerly suggested.[99] These processes include alkene isomerization, methoxycarbonylation of alkynes to acrylic esters, and the aryloxycarbonylation of allyl alcohol. There is little speculation on the role of Pd(III) in synthesis, although its involvement in the reactivity of electrochemically generated Pd(I) species has been canvassed[13] as well as its possible role in oxidatively induced decomposition of Pd(II) species by organic halides to generate reactive intermediates.[100] Synthetic procedures for which Pd(IV) intermediates have been proposed, usually with reservations by the authors on the potential involvement of Pd(0) and/or Pd(II) as alternative intermediates, include the synthesis of triphenylenes and related compounds formed by linking norbornene with aryl groups,[101]–[113] benzo[e]pyrenes,[104],[108],[110]
198
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
2,6-disubstituted arenes and vinylarenes,[111],[114],[115] 6H-dibenzo[b,d]pyrans,[116]–[118] acenaphthylenes,[117],[119] annulated pyrans and furans,[120] dihydrocyclobutabenzenes,[121] benzo[b]furans,[117],[122] 2-substituted indoles,[123],[124] 2-aroyldimethylaminomethylarenes,[37] 2,6-dialkylated benzaldehydes,[125] 2-aroylphenols,[126] indenones,[127] polyfused heterocycles,[128],[129] substituted pyrrolidines,[130] cyclopentenes,[131] esters and diynes from terminal acetylenes and oxalate esters,[132] stannoles from ethyne and SnR2[133]; the Heck[118],[134 ]–[140] and Suzuki reactions[141]; coupling of terminal alkynes with aryl bromides,[142] coupling of -bromostyrene with norbornadiene,[143] reactions of 2-bromobenzaldehyde with methyl acrylate,[144] exchange and isomerization reactions of alkenes,[145]–[150] dimerization of alkenes,[151]–[153] dimerization of allenyl ketones,[154],[155] cooligomerization of butadiene with 1-azadienes,[156] addition of vinyl compounds to dimethylacetylenedicarboxylate,[157] acetoxylation of arenes[158],[159] and related reactions[51] forming C—O bonds, chlorination of azobenzenes,[160] orthoalkylation of acetanilide,[41] reaction of arylazoxyarylsulfones with norbornene,[161] cyclization and cycloisomerization of enynes,[117],[130],[131],[162]–[175] cycloisomerization of alkynyl Nacylenamines,[169] addition of terminal alkynes to acceptor alkynes,[176],[177] double carbonylation of prop-2-ynal acetals with subsequent reactions to give vinyl ethers,[178] carbonylation of iodomethane and methanol to methyl acetate[179]; the synthesis of conjugated dienes from alkynes, tetramethyltin, and an organic halide;[55],[57] the preparation of poly-p-phenylene,[180] and reactions of Si—Si bonded reagents with alkynes[181] and Si—Si bond metathesis.[29],[182] Examples of some of these reactions are discussed below to illustrate key principles, reactions that have support for Pd(IV) intermediacy from model reactions, and reactions that are frequently interpreted by some researchers (but not others) as involving Pd(IV) intermediates. In most of the mechanistic schemes presented below, an estimate of the full coordination sphere of palladium species has not been attempted. Classic examples of the difficulties in assigning a mechanism include that for C—C coupling reactions (Scheme 8), where the Pd(0)–Pd(II) cycle appears to exclude homocoupling, but is apparently readily achievable for Pd(II)–Pd(IV) cycles (R—R from PdIVR2R ) and for which there is ample precedent, for example, oxidative additions in Scheme 3 (to form 9) and Scheme 4 (to form 12–14, 17, and 19) and reductive eliminations from Pd(IV) complexes. However, there is evidence for the formation of bridging species such as 33–35 in Pd(II) chemistry,[100],[183]–[188] thus allowing homocoupling via Pd(0)–Pd(II) catalysis by, for example, Ar group exchange between PdIIXAr and PdIIArAr’ via L(Ar)PdII(-Ar )(-Ar)PdIIXL 2 (as 34) to form PdIIAr2, which may decompose to Ar—Ar and Pd(0). Exchange of organic groups has also been demonstrated to occur between monoorganopalladium(II) complexes and organometal reagents[188],[189] and via the formation of palladates, for example, NMR spectra indicate the formation of [PdPh2Me(PEt3)] and [PdPh2Me2] 2 on the reaction of trans-PdPh2(PEt3)2 with LiMe.[190] Although there are ample precedents for the formation and decomposition of Pd(IV) complexes, including for undetected phosphine complexes (Scheme 5), where the oxidants involve C(sp3)—X bonds, two-electron oxidative addition of aryl halides has not been definitively demonstrated. Alternatives to oxidative addition may include oneelectron oxidation giving [ArX]• and decomposition of “Pd(III)” species thus formed leading to Pd(0) involvement, formation of bridging species after oxidative addition of ArX to traces of Pd(0), and heterogeneous catalysis at Pd(0) or Pd(0)/Pd(II) species adsorbed at Pd(0) surfaces. Despite these reservations, two-electron oxidative addition of
199
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
RX
+
[Pd]
R′m
R
R′ +
mX
R
RX
R′
PdIIXR R′m Pd0
PdIVXR2R′
mX PdIIRR′
R
R′
RX R′m = organometal
L L R
II R Pd R
Pd
R II
X
L R
II R Pd R
L 33
Pd
II
L
L R
II R Pd R
Mg
R
L 34
35
Scheme 8
aryl halides to Pd(II) provides the simplest rationale for many observations, particularly for systems where formation of Pd(0) or of bridging species appears difficult, for example, the reaction of PdPh(PCP) with PhI to form PdI(PCP) and biphenyl ([PCP] 2,6-(Pri2PCH2)2C6H3]).[136] However, even in this case, the formation of bridging intermediates cannot be completely excluded. Systems for which suggestions of intermediate Pd(IV) species formed by aryl halide oxidative addition have been proposed include reactions such as that of Scheme 9 developed by Catellani, Chiusoli and co-workers[62],[74],[76],[102],[105],[111],[115] and de Meijere and co-workers.[104],[108]–[110] In this proposal,[62],[74],[76],[102],[105],[111],[115] oxidative addition of aryl halide to Pd(0) is followed by alkene insertion to give pallada(II)cyclic Pd(C6H3Y—C7H10-C,C )(PPh3)2, followed by oxidative addition of aryl halide to give the putative palladium(IV) complex PdBr(C6H4Y)(C6H3Y—C7H10-C,C )(PPh3)2 and subsequent reductive elimination by C—C bond formation. Subsequent cyclization at Pd(II) and reductive elimination generates the products and Pd(0). The potential role of Pd(IV) is modeled by the formation of 27 (formed by oxidative addition of MeI) and its decomposition to form 28.[62],[74] A similar model sequence has been demonstrated for p-nitrobenzyl bromide.[76] There has been extensive discussion of the possible role of Pd(IV) in Heck and related reactions catalyzed by Pd(II) intramolecular coordination complexes such as 36–38.[118],[134]–[139],[180],[191],[192] The proposals for Pd(IV) involvement require oxidative addition by aryl halides. Opinion is currently divided on whether Pd(IV) is involved and,
200
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
R + 2R
Br
[Pd]
R
+
R
R
O2CMe
O2CMe
Pd P (o-tol)2
Pd 2
Pri2P
Pd
PPri2
O
N
2
O2CCF3 36
37
38
Scheme 9
as noted by Herrmann in particular,[135] further research is needed to resolve whether a Pd(0)–Pd(II) or Pd(II)–Pd(IV) pathway occurs. Systems for which Pd(II)–Pd(IV) cycles are consistent with model reactions involve alkyl halide oxidative addition or oxidation by strong inorganic oxidants. Thus, the reaction of Scheme 10 may be explained by a process very similar to that for Scheme 9 but involving alkyl halide (R I) addition modeled by formation of 27 and its decomposition to 28, cyclization and repetition of this process, and subsequent elimination of norbornene.[114] In this proposal the sequence for the alkylation of the ortho positions of the aryl group in the intermediate “Pd(C6H4—C7H10-C,C )L,2,” involving Pd(IV),[118],[134 ]–139],[180],[191],[192] is similar to that proposed for the exchange of ortho hydrogen atoms of Pd(C6H5—C7H10-C,C )(NMe2CH2CH2N(Me)CH2CH2NMe2-N,N ) with protons of the solvent where,[49] in the latter case, the electrophile is H rather than Alk.
R′ R
I + 2 R′I + H2C CHR′′
[Pd]
CH
R
CHR′′
R′ Scheme 10
The reaction of Scheme 11 is validated for RX Br2 by the NMR detection of all four species in the proposed cycle[55] and illustrates again a system where aryl halide involvement is readily explained in the same way but with the severe reservations expressed above for other systems. Facile cyclopalladation of azobenzene, oxidation of Pd(II) by chlorine (e.g., formation of 16), and reductive elimination via C—Cl coupling
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
E E E
N E
E
Ar II N Pd
Ar R
N IV Pd
E
RX
201
E
X E
Ar
N Ar
40
39
2E
C
C
E SnMe4
E
E
R Me E
E
E
E
R
Ar II N Pd
E
E 41
Me
N Ar
RX = Br2 (40 detected); E = CO2Me; catalysis also occurs for RX = BnBr, MeI, PhI Scheme 11
(e.g., decomposition of 16) provide support for the proposal that Pd(IV) intermediates occur in the chlorination of azobenzene by PdCl2/Cl2 to form 2,6,2 ,6 -polychloroazobenzenes.[160] In the reactions of Schemes 10 and 11, and in chlorination of azobenzene, electrophilic attack at Pd(II) is assumed to occur, leading to Pd(IV), but these syntheses and the proposals shown in Scheme 12,[41] Scheme 13,[123],[124] and Scheme 14[127] illustrate typical dilemmas in assignment of mechanism, generally recognized by the authors of these proposals. Thus, electrophilic attack at Pd(II) [43:44, 47:48 giving Pd(IV)] or at carbon [43:45, 47:49, remaining as Pd(II) may give rise to acetanilides (42:46) or indoles (47:50); and C—H oxidative addition [52:53 giving Pd(IV)] or cyclopalladation [52:54 involving Pd(II)] may occur to give indenones (55). Cyclopalladation (42:43) is generally believed to occur via electrophilic attack by Pd(II) without involvement of Pd(IV) intermediates,[193],[194] although in view of a recent report on cyclometallation at Rh(I),[195] direct deprotonation from an agostically bonded arene ring cannot be discounted. Both experimental[196] and theoretical studies[197] indicate that, for platinum, formation of the stable Pt(II) arenonium species 58 (Scheme 15) most likely occurs via a Pt(IV) intermediate (57), suggestive of Pd(IV) involvement in the synthesis of orthosubstituted acetanilides but modified to give the sequence 42:43:44:45:46 (Scheme 12). The subtleties of electrophilic attack at metal or carbon atoms in M—C bonds for d8 metal centers, and the reverse reaction, relevant to Schemes 12–15, have been reviewed recently.[194],[195] In addition to consideration of whether electrophiles interact with Pd or C atoms in Pd—C bonds, -bond metathesis (interaction of reagent X—Y across a Pd—C bond) may be appropriate for some systems.
202
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
R Pd
HN
IV
O Me 44 Pd(O2CMe)2
HN
II O2CMe Pd
HN
O
O
RX
42
+ PdII
O
2
Me
Me
Me
R
HN
OR
43
46
+ R II Pd
HN O Me 45
Scheme 12
R [Pd]
R N H
NH2
PdIVHCl2
via
R N H 48
PdIICl2− R
H+
Cl−
OR
R + Pd IICl3−
N H
N H
47
50 H
PdIICl2− R N+ H
49 Scheme 13
203
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
O CHO
[Pd]
+
R
R
R
Br R O PdIVHBr R R CHO
R
CHO
R
−PdIIHBr
53 PdIIBr
O R
OR
PdIIBr R 51
R
−HBr
R
−Pd0
O
55
52 PdII R R 54
Scheme 14
+ Me 2 N II Pt Ar
Me 2 N Me IV Pt Ar
MeI −I−
N Me 2 56
Me 2 N Me +
Pt
N Me 2 57
II
Ar
N Me 2 58
Scheme 15
A range of cyclization and cycloisomerization reactions of enynes, including enynes with heteroatoms in the skeleton, have been reported for which the possibility of Pd(IV) intermediates has been canvassed.[117],[130],[131],[162]–[175] A typical example is shown in Scheme 16, where supporting ligands at palladium include palladacyclopentadienes, acetate, acetate/PPh3, and acetate/P(o-tol)3. An alternative pathway involving a Pd(0)–Pd(II) cycle has been acknowledged (Scheme 16), and different reaction conditions may favor each pathway.[166],[167],[172],[175] Alkylidene complexes as intermediates have also been proposed for some reactions of enynes.[131],[165],[170] There is support for the occurrence of Pd(IV) species in the acetoxylation of arenes,[158],[159] with the most recent proposal shown in Scheme 17, consistent with demonstrated palladation of benzene, for example, by Pd(O2CMe)2/SEt2 to form
204
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
IV Pd −PdII
PdII
60 and/or PdII–H
OR
59 II Pd
II Pd
−PdIIH
61
63
64
62 Scheme 16
{PdPh(SEt2)(-O2CMe)2}2Pd.[198] In related reactions, formation of alcohols and ethers in the presence of MoO(O2)2 HMPT H2O is proposed to occur via cyclopalladation, oxidation by Mo(VI), and C—O bond formation involving an oxygen atom of the molybdenum species or methoxide from the methanol solvent.[51] (1 − n )+
Pd(O2CMe)2
PdII(O2CMe)n
MeCO2H
I(O2CMe)2Ph
(3 − m )+
PdIV(O
O2CMe + PdII
2CMe)m
Scheme 17
The synthesis of 11 (Scheme 3)[29],[30] and the related complex Pd{1,2-(H2Si)2C6H4Si,Si}2(dmpe-P,P ),[199] both of which have been examined by X-ray diffraction, are relevant to the potential role of Pd(IV) in silane chemistry,[29],[30],[181],[182],[199] and to the role of phosphine ligands in Pd(IV) catalysis. For example, 11 (R H) is formed in the reaction shown in Scheme 3, and reactions of this type can be assumed to occur in the catalytic formation of {SiMe2(CH2)3SiMe2}n from (SiMe2CH2)2CH2 catalyzed by PdCp(3-C3H5) or 11 (Scheme 18).[29],[182]
F. CONCLUDING REMARKS Oxidation state 4 is well established as a key oxidation state in the organometallic chemistry of palladium, but there are few reports of Pd(I) chemistry except for polyhalogenophenyl derivatives, and scanty evidence for Pd(III) chemistry. Catalysis involving palladium complexes is dominated by Pd(0) and Pd(II) species, with evidence for Pd(I)
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
205
PdII
Me2Si
SiMe2
Me2Si
PdIV
PdII Me2 Si Me2Si
Si Me2
Me2Si
Me2 Me2 Si Si
IV
PdII n
Me2Si
Me2 Si
Me2 Me2 Si Si
Me2Si
Pd
SiMe2
Me2 Me2 Si Si
Si Me2
Scheme 18
involvement in a few systems. There are several catalysis and organic synthesis procedures for which proposals of Pd(IV) intermediates are supported by studies of model reactions, and isolated or spectroscopically detectable complexes, in particular those involving reactions in the presence of strong inorganic oxidants and organosilicon chemistry. Organic syntheses involving alkyl halide oxidative addition to Pd(II) appear to be feasible and, in addition, there are a range of reactions for which Pd(IV) intermediacy is enticing but as yet not supported by model reactions. This group of reactions include elegant syntheses involving enynes and aryl halide reagents.
REFERENCES [1]
[2] [3]
[4] [5] [6]
P. M. Maitlis, P. Espinet, and M. J. H. Russell, in Comprehensive Organometallic Chemistry., G. Wilkinson, F. G. A. Stone, and E. W. Abel, Eds., Pergamon, New York, 1982, Vol. 6, Chap. 38.3, 265–278. T. Tanase, T. Nomura, Y. Yamamoto, and K. Kobayashi, J. Organomet. Chem., 1991, 410, C26. J. A. Davies, in Comprehensive Organometallic Chemistry II, E. W. Abel, F. G. A. Stone, and G. Wilkinson, Eds. (R. J. Puddephatt, Vol. 9, Ed.), Pergamon, Oxford, UK, 1995, Vol. 9, Chap. 6, 291–390. T. Murahashi, N. Kanehisa, Y. Kai, T. Otani, and H. Kurosawa, Chem. Commun., 1996, 825. A. Behr, G. v. Ilsemann, W. Keim, C. Krüger, and Y.-H. Tsay, Organometallics, 1986, 5, 514. K. Osakada, T. Chiba, Y. Nakamura, T. Yamamoto, and A. Yamamoto, Organometallics, 1989, 8, 2602.
206 [7] [8] [9] [10] [11] [12]
[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41]
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
J. Sieler, M. Helms, W. Gaube, A. Svensson, and O. Lindqvist, J. Organomet. Chem., 1987, 320, 129. P. W. Jolly, C. Krüger, K.-P. Schick, and G. Wilke, Z. Naturforsch., 1980, 35B, 926. K. Broadley, N. G. Connelly, G. A. Lane, and W. E. Geiger, J. Chem. Soc. Dalton Trans., 1986, 373. G. A. Lane, W. E. Geiger, and N. G. Connelly, J. Am. Chem. Soc., 1987, 109, 402. J. A. DeGray, W. E. Geiger, G. A. Lane, and P. H. Rieger, Inorg. Chem., 1991, 30, 4101. A. J. Canty, in Comprehensive Organometallic Chemistry II, E. W. Abel, F. G. A. Stone, and G. Wilkinson, Eds. (R. J. Puddephatt, Vol. 9, Ed.), Pergamon, Oxford, UK, 1995, Vol. 9, Chap. 5, 225–290. R. van Asselt, C. J. Elsevier, C. Amatore, and A. Jutand, Organometallics, 1997, 16, 317. C. Amatore, E. Carré, and A. Jutand, Acta Chem. Scand., 1998, 52, 100. S. J. Young, B. Kellenberger, J. H. R. Reibenspies, S. E. Himmel, M. Manning, O. P. Anderson and J. K. Stille, J. Am. Chem. Soc., 1988, 110, 5744. J. Forniés, F. Martinez, R. Navarro, A. Redondo, M. Tomas, and A. J. Welch, J. Organomet. Chem., 1986, 316, 351. R. Uson and J. Forniés, Adv. Organomet. Chem., 1988, 28, 219–297. E. R. Milaeva, A. Z. Rubezhov, A. I. Prokof’ev, and O. Y. Okhlobystin, J. Organomet. Chem., 1980, 193, 135. A. Jouati, M. Geoffroy, G. Terron, and G. Bernardinelli, J. Chem. Soc. Chem. Commun., 1992, 155. A. M. Bond, A. J. Canty, J. B. Cooper, V. Tedesco, P. R. Traill, and D. M. Way, Inorg. Chim. Acta, 1996, 251, 185. R. Uson, J. Forniés, and R. J. Navarro, J. Organomet. Chem., 1975, 96, 307. R. Uson, J. Forniés, and R. J. Navarro, Synth. React. Met.-Org. Chem., 1977, 7, 235. P. K. Byers, A. J. Canty, B. W. Skelton, and A. H. White, J. Chem. Soc. Chem. Commun., 1986, 1722. P. K. Byers, A. J. Canty, B. W. Skelton, and A. H. White, Organometallics, 1990, 9, 826. A. J. Canty, Acc. Chem. Res., 1992, 25, 83–90. A. J. Canty, Platinum Metals Rev., 1993, 36, 2–7. A. J. Canty, P. R. Traill, B. W. Skelton, and A. H. White, J. Organomet. Chem., 1992, 433, 213. W. Klaüi, M. Glaum, T. Wagner, and M. A. Bennett, J. Organomet. Chem., 1994, 472, 355. M. Suginome and Y. Ito, J. Chem. Soc. Dalton Trans., 1998, 1925–1934. M. Suginome, Y. Kato, N. Takeda, H. Oike, and Y. Ito, Organometallics, 1998, 17, 495. P. K. Wong and J. K. Stille, J. Organomet. Chem., 1974, 70, 121. J. K. Stille and K. S. Y. Lau, J. Am. Chem. Soc., 1976, 98, 5841. T. Ito, H. Tsuchiya, and A. Yamamoto, Bull. Chem. Soc. Jpn., 1977, 50, 1319. A. Gillie and J. K. Stille, J. Am. Chem. Soc., 1980, 102, 4933. M. K. Loar and J. K. Stille, J. Am. Chem. Soc., 1981, 103, 4174. A. Moravskiy and J. K. Stille, J. Am. Chem. Soc., 1981, 103, 4182. R. A. Holton and K. J. Natalie, Tetrahedron Lett., 1981, 22, 267. H. M. McPherson and J. L. Wardell, Inorg. Chim. Acta, 1983, 75, 37. H. Kurosawa, M. Emoto, and A. Urabe, J. Chem. Soc. Chem. Commun., 1984, 968. H. D. McPherson and J. L. Wardell, Inorg. Chim. Acta, 1984, 81, 39. S. J. Tremont and H. U. Rahman, J. Am. Chem. Soc., 1984, 106, 5759.
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
[42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72]
207
P. Diversi, D. Fasce, and R. Santini, J. Organomet. Chem., 1984, 269, 285. C. Cornioley-Deuschel and A. von Zelewsky, Inorg. Chem., 1987, 26, 3354. R. P. Thummel and Y. Jahng, J. Org. Chem., 1987, 52, 73. F. Maassarani, M. Pfeffer, G. Le Borgne, J. T. B. H. Jastrzebski, and G. van Koten, Organometallics, 1987, 6, 1111. W. de Graaf, S. Harder, J. Boersma, G. van Koten, and J. A. Kanters, J. Organomet. Chem., 1988, 358, 545. A. Albinati, S. Affolter, and P. S. Pregosin, J. Organomet. Chem., 1990, 395, 231. K.-C. Kong and C.-H. Cheng, J. Am. Chem. Soc., 1991, 113, 6313. B. A. Markies, P. Wijkens, H. Kooijman, A. L. Spek, J. Boersma, and G. van Koten, J. Chem. Soc. Chem. Commun., 1992, 1420. H. Nakazawa, Y. Matsuoka, I. Nakagawa, and K. Miyoshi, Organometallics, 1992, 11, 1385. P. L. Alsters, J. Boersma, and G. van Koten, Organometallics, 1993, 12, 1629. S. Strömberg, M. Oksman, L. Zhang, and K. Zetterberg, Acta Chem. Scand., 1995, 49, 689. R. McCrindle, G. Ferguson, A. J. McAlees, G. J. Arsenault, A. Gupta, and M. C. Jennings, Organometallics, 1995, 14, 2741. J.-M. Valk, J. Boersma, and G. van Koten, Organometallics, 1996, 15, 4366. R. van Belzen, H. Hoffmann, and C. J. Elsevier, Angew. Chem. Int. Ed. Engl., 1997, 36, 1743. J. Cámpora, C. Graiff, P. Palma, E. Carmona, and A. Tiripiccio, Inorg. Chim. Acta, 1998, 269, 191. R. van Belzen, R. A. Klein, H. Kooijman, N. Veldman, A. L. Spek, and C. J. Elsevier, Organometallics, 1998, 17, 1812. J. Cámpora, J. A. Lopez, P. Palma, P. Valerga, E. Spillner, and E. Carmona, Angew. Chem. Int. Ed. Engl., 1999, 38, 147. K. Kamaraj and D. Bandyopadhyay, Organometallics, 1999, 18, 438. P. K. Byers, A. J. Canty, B. W. Skelton, and A. H. White, J. Chem. Soc. Chem. Commun., 1987, 1093. A. J. Canty and P. K. Byers, J. Chem. Soc. Chem. Commun., 1988, 639. M. Catellani and G. P. Chiusoli, J. Organomet. Chem., 1988, 346, C27. P. K. Byers, A. J. Canty, M. Crespo, R. J. Puddephatt, and J. D. Scott, Organometallics, 1988, 7, 1363. K.-T. Aye, A. J. Canty, M. Crespo, R. J. Puddephatt, J. D. Scott, and A. A. Watson, Organometallics, 1989, 8, 1518. W. de Graaf, J. Boersma, W. J. J. Smeets, A. L. Spek, and G. van Koten, Organometallics, 1989, 8, 2907. P. K. Byers, A. J. Canty, R. T. Honeyman, and A. A. Watson, J. Organomet. Chem., 1990, 385, 429. M. Catellani and B. E. Mann, J. Organomet. Chem., 1990, 390, 251. P. K. Byers, A. J. Canty, P. R. Traill, and A. A. Watson, J. Organomet. Chem., 1990, 390, 399. D. G. Brown, P. K. Byers, and A. J. Canty, Organometallics, 1990, 9, 1231. W. de Graaf, J. Boersma, and G. van Koten, Organometallics, 1990, 9, 1479. P. K. Byers, A. J. Canty, B. W. Skelton, P. R. Traill, A. A. Watson, and A. H. White, Organometallics, 1990, 9, 3080. P. K. Byers, A. J. Canty, R. T. Honeyman, B. W. Skelton, and A. H. White, J. Organomet. Chem., 1992, 433, 223.
208 [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106]
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
P. K. Byers, A. J. Canty, B. W. Skelton, P. R. Traill, A. A. Watson, and A. H. White, Organometallics, 1992, 11, 3085. M. Catellani and G. P. Chiusoli, Gazz. Chim. Ital., 1993, 123, 1–7. M. A. Bennett, A. J. Canty, J. K. Felixberger, L. M. Rendina, C. Sutherland, and A. C. Willis, Inorg. Chem., 1993, 32, 1951. G. Bocelli, M. Catellani, and S. Ghelli, J. Organomet. Chem., 1993, 458, C12. P. L. Alsters, P. F. Engel, M. P. Hogerheide, M. Copijn, A. L. Spek, and G. van Koten, Organometallics, 1993, 12, 1831. D. J. Cárdenas, C. Mateo, and A. M. Echavarren, Angew. Chem. Int. Ed. Engl., 1994, 33, 2445. R. van Asselt, E. Rijnberg, and C. J. Elsevier, Organometallics, 1994, 13, 706. B. A. Markies, A. J. Canty, J. Boersma, and G. van Koten, Organometallics, 1994, 13, 2053. C. Dücker-Benfer, R. van Eldik, and A. J. Canty, Organometallics, 1994, 13, 2412. A. J. Canty, H. Jin, A. S. Roberts, B. W. Skelton, P. R. Traill, and A. H. White, Organometallics, 1995, 14, 199. G.-X. Liu and R. J. Puddephatt, Inorg. Chim. Acta, 1996, 251, 319. A. J. Canty, H. Jin, A. S. Roberts, B. W. Skelton, and A. H. White, Organometallics, 1996, 15, 5713. D. Kruis, B. A. Markies, A. J. Canty, J. Boersma, and G. van Koten, J. Organomet. Chem., 1997, 532, 235. A. J. Canty, J. L. Hoare, N. W. Davies, and P. R. Traill, Organometallics, 1998, 17, 2046. A. J. Canty, A. Dedieu, H. Jin, A. Milet, B. W. Skelton, and A. H. White, Inorg. Chim. Acta, 1999, 287, 27. A. J. Canty, H. Jin, and J. Penny, J. Organomet. Chem., 1999, 573, 30. A. J. Canty, J. L. Hoare, J. Patel, M. Pfeffer, B. W. Skelton, and A. H. White, Organometallics, 1999, 18, 2660. N. J. Hovestad, J. L. Hoare, J. T. B. H. Jastrzebski, A. J. Canty, W. J. J. Smeets, A. L. Spek, and G. van Koten, Organometallics, 1999, 18, 2970. A. J. Canty, H. Jin, B. W. Skelton, and A. H. White, Inorg. Chem., 1998, 37, 3975. A. J. Canty and H. Jin, J. Organomet. Chem., 1998, 565, 135. A. Milet, A. Dedieu, and A. J. Canty, Organometallics, 1997, 16, 5331. E. L. Weinberg, B. K. Hunter, and M. C. Baird, J. Organomet. Chem., 1982, 240, 95. B. A. Markies, A. J. Canty, M. D. Janssen, A. L. Spek, J. Boersma, and G. van Koten, Recl. Trav. Chim. Pays-Bas, 1991, 110, 447. A. J. Canty and P. R. Traill, J. Organomet. Chem., 1992, 435, C8. A. J. Canty, P. R. Traill, R. Colton, and I. M. Thomas, Inorg. Chim. Acta, 1993, 210, 91. A. J. Canty, A. A. Watson, B. W. Skelton, and A. H. White, J. Organomet. Chem., 1989, 367, C25. I. I. Moiseev and M. N. Vargaftik, New J. Chem., 1998, 22, 1217. F. Ozawa, M. Fujimori, T. Yamamoto, and A. Yamamoto, Organometallics, 1986, 5, 2144. M. Catellani, G. P. Chiusoli, S. Ricotti, and F. Sabini, Gazz. Chim. Ital., 1985, 115, 685. M. Catellani and G. P. Chiusoli, J. Organomet. Chem., 1985, 286, C13. M. Catellani G. P. Chiusoli, and S. Ricotti, J. Organomet. Chem., 1985, 296, C11. O. Reiser, M. Weber, and A. de Meijere, Angew. Chem. Int. Ed. Engl., 1989, 28, 1037. M. Catellani, G. P. Chiusoli, and M. Costa, Pure Appl. Chem., 1990, 62, 623. M. Catellani, G. P. Chiusoli, and C. Castagnoli, J. Organomet. Chem., 1991, 407, C30.
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
[107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145]
209
M. Catellani and M. C. Fagnola, Gazz. Chim. Ital., 1992, 122, 481. K. Albrecht, O. Reiser, M. Weber, and A. de Meijere, Synlett, 1992, 521. A. de Meijere, and F. E. Meyer, Angew. Chem. Int. Ed. Engl., 1994, 33, 2379–2411. K. Albrecht, O. Reiser, M. Weber, B. Knieriem, and A. de Meijere, Tetrahedron, 1994, 50, 383. M. Catellani, G. P. Chiusoli, and M. Costa, J. Organomet. Chem., 1995, 500, 69. M. Catellani and L. Ferioli, Synthesis, 1996, 769. M. Catellani and E. Motti, New J. Chem., 1988, 759. M. Catellani and M. C. Fagnola, Angew. Chem. Int. Ed. Engl., 1994, 33, 2421. M. Catellani, F. Frignani, and A. Rangoni, Angew. Chem. Int. Ed. Engl., 1997, 36, 119. G. Dyker, Angew. Chem. Int. Ed. Engl., 1992, 31, 1023. G. Dyker, Chem. Ber./Recueil, 1997, 130, 1567–1578. G. Dyker and A. Kellner, J. Organomet. Chem., 1998, 555, 141. G. Dyker, J. Org. Chem., 1993, 58, 234. G. Dyker, Chem. Ber., 1994, 127, 739. G. Dyker, Angew. Chem. Int. Ed. Engl., 1994, 33, 103. G. Dyker, J. Org. Chem., 1993, 58, 6426. D. E. Rudisill and J. K. Stille, J. Org. Chem., 1989, 54, 5856. S. Cacchi, V. Carnicelli, and F. Marinelli, J. Organomet. Chem., 1994, 475, 289. J. S. McCallum, J. R. Gasdaska, and L. S. Liebeskind, Tetrahedron Lett., 1989, 30, 4085. T. Satoh, T. Itaya, M. Miura, and M. Nomura, Chem. Lett., 1996, 823. R. C. Larock, M. J. Doty, and S. Cacchi, J. Org. Chem., 1993, 58, 4579. D. Brown, R. Grigg, V. Sridharan, and V. Tambyrajah, Tetrahedron Lett., 1995, 36, 8137. R. Grigg, V. Loganathan, and V. Sridharan, Tetrahedron Lett., 1996, 37, 3399. B. M. Trost and S.-F. Chen, J. Am. Chem. Soc., 1986, 108, 6053. B. M. Trost and A. S. K. Hashmi, J. Am. Chem. Soc., 1994, 116, 2183. H. Alper and M. Saldana-Maldonada, Organometallics, 1989, 8, 1124. J. Krause, K.-J. Haack, K.-R. Pörschke, B. Gabor, R. Goddard, C. Pluta, and K. Seevogel, J. Am. Chem. Soc., 1996, 118, 804. W. A. Hermann, C. Brossmer, K. Öfele, C-P. Reisinger, T. Priermeier, M. Beller, and H. Fischer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1844. W. A. Herrmann, C. Brossmer, C.-P. Reisinger, T. H. Riermeier, K. Öfele, and M. Beller, Chem. Eur. J., 1997, 3, 1357. M. Ohff, A. Ohff, M. E. van der Boom, and D. Milstein, J. Am. Chem. Soc., 1997, 119, 11687. B. L. Shaw, S. D. Perera, and E. A. Staley, Chem. Commun., 1998, 1361. B. L. Shaw and S. D. Perera, Chem. Commun., 1998, 1863. G. T. Crisp, Chem. Soc. Rev., 1998, 27, 427. B. L. Shaw, New J. Chem., 1998, 77. M. Beller, H. Fischer, W. A. Herrmann, K. Öfele, and C. Brossmer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1848. W. A. Herrmann, C.-P. Reisinger, K. Öfele, C. Brossmer, M. Beller, and H. Fischer, J. Mol. Catal.(A), 1996, 108, 51. K. Albrecht and A. de Meijere, Chem. Ber., 1994, 127, 2539. S. K. Meegalla, N. J. Taylor, and R. Rodrigo, J. Org. Chem., 1992, 57, 2422. N. R. Davies, Aust. J. Chem., 1964, 17, 212.
210 [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184]
II PALLADIUM COMPOUNDS: STOICHIOMETRIC PREPARATION
J. F. Harrod and A. J. Chalk, J. Am. Chem. Soc., 1966, 88, 3491. F. T. T. Ng and P. M. Henry, J. Org. Chem., 1973, 38, 3338. B. M. Trost, P. E. Strege, L. Weber, T. J. Fullerton, and T. J. Dietsche, J. Am. Chem. Soc., 1978, 100, 3407. A. D. Ryabov, A. V. Eliseev, and A. K. Yatsimirsky, Appl. Organomet. Chem., 1988, 2, 101. J. W. Francis and P. M. Henry, Organometallics, 1991, 10, 3498. A. D. Ketley, L. P. Fisher, A. J. Berlin, C. R. Morgan, E. H. Gorman, and T. R. Steadman, Inorg. Chem., 1967, 6, 657. G. Oehme and H. Pracejus, J. Prakt. Chem., 1980, 322, 798. I. Guibert, D. Neibecker, and I. Tkatchenko, J. Chem. Soc. Chem. Commun., 1989, 1850. A. S. K. Hashmi, Angew. Chem. Int. Ed. Engl., 1995, 34, 1581. A. S. K. Hashmi, T. L. Ruppert, T. Knöfel, and J. W. Bats, J. Org. Chem., 1997, 62, 7295. H. tom Dieck, C. Müller, E. T. K. Haupt, and D. Bolze-Kuhrt, Z. Naturforsch., 1987, 42B, 853. C. Stephan, C. Munz, and H. tom Dieck, J. Organomet. Chem., 1993, 452, 233. L. M. Stock, K.-W. Tse, L. J. Vorvick, and S. A. Walstrum, J. Org. Chem., 1981, 46, 1757. T. Yoneyama and R. H. Crabtree, J. Mol. Catal.(A), 1996, 108, 35. D. R. Fahey, J. Organomet. Chem., 1971, 27, 283. N. Kamigata, M. Satoh, and M. Yoshida, J. Organomet. Chem., 1991, 401, C26. B. M. Trost and M. Lautens, J. Am. Chem. Soc., 1985, 107, 1781. B. M. Trost and M. Lautens, Tetrahedron Lett., 1985, 26, 4887. B. M. Trost and G. J. Tanoury, J. Am. Chem. Soc., 1987, 109, 4753. B. M. Trost and G. J. Tanoury, J. Am. Chem. Soc., 1988, 110, 1636. B. M. Trost, Acc. Chem. Res., 1990, 23, 34. B. M. Trost, M. Lautens, C. Chan, D. J. Jebaratnam, and T. Mueller, J. Am. Chem. Soc., 1991, 113, 636. B. M. Trost and M. K. Trost, Tetrahedron Lett., 1991, 32, 3647. B. M. Trost and C. Pedregal, J. Am. Chem. Soc., 1992, 114, 7292. B. M. Trost and A. S. K. Hashmi, Angew. Chem. Int. Ed. Engl., 1993, 32, 1085. B. M. Trost, G. J. Tanoury, M. Lautens, C. Chan, and D. T. MacPherson, J. Am. Chem. Soc., 1994, 116, 4255. B. M. Trost, D. L. Romero, and F. Rise, J. Am. Chem. Soc., 1994, 116, 4268. J. Castro, G. Balme, and J. Goré, J. Chem. Res.(S), 1995, 504. H. Yamada, S. Aoyagi, and C. Kibayashi, J. Am. Chem. Soc., 1996, 118, 1054. B. M. Trost and M. J. Krische, Synlett, 1998, 1. B. M. Trost and A. S. K. Hashmi, J. Am. Chem. Soc., 1987, 109, 3486. B. M. Trost, M. T. Sorun, C. Chan, A. E. Harms, and G. Rühter, J. Am. Chem. Soc., 1997, 119, 698. A. Bonardi, M. Costa, B. Gabriele, G. Salerno, and G. P. Chiusoli, J. Chem. Soc. Chem. Commun., 1994, 2429. J. Yang, A. Haynes, and P. M. Maitlis, J. Chem. Soc. Chem. Commun., 1999, 179. F.-T. Luo, A. Jeevanandam, and M. K. Basu, Tetrahedron Lett., 1998, 39, 7939. A. Naka, T. Okada, and M. Ishikawa, J. Organomet. Chem., 1996, 521, 163. Y. Uchimaru and M. Tanaka, J. Organomet. Chem., 1996, 521, 335. F. Ozawa, T. Ito, Y. Nakamura, and A. Yamamoto, Bull. Chem. Soc. Jpn., 1981, 54, 1868. F. Ozawa, K. Kurihara, T. Yamamoto, and A. Yamamoto, J. Organomet. Chem., 1985, 279, 233.
II.4 PALLADIUM COMPLEXES CONTAINING Pd(I), Pd(III), OR Pd(IV)
[185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199]
211
D. A. Widdowson and Y.-Z. Zhang, Tetrahedron, 1986, 42, 2111. F. Ozawa, T. Hidaka, T. Yamamoto, and A. Yamamoto, J. Organomet. Chem., 1987, 330, 253. F. Ozawa, K. Kurihara, M. Fujimori, T. Hidaka, T. Toyoshima, and A. Yamamoto, Organometallics, 1989, 8, 180. R. van Asselt and C. J. Elsevier, Organometallics, 1994, 13, 1972. N. Bumagin, A. B. Ponomarev, and I. P. Beletskaya, J. Org. Chem. USSR, 1987, 23, 1215. H. Nakazawa, F. Ozawa, and A. Yamamoto, Organometallics, 1983, 2, 241. J. Louie and J. F. Hartwig, Angew. Chem. Int. Ed. Engl., 1996, 35, 2359 M. Ohff, A. Ohff, and D. Milstein, J. Chem. Soc. Chem. Commun., 1999, 357. A. D. Ryabov, Chem. Rev., 1990, 90, 403. A. J. Canty and G. van Koten, Acc. Chem. Res., 1995, 28, 406. A. Vigalok, O. Uzan, L. J. W. Shimon, Y. Ben-David, J. M. L. Martin, and D. Milstein, J. Am. Chem. Soc., 1998, 120, 12539. J. Terheijden, G. van Koten, I. C. Vinke, and A. L. Spek, J. Am. Chem. Soc., 1985, 107, 2891. J. V. Ortiz, Z. Havlas, and R. Hoffmann, Helv. Chim. Acta, 1984, 67, 1. Y. Fuchita, K. Hiraki, Y. Kamogawa, M. Suenaga, K. Tohgoh, and Y. Fujiwara, Bull. Chem. Soc. Jpn., 1989, 62, 1081. S. Shimada, M. Tanaka, and M. Shiro, Angew. Chem. Int. Ed. Engl., 1996, 35, 1856.
PART III Palladium-Catalyzed Reactions Involving Reductive Elimination
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
R1M + R2X
III.1
Pd
R1R2
Background for Part III
EI-ICHI NEGISHI
A. DEFINITION OF Pd-CATALYZED CROSS-COUPLING As discussed in Sect. I.2, reductive elimination is one of only a few to several basic patterns permitting the formation of various types of single bonds in organic compounds including C—C, C—H, C—X, where X is N, O, or a related heteroatom, and even bonds between two heteroatoms. Reductive elimination is thought to be an important microstep in Pd-catalyzed cross-coupling. In this Part, these Pd-catalyzed cross-coupling reactions leading to the formation of C—C (Sect. III.2), C—H (Sect. III.3.1), C—N and C—O (Sects. III.3.2 and III.3.3), as well as C—M (Sect. III.3.4) bonds are discussed. It should be noted, however, that reductive elimination occurs in many other types of Pd-catalyzed reactions as well, and it is discussed throughout this Handbook. Thus, for example, the Heck reaction (Part IV) must involve regeneration or Pd(0) complexes via reductive elimination of H(X)Pd(II) complexes, and a similar reduction of Pd(II) species must occur in the Tsuji – Trost reaction (Part V). Reductive elimination is also a critical step in the generation of organic acyl derivatives from acylpalladium intermediates with concomitant two-electron reduction of Pd(II) complexes (Part VI), while it is well accepted that reductive elimination to form the C—H bond is the product-forming step in various Pd-catalyzed hydrogenations (Part VII). So, the scope of reductive elimination of Pd(II) complexes is far wider than that in Pd-catalyzed cross-coupling. With this understanding, however, our attention in this Part will be focused on Pd-catalyzed cross-coupling leading to the formation of C—C, C—H, C—N, C—O, and C—M bonds within the context of cross-coupling. Cross-coupling between organometals (R1M) and organic electrophiles (R2X) is undoubtedly one of the most straightforward methods for the formation of carbon – carbon bonds (Scheme 1). As discussed in Sect. I.1, the use of Grignard reagents and organolithiums without involving any transition metal catalysts was first introduced many decades ago. Both stoichiometric and catalytic use of Cu[1],[2] revolutionized the art of crosscoupling mainly during the 1960s and 1970s. Most notably, organic electrophiles containing Csp2—X and Csp—X bonds became usable and useful in cross-coupling. Over the past three decades Ni- and Pd-catalyzed cross-coupling, the latter in particular, has substantially improved and expanded the cross-coupling methodology. The historical evolution of Pd-catalyzed cross-coupling is discussed in Sect. I.1, and many reviews are available on this topic.[3]–[17] The narrow definition of cross-coupling presented above may be
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
215
216
III Pd-CATALYZED CROSS-COUPLING
expanded so as to include H, N, O, and other heteroatom groups, as well as metals and metal-containing groups in R1 or R2 in Scheme 1. The relationships between the cross-coupling reaction shown in Scheme 1 and some other related reactions should briefly be discussed here. Whether or not one should consider those Pd-catalyzed reactions in which M is H in Scheme 1, such as the Heck reaction with alkenes and the Sonogashira reaction with alkynes, as cross-coupling reactions is largely a matter of semantics or a personal preference. For mainly historical and practical as well as somewhat vague mechanistic and other chemical reasons, the Heck alkene hydrogen substitution reaction is discussed mostly in Part IV as a representative carbopalladation reaction. On the other hand, the Sonogashira and related Heck-type alkyne hydrogen substitution reactions are discussed in this section in part because ammonium or copper acetylides are considered to serve as R1M in these reactions. In contrast, no such species derived from alkenes are considered for the Heck alkene substitution. It should, however, be noted that, even if discrete acetylide anions are involved as actual reactive species in the alkyne substitution, they may still undergo the Heck-type non-redox addition–elimination process suggested as early as 1978[3] (Scheme 2). Furthermore, it is not unreasonable to consider some of the more genuine cross-coupling reactions, such as the reaction of preformed alkynylmetals with organic halides (Sect. III.2.8.2) and the conjugate substitution reaction (Sect. III.2.15) shown in Scheme 2, as non-redox carbometallation–elimination reactions. Irrespective of their mechanistic details, however, these are genuine examples of Pd-catalyzed cross-coupling reactions discussed in this Part.
R1M + R2X
cat. PdLn
R1
R2 + MX
Scheme 1
cat. PdLn
R1C CM (or H) + R2X R1 XLnPd
R1C CM (or H) + R2PdLnX
M (or H) R1C CR2 + M (or H)PdLnX
R2
R1M X2PdLn
C C C O
PdLnX
X
R1PdLnX
R1
C C C O
R1
C C C O + X2PdLn
X Scheme 2
The Tsuji–Trost allylation of enolates can be viewed as a variant of Pd-catalyzed cross-coupling involving allylic electrophiles (Sects. III.2.9 and III.2.10). In recognition of the widely accepted mechanism involving a nucleophilic attack by enolates at the -allyl ligand of an allylpalladium derivative on the side opposite to Pd, however, it is discussed separately in Part V together with the Wacker and related reactions, which are
III.1 BACKGROUND FOR PART III
217
also thought to involve nucleophilic attack on -ligands of Pd -complexes. However, the same mechanistic interpretation cannot be applied to most of the other Pd-catalyzed substitution of enolates and related compounds including -arylation and -alkenylation. These reactions are therefore viewed as Pd-catalyzed cross-coupling reactions and discussed in Sect. III.2.14.1 (Scheme 3). Various Pd-catalyzed carbonylation reactions have often been referred to as carbonylative cross-coupling reactions (Scheme 4). However, these reactions involving the formation of two C—C bonds with incorporation of CO clearly display a pattern of chemical transformation that is different from Scheme 1. So, these reactions are discussed in Parts VI and VIII. On the other hand, Pd-catalyzed acylation with acyl halides and related derivatives are examples of the reaction represented by Scheme 1, where R2 is acyl, and they are therefore discussed in this Part (Sect. III.2.12.1), even if CO may be used to prevent decarbonylation.
X
O C C
cat. PdLn Part V (Sect. V.2)
MO
the Tsuji−Trost reaction
C C O
RX, cat. PdLn Part III (Sect. III.2.14.1)
R C C R = aryl, alkenyl, etc.
Scheme 3
R1M + R2X
R1M + R2COX
CO, cat. PdLn Part VI
CO, cat. PdLn Part III (Sect.III.2.12.1)
R1COR2
R1COR2
Scheme 4
Finally, most Pd-catalyzed hydrogenation reactions are discussed in Part VII. However, Pd-catalyzed hydrogenolysis of organic halides and related electrophiles can be viewed as Pd-catalyzed cross-coupling of organic electrophiles with hydrides. The corresponding reactions of metal-centered nucleophiles have also been developed. Although these reactions are closely related to hydrogenation and related reduction reactions discussed in Part VII, those that are discussed in Part VII generally involve addition of metal–hydrogen and metal–metal bonds to alkenes and alkynes, displaying different patterns of chemical transformation. These two discrete patterns are shown in Scheme 5. As discussed above, distinctions among many closely related reactions and processes are often vague and somewhat arbitrary. Some are based on chemical and mechanistic
218
III Pd-CATALYZED CROSS-COUPLING
cat. PdLn
RX + MH (or MM1Ln)
RH(or RM1Ln) + MX
Part III (Sects. III.3.1 and III.3.4)
C C
+ MH (or MM1Ln)
cat. PdLn Part VII
(M1Ln)H C C M
Scheme 5
reasonings, but many other factors including historical and semantic ones have also been taken into consideration. After all, inasmuch as many Pd-catalyzed reactions involve more than one microstep and are hence multidimensional, some compromises are necessary in any unidimensional arrangement of Pd-catalyzed reactions.
B. OVERVIEW OF Pd-CATALYZED CARBON–CARBON CROSS-COUPLING B.i. General Cross-coupling as defined above is, in general, thermodynamically favorable. In Scheme 1, M and X are typically the most electropositive and most electronegative elements and/or groups, respectively, and the formation of MX as the by-product generally makes the overall process thermodynamically favorable. The discoveries and developments of various cross-coupling reactions have been guided and aided by a simplistic mechanistic hypothesis that the reaction shown in Scheme 1 catalyzed by either Ni or Pd complexes can proceed via (i) oxidative addition, (ii) transmetallation, and (iii) reductive elimination (Scheme 6). As discussed in Sect. III.2.19, the three-step mechanism shown in Scheme 6 is, in most cases, a gross oversimplification. In some cases, the reaction may even involve totally different paths as indicated in Schemes 2 and 3. Despite all these, it is still a useful working hypothesis so long as one is aware that many additional processes involving (i) interconversions between intermediates in the catalytic cycle and the resting states and (ii) other additional interactions, such as complexation including solvation and dissociation, may occur, thereby substantially complicating the overall mechanistic schemes. Furthermore, some of the microsteps may not occur discretely. It is likely, for example, that reductive elimination and oxidative addition may be more tightly coupled than indicated in Scheme 6 so as to make the overall kinetics more favorable. With these in mind, however, the mechanism shown in Scheme 6 will be used as a convenient tool for the discussion of various aspects of Pd-catalyzed cross-coupling. It is also important to fully realize that each microstep, that is, oxidative addition, transmetallation, or reductive elimination, need not be thermodynamically favorable but that each must be kinetically favorable. As in any catalytic processes, the only two crucial requirements are that the overall thermodynamics independent of catalysis be favorable and that each catalytic microstep be kinetically readily accessible. The historical evolution in the discoveries and developments of Pd-catalyzed crosscoupling are presented in Sect. I.1 and will not be repeated here. In this section, several parameters in Scheme 1, that is, M, R1, R2, X, catalysts, added reagents, solvents, and so on, are discussed in a general manner.
III.1 BACKGROUND FOR PART III
R2 MTLnX
R2X (i)
R1M (ii)
MT Ln
(iii) R1
219
R2 MTLn
R1
R2
(i) oxidative addition, (ii) transmetallation, (iii) reductive elimination MT = Pd or Ni. M = metal countercation. R1, R2 = C groups. X = I, Br, Cl, OTf, etc. Scheme 6
B.ii. Metal Countercations (M) Some of the earliest investigations of Pd-catalyzed or Pd-promoted cross-coupling were performed with alkali metals, for example, Na[18] and Li,[19] and Mg.[20] While Mg is still widely used, alkali metals are generally inferior to many other metals for various reasons. In short, organometals containing them are generally of low chemoselectivity. Moreover, their intrinsically high reactivity evidently interferes with Pd catalysis in many cases. Today, they are indeed rarely used, even though organolithiums are widely used as precursors to other organometals. The discoveries that alkenylalanes[21],[22] and alkenylzirconium derivatives[23],[24] readily participate in Pd- or Ni-catalyzed cross-coupling are significant milestones for at least two reasons. First, they clearly indicated that Pd- or Ni-catalyzed cross-coupling might be observed with a wide variety of metal countercations other than Mg and Li. Equally significant is that, for the first time, stereo- and regiodefined alkenylmetals generated in situ by hydrometallation of alkynes are used in Pd- or Ni-catalyzed cross-coupling. Prompted by these discoveries and developments, the first systematic screening of metal countercations was conducted by using the Pd-catalyzed reaction of readily and widely available alkynylmetals with o-tolyl iodide. The latter was to probe the regiospecificity and the effects of steric hindrance. The results of the systematic survey summarized in Table 1 have indicated the following. The Pd-catalyzed alkynyl–aryl coupling is indeed quite general with respect to the metal countercations (M). Metals covering a wide range of electronegativity can participate in the reaction. Under the mild conditions at room temperature, Zn exhibits the highest reactivity. Although the results observed with Mg in the initial screening were not highly satisfactory, later studies[25],[26] have shown that alkynylmagnesiums not only are very reactive but also can yield highly satisfactory results in many cases. Significantly, this survey also identified two unexpected metals—B and Sn. The alkynylmetals containing them were relatively slow-reacting, but the product yields observed with them were comparable to those observed with Zn. The alkynylboron reaction appears to be the first reported example of the Pd-catalyzed cross-coupling reaction with B, and the alkynyltin reaction is one of the earliest examples. It is striking to note that Zn, B, and Sn are indeed the three most widely used metal countercations. These three and Mg as well as three other metals that can be used in conjunction with their hydrometallation and/or carbometallation (i.e., Al, Zr, and Cu) are seven countercations to be seriously considered in a given case of Pd-catalyzed cross-coupling. In addition to
220
III Pd-CATALYZED CROSS-COUPLING
TABLE 1. Reaction of 1-Heptynylmetals with o-Tolyl Iodide in the presence of Cl2Pd(PPh3)2 and 2 DIBAH H3C
H 3C n-PentC CM + I
cat. PdLn
n-PentC C
THF
Temperature(C)
Time (h)
Product Yield (%)
Starting Material (%)
Li Li Na[18] MgBr MgBr
25 25 Reflux 25 25
1 24 24 1 24
Trace 3 58 29 49
88 80 41 55 33
ZnCl
25
1
91
8
ZnCl HgCl HgCl BBu3Li
25 25 Reflux 25
3 1 6 3
88 Trace Trace 10
2 92 88 76
BBu3Li
Reflux
1
92
5
Al(Bu-i)2 AlBu3Li AlBu3Li SiMe3 SnBu3
25 25 Reflux Reflux 25
3 3 1 1 1
49 4 38 Trace 75
46 80 10 94 14
25
6
83
6
25 Reflux
1 3
0 0
91 80
M
SnBu3 ZrCp2Cl ZrCp2Cl
Li and Na mentioned above, Cd,[27] Hg,[28] Si,[29] and Mn[30] have also been used (Sect. III.2.4), and others will undoubtedly be reported in the future. Some of the metals mentioned above, for example, Si and Mn, might become widely used. However, their scope, limitations, and merits must be further delineated before any of these other metals become widely used in preference to some of the seven metals mentioned above. B.iii. Carbon Groups (R1 and R2) Since both R1 and R2 are to be incorporated into the product (R1—R2), these are not changeable parameters in a given synthesis. It should, however, be noted that crosscoupling between R1 and R2 can be achieved either by the reaction of R1M with R2X or by that of R1X with R2M. Inasmuch as these two reactions are to converge at R1R2MTLn in Scheme 6, one might think that two reactions are synthetically equivalent, but that is far from being true. Both may work comparably in many cases. In many other cases, however, only one may work well, while the other may not work well or at all, as amply
III.1 BACKGROUND FOR PART III
221
demonstrated later in this chapter. In order to readily distinguish the two modes of crosscoupling, an adjective consisting of the names of the R1 group in R1M and R2 group in R2X is generated by linking R1 and R2 in this order with a dash. Thus, the reaction of alkynylmetals with aryl iodide in Table 1 is referred to as the alkynyl–aryl coupling reaction, while the reaction of arylmetals with alkynyl halides is referred to as the aryl–alkynyl coupling reaction. In this Handbook, the organometals (R1M) and organic electrophiles (R2X) are classified into roughly ten categories each. This, in turn, generates roughly 100 different classes of cross-coupling reactions, most of which are shown in Table 2. The currently available data clearly indicate that each and every one of these 100 or so classes of cross-coupling displays its own unique characteristics and limitations, demanding separate and individualized attention. For practical reasons, however, they are divided into about ten groups, as indicated in Table 2. At the risk of ignoring many exceptions, the current overall status of each group of cross-coupling reactions is labeled as (a) generally favorable and less demanding (indicated by bold frame), (b) favorable but demanding and delicate (indicated by regular solid-line frame), and (c) generally unfavorable (indicated by broken-line frame). B.iv. Leaving Groups (X) Some of the most reactive leaving groups and their approximate reactivity order are I OTf Br Cl. With aryl and alkenyl as well as alkynyl groups as R2, good leaving groups, such as I, OTf, and Br, are generally required. Clearly, the development of satisfactory procedures permitting the widespread use of aryl and alkenyl chlorides is highly desirable. With acyl and benzyl as R2, Cl is generally sufficiently reactive and widely used. Allyl and propargyl derivatives are some of the most reactive electrophiles. Allyl and propargyl iodides and bromides are generally unnecessary and rarely used. Moreover, these compounds are generally unstable and difficult to handle. In addition to chloro derivatives, those containing a wide range of oxy groups including carbonates, carboxylates, aryl ethers, phosphates, and even silyl ethers as well as other heteroatom groups containing S, N, and so on have been successfully used (Sects. III.2.9 and V.2). At the other end of the spectrum lie alkyl electrophiles other than allyl, propargyl, and benzyl derivatives. The difficulties associated with alkyl electrophiles are at least twofold. First, the absence of an ,- or ,-unsaturated group renders their oxidative addition an inherently difficult and slow process. Second, even if alkylpalladium derivatives are formed, those containing -H atoms are prone to undergo -dehydropalladation in competition with the desired cross-coupling. Promotion of oxidative addition through the use of highly nucleophilic ligands, for example, dippp,[31] might provide a solution to the problem associated with oxidative addition. However, it is expected to retard reductive elimination. Clearly, this is an interesting and largely pending problem to be solved. B.v. Pd Catalysts Both Pd(II) and Pd(0) complexes have been used as Pd catalysts or precatalysts. Some of the Pd(II) complexes [e.g., Cl2Pd(PPh3)2] have been convenient and preferred precatalysts because of their longer shelf lives as compared with some of the commonly used Pd(0) complexes [e.g., Pd(PPh3)4]. However, the initial generation of Pd(0) complexes from Pd(II) complexes may require nonproductive consumption of the organometallic reagents
222
M
X
III.2.6
III.2.6 III.2.7
III.2.14.1
III.2.13.1(a)
III.2.9(b)
III.2.8(a)
III.2.5 III.2.7 III.2.6 III.2.7
ArX X
V.2
III.2.11.1 and III.2.11.2
III.2.8(b)
X X
III.2.14.1
III.2.13.1(b)
III.2.10
III.2.9(a)
Ar
V.2
X
III.2.11.3
Alkyl X
III.2.12.1
RCOX
numbers in the frames indicate the pertinent sections. Bold-line frame: generally favorable and not highly demanding; broken-line frame: generally unfavorable; solid-line frame: others.
a The
C C OM
N C M
M
M
M
M
Alkyl M
Ar
ArM
R1M
R2X
TABLE 2. Classification and Current Status of Pd-Catalyzed Cross-Coupling Reactions a
III.1 BACKGROUND FOR PART III
223
(R1M). This problem has been circumvented by using an added reducing agent [e.g., DIBAH].[21] In some cases, phosphine-free Pd complexes have been satisfactorily used.[32] In most cases, however, Pd–phosphine complexes are used, and triphenylphosphine is by far the least expensive and generally satisfactory phosphine ligand. In less demanding cases of Pd-catalyzed cross-coupling, it is advisable to consider first Pd–PPh3 complexes. The following Pd(0)–PPh3 and Pd(II)–PPh3 complexes are some of the most commonly used. Pd(0)–PPh3 Complexes: Pd(PPh3)4, Pdm(dba)n x PPh3 Pd(II)–PPh3 Complexes: Cl2Pd(PPh3)2, Li2PdCl4 x PPh3 Pd(OAc)2 x PPh3, Cl2Pd(RCN)2 x PPh3 (m 1 or 2; n 2 or 3; x 2–4) In more demanding cases where Pd–PPh3 complexes are unsatisfactory, the use of more effective, if more expensive, phosphines and other ligands may be profitably considered. In principle, there can be a large number of phosphines and other ligands available for consideration (Sect. II.2). At present, several phosphines including tris(2-furyl)phosphine (TFP)[33] and some bidentate phosphines, for example, dppp and dppf,[34] have been shown to be superior to PPh3 in many demanding cases, as detailed later. This aspect of Pd-catalyzed cross-coupling will be significantly advanced in the near future, and many additional ligands in many different forms including chiral, water-soluble, and polymerbound ligands will be developed. Along with the catalytic reactivity, many other practically important aspects associated with ligands and catalysts, such as catalyst recovery, attrition rate, and especially toxicity, will become increasingly important. The use of Ph3As, for example, has been effective in the reactions of organotins[35] and organoborons.[36] However, its toxicity has been a serious concern, and it should be carefully examined and evaluated. This concern, of course, applies to any other ligands and reagents used in organic synthesis as well. B.vi. Added Reagents and Cocatalysts The Pd-catalyzed reaction of sterically demanding alkenylalanes and alkenyzirconium derivatives was significantly accelerated by the addition of ZnCl2 or ZnBr2.[37] This probably was the first reported example of cocatalysis by an added reagent in Pd- or Ni-catalyzed cross-coupling. Since then, many additional examples of rate acceleration by added reagents have been reported. A noteworthy example is the finding that relatively unreactive triaorganylboranes can be significantly activated with appropriate bases, which not only boost the nucleophilicity of organoboron compounds but also are thought to facilitate the transfer of a carbon group from B to Pd through coordination[13] (Scheme 7). In principle, this concept should be applicable to the Pd-catalyzed reaction of other organometals as well. In general, promotion of Pd-catalyzed cross-coupling with added reagents will be further investigated and advanced. B.vii. Solvents A wide range of solvents have been used in Pd-catalyzed cross-coupling. They include (i) relatively nonpolar hydrocarbons (e.g., benzene and toluene), (ii) ethereal solvents (e.g., THF, dioxane, and DME), (iii) polar double and triple bond-containing solvents
224
III Pd-CATALYZED CROSS-COUPLING
R2PdLnX + M+R1−B
OR
R2 MX
PdLn O+R R − B 1
R2
PdLn +
B OR
R1
Scheme 7
(e.g., MeCN and acetone), (iv) other polar aprotic solvents (e.g., DMF, DMSO, HMPA, and NMP), and (v) polar protic solvents (e.g., alcohols and water). In early investigations, THF was probably the most commonly used solvent, and it is still widely used in many less demanding cases. In more demanding cases, however, DMF and other polar aprotic solvents have proved to be superior to THF. One of the potential advantages associated with more electronegative metals, for example, B, Si, and Sn, is that they are, in most cases, compatible with many polar protic solvents, allowing even aqueous conditions for Pd-catalyzed cross-coupling (Sect. X.1). The range of solvents available for Pd-catalyzed cross-coupling is considerably more limited than those of ligands and added reagents. At the same time, their systematic investigations within the context of Pd-catalyzed crosscoupling have also been rather limited. So, further systematic investigations along this line are expected to bring about some significant advances in Pd-catalyzed crosscoupling. B.viii. Side Reactions As simple as the cross-coupling reaction is, it can still be associated with a number of side reactions. Cross-homo scrambling processes of various origins that lead to the formation of one or both of the two possible homo-coupled products have been widely observed. Another commonly encountered side reaction is the reduction of organic electrophiles (R2X) to the corresponding hydrocarbons (R2H). The most common path leading to this side reaction appears to be the conversion of the oxidative addition intermediates (R2PdLnX) into R2PdLnH, which can then undergo reductive elimination to give R2H. On the other hand, protonolysis of R2PdLnX is rather rare. -Dehydropalladation is a widely observable route to R2PdLnH, but various other routes are also conceivable. -Dehydropalladation of alkylpalladium derivatives leads to the formation of alkenes. Various side reactions that have been observed in Pd-catalyzed cross-coupling, including those mentioned above, are listed in Table 3. These reactions are diverse in nature, and their concise discussion cannot be presented in a generalized manner. So, they will be discussed in pertinent sections. It is, however, useful to consult with this table for some clues to identifying the origin of side products. B.ix. Special Topics on Pd-Catalyzed Carbon–Carbon Cross-Coupling Essentially all types of organic compounds can be synthesized via Pd-catalyzed crosscoupling. The syntheses of the following classes of compounds are particularly noteworthy. So, special discussion of their syntheses are presented in the sections indicated in parentheses. • Heteroaromatics (Sect. III.2.7) • Chiral compounds and their asymmetric synthesis (Sect. III.2.16)
III.1 BACKGROUND FOR PART III
225
TABLE 3. Side Reactions in Pd-Catalyzed Cross-Coupling Entry
Side Reaction Formation of R1—R1 Formation of R2—R2 Reduction of R2X to give R2H -Elimination of alkylpalladium derivatives to give alkenes Stereoisomerization of alkenyl and other compounds Regioisomerization of allyl, propargyl, and other derivatives Reactions of functional substituents (chemoselectivity problems) Other undesirable reactions of the starting compounds and organic products (e.g., alkyne cyclotrimerization to give benzenes) Other undesirable reactions of organopalladium intermediates Undesirable reactions of ligands, solvents, added reagents, and adventitious chemicals (e.g., water and O2)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
• Conjugated oligomers of biological significance (Sect. III.2.17.1) • Conjugated oligomers and polymers of materials chemical interest (Sect. III.2.17.2) • Natural products (Sect. III.2.18) Finally, any cross-coupling procedures should, in principle, be applicable to the synthesis of homodimers. In addition, other Pd-catalyzed protocols specifically aimed at the synthesis of homodimers have also been developed. Most of them involve Pd-catalyzed dimerization of organometals or organic electrophiles, rather than the reaction of an organometal with an organic electrophile. Some of these homocoupling procedures can be applied to the synthesis of cyclic cross-dimers. These reactions are discussed in Sect. III.2.20.
C. Pd-CATALYZED CARBON–HYDROGEN, CARBON – HETEROATOM, AND CARBON–METAL BOND FORMATION With due modifications, the discussions presented in Sect. B are applicable to the other types of the Pd-catalyzed cross-coupling reactions discussed in Sect. III.3.
REFERENCES [1] [2]
G. H. Posner, Org. React., 1975, 22, 253–400. B. H. Lipshutz, in Organometallics in Synthesis, M. Schlosser, Ed., Wiley, New York, 1994, p. 283–382.
Reviews on the Negishi Coupling [3] E. Negishi, in Aspects of Mechanism and Organometallic Chemistry, J. H. Brewster, Ed., Plenum Press, New York, 1978, 285–317. [4] E. Negishi, Acc. Chem. Res., 1982, 15, 340–348.
226 [5] [6] [7] [8]
III Pd-CATALYZED CROSS-COUPLING
E. Negishi, in Current Trends in Organic Synthesis, H. Nozaki, Ed., Pergamon, New York, 1983, 269–280. E. Negishi, T. Takahashi, and K. Akiyoshi, in Catalysis of Organic Reactions, P. N. Rylander, H. Greenfield, and R. L. Augustine, Eds., Marcel Dekker, New York, 1988, 381–407. E. Negishi and F. Liu, in Cross Coupling Reactions, F. Diederich and P. J. Stang, Eds., VCH, Weinheim, 1998, 1–47. E. Negishi, in Organozinc Reagents: A Practical Approach, P. Knochel and P. Jones, Eds., Oxford University Press, Oxford, 1999, 213–243.
Reviews on the Stille Coupling [9] J. K. Stille, Pure Appl. Chem., 1985, 57, 1771–1780. [10] J. K. Stille, Angew. Chem. Int. Ed. Engl., 1986, 25, 508–524. [11] V. Farina, V. Krishnamurthy, and W. J. Scott, Org. React., 1997, 50, 1–652. [12] T. N. Mitchell, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 167–202. Reviews on the Suzuki Coupling [13] N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483. [14] A. Suzuki, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 49–97. Reviews on the Sonogashira Coupling [15] K. Sonogashira, Comp. Org. Synth., 1991, 3, 521–549. [16] K. Sonogashira, Comp. Org. Synth., 1991, 3, 551–561. [17] K. Sonogashira, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 203–229. General References [18] L. Cassar, J. Organomet. Chem., 1975, 93, 253. [19] S. I. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, and K. Kondo, J. Org. Chem., 1979, 44, 2408. [20] M. Yamamura, I. Moritani, and S. I. Murahashi, J. Organomet. Chem., 1975, 91, C39. [21] E. Negishi and S. Baba, J. Chem. Soc. Chem. Comm., 1976, 596. [22] S. Baba and E. Negishi, J. Am. Chem. Soc., 1976, 98, 6729. [23] E. Negishi and D. C. Van Horn, J. Am. Chem. Soc., 1977, 99, 3168. [24] N. Okukado, D. E. Van Horn, W. L. Klima, and E. Negishi, Tetrahedron Lett., 1978, 1027. [25] E. Negishi, C. Xu, Z. Tan, and M. Kotora, Heterocycles, 1997, 46, 209. [26] M. Kotora, C. Xu, and E. Negishi, J. Org. Chem., 1997, 62, 8957. [27] E. Negishi, T. Takahashi, S. Baba, D. E. Van Horn, and N. Okukado, J. Am Chem. Soc. 1987, 109, 2393. [28] L. P. Beletskaya, J. Organomet. Chem., 1983, 250, 551. [29] T. Hiyama, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 421–453. [30] G. Cahiez and S. Marquais, Tetrahedron Lett., 1996, 37, 1773. [31] Y. Ben-David, M. Portnoy, and D. Milstein, J. Am. Chem. Soc., 1989, 111, 8742. [32] N. A. Bumagin, I. G. Bumagina, and I. P. Beletskaya, Dokl. Akad. Nauk SSSR, 1984, 274, 1103. [33] V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585.
III.1 BACKGROUND FOR PART III
[34] [35] [36] [37]
227
T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Higuchi, and K. Hirotsu, J. Am. Chem. Soc., 1984, 106, 158. T. Kobayashi and M. Tanaka, J. Organomet. Chem., 1981, 205, C27. C. R. Johnson and M. P. Braun, J. Am. Chem. Soc., 1993, 115, 11014. E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, and B. I. Spiegel, J. Am. Chem. Soc., 1978, 100, 2254.
R1M(Zn, Al, Zr) + R2X
Pd cat.
III.2
Palladium-Catalyzed Carbon–Carbon Cross-Coupling III.2.1 Overview of the Negishi Protocol with Zn, Al, Zr, and Related Metals EI-ICHI NEGISHI
A. HISTORY AND SCOPE OF THE NEGISHI PROTOCOL The Negishi coupling (or reaction or protocol) may loosely be defined as the Pd- or Nicatalyzed cross-coupling through the use of organometals containing metals of intermediate electronegativity, such as Zn (1.6), Al (1.5), and Zr (1.4), the numbers in parentheses being the Pauling electronegativity values.[1] Additionally, the use of cocatalysts containing metal salts, most notably Zn salts (e.g., ZnCl2 and ZnBr2),[2] has also been included in this protocol. The selection of these metals stemmed from the following observations in a broad-range systematic investigation made mostly in the 1970s.[3],[4] 1. Metals of intermediate electronegativities exhibited, in general, the highest catalytic activities in Pd-catalyzed cross-coupling,[3] as observed first in alkynyl–aryl coupling reaction (Table 1 in Sect. III.1). 2. The use of Al and Zr permits not only generation of certain stereo- and regiodefined alkenylmetals and the corresponding halides via hydrometallation and carbometallation but also in situ cross-coupling under the influence of Pd or Ni catalysts.[2],[3],[5]–[16] A series of papers cited above established, for the first time, the hydrometallation– cross-coupling and carbometallation–cross-coupling tandem processes (Scheme 1). On the other hand, the corresponding alkenylboron compounds generally exhibited either a very low or no reactivity under similar reaction conditions,[5] ,[6] even though alkynylborates[3] and -silylalkenylborates[13] did participate satisfactorily in Pd-catalyzed crosscoupling (Scheme 2). This limitation associated with B has since been overcome by the Suzuki protocol (Sect. III.2.2). 3. In cases where the Pd- or Ni-catalyzed cross-coupling reactions of alkenylaluminum and alkenylzirconium derivatives are sluggish, addition of Zn salts (e.g., ZnCl2 and ZnBr2) has significantly accelerated these reactions in many cases (double metal
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
229
230
III Pd-CATALYZED CROSS-COUPLING I
H
H C4H9-n 5% MLn
n-C5H11
H H
H
[6]
C4H9-n
H H
n-C5H11 H
M = Ni 70%,95% E,E M = Pd 74%, 99% E,E I
Al(Bu-i)2
C4H9-n
n-C5H11
H H 5% MLn
H C4H9-n
H
[6]
H H M = Ni 55%,90% E,Z M = Pd 55%, 99% E,Z HAl(Bu-i)2
PhC CH
[5]
ArX cat. Ni(PPh3)4
R
H
H
Al(Bu-i)2
R
H
H
Ar
R = n-Bu, ArX = 1-NaphBr, 93% R = Cy, ArX = p-TolBr, 75%
EtOC CH
EtO
HZrCp2Cl [7]
H ZrCp2
H
EtO
PhI cat. Ni(PPh3)4
H
Cl THPOCH2
H
Br
ZrCp2
H
Ph 99%, >98% E
Cl2Pd(PPh3)2 THPOCH2 i-Bu2AlH
H
+ H
H
H
H
[8]
COOMe
H
H
Cl
COOMe
70%, >98% E,E
Cl
Me3Al Cl2ZrCp2
5% Pd(PPh3)4
AlMe2
[9] α-farnesene (86%) >98% isomerically pure
n-Hex + Me
Br
Ph
AlMe2
cat. Pd(PPh3)4 [10]
n-Hex Me 93%
Ph
n-Bu n-Bu
O
cat. Pd(PPh3)4
+ Me
[12]
AlMe2
Me 90%
O HOOC
n-Pent + Me
AlMe2
OMe
1. cat. Pd(PPh3)4 2. H3O+ [16]
OMe
Scheme 1
n-Pent Me
CHO 59%
III.2.1 OVERVIEW OF THE NEGISHI PROTOCOL
1. HBR2 2. n-BuLi
n-Hex
CSiMe3
[13]
231
Br
n-Hex
SiMe3
H
n-Hex
cat. Pd(PPh3)4
BR2BuLi
SiMe3
H 68%
Scheme 2
catalysis)[2] (Scheme 3). Similar beneficial effects of Zn salts have also been observed in the Pd-catalyzed cross-coupling reactions of alkenylcoppers.[17] 4. Organometals containing more electropositive metals (e.g., Li and Mg) are generally most reactive in many different kinds of reactions. And yet, the catalytic reactivity of these metals, especially Li, in the Pd-catalyzed reaction is lower than that of Zn in many cases. Because of their high intrinsic reactivity toward many functional groups, they are not very chemoselective in a traditional sense. As a consequence of these two generally Et 5% Pd(PPh3)4 1 week, 25 °C
Me Et
Et
H
no additive
Me
Et
99 :
0 :
4
0 : 97% E
BuC CBu
HZrCp2Cl
Bu H
Bu
PhI 5% Pd(PPh3)4, ZnCl2 (1 equiv)
Bu
Bu
H
[18]
ZrCp2Cl
80%, >97% E Me MgBr
+ ArX
cat. Cl2Ni(dmpe)
Ar
[ 21]
Ar PhBr p-ClC6H4Br 1-NaphBr Scheme 2
Me
Yield (%) 85 68 78
337
338
III Pd-CATALYZED CROSS-COUPLING
Aryl−alkenyl coupling Ph
50−75%
[13]
Br
ArMgX
Ph
NiX2
ArMgBr +
Ar
Cl
Cl
NiX2
+
[13]
Cl PhMgBr +
H2C CHCl
PhMgBr +
Cl2C CH2
PhMgBr +
Cl
40−50%
Ar
cat. Ni
ArHC CH2
78−95%
Ph2C CH2
82%
PhHC CHCl
91%, Z/E = 90 : 10
PhHC CHCl
100%, Z/E = 80 : 20
[12],[21]
cat. Ni [21]
cat. Ni
Cl
[21]
Cl
cat. Ni
PhMgBr +
[21]
Cl Cl
Ph
cat. Ni
PhMgBr +
65%
[21]
Ph Pd(PPh3)4
Br
Ph
PhMgX
PhMgX
Ar
[20]
Pd(PPh3)4
ArLi + Br
[20]
Hex
I
+
+
Hex
Yield (%) Selectivity
Ar
Ph
ArLi +
Ph
Ar
p-MeC6H4 o-Me2NC6H4 o-Me2NCH2C6H4
98 92 82
100% E 100% E 100% E
p-MeC6H4 o-Me2NC6H4
98 96
99% Z 100% Z
cat. Pd(PPh3)4 [22]
cat. Pd(PPh3)4 [22]
I Scheme 3
Hex
Ph
82%, >97% E
Hex 80%, >97% Z Ph
III.2.6 Pd-CATALYZED ALKENYL–ARYL
Alkenyl−alkenyl coupling R1C CH
H
R2
R1
H H
[15]
H
H
AliBu2
Ni(PPh3)4 Pd(PPh3)4
70 74
95% E,E >99% E,E
Ni(PPh3)4 Pd(PPh3)4
55 55
90% E,Z >99% E,Z
R2
R2
I
= n-C5H11 = n-C4H9
Yield (%) Selectivity
Catalyst
H
H
R1
R2
H
5% Cat.
HAliBu2
R1
I
H H 5% Cat.
R1
[15]
H
H R2 H
H
R1C CH HZrCp2Cl
R1 H
H
I
H
H
R2
R1
H
5% Pd(PPh3)4
H
ZrCp2Cl
91%, >97% E, E
H
[16]
H R2 R = n-C5H11, R2 = n-C4H9 1
Br
R1C CH
R1
5% Pd(PPh3)4 ZnCl2 (1 equiv)
Me3Al cat. Cp2ZrCl2
H Me
[18]
R1 Me
H
H
H AlMe2
I
H
H
R2
H
73%, >99% E
5% Cl2Pd(PPh3)2 + DIBAH ZnCl2 (1 equiv) [18]
R1
H H
Me H R2 65%, >97% E,E
Ph
Pd(PPh3)4
+ MgBr CH3
81%, 99% E Br
[19, 20]
CH3
cat. Ni
+ MgBr
Ph
Br
[21]
CH3 79% H3C
Scheme 4 (Continued )
339
340
III Pd-CATALYZED CROSS-COUPLING
Hex R
cat. Pd(PPh3)4 Hex H
R′
R
MgBr
R′ I
[22]
cat. Pd(PPh3)4 I
R′
Yield Selectivity (%) (%)
H H H CH3
H CH3 H
81 82 87
>97 E >97 E >97 Z,E
R
H CH3 H
75 84 79
>97 Z >97 Z
Hex Hex
R′
R
H
H H CH3
−
Scheme 4 (Continued )
Over the past two decades, Pd- or Ni-catalyzed cross-coupling, especially Pdcatalyzed version, has become one of the most common methods (possibly the most common method) for highly selective synthesis of arylated alkenes, conjugated dienes, conjugated enynes (Sect. III.2.8), and other related alkene derivatives. In addition to Mg, Zn, Al, and Zr used since the 1970s,[23] several other metals including B,[24] Si,[25] Sn,[26],[27] and Cu[28]–[33] have been extensively employed since around 1980. In the following three subsections, the alkenyl–aryl (Sect. B), aryl–alkenyl (Sect. C), and alkenyl – alkenyl (Sect. D) coupling reactions catalyzed by Pd complexes are discussed primarily in the forms of schemes and tables. Some related Ni-catalyzed reactions are also presented, as deemed appropriate. Alkenylmetals and alkenyl electrophiles may be classified into eight structural types according to the number and positions of the substituents relative to the metal or the electrophilic leaving group in the alkenyl group (Scheme 5). The entries in the tables are arranged according to the alkenyl structural types in the order shown in Scheme 5 except in Tables 2 and 8, which are arranged according to the aryl structural types, and their priority order is as detailed in Sect. III.2.5. Within the same structural type, the alkenyl groups are listed in the following order of the substituent type: alkyl, alkenyl, aryl, and alkynyl, and the carbon numbers are used as the tie breakers. Heteroatom
CH CH2
Vinyl H
R
Monosubstituted
((E)-β-),
H
H H
R1
Disubstituted
((Z)-β-),
R
R (β ,β′ -),
R1
R2 R1
H
R2 H
R2
Trisubstituted R3 Scheme 5
H
(α-)
H (cis-α ,β -),
R1
H
(trans-α ,β -)
R2
III.2.6 Pd-CATALYZED ALKENYL–ARYL
341
group-containing alkenyl groups are listed in increasing order of priority determined by the Cahn–Ingold–Prelog rule. Alkenylmetals containing the same alkenyl group are finally arranged according to the group numbers of the metal countercations, that is, Li, Mg, Zn, B, Al, Si, Sn, Cu, Zr, and so on, while the alkenyl electrophiles containing the same alkenyl group are arranged according to decreasing number of the group numbers of alkenyl-bound atoms, that is, halogens (I, Br, Cl, F), O, S, N, P, and so on.
B. ALKENYL–ARYL COUPLING B.i. Alkenyl–Aryl Coupling versus Aryl–Alkenyl Coupling Alkenylated arenes or arylated alkenes by cross-coupling can, in principle, be prepared via either alkenyl–aryl or aryl–alkenyl coupling. Although Pd- or Ni-catalyzed crosscoupling is well-suited for either of these two categories, one may be more satisfactory than the other in a given case, and the relative merits and demerits depend on a number of factors, of which the substitution pattern and other structural parameters of the alkenyl group are especially significant. More specifically, many of the alkenylmetals and alkenyl electrophiles can be prepared by appropriate addition reactions, such as hydrometallation, carbometallation, and heterometallation, of alkynes. In cases where such addition reactions generate the desired alkenylmetals, one-pot procedures for the alkenyl–aryl coupling can be devised, as indicated by Protocol I in Scheme 6, and such procedures are usually preferred to the others. On the other hand, the required alkenyl halides and related electrophiles, such as vinyl bromide and 2-iodo-1-alkenes, may be more readily accessible than the corresponding alkenylmetals. In such cases, the aryl–alkenyl coupling represented by Protocol II in Scheme 6 may be a viable option. In yet other cases, the required alkenyl electrophiles and alkenylmetals may have to be generated from alkynes via addition–trapping by electrophiles and from alkenyl electrophiles via metallation (Protocol III) or metallation–transmetallation (Protocol IV), respectively, for observing the optimal results. It is, however, clear that, in cases where all four protocols, that is, Protocols I–IV, are at least reasonably satisfactory, the general order of preferences should be (i) Protocol I, (ii) Protocol II, (iii) Protocol III, and (iv) Protocol IV. Although less critical, the accessibility of aryl electrophiles and arylmetals is also an important factor. The majority of arylmetals containing relatively electropositive metals, such as Li and Mg as well as Zn in some cases, are prepared by oxidative metallation of aryl halides, while those containing relatively electronegative metals, such as B, Al, Si, Cu, and Sn, as well as Zn, are most commonly prepared by transmetallation of aryllithiums and arylmagnesium halides. These facts indicate that aryl halides are generally more readily available than arylmetals, even though directed metallation[34] of arenes and possibly some other methods would make arylmetals more readily available than aryl halides. Overall, the alkenyl–aryl coupling by the reaction of alkenylmetals generated in situ by suitable addition reactions with aryl halides and sulfonates accessible via phenols[35] (Protocol I) would be the most efficient route to arylated alkenes in the absence of overriding difficulties. Indeed, the alkenyl–aryl coupling has been much more frequently employed than the aryl–alkenyl coupling for the synthesis of arylated alkenes.
342
III Pd-CATALYZED CROSS-COUPLING
R
H
(R′)H
M
HM (or R′M)
RC CH 1
ArX cat. PdLn or NiLn Protocol I
R
H
(R′)H
Ar
R
H
2a
R
H ArM, cat. PdLn or NiLn
(R′)H
X
Protocol II
(R′)H
3
H
ArX cat. PdLn or NiLn
M1
Protocol III
R (R′)H
R (R′)H
Ar
H Ar
2b X2M2
H
ArX cat. PdLn or NiLn
M2
Protocol IV
R (R′)H Starting Compounds
2c Alkenylmetals
R (R′)H
H Ar
Arylated Alkenes
Scheme 6
Table 1 summarizes some of the most satisfactory routes to the alkenyl reagents of various classes and the preferred cross-coupling protocols. B.ii. Alkenyl–Aryl Coupling with Vinylmetals Since both vinyl halides and various aryl electrophiles are commercially available, either of them may be metallated to generate organometallic partners for crosscoupling. Indeed, various types of vinylmetals containing Mg, B, Zn, Al, Si, and Sn have been employed for converting aryl electrophiles into styrene derivatives. Table 2 summarizes some of the currently viable results of cross-coupling with vinylmetals. The results with different metals are comparably favorable. In cases where the required aryl electrophiles are readily available as aryl sulfonates from phenols, the alkenyl – aryl coupling is generally preferred over aryl – alkenyl coupling. Even sterically hindered aryl sulfonates can readily be vinylated as indicated by the results shown in Scheme 7.[61],[62] In general, critical comparisons among various metal countercations is lacking. Since many of them are comparably effective, vinylmagnesium halides that can readily be obtained as the first-generation vinylmetals should be considered first. Only if it is unsatisfactory for one reason or another, should one then consider other metals such as Zn, Si, and Sn. For yet unclear reasons, vinylboron derivatives have rarely been used.
III.2.6 Pd-CATALYZED ALKENYL–ARYL
343
TABLE 1. Some Preferred Alkenyl Reagents for the Synthesis of Arylated Alkenes via Pd- or Ni-Catalyzed Cross-Coupling and Preferred Cross-Coupling Protocols
Generally Preferred Cross-Coupling Protocol
Structural Type of the Alkenyl Group
Generally Preferred Reagents
Generally Preferred Route
H2C CH (Vinyl)
H2C CHX
Commercially available
Aryl−alkenyl (Protocol II) and alkenyl−aryl (Protocol I)
syn-Hydrometallation
Alkenyl−aryl (Protocol I)
Hydroboration−
Alkenyl−aryl (Protocol I)
R
X = Br, I, or Cl
H
H
(E-β-mono) H
H
R
H
H
M
(M = Zn, B, Al, Si, Zr) H
H
R
R
(Z-β-mono)
(M = B, Cu)
H
H
R
H
H
R X
Carbocupration[38]
Markovnikov addition of HX
39
Sulfonation of enolates [38]
Aryl−alkenyl (Protocol II) and alkenyl−aryl (Protocol I)
(X = Br, I, OTf, Cl)
(α-mono) R′
M
hydride migration[36],[37]
R
H
R′
R
H
M
R
H
R′
M
Hydrometallation
Alkenyl−aryl (Protocol I)
Carbometallation[38],[40]−[42]
Alkenyl−aryl (Protocol I)
Hydroboration−
Alkenyl−aryl (Protocol I)
(E- or Z-α,β-di) R
H
R′
(M = Al, Zn, Cu)
(β,β-di) H
R′
H
R′
C-Migration [43],[44] R′
R′
(trans-α,β-di)
R R″
R′
M
(M = B) R
R′
R″
M
(M = Zn, Al)
Carbometallation [38],[40]−[42]
Alkenyl−aryl (Protocol I)
344
III Pd-CATALYZED CROSS-COUPLING
TABLE 2. Pd-Catalyzed Cross-Coupling of Vinylmetals with Aryl Electrophiles a
M
Type of Aryl Electrophile Phenyl
Conditions
Ar−X I
Yield (Selectivity) %
Reference
95
[45]
94
[46]
>95
[47]
Cl2Pd(dppf ), THF
MgBr I
Pd2dba3, KF,
SiMe3
n
I
Bu4NCl, toluene
Pd2dba3, LiCl, NMP,
SnBu3
TFP or AsPh3
SnBu3 SnBu3
p-Mono
FO2SO
Cl2Pd(PPh3)2, LiCl, DMF
80
[48]
F4BN2
Pd(OAc)2, 1,4-dioxane
44
[49]
or Pd(dba)2
80
[ClPd(π-C3H5)]2 , TASF, HMPA
89
[50]
Cl2Pd(dppf ), THF
98
[51]
[ClPd(π-C3H5)]2, TASF, HMPA
86
[50]
100
[51],[52]
10%Pd/C, CuI, AsPh 3
79
[53]
Pd(PPh3)4, toluene
82
[54]
75
[48]
I
SiMe3 I
Me
ZnCl CN I SiMe3 COMe I SnMe3 COMe
Cl2Pd(MeCN)2, DMF-THF
I SnBu3 COMe Br SnBu3 COMe FO2SO
SnBu3
Cl2Pd(PPh3)2, LiCl, COMe DMF
p-MonoI
[ClPd(π-C3H5)]2, toluene
SnBu3 CO2Et F4BN2 BF3K I
90
[55]
Pd(OAc)2, 1,4-dioxane
65
[56]
[ClPd(π-C3H5)]2, TASF, HMPA
85
[50]
N
Ph
PPh2
CO2Et
SiMe3 NH2
III.2.6 Pd-CATALYZED ALKENYL–ARYL
345
TABLE 2. (Continued )
M
Type of Aryl Electrophile
Yield (Selectivity) %
Reference
83
[50]
100
[51], [52]
Pd(PPh3)4, toluene
80
[54]
Cl2Pd(PPh3)2, LiCl, DMF
85
[48]
Cl2Pd(dppf ), THF
98
[45]
Cl2Pd(dppf ), THF
100
[51]
Pd(PPh3)4, toluene
76
[54]
Cl2Pd(PPh3)2, LiCl, dioxane
82
[57]
Cl2Pd(MeCN)2 , DMF-THF
99
[51]
Cl2Pd(MeCN)2, DMF-THF
100
[51]
Pd(PPh3)4, LiCl, dioxane/DMF
80
[57]
Cl2Pd(MeCN)2, DMF-THF
95
[51]
Conditions
Ar−X I
SiMe3 NO2
[ClPd(π-C3H5)]2, TASF, HMPA
I SnMe3 NO2
Cl2Pd(MeCN)2, DMF-THF
Br SnBu3 NO2 FO2SO SnBu3 NO2 I MgBr OMe I ZnCl OMe Br SnBu3 OMe TfO SnBu3 OMe
m-Mono-
I
CO2H
SnMe3
m-Mono-
I
NO2
SnMe3
o-Mono-
TfO
SnBu3 TsHN I SnMe3 O 2N
(Continued )
346
III Pd-CATALYZED CROSS-COUPLING
TABLE 2. (Continued )
M
Type of Aryl Electrophile
Yield (Selectivity) Ref% erence
Conditions
Ar−X OSO2Ph-p-F
2,3-DiSnBu3
Pd(OAc)2, LiCl, DMF, dppp
50
[58]
Pd(PPh3)4, toluene
86
[59]
Pd(PPh3)4, toluene
76
[59]
Pd(PPh3)4
87
[60]
Br
2,6-DiSnBu3
(OAc)2CH
SnBu3
MeO
NHTs
Br NHTs
Br
2,3,5-Tri-
OMOM
SnBu3 OHC
OMOM
a The entries are arranged according to the substitution patterns in the Ar groups, that is, degree of substitution and their regiochemistry. Within the same category, the Cahn–Ingold–Prelog rule is applied in increasing order. Finally, the leaving groups and then the metal countercations are arranged as discussed in the text.
OMe OTf
+
Bu3Sn
OMe
Cl2Pd(PPh3)2 PPh3, LiCl, DMF
85%
[61]
OMe
OMe OTf Pr Cr(CO)3 + Bu3Sn
Pd(PPh3)4, LiCl, THF
Pr Cr(CO)3
[62]
NMe2
87%
NMe2 Scheme 7
B.iii. Alkenyl–Aryl Coupling with Disubstituted Alkenylmetals There are three types of disubstituted alkenylmetals according to the classification discussed in Sect. A. Tables 3, 4, and 5 summarize some representative examples of their coupling reactions, arranged in the order of (E)--, (Z)--, and -substituted alkenylmetals. B.iii.a. (E)- -Substituted Alkenylmetals. Some prototypical examples of this type of coupling are shown in Scheme 2. In these early studies, the reactions were mainly catalyzed by Ni–phosphine complexes,[14][16][21] even though Pd – phosphine complexes
III.2.6 Pd-CATALYZED ALKENYL–ARYL
347
TABLE 3. Pd-Catalyzed Cross-Coupling of (E)--Substituted Alkenylmetals with Aryl Electrophiles a
R Me
I
O Br
O B O
Bu
Br AliBu2 Br
Bu
[70]
Pd(PPh3)4, NaOH, EtOH
100(99)
[66]
Pd(PPh3)4, NaOH, EtOH
98(99)
[66]
Pd(PPh3)4
89
[14]
Pd(OAc)2 , NaOH, THF
80
[88]
Cl2Pd(PEt3)2, TBAF, DMF
83
[83]
Pd(PPh3)4, K3PO4, dioxane
95
[91]
Pd(PPh3)4
84
[92]
[ClPd(π-C3H5)]2, P(OEt)3, TBAF, THF
91(>99)
[82]
Pd(PPh3)4, C6H6
70−85
[93]
Cl2Pd(PPh3)2, LiCl, DMF
82
[57]
Pd(PPh3)4, LiCl, DMF
51
[57]
Pd(PPh3)4, LiCl, DMF
88
[60]
Pd(PPh3)4, NaOH
48
[73]
Pd(PPh3)4, NaOH
B
Bu
87
Br B O
Bu
Reference
Conditions
Ar–X
M
Yield (Selectivity) %
SiMeCl2 CN Cl
Bu
SiMeCl2 CN
Bu
O
TfO
B O
OMe Br
Pent
AliBu2 Me
Hex
SiMe(OiPr)2
I
Br HO
SnBu3
HO
SnBu3
TfO
TfO THPO
Br THPO
NHTs
SnBu3 OMOM OMOM
SnBu3 CHO
CF3
I B(OiPr)2
(Continued )
348
III Pd-CATALYZED CROSS-COUPLING
TABLE 3. (Continued )
R
Ar–X
M
Conditions
Yield (Selectivity) Ref% erence
CF3 I
B(OiPr)2 O
Ph
81
[73]
98(99)
[66]
Pd(OAc)2, LiCl, DMF, DPPP
69
[58]
Pd(PPh3)4, NaOH
60
[70]
82(~100)
[53]
80
[70]
Pd(PPh3)4, NaOH
Br
B
Pd(PPh3)4 , NaOH, EtOH
O X
Ph
SnBu3 COCH3 X = 4-F-C6H4O2SOBr
Ph
B NMe2
I
Ph
SnBu3 OMe
10% Pd/C, CuI, AsPh3
Br Ph
Pd(PPh3)4, NaOH
B OMe
a The alkenyl groups are arranged (i) according to the types of substitutions, i.e., alkyl > alkenyl > aryl > alkynyl and (ii) in the increasing order of priority determined by the Cahn–Ingold–Prelog rule. For a given alkenyl group, the aryl electrophiles are arranged according to their substitution patterns, i.e., the degree and regiochemistry of substitution. Finally. the leaving group and then the countercations are arranged as discussed in the text.
TABLE 4. Pd-Catalyzed Cross-Coupling of (Z)--Substituted Alkenylmetals with Aryl Electrophiles a
R
Conditions
Ar–X
M
FO2SO Me
Pd(PPh3)4, LiCl, DMF
SnBu3
Yield (Selectivity) %
Reference
82
[48]
89(>97)
[98]
Cl2Pd(PEt3)2, TBAF, THF
91
[83]
Pd(PPh3)4, TBAF, THF
73
[104]
Me I Bu
B(OiPr)2 Me
Me
Pd(PPh3)4, NaOEt, EtOH
Cl C6H13
SiMeCl2 CN TfO
C6H13
SiMeF2 CHO
III.2.6 Pd-CATALYZED ALKENYL–ARYL
349
TABLE 4. (Continued )
R
Conditions
Ar–X
M Cl
C6H13
SiMeCl2
CF3 Cl
C6H13
CF3 Br
COMe
Br
CF3
Reference
58
[86]
55
[88]
Pd(OAc)2, THF
70
[88]
Pd(OAc)2, THF
66
[88]
93(>90)
[98]
60
[99]
96(>84)
[98]
Cl2Pd(dcpe),
SiEtCl2
C6H13
Cl2Pd(PEt3)2, TBAF, THF
Yield (Selectivity) %
C6H6, 80 °C
SiEtCl2
C6H13
SiEtCl2 CF3 i
B(O Pr)2
I
Pd(PPh3)4, NaOEt, EtOH
I Bu
Pd(PPh3)4, THF
ZnBr OtBu
OMe I
Pd(PPh3)4, NaOEt, EtOH
B(OiPr)2 a
See Table 3.
TABLE 5. Pd-Catalyzed Cross-Coupling of -Substituted Alkenylmetals with Aryl Electrophiles a
R
Ar–X
M
Reference
Pd(PPh3)4, NaOH,
96
[117]
Pd(PPh3)4, NaOH,
83
[117]
Pd(PPh3)4, NaOH,
76
[117]
Pd(PPh3)4, THF
96
[108]
Br
Bu BBu(OBu) i
Conditions
Yield (Selectivity) %
Bu
Br
BiBu2 iPr
Br
BiPr2 CF3 ZnBr
I
(Continued )
350
III Pd-CATALYZED CROSS-COUPLING
TABLE 5. (Continued )
R CF3
ZnBr CF3 ZnBr
90
[108]
Pd(PPh3)4, THF
95
[108]
Pd(PPh3)4, THF
85
[108]
Pd(PPh3)4, THF
83
[108]
COCH3 I
ZnBr CF3
Pd(PPh3)4, THF
Br
ZnBr CF3
Reference
Conditions
Ar–X
M
Yield (Selectivity) %
NO2 Br OHC Br AcO
a
See Table 3.
were also shown to be very satisfactory.[14] These studies also introduced a one-pot hydrometallation–cross-coupling tandem process for the stereoselective conversion of alkynes into arylated (E)-alkenes[14] (Protocol 1). Alkenylaluminums or alkenylzirconiums, generated in situ by hydroalumination[63] or hydrozirconation[64] of alkynes, respectively, were reacted with aryl halides in the presence of Pd or Ni catalysts to produce arylated E-alkenes in high yield with excellent stereoselectivity. This tandem protocol has been investigated extensively in other cross-coupling reactions involving Sn, Si, and particularly B. Stereodefined (E)-alkenylborons are readily available by monohydroboration of alkynes[65] and their cross-coupling with aryl halides was demonstrated in 1979.[66] The reaction was effected by the use of a suitable base, such as sodium hydroxide and sodium ethoxide. The effect of bases is believed to promote the formation of four-coordinated borates, which had been shown to be reactive in Pd-catalyzed cross-coupling with carbon electrophiles.[67] Various functional groups such as OMe, esters, and halogens can be tolerated in this reaction. Although the reaction proceeds with retention of stereochemistry in alkenylboranes, loss of regiochemistry is observed in some cases. In the presence of palladium black, alkenylborane was reacted with iodobenzene to give the desired cross-coupling products (1)[68] only as the minor product, the major product being the “head-to-tail” isomer (2) (Scheme 8). The ratio of products 1 and 2 varies from 39 : 61 to 97 : 3 depending on the reaction conditions. However, even under optimal conditions, the coupling of (E)-phenylethenylborane with iodobenzene gives a mixture of (E)-stilbene and 1,1-diphenylethylene in the 36:46 ratio. An intramolecular version of this unusual “head-to-tail” coupling was reported in the synthesis of methylenecycloalkenes.[69] The mechanism for the reaction was believed to consist of (i) addition of an organopalladium iodide to the alkenylborane, (ii) isomerization of the intermediate, and (iii) elimination of IPdBX2. Dihydroboration–dehydroboration of terminal alkynes has been developed to prepare (E)alkenyl-9-BBN derivatives, and they are successfully cross-coupled with aryl electrophiles to give arylated (E)-alkenes.[70] Alternatively, (E)-alkenylboron compounds are generated from
351
III.2.6 Pd-CATALYZED ALKENYL–ARYL
H
Bu H
H
Ph Ph H 1 2 19−94% ( See text for product ratios) Ph
Pd black, Et3N
+ PhI
H
Ph
H
Ph
H
+
BY2
BY2 = B
Bu
H
H
H
H +
BY2
Ph
Bu
Pd catalysts
+ PhI
H
Ph 1
O
2 58% (1:2 = 36:64)
O Scheme 8
a one-pot process associated with the heteroboration of acetylenes followed by chemoselective cross-coupling with organic zinc reagents.[71] – [73] The observed chemoselectivity is in agreement with the earlier finding that organozinc compounds are much more reactive in Pdcatalyzed cross-coupling with organic electrophiles than organoboron compounds.[14],[15] The stereodefined alkenylboron derivatives thus obtained can now be reacted with aryl halides in the presence of a Pd catalyst and a base to give arylated (E)-alkenes[71] (Scheme 9).
BBr2
Br
RZnCl, THF Cl2Pd(PPh3)2
PhI, LiOH
B
R BBr3
R = n-Bu(88%), s-Bu(75%), Ph(89%), SiMe3
HC CH
Ph >97% E
R
Hex- C C
(87%),
O O
(61%),
(63%)
Scheme 9
The solid phase and aqueous Suzuki coupling reactions involving alkenylboron compounds and aryl electrophiles have also been demonstrated, as shown in Scheme 10.[74],[75] O 1. Pd(0), DMF, r.t. 2. TBAF, THF MeO 3. MeOH, MeONa, THF
O O TMSO
+
B
P
O
O I
OH
Pd(0) = Pd(PPh3)4 (50%) Cl2Pd(dppf) (68%)
[74]
Pd(OAc) 2
Hex
Br 2.5 K2CO3 B(OH)2
+ MeO
1.0 Bu4NBr H2O, 70 °C [75]
Scheme 10
Hex MeO
74%
352
III Pd-CATALYZED CROSS-COUPLING
Although hydrostannation of monosubstituted alkynes to give alkenylstannanes is mostly regiospecific, E/Z mixtures are often obtained.[26] Therefore, the hydrostannation – cross-coupling tandem is not generally well suited for the synthesis of stereodefined arylated alkenes.[76] However, this difficulty may be circumvented by the use of an excess amount of alkenyltin reagents in some cases. For example, when 1.3 equiv of an alkenyltin reagent generated as an E/Z (85 : 15) mixture by hydrostannation of but-3ynoic acid was coupled with aryl halides, only the E-isomer of the desired product was produced under the reaction conditions[77] (Scheme 11).
O OH
Bu3SnH, 2.1 equiv AIBN, toluene 100 °C, 3h
O OSnBu3 1. Pd(PPh3)4 toluene, 100 °C 2. H+
O +
Bu3Sn
83% (E/Z = 85:15)
Bu3Sn
O
ArX
Ar
OSnBu3 1.3 equiv
1.0 equiv
OH 55−88%
Scheme 11
E-Alkenyltin compounds may be prepared by transmetallation using triorganyltin halides. Several (E)-alkenylstannyl alcohols have been prepared from -alkynols via hydrozirconation chemistry[42] and used in Pd-catalyzed intramolecular cross-coupling in the synthesis of zearalenone shown in Scheme 12.[78] O OH I
HO(CH2)n
O
SnBu3
O
DCC, DMAP, Et 2O, 25 °C
(CH2)n
SnBu3
I O
Pd(PPh3)4 toluene, 105 °C
O
OH
n = 4, 65% 6, 37% 8, 67% 9, 66%
Me
O O
HO
(CH2)n
(S)-zearalenone O
Scheme 12
Alkenylsilicon compounds themselves are generally inert in Pd-catalyzed cross-coupling with aryl electrophiles. However, their reactivity could be remarkably enhanced by the addition of fluorides to generate pentacoordinate alkenylsilicon derivatives that can undergo the desired cross-coupling. Some typical examples are shown in
353
III.2.6 Pd-CATALYZED ALKENYL–ARYL
Scheme 13.[79],[80] Earlier, the use of benzenediazonium salts as cross-coupling partners was demonstrated.[81] However, it was not until 1988 that a more convenient and practically useful protocol for the cross-coupling of alkenylsilicon compounds was developed. Initially, at least one Si—F bond in the alkenylsilicon reagents requiring an excess of TBBF or TASF was shown to be necessary.[80] However, further studies have indicated that the alkenylsilicon compounds containing Si—OR,[82] Si—Cl,[83] and Si—OH[84],[85] are also effective substrates for cross-coupling. Most notably, the cross-coupling of alkenylchlorosilanes with aryl chlorides has recently been achieved.[83] The favorable results may, in part, be ascribed to the exceptional thermal stability of organochlorosilanes, which show no sign of decomposition even under drastic conditions (90–150 °C, 24–48 h). However, the use of trialkylphosphine–Pd complexes as catalysts is also essential. Electron-rich trialkylphosphine ligands must significantly increase the nucleophility of the palladium complexes, thereby promoting their oxidative addition reaction with aryl chlorides. Indeed, bulky trialkylphosphine–palladium complexes are effective catalysts for various reactions of organic chlorides.[86],[87] More recently, this reaction has been improved by using NaOH as a base instead of TBAF. With this modification the reaction could be completed under relatively mild conditions (80 C),[88] as shown in Scheme 14. It should be noted that the required alkenylsilanes can readily be prepared by either hydrosilylation[89] of alkynes or silylation of alkenyl halides.[90]
K2 Ph
Hex
Pd(OAc) 2, 2PPh3 Et3N, 135 °C
+
SiF5
PhI
[79]
[(π-C3H5)PdCl]2 TASF, THF, 50 °C
I SiMe3-nFn +
Ph
Ph
51%
Hex
[80]
n = 0 (0%), 1 (81%), 2 (74%), 3 (0%) Scheme 13
Cl2Pd(PiPr3)2 benzene, 80 °C NaOH, 12 h
Cl Bu
SiMeCl2 +
R
Bu R
R = p-CF3 (95%), p-COMe (65%), m-Me (91%) Scheme 14
B.iii.b. (Z)--Substituted Alkenylmetals. The stereodefined (Z)--substituted alkenylmetals can generally be prepared by either metallation or metallation–transmetallation of the corresponding (Z)-alkenyl electrophiles. However, several other methods are notable.[36]–[38],[94],[95] A stereoselective synthesis of (Z)-alkenylboranes via hydroboration
354
III Pd-CATALYZED CROSS-COUPLING
of 1-haloalkynes followed by migratory insertion was developed by Negishi and coworkers in 1975[36] (Scheme 15). Its variants involving the use of t-BuLi[37] and KHB(OPr-i)3[96],[97] have also been reported (Scheme 15). The (Z)-alkenylboron derivatives thus obtained readily participate in Pd-catalyzed cross-coupling under the Suzuki conditions[98] (Scheme 16). R
HBR′2
RC CX
X
H
1. HBBr2 . SMe 2
RC CX
X B(OiPr)2
H
H
KHB(OiPr)3
C C
2. iPrOH
BR′2 C C
[36],[37]
BR′2
R
R
MH
C C
H B(OiPr)2
R C C
[96],[97]
H
H
Scheme 15
Bu
Pd(PPh3)4 NaOEt, EtOH reflux
BY2
BY2 = B(Sia)2 Bu
Ph
+ PhI H
B
58% (>94% Z) 2
B(OiPr)2
H
H
49% (>82% Z) 98% (>97% Z)
H
Scheme 16
A chelation effect has been observed in Pd-catalyzed cross-coupling of (Z)-4-alkoxy1-alkenylzinc bromides with p-iodoanisole. When R is a bulky alkoxy group, such as t-BuO and ThexMe2SiO groups, the reaction proceeds very well to give the desired products as shown in Scheme 17.[99] However, when R is sterically less hindered (e.g., Me), no cross-coupling is observed. The results point to a strong chelation between O and Zn. Similar (Z)--substituted alkenylzinc bromides bearing either a primary or a secondary allylic or homollylic Ot Bu group have been reacted with p-iodoanisole to give the corresponding arylated (Z)-alkenes[99] (cf. Table 4).
I
OR I
1. t-BuLi 2. ZnBr2
OMe Pd(PPh3)4
OR THF, 20 °C ZnBr
OMe
R
Yield
Me 0% t-Bu 82% SiMe2Thex 70%
RO Scheme 17
(Z)-3-(tri-n-butylstannyl)-2-propen-1-ol, prepared from propargylic alcohol by metal hydride reduction and transmetallation,[100] has been coupled with 1-naphthyl triflate to give (Z )-3--naphthyl-2-propen-1-ol with retention of the double bond
355
III.2.6 Pd-CATALYZED ALKENYL–ARYL
geometry.[57] However, the reaction of benzyl (Z )-3-(tri-n-butylstannyl)propenoate[101] with p-nitrophenyl triflate gives a 2 : 1 mixture of the Z and E isomers of the desired product (Scheme 18). On the other hand, the reaction of (Z )-1-propenyltributyltin and phenyl fluorosulfonate has been reported to produce exclusively (Z )--methylstyrene.[48] Stannoxanes, prepared from propargyl alcohol and 3-butyn-2-ol,[102] are utilized to synthesize arylated (Z )-allylic alcohols by Stille coupling.[103] The use of nitrobenzene as solvent dramatically improves the yields in many cases (Scheme 19). OTf SnBu3 +
HO
2% Cl2Pd(PPh3)2 DMF, LiCl 60 °C, 18 h
HO
OH + 62%
NO2 BnO2C
2% Cl2Pd(PPh3)2 DMF, LiCl 100 °C, 5 h
SnBu3 + TfO
33%
NO2 + (E)-isomer
CO2Bn
2:1 (47%) Scheme 18 Pd(PPh3)4 PhNO2, LiCl
I R O
SnBu2
+
R OH
R′
R′ Yield (%) Z /E
R
R′
H H H Me
Me NO2 OMe Me
89 66 96 94
96:4 97:3 96:4 —
Me NO2
94
—
Scheme 19
The Pd-catalyzed cross-coupling reactions of (Z)--substituted alkenylsilanes with aryl electrophiles, such as aryl bromide,[88] aryl chloride,[83],[88] and aryl triflate,[104] have been demonstrated (Table 4). In these reactions, the presence of either two Si—F bonds or Si—Cl bonds appears to be required for successful coupling, and the addition of bases, such as TBAF and NaOH, is also necessary. In addition, when chloroarenes are used as electrophiles, trialkylphosphines, such as iPr3P, Et3P, and dcpe, must be used as effective ligands. The reaction proceeds with retention of the stereochemistry of the alkenylsilicon derivatives. More recently, a highly stereospecific cross-coupling of alkenylsilanols has been demonstrated,[84] as shown in Scheme 20. The product yields and stereoselectivities are generally high, and the (Z)-alkenyldiisopropylsilanols are superior to the
356
III Pd-CATALYZED CROSS-COUPLING
corresponding (Z)-alkenyldimethylsilanols with respect to the stereoselectivity. The major advantage over the previous methods is the mild reaction conditions (room temperature, 10–30 min).
Pent
Pent
SiMe2OH
SiiPr
2OH
Pd(dba)2 ArI, TBAF THF, r.t.
Pd(dba)2 ArI, TBAF THF, r.t.
Ar
Pent
Ph 1-Naphthyl Ar p-MeCOC6H4
Ar
Pent
Ph 1-Naphthyl Ar p-MeCOC6H4
Time (min) Yield (%) 90 85 92
10 30 10
97.3:2.7 96.7:3.3 95.2:4.8
Time (min) Yield (%) 81 79 86
10 30 10
Z/E
Z/E 99.4:0.6 97.7:2.3 99.0:1.0
Scheme 20
B.iii.c. -Substituted Alkenylmetals. -Substituted alkenylmetals containing Mg and Zn can be prepared by oxidative metallation of the corresponding alkenyl halides. 2-(1,3-Butadienyl)magnesium chloride, prepared from 2-chloro-1,3-butadiene and magnesium,[105] was coupled with several aryl iodides in the presence of Pd(PPh3)4 to give 2-arylated 1,3-butadienes in fair to good yields.[106] Neither Ni(acac)2 nor Ni(pph3)4 was effective for this reaction, since either polymerization occurred or no reaction ensued. In cases where both an alkyl iodide and an aromatic iodide are present in an electrophile, the aromatic iodides preferentially reacted,[107] as exemplified by the results shown in Scheme 21. 3% Pd(PPh3)4 THF-C6H6
MgCl +
ArI
Ar
[106]
Ar = Ph (75%), p-MeC6H4 (56%), p-MeOC6H4 (50%), 1-Naphthyl (40%)
MgCl
+ I
(CH2)3I
3% Pd(PPh3)4 THF-toluene
(CH2)3I
[107]
60% Scheme 21
Trifluoroisopropenylzinc reagent is prepared in nearly quantitative yield by the direct zincation of 2-bromo-3,3,3-trifluoropropene in the presence of TMEDA. This organozinc reagent readily undergoes Negishi coupling with a wide variety of aryl halides. Various functional groups, such as Br, Ac, OMe, NO2, OAc, and CHO, are tolerated. Excellent yields are achieved in most cases. However, o-amino- and acetylamino-substituted
357
III.2.6 Pd-CATALYZED ALKENYL–ARYL
bromobenzenes fail to react with the reagent under the same conditions.[108] This zincation – cross-coupling procedure (Protocol III) has been used in the synthesis of fluorovinylsalicyclic acid derivatives[109] (Scheme 22). The zinc reagents are often generated by lithiation of the alkenyl halides followed by transmetallation with zinc halides. Some chemoselective and regioselective coupling reactions of alkenylzinc reagents, generated by a lithiation – transmetallation procedure, with o-dihaloarenes have been demonstrated, as shown in Scheme 23.[110]
CF3
X
CF3
Pd(PPh3)4 THF
CF3 + ZnBr
+
CO2Me OCOMe
CF3 (CH3)2S AlBr3
CO2Me OCOMe
CO2Me
CO2H
OH
25%
OH
29% Scheme 22
ZnX
I Br Pd(PPh3)4
O
Br
O 65%
1. t-BuLi, THF/DME −78 °C 2. ZnCl2
I Br
OMe I OMe
Pd(PPh3)4 O
I
O 72% Scheme 23
Although Markovnikov alkenylboranes have been known since 1975,[111]–[114] their Pd-catalyzed cross-coupling had not been reported until an improved procedure for the preparation of Markovnikov alkenylboranes in pure form was recently reported.[115] In these reactions, however, the primary alkyl groups compete with the 2-alkenyl groups and produce alkylbenzenes, but iPr, sBu, and iBu virtually do not. On the other hand, when the alkenylboranes are treated first with 1 equiv of trimethylamine N-oxide, which presumably gives alkenylalkoxyborane,[116] the yields of the desired -substituted styrenes increase dramatically[117] (Scheme 24).
358
III Pd-CATALYZED CROSS-COUPLING
H
R
H
BR2
Me3NO
PhBr Pd(PPh3)4 NaOH, H2O, THF
H
R
H
BR(OR)
H
R
H
Ph
R = Bu R = CH2SiMe3
96% 70%
+ Ph
R
4% 11%
Scheme 24
It is noteworthy that -alkoxy- and -alkylthio-substituted vinylzinc reagents, generated by treating the corresponding organolithium reagents with zinc chloride, undergo Negishi coupling with aryl halides to produce the corresponding arylated -heterosubstituted alkenes in high yields[118] (Scheme 25). This approach has been demonstrated repeatedly in related Stille and Suzuki coupling reactions (Sect. III.2.13.2).
Z
H
+ ArI H
Z
5% Pd(PPh3)4 THF, 22 °C
ZnCl2
H
Z
H
Ar
OEt OEt SEt
Yield (%)
Ar C6H5 p-C6H4 C6H5
91 91 80
Scheme 25
-Substituted alkenyltins or alkenylsilicons have not been used as often as their Zn and B counterparts. One problem associated with the use of -phenyl-substituted vinylfluorosilane with aryl iodides is the formation of a mixture of regioisomers. Their ratio depends on the nature of the substituents in the aryl iodides.[18] -Substituted alkenylzirconiums can be prepared by oxidative addition of 2-haloalkenes to zirconocene, and their subsequent Negishi-type coupling with aryl halides has been demonstrated[119] (Scheme 26).
Ph
Cp2ZrBu2
Ph
PhI Pd(PPh3)4 ZnCl2
Ph 78%
Cl
ZrCp2Cl
Ph
Scheme 26
B.iv. Trisubstituted Alkenylmetals Some representative examples of the cross-coupling of three different types of trisubstituted alkenylmetals with aryl electrophiles are shown in Table 6 and arranged in the order: ,-, cis-,-, and trans-,-substituted alkenylmetals.
III.2.6 Pd-CATALYZED ALKENYL–ARYL
359
TABLE 6. Pd-Catalyzed Cross-Coupling of Trisubstituted Alkenylmetals with Aryl Electrophiles a
Alkenylmetals
Ar−X
Yield (Selectivity) %
Reference
Cl2Pd(PPh3)2, MeOLi, MeOH
65(97)
[122]
Cl2Pd(PPh3)2, MeOLi, MeOH
73(99)
[122]
Pd(PPh3)4, THF
80
[99]
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
79(95)
[82]
Pd(PPh3)4, NaOEt, EtOH
87(99)
[66]
Pd(PPh3)4, ZnCl2
88(>97)
[18]
Pd(PPh3)4, THF
85(99.5)
[131]
Pd(PPh3)4, THF
72(>99)
[131]
Pd(PPh3)4, THF
50(>99)
[131]
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
90(>99)
[82]
Ni(PPh3)4, ZnCl2
80(>97)
[18]
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
77(>99)
[82]
43
[137]
Conditions
β,β−DiHex
I
BBr2 Bu
Hex
I
BBr2
TMS ZnX
I
OtBu
OMe
SiMe2(OiPr)
I
cis-α,β−Di Br
Et Et
BY2 Et
Et
I AliBu2 I
Pr Pr
ZnX I
Pr Pr
CO2Et
ZnX I
Pr Pr
ZnX
CHO I
Bu Bu
SiMe(OEt)2 I
Bu Bu
ZrCp2Cl I
Bu Bu
SiMe(OEt)2 OTBS
TBSO
Me
SnBu3
COMe CO2Me I Me
Cl2Pd(PPh3)2, ZnCl2, LiCl, dioxane
(Continued )
360
III Pd-CATALYZED CROSS-COUPLING
TABLE 6. (Continued )
Alkenylmetals
Yield (Selectivity) %
Reference
Pd(PPh3)4, K3PO4, dioxane
68
[138]
Pd(PPh3)4 , CsF, DMF
29
[124]
Pd(PPh3)4 , CsF, DMF
34
[124]
Conditions
Ar−X
trans-α,β− Di Me
TfO B(OiPr)2
Bu Ph
I
B O O
I
Bu
Bu
Me a
See Table 3.
B.iv.a. ,-Substituted Alkenylmetals. Carbometallation reactions of 1-alkynes, most notably carboalumination[40] and carbocupration,[38] collectively provide a powerful route to the synthesis of ,-substituted alkenylmetals. The alkenylmetals generated in situ may be used directly for Pd- or Ni-catalyzed cross-coupling with aryl electrophiles (Protocol 1). One prototypical example of the carbometallation–cross-coupling tandem process is shown in Scheme 27.[120] N Me3Al Cp2ZrCl2
Hex
Hex
H
Me
AlMe2
H
Hex
H
Br 3% Pd(PPh3)4 THF, 22 °C
Me
N
82%, 99% purity Scheme 27
In addition to the carbometallation reactions mentioned above, there are various additional methods for the synthesis of trisubstituted alkenes, as discussed below. Various ,-substituted alkenylboron compounds can be prepared from 1-alkynes by a haloboration[121]–chemoselective cross-coupling tandem process similar to that shown in Scheme 9. Their subsequent reaction with iodobenzene is effected by the addition of a base to give stereodefined arylated alkenes in fair to good yields.[122] A series of 1,3-dibora-1,3-butadienes have been prepared by a zirconocene-mediated reductive cyclization of 1-alkynyl boronates using Negishi’s reagent[123] (Cp2ZrCl2 2 n-BuLi). Their cross-coupling with aryl halides proceeds to selectively replace the terminal B group giving 2-bora-1,3-butadiene derivatives[124],[125] (Scheme 28). The synthetic utility of this method is severely limited due to the restriction that the two R groups be the same.
361
III.2.6 Pd-CATALYZED ALKENYL–ARYL
R
R
1. Cp2ZrBu2 2. H+ B
O B
R
O
Pd(PPh3)4 ArI, THF CsF Ar
R R
B
B
R = n-Bu, Ar = Ph (97%), p-MeC6H4 (92%), 2-Thienyl (90%) Scheme 28
The reaction of 2-bis(trimethylstannyl)-1-alkenes, readily available by the addition of hexamethylditin to 1-alkynes using Pd(PPh3)4 as catalyst,[126],[127] with -chloroarene chromium complexes give regio- and stereospecifically the corresponding cross-coupling products in 34 – 85% yields[128] (Scheme 29). On the other hand, uncomplexed haloarenes, such as chlorobenzene or even bromobenzene, fail to undergo the desired cross-coupling. The success with the chromium complexes may be attributable to the electron-withdrawing tricarbonylchromium group, which favors the oxidative addition of aryl chlorides to Pd(0) complexes.[129] The Pd-catalyzed reaction of (Z)-exocyclic silyldienes[130] with aryl halides has been reported to proceed with some loss of stereochemistry (5–10%)[82] (Table 6). Cl
RC CH
Pd(PPh3)4 (Me3Sn)2 R
H
Cr(CO)3
H
R
Me
SnMe3 SnMe3
Cr(CO)3
5% Pd(PPh3)4 Me3Sn THF, 70 °C
Me
R = Ph (70%), MeOCH 2 (62%), MeCH(OH) (34%), Me 2C(OH) (85%) Scheme 29
B.iv.b. cis- , -Substituted Alkenylmetals. cis-,-Substituted alkenylmetals containing B, Al, Zr, Sn, and Si can conveniently be prepared via hydrometallation of internal alkynes, and their Pd-catalyzed cross-coupling with aryl electrophiles has been investigated extensively. Some representative results are shown in Table 6. The recently reported Ti-catalyzed hydrozincation that can directly provide stereodefined alkenylzinc reagents[131] from alkynes permits a one-pot Negishi coupling with aryl halides to give arylated alkenes in good yields and in high stereoselectivity. Hydrozincation of unsymmetrically alkyl-substituted alkynes generally produces mixtures of two regioisomers in nearly 1:1 ratios, even though the presence of Ph or an Me3Si group can result in ca. 90:10 regioselectivity. Their cross-coupling with iodobenzene gives mixtures of two regioisomers also in ca. 90:10 ratio[131] (Scheme 30).
Ph
Pr
Cp2TiCl 2 ZnI2-LiH, THF
PhI Pd(PPh3)4
Ph Ph
Me3Si
Hex
Cp2TiCl 2 ZnI2-LiH, THF
Ph +
PhI Pd(PPh3)4
Pr Ph 86% (88:12) Ph Me3Si
Scheme 30
Pr
+ Hex Me3Si 70% (90:10)
Ph Hex
362
III Pd-CATALYZED CROSS-COUPLING
An alternative preparation of stereodefined cis-,-substituted alkenylzinc reagents involves transmetallation of the corresponding trialkenylboranes or alkenyl tellurides with diethylzinc.[132],[133] The alkenylzincs thus obtained undergo Negishi coupling with aryl iodides in good yields (Scheme 31).
Et
Et
3 Et2Zn hexanes −Et3B
Et
) 3
H
B
Et
0.28% Pd(PPh3)4 ArI
3 H
dioxane
Et
Et
H
Ar
ZnEt
Ar = p-MeC6H4 (82%), m-BrC6H4 (87%), p-MeC6H4 (77%) t-Bu
Ph
H
TeBu
Et2Zn
t-Bu
20 °C −BuTeEt
5% Pd(PPh3)4 p-MeC6H4I
Ph
H
0− 20 °C, 1 h
ZnEt
Ph
t-Bu H 72%
C6H4-p-Me
Scheme 31
The use of cis-,-substituted alkenylalkoxysilanes in Pd-catalyzed cross-coupling with aryl halides has been demonstrated.[82] The synthetic utility of these coupling reactions has further been demonstrated by the one-pot transformation of a homopropargyl alcohol to regioand stereodefined trisubstituted homoallyl alcohol (Protocol 1), as shown in Scheme 32. 2.5% [ClPd(π-C3H5)]2 5% P(OEt)3, PhI TBAF, THF, 12 h
Hex Hex
[134]
OH Me2Si
67% (>99% E)
O
Hex OH Ph
Scheme 32
B.iv.c. trans- , -Substituted Alkenylmetals. The accessibility of trans-,-substituted alkenylmetals is still rather limited, and only a few examples of this type of crosscoupling reactions have been reported (Table 6). Notably, trans-,-substituted alkenylboronates can be prepared by hydroboration of 1-bromo-1-alkynes followed by subsequent treatments with organolithiums and bases, a procedure similar to that for the preparation of (Z)--substituted alkenylboron compounds.[94]–[97] The Pd-catalyzed crosscoupling reaction of the resultant organoboranes with aryl halides proceeds with complete retention of alkenyl stereochemistry to give trisubstituted alkenes[135] (Scheme 33).
BuC CBr
1. HBBr2.SMe2 2. iPrOH 3. RLi 4. Base
B(OiPr)2
Bu C C H
PhI Pd(PPh3)4 KOH, H2O
Bu
R
R = Me(85%), Bu(89%), 2-Methylpropenyl(61%), 2-Thienyl(98%) Scheme 33
Ph C C
H
R
III.2.6 Pd-CATALYZED ALKENYL–ARYL
363
Alternatively, hydrozirconation of 1-alkynyldioxaborolanes with HZrCp2Cl affords 1,1-dimetalloalkenes containing both B and Zr, which can then be reacted with various electrophiles to give trans-,-substituted alkenylboronates via preferential reaction of the carbon – zirconium bond[136] as shown in Scheme 34. The subsequent Suzuki coupling with iodobenzene gives trisubstituted alkenes in good yields.
Bu BX2 =
BX2 B
ZrCp2Cl
Cp2ZrHCl H
Bu
O
Bu
Pd(PPh3)4 82% PhI Pd(PPh3)4 NaOEt, EtOH
Br
Bu
Ph
BX2 PhI Pd(PPh3)4 NaOEt, EtOH
H
H
84%
Bu
H
THF, 25 °C
BX2
O
H
Br CuCN
Bu
BX2
Ph
Scheme 34
B.v. Tetrasubstituted Alkenylmetals Several coupling reactions of 2-substituted cycloalkenylmetal reagents have been reported.[139]–[141] For example, cyclobutenylmetals, generated in situ via carbometallation of 4-halo-1-metallo-1-alkynes, are reacted with iodobenzene to give 1,2-disubstituted cyclobutenes,[139] as shown in Scheme 35.
M
R
M
RM
X M = Al or Zr group R, R′ = C group, X = I, Br
R
M
R′X PdLn
R
R′
M X R = allyl, R′ = Ph, 75% Scheme 35
1,2-Bis(boryl)alkenes can be prepared by the Pt-catalyzed stereoselective diboration of alkynes.[142] Their two consecutive Suzuki coupling reactions have provided some polymer-bound tetrasubstituted alkenes (Scheme 36).[143] The second coupling is carried out on a solid support permitting easy separation of the undesired tetrasubstituted alkenes formed in the first coupling reaction. This approach has been applied to the parallel synthesis of tamoxifen and related derivatives.[144] ,,-Trifluorosytrenes can be prepared in good yields by Negishi coupling of perfluorovinylzinc reagents with aryl halides. A wide variety of substituents in the aryl group can be tolerated.[145]–[148] The perfluorovinylzinc reagents are prepared by either transmetallation of perfluorovinyllithium with zinc halides[145] ,[149] or direct zinc insertion into 1iodo- and 1-bromo-trifluoroethylene[146],[147] (Scheme 37).
364
III Pd-CATALYZED CROSS-COUPLING
R
R
X2BBX2 Pt(PPh3)4 DMF, 80 °C
R
X2B O X2BBX2 =
R
R′X Cl2Pd(PPh3)2 3 M KOH DME, 80 °C
R
R
R
′R
R′
+ X2B
BX2
O
R′
I
B B O
R
O
P HN
R O
R = Ph, R′ = Bu (>95%), 4-tolyl (83%) R = Et, R′ = 4-tolyl (85%), 2-propenyl (>95%)
R P HN
R′ O
Scheme 36
F
F
F
I(Br)
F
F
F
Cl
Zn, r.t.
1. BuLi, −100 °C 2. ZnCl2, −100 °C
F
F
ArI Pd(PPh3)4
F
F
ZnI(Br)
[146],[147]
F Ar 61−81%
F
F
ArI Pd(PPh3)4
F
ZnCl
[145],[148]
F
F
F
F Ar 60−87%
Scheme 37
Some other related synthesis of - and/or -fluorine-substituted styrenes by the reaction of the corresponding alkenylmetals containing Zn,[150] B,[151],[152] and Sn[153],[154] with various aryl electrophiles are also summarized in Table 7.
TABLE 7. Pd-Catalyzed Cross-Coupling with Tetrasubstituted Alkenylmetals a R2
R3
R1
M
Ar–X
Conditions
Yield (Selectivity) Ref% erence
I Hex
Pd(PPh3)4, CuI
66
[141]
Pd(PPh3)4, THF
47
[140]
ZrCp2Cl I ZnBr
III.2.6 Pd-CATALYZED ALKENYL–ARYL
365
TABLE 7. (Continued ) R2
R3
R1
M
ZnBr
F F
R
Conditions
Ar–X
I
Pd(PPh3)4, THF
I
Yield (Selectivity) Ref% erence
69
[140]
R′
Cl2Pd(PPh3)2+BuLi, TBAF, K3PO4
63−86
[151]
R′
Pd2dba3, PPh3, CuI, THF
91−94
[152]
R
Pd(PPh3)4, THF/TG
45−75
[150]
Pd(PPh3)4, TG
48
[109]
Pd(PPh3)4, CuI, DMF
85−92
Pd(PPh3)4, THF
80(100)
[146]
Pd(PPh3)4, THF
100(100)
[147]
Pd(PPh3)4, THF
75
[148]
Pd(PPh3)4, THF
85
[148]
B(OR)2
R = nBu, sBu F F
R
I
BR2
R = nBu, sBu F
CF3
F
ZnCl
F
CF3
F
ZnCl
R
F
I
I
CO2CH3
CO2CH3 I R′
F
SnBu3
[154]
R = CH3, nBu, sBu, tBu, C6H5, nHex CF3
F
F
ZnX
F
F
CF3
I
I
ZnX
F
F
F
ZnX
F
F
F
ZnX
I CH3 I OCH3
(Continued )
366
III Pd-CATALYZED CROSS-COUPLING
TABLE 7. (Continued ) R2
R3
R1
M
F
F
F
ZnX
F
F
F
ZnX
F
F
F
Pd(PPh3)4, THF
60
[148]
Pd(PPh3)4, THF
71
[109]
Pd(PPh3)4, THF
41
[109]
Pd(PPh3)4, THF
83
[155]
I I I
CO2CH3 CO2CH3
Br
CO2CH3
ZnX
CO2CH3 F3C
F
Reference
Conditions
Ar–X
OTMS
I F
Yield (Selectivity) %
F
CF3
ZnX F 3C
CF3 OTMS
a The alkenyl groups are arranged according to the increasing order of priority as determined by the Cahn–Ingold–Prelog rule. In cases where the same alkenyl group is used, the entries are arranged according to the degree of substitution and regiochemistry of the aryl groups. Finally, the leaving groups and then the countercations are arranged as discussed in the text.
C. ARYL–ALKENYL COUPLING An alternative approach to the synthesis of stereodefined arylated alkenes by the Pdcatalyzed cross-coupling involves the reaction of arylmetals with alkenyl electrophiles, i.e., aryl-alkenyl coupling (Sect. A). Table 8 summarizes some representative examples of the Pd-catalyzed aryl-alkenyl coupling reactions. TABLE 8. Pd-Catalyzed Aryl–Alkenyl Cross-Coupling a Type of Aryl Group Phenyl
Ar−M
X Sn[N(TMS)2]2 I
I
Bu
Conditions
Yield (Selectivity) Ref% erence
Pd(PPh3)4, TBAF THF, dioxane
75
[176]
Pd(PPh3)4, C6H6
82(>97)
[22]
MgX I
Hex
III.2.6 Pd-CATALYZED ALKENYL–ARYL
367
TABLE 8. (Continued ) Type of Aryl Group
Ar−M
Conditions
X
Yield (Selectivity) Reference %
I
B(OH)2
Pd(OAc)2, TPPTS
53
[171]
82(>97)
[22]
Cl2Pd(PPh3)2, DMF
77
[177]
Pd2(dba)3
72
[174]
Pd(PPh3)4, DMF
65−73
[178]
Pd(PPh3)4, THF
83(50)
[179]
Pd(PPh3)4
75(>97)
[139]
Pd(PPh3)4
86(>97)
[139]
85(99)
[19],[20]
93(>98)
[180]
Pd2(dba)3 AsPh3, DMF
79
[181]
Pd2(dba)3 AsPh3, DMF
85
[181]
MgX I
Pd(PPh3)4, C6H6
Hex
ZnCl
O I
OH
TfO
SnBu3
Ph TfO
BPh3Na
Ph I
ZnCl
Pent
COMe ZnCl
I
ZnCl
para-
Me
I
MgBr
I
Pd(PPh3)4, C6H6 Ph
Me
para-
ZnCl
OH
SnMe3
Cl2Pd(PPh3)2 + BuLi DMF
Me
Me E
I
I
X
E = COOMe X = NHBoc
TfO
Ph
(Continued )
368
III Pd-CATALYZED CROSS-COUPLING
TABLE 8. (Continued ) Type of Aryl Group
Ar−M
Conditions
X SnBu3
TfO t
F3C SnBu3
Bu
Yield (Selectivity) Ref% erence
Pd(0)/AsPh3 /NMP/LiCl
87
[174]
Pd(0)/AsPh 3 /NMP/ZnCl2
89
[182]
Pd(0)/AsPh 3 /NMP
83
Pd2(dba)3, LiCl
60
[174], [182]
Pd(PPh3)4 TBAF
62
[104]
Pd2(dba)3, AsPh3
89
[174], [182]
Cl2Pd(PPh3)2, Et2O
75
[163]
97(>98)
[180]
68
[174]
Pd(PPh3)4, C6H6
60(99)
[20]
Pd(PPh3)4, C6H6
75(100)
[20]
Pd(PPh3)4, C6H6
87(100)
[20]
TfO
F3C SiEtF2
TfO Hex
MeO SnBu3
TfO t
MeO MgBr
Cl
Bu
Ph
Ph
MeO ZnCl
I
OH
DMF
Me
Cl SnBu3
Pd(PPh3)4
TfO
Pd2(dba)3 Cl
ortho-
Li
Br Ph
CH2NMe2
ortho-
Li
Br Ph
NMe2 Li Br NMe2
Ph
III.2.6 Pd-CATALYZED ALKENYL–ARYL
369
TABLE 8. (Continued ) Type of Aryl Group
X
Ar–M ZnCl
I
OH
Me
OMe
3,4-
Conditions Pd(PPh3)4 DMF
Yield (Selectivity) %
Reference
97(>98)
[180]
Ar MeO
ZnBr TfO
N
Pd(PPh3)4, THF
MeO
[183] 97
a
The entries are arranged according to the degree of substitution and regiochemistry of the aryl groups. In cases where the same aryl group is used, they are arranged according to the type of the alkenyl groups. Finally, the leaving groups and then the countercations are arranged as discussed in the text.
C.i. Accessibility of Arylmetals Although arylmetals containing various metals, such as Li, Mg, Zn, B, Al, Sn, Si, and Cu, have been used in Pd-catalyzed aryl – alkenyl (Table 8), aryl – aryl (Sect. III.2.5), and other cross-coupling reactions, their accessibility varies widely depending on the metal counterions. Scheme 38 summarizes four representative methods for the preparation of various arylmetals. Aryl electrophiles including halides and triflates have been used as the starting materials in nearly all cases except in the directed metallation of arenes.[34] Arylmetals containing relatively electropositive metals, such as Li and Mg, are readily prepared by oxidative metallation of aryl halides. Aryllithiums are also accessible via Li–halogen exchanges. On the other hand, those containing relatively electronegative metals, such as B, Al, Si, Cu, and Sn, are most commonly prepared via transmetallation of aryllithiums and arylmagnesium halides. Arylzincs represent an interesting class of arylmetals in that they can be prepared either by direct metallation of aryl bromides and
Metal X = Br, I, F
ArM
M = Zn, B, Si, Sn, Cu,...
M = Li, Mg, Zn RLi X = Br or I
ArX
cat. Pd(0) LnMH X = I, Br, OTf cat. Pd(0) LnMMLn X = I, Br
ArLi
ArM′X′n −1
M′X′n
M′X′n
ArM′X′n −1 M = Zn, B, Si, Sn, Cu,...
ArMLn
M=B
ArMLn
M = B, Sn, Si
Scheme 38
370
III Pd-CATALYZED CROSS-COUPLING
iodides[156] or via transmetallation. In addition to the methods discussed above, Pdcatalyzed stannation,[157]–[159] borylation,[160],[161] and silylation[162] of aryl halides or triflates provide promising routes to arylmetals containing Sn, B, and Si, respectively. At present, however, the required dimetallic reagents are rather expensive, and this problem would have to be resolved before these reactions become truly useful. C.ii. Scope of Pd-Catalyzed Aryl–Alkenyl Coupling Aryllithiums are rarely used in Pd-catalyzed aryl – alkenyl coupling, although aryllithiums containing a chelating orthosubstituent (e.g., NMe2 and CH2NMe2) have been reported to undergo Pd-catalyzed cross-coupling in good yields.[20] On the other hand, Pd-catalyzed reaction of arylmagnesium derivatives with alkenyl electrophiles has been extensively investigated (Table 8). It is noteworthy that some even alkenyl chlorides, which are generally much less reactive than the corresponding bromides and iodides, have been successfully coupled with arylmagnesiums[163]–[165] (Scheme 39). It should be clearly noted,
MgBr + p-MeOC6H4 MeO
Cl
MgBr + Ph
[163]
Cl
[163]
Cl
C5H11
81%
Ph
C6H4-p-Cl 65% Ph
C6H4-p-OMe Ph
p-MeOC6H4 Ph
[164]
68% C6H4-p-Cl
C5H11 81%
Cl2Pd(PPh3) 2 p-MeC6H4 Et3N
C5H11
Ph
95% C5H11
[164]
Cl2Pd(PPh3)2 Et3N
Ph Ph
[164] Cl2Pd(PPh3)2 Ph Et3N
Cl SiMe3 Cl C5H11
[164]
PhMgCl Cl2Pd(PPh3)2 Et3N Ph C6H4-p-MeO [165]
Scheme 39
93%
70% SiMe3
[164]
Cl2Pd(PPh3)2 Et3N
MgCl +
Cl
[163]
Cl
Cl MgCl +
MgCl +
p-MeOC6H4
Ph Cl Pd(PPh ) 2 3 2
Cl2Pd(PPh3)2 Et3N
Cl MgCl +
C6H4-p-Cl
C6H4-p-Cl Cl2Pd(PPh3)2
MgBr + p-MeOC6H4 MgCl + Cl
Me
C6H4-p-Cl Cl Pd(PPh ) 2 3 2
Ph 86% C5H11
C6H4-p-MeO 82%
371
III.2.6 Pd-CATALYZED ALKENYL–ARYL
however, that the alkenyl chlorides used in these reactions are limited to arylated alkenyl chlorides and conjugated chloroenynes and chlorodienes. Thus, the general applicability of alkenyl chlorides in Pd-catalyzed aryl–alkenyl coupling needs to be further delineated. As in other cases of Pd- or Ni-catalyzed cross-coupling, Grignard reagents should probably be considered first in the aryl–alkenyl coupling because of their ready accessibility as the first-generation arylmetals. As needed, other metals should then be considered as potentially superior alternatives, and Zn, B, and Sn may have been the three most widely used metals, although some other metals including Al, Si, and Cu may also prove to be useful and even superior to the others mentioned above in some cases. Rigorous comparisons of metal countercations are still relatively rare. In the synthesis of (Z)-tamoxifen and related compounds,[166]–[168] Mg and Zn appear to be superior to Sn in terms of stereospecificity and operational simplicity[167] (Scheme 40). In cases where chemoselectivity is critically important, as in the synthesis shown in Scheme 41,[169] Zn would have to be chosen over Mg. O
NMe2
Cl
ArMX
Ph
O
O Cl
Ph
Ph
(Z)-tamoxifen
[Pd] Br
Ph
Ar
ArMX
Conditions Pd(PPh3)4, PhMe, 110 °C, 1 h Pd(PPh3)4, PhMe, 110 °C, 1 h [ClPd(π-C3H5)]2 , 25 °C, 24 h LiBr, Me 2NCOMe [ClPd(π-C3H5)]2 , 25 °C, 24 h LiBr, HMPA
PhMgCl PhZnCl PhSnBu3 PhSnBu3
Isolated Yield (%)
Z (%)
99 98 94
95 94 72
96
91
Scheme 40
Me Br
Me
O
)2 Zn
MeO
OMe
OMe Pd(PPh3)4
MeO
O
73%
Scheme 41
In some cases, more highly contrasting results may be obtained by using two or more different metals. In the reactions shown in Scheme 42, the aryl–alkenyl coupling using PhZnCl is regiospecific with retention. In sharp contrast, the alkenyl–aryl coupling using the corresponding alkenyltin derivative produces the unexpected regioisomer to the extent of 91%.[170] The reaction of arylboron compounds with alkenyl electrophiles has not been extensively investigated, and unfavorable results associated with fair yields in Pd-catalyzed
372
III Pd-CATALYZED CROSS-COUPLING
Me3SnSnMe3 Pd(PPh3)4, LiCl THF, reflux, 81%
OTf
SnMe3
PhZnCl, Pd(PPh3)4 THF, r.t., 55%
PhBr, BHT, iPr2NET Pd(PPh3)4, toluene reflux, 58%
Ph
Ph
+ 9:91
Ph
Scheme 42
aryl–alkenyl coupling have been observed.[171] However, in the light of their extensive involvement in Pd-catalyzed aryl–aryl coupling (Sect. III.2.5), arylboron compounds are expected to participate in Pd-catalyzed aryl–alkenyl coupling much more extensively, as exemplified by a recent favorable result shown in Scheme 43.[172] MeO2C
5% Pd(PPh )
B(OH)2
+
MeO2C
3 4 OMe K PO , dioxane, 3 4
OMe
reflux, 6 h
Br R
R R = H (95%), Me (90%) Scheme 43
Arylaluminums have not been used as extensively as some other arylmetals in Pd-catalyzed cross-coupling. However, the intrinsic reactivity of arylaluminums appears to be somewhere between that of Zn and Sn. It is this relatively low intrinsic reactivity of arylaluminums that is critically required in the cyclic carbopalladation–cross-coupling tandem process shown in Scheme 44. The high intrinsic reactivity of Zn leads to the formation of the unwanted direct cross-coupling product in 57% yield, while the corresponding reaction of PhSnBu3 does not produce either product under the conditions used.[173]
Pd(PPh3)4
+ PhM I
+ Ph
Me
Ph M = ZnCl AlPh2 SnBu3 Scheme 44
34% 93% Trace
Me 57% 97)
[22]
[ClPd(π-C3H5)]2 , TASF, P(OEt)3, THF
100
[50]
(CH2)9CHO
[ClPd(π-C3H5)]2, TASF, P(OEt)3, THF
70
[50]
(CH2)9CO2CH3
[ClPd(π-C3H5)]2 , TASF, P(OEt)3, THF
52
[50]
[ClPd(π-C3H5)]2 , TASF, P(OEt)3, THF
85
[50]
Ph
[ClPd(π-C3H5)]2 , TASF, P(OEt)3, THF
93
[50]
Ph
Cl2Pd(MeCN)2, DMF
85
[184]
Ph
Cl2Pd(MeCN)2, DMF
79
[185]
Ph
Pd(PPh3)4, C6H6
91(99.5)
[19]
71
[164]
75(>97)
[22]
76
[50]
67(99)
[186]
C6H13
Pd(PPh3)4, C6H6
C6H13
I
Ph
SiMe3
I
SiMe3
I
SnBu3
– BF Br
MgBr
(Z )-β-
I
C5H11 C6H13
I SiMe3
ZnBr
4
Cl
MgBr
MgX
Ph
+I
SnBu3
I
Yield (Selectivity) Ref% erence
C6H13
(CH2)8OAc
Cl2Pd(PPh3)2, Et3N
Pd(PPh3)4, C6H6 [ClPd(π-C3H5)]2 , TASF, P(OEt)3, THF Pd(PPh3)4, THF
375
III.2.6 Pd-CATALYZED ALKENYL–ARYL
TABLE 9. (Continued )
M
Type of Alkenyl Electrophiles
Conditions
X Me
Yield (Selectivity) Ref% erence
Me
I ZnBr BMPO
α-
Pd(PPh3)4, THF
79
[187]
Cl2Pd(MeCN)2, DMF
60
[177]
[ClPd(π-C3H5)]2, TASF, P(OEt)3, THF
100
[50]
80
[184]
Pd(PPh3)4, LiCl, THF
91
[188], [189]
Cl2Pd(PPh3)2, LiCl, NMP
81
[190]
OTBS
I
SnBu3 CO2H
(E )-α,βI SiMe3
TfO
Cl2Pd(MeCN)2,
SnMe3 tBu
TfO SnBu3
DMF, 25 °C
t
Bu
TfO SnBu3
Fe(CO)3
a
The entries are arranged according to the structural types of alkenyl electrophiles summarized in Scheme 5. With the same category, they are arranged (i) according to the types of substituents, i.e., alkyl > alkenyl > aryl > alkynyl, and (ii) in the increasing order of priority determined by the Chan–Ingold–Prelog rule. Finally, the leaving groups and then the countercations are arranged as discussed in the text.
D.ii. (E)--Sustituted Alkenylmetals Alkenylmetals containing Mg, Zn, B, Al, Si, Sn, and Zr have been successfully coupled with alkenyl electrophiles, mainly halides and triflates. Alkenyl electrophiles of all eight possible structural types have been used in these coupling reactions as shown in Table 10. Earlier systematic investigations on the Pd- or Ni-catalyzed alkenyl–alkenyl crosscoupling addressed several fundamentally important issues[15][16][92] that are still critically important, such as stereochemistry, comparison of different metal countercations, comparison of Pd- and Ni-catalysts, and hydrometallation–cross-coupling tandem process for the conversion of alkynes to stereo- and regio-defined conjugated dienes. It should be recalled that palladium catalysts have been shown to be superior to nickel catalysts in terms of stereoselectivity in the alkenyl–alkenyl coupling, permitting nearly 100% retention of the stereochemistry of each alkenyl group. On the contrary, stereochemical scrambling has been observed to significant extents in the corresponding Ni-catalyzed reactions. Generally, alkenylmetals containing Zn and Mg display the highest intrinsic reactivity in a given
376
C5H11
Bu
Bu
Bu
Et
Me
Me
THPO
THPO
R
()
B
B
AliBu2
O
O
O
O
SiMe2Cl
O
O
MgBr
B
ZrCp2Cl
B(Sia)2
ZnBr
MgBr
CO2Et
2
M
(E)-β-
Vinyl
Type of Alkenyl Electrophile
I
Br
Br
I
Br
Cl
Cl
()8
C5H11
C 4H 9
Ph
C6H13
C6H13
OTHP
C5H11
Cl2Pd(PPh3)2 + DIBAH
Pd(PPh3)4 , NaOH, THF
Pd(PPh3)4, NaOEt, C6H6
Pd(OAc)2, NaOH, THF
74(>98)
86(>98)
86(~100)
58
87
90
Cl2Pd(PPh3)2, Et3N(8 equiv) Pd(PPh3)4, BHA, NaOEt, EtOH
70
95
Cl2Pd(PPh3)2, Et3N(8 equiv)
Pd(PPh3)4, THF
77(>97)
Pd(PPh3)4, THF
Br
Br
−
Pd(PPh3)4, NaOH
Conditions
Yield (Selectivity) %
Br
X
TABLE 10. Pd-Catalyzed Coupling of (E)--Substituted Alkenylmetals with Alkenyl Electrophiles a
[15]
[196]
[194],[195]
[88]
[193]
[164]
[164]
[192]
[17]
[191]
Reference
377
C8H17
THPO
MeO2C
OTHP
2
3
( )
3
( )
( )
9
( )
MeO2C
HO
C8H17
C8H17
C6H13
C6H13
C5H11
C5H11
i
SnBu3
B(Sia)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
ZnCl
AlBu2
SiMe(O Pr)2
ZnBr
ZrCp2Cl
(E)-β-
Br
I
I
I
I
Cl
Br
MeO2C
Br
I
I
I
3
( )
OAc
O
C5H11
t-Bu
(CH2)5OH
C3H7
C4H9
C4H9
Cl
Ph
OZnX
7
()
C 4H 9
74(99)
Pd(PPh3)4, NaOH
Pd(PPh3)4 , toulene
54
23(>98)
82(>98)
Cl2Pd(PPh3)2 + DIBAH Pd(PPh3)4, NaOH, H2O
50
Pd(PPh3)4, NaOEt, C6H6
66
95
Pd(PPh3)4, THF
Pd(PPh3)4, NaOEt, C6H6
80(>99)
71(>99)
94(99.9)
91(>97)
Ni(PPh3)4, THF
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
Pd(PPh3)4, THF
Pd(PPh3)4, THF
(Continued )
[203]
[202]
[92]
[201]
[200]
[199]
[92]
[198]
[82]
[197]
[17],[92]
378
C3H7
Et
Ph
Ph
Ph
Ph
Ph
R
M
B
B
O
O
O
O
SnBu3
SnMe3
SnMe3
SiMe3
Sn[N(TMS)2]2I
SiMe3
TABLE 10. (Continued )
(Z)-β-
Type of Alkenyl Electrophile
Br
Br
–BF
+I
– BF
+I
I
I
I
I
X
4
Ph
4
Ph
()
8
9
()
OH
OTHP
C4H9
C4H9
Ph
Ph
C4H9
C6H13
32
71(86)
[ClPd(π-C3H5)]2, TASF, P(OEt)3, THF Cl2Pd(MeCN)2, DMF
Pd(PPh3)4, NaOEt, C6H6
Pd(PPh3)4, BHA, NaOEt, EtOH
Cl2Pd(MeCN)2, DMF
91
73−87
69
53
77
Pd(PPh3)4, TBAF, THF, dioxane
Cl2Pd(MeCN)2, DMF
78
[ClPd(π-C3H5)]2, TASF, P(OEt)3, THF
Conditions
Yield (Selectivity) %
[200]
[193]
[185]
[185]
[184]
[50]
[176]
[50]
Reference
379
()
9
MeO2C
C6H13
C4H9
t-Bu
MeO2C
HO
C8H17
C8H17
C5H11
()
7
Me
O
O
SnBu3
SiMe(OiPr)2
B
AliBu2
BX2
B(Thx)
B(OH)2
AliBu2
B(OH)2
ZnBr
-α
TfO
Br
Br
I
Br
Br
Br
I
I
Br
H
CH2C6H5
Ph
C 4H 9
8
O
() 2
Ph
CO2Me
C5H11
OTBS
C3H7
C 4H 9
C4H9
()
OH
Pd(PPh3)4 , Cs, THF
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
Pd(PPh3)4 , NaOEt, C6H6
Cl2Pd(PPh3)2, + DIBAH
Pd(PPh3)4 , NaOEt, C6H6
Cl2Pd(PPh3)2 , NaOH, THF
58
31(>99)
80(~100)
36(97)
40−50
54
82
55(>98)
Cl2Pd(PPh3)2 + DIBAH Pd(PPh3)4, NaOEt, C6H6
74(99)
88(99)
Pd(PPh3)4, NaOH, THF
Pd(PPh3)4, THF
(Continued )
[206]
[82]
[196]
[92]
[205]
[204]
[200]
[92]
[199]
[197]
380
C4H9
Ph
C4H9
C4H9
Ph
EtO
R
OEt
SnBu3
O
ZnCl
SnBu3
B
O
O
ZnBr
O
B
CO2Et
SnBu3
M
TABLE 10. (Continued )
trans-α,β-
cis-α,β-
β,β-
Type of Alkenyl Electrophile
I CH3
CH2OH
CH3
CH3
CH3
CH2CO2H
CH2CO2H
TfO
TfO
Br
Br
I
I
X
Pd(PPh3)4, DMF
10% Pd/C, CuI, AsPh3
Pd(PPh3)4, K3PO4, dioxane
Pd(PPh3)4, NaOEt, C6H6
Pd(PPh3)4, THF
Cl2Pd(MeCN)2, DMF
Cl2Pd(MeCN)2, DMF
Conditions
81(>98)
80(100)
76
81(~100)
93
82
50
Yield (Selectivity) %
[180]
[53]
[91],[138]
[194],[196]
[192]
[177]
[177]
Reference
381
O
AliBu2
O
O
B(Sia)2
B
O
O
B
O
α,β,β-
H3C
TfO
Br
I
Br
O
I
CH3
CH3
CH3
CH3
CH3
CH2OH
CH3
CH3
O
Pd(PPh3)4, THF
Pd(PPh3)4, K3PO4, dioxane
Pd(PPh3)4, NaOEt, C6H6
Pd(PPh3)4, NaOEt, C6H6
Pd(PPh3)4, NaOEt
78(>97)
97
52
45(>96)
51
[139]
[91],[138]
[208]
[180]
[207]
The entries are arranged according to the structural types of the alkenyl electrophiles summerized in Scheme 5. With the same category, they are arranged according to the substituents in the alkenylmetals as in the previous tables. For a given alkenyl group in the alkenylmetal reagents, the entries are arranged according to the priority order of the substituents in the alkenyl electrophiles. Finally, the leaving groups and then the countercations are arranged as discussed in the text.
a
C4H9
B
CH2OBn
O
CH3
C4H9
O
R
382
III Pd-CATALYZED CROSS-COUPLING
alkenyl–alkenyl coupling, but the reaction of alkenylmagnesium derivatives has been associated with various undesirable features including low chemoselectivity and low product yields. Although generally less reactive, alkenylmetals containing Al and Zr are attractive reagents, since they are often readily accessible via hydrometallation and carbometallation of alkynes and since highly satisfactory results have in fact been obtained in many cases. As is well known, various (E)--substituted alkenylmetals are most generally and reliably obtainable by hydroboration of alkynes. This advantage, however, is offset to considerable extents by the low intrinsic reactivity of alkenylboranes in Pd-catalyzed cross-coupling. Despite the development of the Suzuki protocol for alkenyl–alkenyl coupling, the overall synthetic scope of B-based methods appears to be more limited than that of Zn-based methods. Another widely used metal for Pd-catalyzed alkenyl–alkenyl coupling is Sn. Its intrinsically low reactivity and toxicity are two main limitations associated with Sn. In many favorable cases, its reactions are often as favorable as those of other favorable metals mentioned above. In more demanding cases, however, Sn has often been shown to be significantly inferior to Zn, B, and some other metals,[209]–[211] as illustrated later. Another complication associated with Sn is the capricious and often difficult-to-predict courses of hydrostannation of alkynes.[26] On the other hand, Sn as well as B has been very useful in achieving intramolecular alkenyl–alkenyl coupling, which often requires the generation of cyclization precursors containing both a nucleophilic alkenylmetal moiety and an electrophilic alkenyl moiety.[212] Other less frequently used metals in Pd-catalyzed crosscoupling include Li, Cd, Si, and Cu; Si[25] and Cu[28] have provided some promising results. It is entirely possible that they may become widely used metal countercations in the future. The following specific examples are presented to further support the above-mentioned generalizations. The use of alkenylzincs as excellent organometallic partners in Pd-catalyzed alkenyl– alkenyl coupling has amply been demonstrated.[180],[192],[197],[213] In most cases, reactions proceed smoothly to produce the desired products in excellent yields and high stereoselectivities, as exemplified by the synthesis of methyl dimorphecolates shown in Scheme 46.[197] I
Pent
I 1. 2 t-BuLi 2. ZnBr2
Pent
(CH2)7CO2Me OH 3% Pd(PPh3)4
Pent
OH I (CH2)7CO2Me ZnBr 3% Pd(PPh3)4
OH OH
94%, ~100% E,E
Pent
CO2Me
CO2Me 88%, 99% E, Z
Scheme 46
Even though Sn and B may have been the two most frequently used metals in Pdcatalyzed alkenyl–alkenyl coupling over the past two decades, it has been demonstrated with increasing frequency that a few of the metals associated with Negishi coupling, especially Zn and Zr in some cases, are more advantageous, leading to decidedly more satisfactory results. For example, the Stille coupling between (E)-Bu3SnCHRCHSnBu3 and (E)--bromomethylacrylate gives no more than 15% of the desired product even with the use of triphenylarsine as ligand of the Pd catalyst.[47] In sharp contrast, the corresponding coupling with (E)-Bu3SnCHRCHZnCl, generated in situ by stepwise transmetallations, proceeds rapidly to produce the desired product in 95% yield (Scheme 47).[209]
383
III.2.6 Pd-CATALYZED ALKENYL–ARYL
SnBu3
Bu3Sn
CO2Me
Br
98% stereoselective Br
Scheme 48
The superiority of alkenylzirconiums to other alkenylmetals has further been demonstrated in the synthesis of papulacandin D (Sect. III.2.18). The initial use of Stille coupling to synthesize the chain moiety resulted in less than 30% of desired product. However, the related coupling by using in situ generated alkenylzirconium gave the desired product in 82% yield[211] (Scheme 49). 1. Cp2ZrHCl 2. A
OZ
3. Cl2Pd(PPh3)2 DIBAL
1. Cp2ZrHCl 2. I2
OTES
OMe 82% OTBS
OTBS I
O
O
Cl2Pd(CH3CN)2 (B)
(E)-BrCH CHCO2Me (A)
30% (E)-Bu3SnCH CHCO2Me (B)
Scheme 49
OMe
384
III Pd-CATALYZED CROSS-COUPLING
Although further comparisons of alkenylzirconiums to other alkenylmetals in Pdcatalyzed cross-coupling are desirable, the results discussed above clearly indicate that alkenylzirconiums are among the best alkenylmetals in alkenyl–alkenyl coupling, and the hydrozirconation–cross-coupling tandem process provides a convenient and satisfactory route to conjugated dienes and polyenes. Although the intrinsic reactivity of alkenyl boranes in Pd-catalyzed cross-coupling is rather low, the use of a base remarkably enhances their reactivity as demonstrated by Suzuki and co-workers.[194]–[196],[200] Compared with other organometals containing Li, Mg, Zn, Al, Cu, and Zr, alkenylborons are very stable, even to alcohols and H2O. Thus, a wide variety of functional groups can be tolerated in their coupling reactions, as shown in Scheme 50.
B(OH)2
HO(CH2)9
I Pd(PPh3)4 NaOEt, C6H6 [200]
MeO2C(CH2)3
HO 66%
OTBS
HO2C(CH2)3
I Pd(PPh3)4 C5H11 aq. LiOH, THF
OTBS B(Sia)2
OTBS
OTBS
85%
[214]
C5H11
Scheme 50
However, the chemoselectivity in Pd-catalyzed cross-coupling of alkenylborons would suffer from the strongly basic condition and elevated reaction temperatures, when substrates with sensitive functional groups are employed. This limitation has been overcome, to some extent, by the use of aqueous solution of TlOH in place of NaOH or KOH as demonstrated by Kishi and co-workers in the synthesis of palytoxin.[215] The dramatic rate enhancement of Suzuki coupling by TlOH allows the reaction to proceed smoothly even at 0 °C. The utility of this method has been demonstrated in other natural product syntheses as well[216]–[220] (Sect. III.2.18). As discussed earlier, the low intrinsic reactivity and high chemical stability of alkenyltins can be exploited in devising intramolecular alkenyl–alkenyl coupling[212] particularly in the synthesis of cyclic natural products (Sect III.2.18). Macrocarbocycles including cyclic ketones and macrolactones have been synthesized by this coupling reaction as shown in Scheme 51. Bu3SnCHBr LiI, CrCl2 THF, DMF
O O
I
I
60%
H SnBu3
Bu3Sn SnBu3
LDA, PhN(Tf) 2 HMPA, THF −78 °C
O O (CH2)n n = 5, 6, 7, 8
O
O
O O
TfO
O
Pd2(dba)3 AsPh3, NMP 70 °C, 18 h [221]
96%
Pd(PPh3)4
(CH2)n
LiCl, THF [222]
(CH2)n 56−57%
Scheme 51
O
O
III.2.6 Pd-CATALYZED ALKENYL–ARYL
385
D.iii. (Z)- -Substituted Alkenylmetals Although stereoselective syn-hydrogenation and its equivalents via syn-hydrometallation of conjugated diynes[231] and enynes[232] have provided some prototypical selective routes to (Z,E )- and/or (Z,Z )-conjugated dienes, Pd-catalyzed alkenyl–alkenyl coupling has proved to be the method of choice for their preparation because of its general applicability, stereoselectivity, and favorable overall results including generally high product yields. (Z,E)-conjugated dienes can, in principle, be prepared by either the reaction of (E)alkenylmetals with (Z)-alkenylelectrophiles, as discussed in Sect. D.ii, or that of (Z)alkenylmetals with (E)-alkenyl electrophiles. Choice between these two options depends on a number of factors including the relative accessibility of the two required reagents. The ready accessiblity of (Z)--substituted alkenylcoppers via carbocupration[38] of ethyne makes Pd-catalyzed reaction of (Z)--substituted alkenylcoppers a very attractive route to (Z,E)- and (Z,Z)-conjugated dienes.[28],[226],[227] Interestingly, the addition of ZnBr2 as a cocatalyst[18] has proved to have favorable effects on this reaction[226],[227] (Scheme 52). 1. ZnBr2, THF 2. 3% Pd(PPh3)4 I (CH2)9CH(OR)2
) 2
CH(OR)2
CuLi 74%, >99% Z,Z 1. MgCl2, ZnBr2, THF 2. 3% Pd(PPh3)4 I
) ZO(CH2)10 2 CuLi
HO
3. H+
72%, >99% Z,Z Scheme 52
As discussed in Sect. B.iii.b, (Z)--substituted alkenylboranes are obtainable via 1-haloalkynes hydroboration – 1,2-hydride migration protocol.[36],[37],[96],[97] Their Pdcatalyzed reactions with (E)- and (Z)-alkenyl electrophiles provide (Z,E)- and (Z,Z)conjugated dienes, respectively (Scheme 53).[48]
Bu
A
+ I B(OiPr) 2
67% >98% E,Z
Bu
Hex B(OiPr) 2
+ Br
Hex
A
Scheme 53 (Continued )
87%
386
III Pd-CATALYZED CROSS-COUPLING
t-Bu
+ Br B(OiPr) 2
t-Bu
B(OiPr) 2
81% >97% Z,Z
Hex
A
Hex
t-Bu
Br A
+
t-Bu
79% OH
OH A = Pd(PPh ) , NaOEt, H C , 80 °C 34 6 6 Scheme 53 (Continued )
At present, (Z)--substituted alkenylmetals containing other metals are less readily accessible than those mentioned above, even though the Zr-catalyzed carboalumination of ethyne has been shown to produce (Z)--substituted alkenylalanes.[228] They are generally prepared via metallation–transmetallation of (Z)--substituted halides. Despite this drawback, (Z)--substituted alkenylzincs generated by this procedure have been shown to be superior reagents in the subsequent Pd-catalyzed cross-coupling reaction[186],[198],[229] (Table 11). TABLE 11. Pd-Catalyzed Coupling of (Z)--Substituted Alkenylmetals with Alkenyl Electrophiles a
R
M
Type of Alkenyl Electrophile (E)-β-
I
CH3
MgX )2 CuLi
I
C2H5 C2H5
)2 CuLi
Br
C3H7
)2 CuLi
I
C3H7
)2 CuLi
I
C4H9
B(OiPr)2
C 4H 9
B(Sia)2
C5H11
)2 CuLi
Conditions
X
Br
Br
I
C6H13
Pd(PPh3)4, C6H6
87(>99)
[22]
C5H11
Pd(PPh3)4, ZnX2, THF
82(99)
[226]
Ph
Pd(PPh3)4, ZnX2, THF
85(97.6)
[226]
Cl
Pd(PPh3)4, ZnX2, THF
89(~100)
[186]
I
Pd(PPh3)4, ZnX2, THF
76(~100)
[186]
C6H13
Pd(PPh3)4, NaOEt, C6H6
70(>99)
[98]
Ph
Pd(PPh3)4, NaOEt, C6H6
49(99)
[196]
Pd(PPh3)4, ZnX2, THF
80(99)
[226]
Pd(PPh3)4, THF
92(~100)
[197]
Pd(PPh3)4, ZnX2, THF
55(99)
[227]
()
()
3
3
C2H5
I
() 6
C5H11
t
ZnBr
OH I
Bu
Cu,MgX2
Yield (Selectivity) Reference %
C5H11
CO2CH3
III.2.6 Pd-CATALYZED ALKENYL–ARYL
387
TABLE 11. (Continued )
R
Type of Alkenyl Electrophile
M
X
Conditions
I HO
CH3
MgX
C2H5
)2 CuLi
C2H5
ZnX
(Z)-β-
C 3H 7
B(Sia)2
Pd(PPh3)4, C6H6
87(>97)
[22]
I
C5H11
Pd(PPh3)4, ZnX2, THF
86(99)
[226]
Pd(PPh3)4, THF
88(99.5)
[229]
()
OAc
8
()
OH
9
Br
C5H11
() 9
(Z)-β-
)2 CuLi
[184]
C6H13
I B(Sia)2
74
I
I
C 3H 7
Cl2Pd(CH3CN)2, DMF
C4H9
SnBu3
Yield (Selectivity) Reference %
I
OH
C2H5
Pd(PPh3)4, NaOEt, C6H6
50
[200]
Pd(PPh3)4, NaOEt, C6H6
69
[200]
Pd(PPh3)4, ZnBr2, THF
86(>99)
[226]
Pd(PPh3)4, THF
95(99)
[197]
53(99)
[227]
78
[184]
Pd(PPh3)4, NaOEt
55(99)
[196]
Pd(PPh3)4, THF
94(~100)
[226]
Pd(OAc)2, NMP
75
[230]
Pd(OAc)2, CH2Cl2
>90
[230]
Cl2Pd(MeCN)2, DMF
61
[184]
OH I C5H11
ZnBr
t
C 4H 9
()
C 4H 9
C5H11
Pd(PPh3)4, ZnX2, THF
I
C4H9
Cl2Pd(MeCN)2, DMF
SnBu3 α-
Br
B(Sia)2
Ph
β,βC5H11
)2 CuLi
H 3C
CH3 I
cis-α,β-
TfO
a
See Table 10
CH3
SnBu3 I
HO
7
I Cu,MgX2
HO
CO2Me
SnBu3
388
III Pd-CATALYZED CROSS-COUPLING
D.iv. -Substituted Alkenylmetals The -substituted alkenylmetals used in Pd-catalyzed cross-coupling have been mainly those containing Mg, Zn, B, and Sn, as shown in Table 12 as well as Schemes 54–57. Of these, -substituted alkenylmetals containing Mg and Zn can readily be prepared by direct oxidative metallation of 2-halo-1-alkenes[192] that are easily accessible by Markovnikov addition of HX to 1-alkynes (Scheme 54). -Substituted alkenyltin compounds have been prepared and used in the construction of bicyclic diene systems via intramolecular Stille coupling, as shown in Scheme 55.[234] TABLE 12. Pd-Catalyzed Coupling of -Substituted Alkenylmetals with Alkenyl Electrophiles a R
Type of Alkenyl Electrophile
M
Conditions
X
Yield (Selectivity) Reference %
(E)-βCH3
I
CH3
Cl
C5H11
MgX CH3
C5H11
Cl MgX iBu
Br BiBu
Br ZnBr
82(>97)
[22]
Cl2Pd(PPh3)2, Et3N (8 equiv)
55
[164]
Cl2Pd(PPh3)2, Et3N (8 equiv)
62
[164]
84(>99)
[117]
C6H13
Pd(PPh3)4, NaOH, H2O, THF
Ph
Pd(PPh3)4, THF
87−91
[233]
Pd(PPh3)4, C6H6
84(>97)
[22]
Pd(PPh3)4, NaOH, H2O, THF
87(>99)
[117]
92
[233]
2
CF3
Pd(PPh3)4, C6H6
C6H13
MgX
(Z )-βCH3
C6H13
I
MgX i
Bu
Br BiBu
C6H13
2
αCF3
Br ZnBr
Ph
Pd(PPh3)4, THF
389
III.2.6 Pd-CATALYZED ALKENYL–ARYL
TABLE 12. (Continued ) R
Type of Alkenyl Electrophile
M
Yield (Selectivity) Reference %
Conditions
X
cis-α,βI
CF3 ZnBr
Pd(PPh3)4, THF
86
[233]
Pd(PPh3)4, THF
90
[233]
I CF3 ZnBr OH a
See Table 10.
Br
Ph
Ph
Ph
Zn*
Br
R = H, 91%
R
R = Me, 86%
5% Pd(PPh3)4, THF
ZnBr
R
Scheme 54
SnBu3
OTf
5% Pd(PPh3)4 THF
R = H, 82%
CO2Me
R = Me, 82%
CO2Me
R
R Scheme 55
CH2
CHOEt
1. t-BuLi (2 equiv) TMEDA(2 equiv) 2. ZnCl2
I Pent-n 5% Pd(PPh3)4
OEt
OEt Pent-n 74%
ZnCl I s-BuLi (1 equiv) THF-HMPA
SEt
Pent-n
SEt
5% Pd(PPh3)4
Li CH2
CHSEt
1. s-BuLi (1 equiv) THF-HMPA 2. ZnCl2
Pent-n 0%
I
SEt
Pent-n 5% Pd(PPh3)4
ZnCl Scheme 56
SEt Pent-n 81%
390
III Pd-CATALYZED CROSS-COUPLING
O
OR
OTf OR
OH [O]
MLn cat. Pd(0)
AcO
AcO AcO R = Bu, MLn = ZnCl, 82% R = Me, MLn = SnBu3, 54% Scheme 57
The Pd-catalyzed reactions of -heterosubstituted alkenylzincs containing alkoxy and thioalkoxy groups were developed with the goal of synthesizing heterosubstituted conjugated dienes for the Diels–Alder reaction[118] (Scheme 56). The use of the parent alkenyllithiums did not produce the desired dienes in detectable amounts. This reaction has been applied to the synthesis of steroidal -hydroxy enones[235] (Scheme 57). It should be noted that Zn has been shown to be decidedly superior to Sn as the countercation. D.v. , -Substituted Alkenylmetals A large number of natural products, such as carotenoids, contain conjugated di- and oligo-ene moieties with at least one (E)-trisubstituted alkene unit, such as 1 and 2 shown in Scheme 58. Although all (E)-isomers are dominant, their stereoisomers are also known.
R2
R1
R2
R1
1
2 Scheme 58
Even today, carotenoids and other natural products represented by 1 and/or 2 are synthesized by using the Wittig and related carbonyl olefination reactions that are often not highly stereoselective, thus requiring delicate and tedious separations. Carbometallation reactions of alkynes,[38],[40] especially the Zr-catalyzed carboalumination discovered in 1978,[236],[237] used in conjunction with Pd-catalyzed cross-coupling[18] have provided a totally different carbometallation – cross-coupling tandem protocol for the synthesis of 1 and 2 (Scheme 59). Since the preparation of ,-substituted alkenylmetals as the first-generation organometals has been achieved mostly by Zr-catalyzed carboalumination[40] and carbocupration,[38] the exploitation of Protocol I has largely resorted to these two carbometallation reactions, as indicated by the results summarized in Table 13. Moreover, since it is impractical to carry out methylcupration of alkynes requiring several days at 25 °C,[238] the synthesis of natural products represented by 1 and 2 by the use of Protocol I has mostly been limited to those cases where Zr-catalyzed carboalumination is
391
III.2.6 Pd-CATALYZED ALKENYL–ARYL
R1C CH
Me3Al cat. Cp2ZrCl2
AlMe2
R1
R2 I cat. PdLn, ZnX2 Protocol I
3 I2
I
R1
1. BuLi 2. ZnX2
MLn
I cat. PdLn
ZnX
R1
R2
Protocol II
4
HMLn
R1
M cat. PdLn
R2 1
R2
Protocol IV
5 Protocol I, II, or IV using XR2 or MR2
Various options
R1
R2
1
R
6 1
R1
2
2
R , R = C groups. X = halogen, etc. M = metal countercations. Scheme 59 TABLE 13. Pd-Catalyzed Coupling of ,-Substituted Alkenylmetals with Alkenyl Electrophiles a R1
Type of Alkenyl Electrophile X
M R2
Conditions
Yield (Selectivity) Ref% erence
Vinyl C5H11
AlMe2 AlMe2
ZO
AlMe2
Br
Pd(PPh3)4, ZnCl2
73(>97)
[18]
Br
Pd(PPh3)4, ZnCl2
70(>98)
[18]
Br
Pd(PPh3)4, ZnCl2
43(94)
[251]
C5H11
Pd(PPh3)4, THF
96(>99)
[226]
C5H11
Pd(PPh3)4, ZnCl2
78(>99)
[227]
Pd(PPh3)4, THF
74(99)
[227]
(E )-βH3C
) 2
CuLi
I
Cu.MgX2
I
Cu.MgX2
Br
CH3 H3C C2H5
H3C C2H5
Ph
(Continued )
392
III Pd-CATALYZED CROSS-COUPLING
TABLE 13. (Continued ) R1
Type of Alkenyl Electrophile X
M R2
C5H11
AlMe2
I
Cu.MgX2
I
BBr2
I
C5H11 C6H13
Pd(PPh3)4, ZnCl2
65(>97)
[18]
C5H11
Pd(PPh3)4, THF
70(>99)
[227]
C6H13
Pd(PPh3)4, LiOH, H2O
52(99)
[122]
Pd(PPh3)4, LiOH, H2O
81(99)
[122]
C4H9
CH3 H3C
Conditions
Yield (Selectivity) Refe% rence
C4H9 TMS I
BBr2
C6H13
C6H13
(Z )-βH3C
) 2
CuLi
I
C5H11
Pd(PPh3)4, ZnX2
92(>99)
[226]
Cu.MgX2
I
C5H11
Pd(PPh3)4
64(>99)
[227]
Cu.MgX2
I
C5H11
Pd(PPh3)4
70(>99)
[227]
I
C4H9
Pd(PPh3)4, LiOH, H2O
62
[122]
I
C2H5
Pd(PPh3)4, THF
70(>99)
[227]
Pd(PPh3)4, ZnX2
94(>99)
[226]
Pd(PPh3)4, THF
55(>99)
[227]
80
[188], [189]
CH3 H3C C2H5 H3C i
C3H7
(Z )-β-
TMS BBr2 C6H13 Ph
Cu.MgX2 C2H5
H3C
) 2
CuLi
β,β-
CH3 I
CH3
CH3 H3C
C4H9
Cu.MgX2
I
C2H5 H3C
SnBu3 CH3
a
See Table 10.
cis-α,β-
CH3 TfO
Pd(PPh3)4, LiCl, THF
393
III.2.6 Pd-CATALYZED ALKENYL–ARYL
involved. Some prototypical examples are shown in Schemes 60–62. Particularly noteworthy is the development of a highly efficient and stereoselective iterative and convergent method for the synthesis of carotenoids and retinoids shown in Schemes 61 and 62.[240] It should be noted that the reactivity of ,-substituted alkenylalanes can be significantly enhanced by the addition of ZnBr2 or ZnCl2.[18] Despite the high efficiency and stereoselectivity associated with Protocol I shown in Scheme 59, its full development as a method for the synthesis of carotenoids, retinoids, and
I OZ cat. 2Pd(PPh Cl 3)2
Me 3Al cat. 2Cp ZrCl 2
OZ
+2n-BuLi [239]
vitamin A(Z=H), 60%
Scheme 60
AlMe2
Me3Al cat. Cp2ZrCl2
Br I cat. Cl2Pd(PPh3)2 + DIBAL, ZnBr2 [240]
β -carotene, 68% Scheme 61
1. Me3Al cat. Cp2ZrCl2 2. Pd(PPh3)4, ZnBr2 Br I [240] A
1. Me3Al cat. Cp2ZrCl2 2. Pd2(dba)3, TFP, ZnBr2, 1
Br 85%
1
A
82%
74%
γ-carotene, 53% A = (1). Me3Al, cat. Cp2ZrCl2; (2). Pd2(dba)3, TFP, ZnBr2,
Scheme 62
Br
TMS ; (3). TBAF
394
III Pd-CATALYZED CROSS-COUPLING
other natural products has been made only within the past few years. Consequently, it has not yet been widely utilized. Although more circuitous, Protocols II and IV have been more widely exploited in the synthesis of a variety of natural products, such as rapamycin,[241],[242] caliculin A,[243]–[245] indanomycin,[246] sanglifehrin A,[247] vitamin A,[239],[248] restrictinol,[249] and - and -carotenes,[240] as exemplified by the results shown in Schemes 63 and 64. The structures of these natural products are shown in Table 3 in Sect. III. 2.18. C [240]
I
A
100% 1. LDA 2. ClPO(OEt)2 3. LDA
C 68%
1. BuLi 2. ZnCl2
O
B [239]
)2 Zn
OZ
87%
A = (1) Me3Al, Cp2ZrCl2; (2) I2 C = (1) Pd2(dba)3, TFP,
vitamin A (Z = H)
B = Pd(PPh3)4, I OZ TMS ; (2) TBAF D = (1) Me3Al, Cp2ZrCl2 ; (2) n-BuLi; (3) (CHO)n
BrZn
Scheme 63 1. Pd(PPh3)4, TlOH
O
I
OSiEt3
O
B(OH)2
OMe 2. TBAF
restrictinol, 69%
OMe
OH
Scheme 64
Haloboration of 1-alkynes followed by chemoselective cross-coupling can provide ,-substituted alkenylborons that undergo Pd-catalyzed coupling with alkenyl halides to give stereodefined trisubstituted alkenes.[122] The use of other ,-substituted alkenylmetals has also been demonstrated. For example, exocyclic alkenylmetals containing Zn and Sn have been used in Pd-catalyzed cross-coupling approach to the vitamin D skeleton[250] as shown in Scheme 65. It should be noted that the alkenylzinc appeared to be distinctly superior to the corresponding alkenyltins. R I
R
R 1. t-BuLi 2. MX
OTBS
H Br
H
H M = ZnBr M = SnMe3 M = SnBu3
Pd(0)
M
OTBS Scheme 65
95% 99)
[82]
Ph
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
73( 99)
[82]
Ph
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
63(>99)
[82]
Ph
[ClPd(π-C3H5)]2, TBAF, P(OEt)3, THF
>42(>99)
[82]
Pd(PPh3)4, NaOH
40
[257]
Pd(PPh3)4, ZnCl2
65( 97)
[18]
Pd(PPh3)4, ZnCl2
85( 97)
[18]
(E )-βI
C4H9
ZrCp2Cl C 4H 9
C 4H 9
Pd(PPh3)4, ZnCl2
Br ZrCp2Cl C2H5
C 2H 5
Reference
Conditions
Vinyl
C2H5 C 2H 5
Yield (Selectivity) %
Type of Alkenyl Electrophile X
1
I
C 4H 9
SiMe(OEt)2 C 4H 9
C 4H 9
Br SiMe(OEt)2 Br SiMe(OEt)2
C6H13
O Si Me2 TMS
C 3H 7
α-
Br
BR2 C 2H 5
C 2H 5
Br
AliBu2
CH3
β,β-
C 4H 9 Br
C2H5 C 2H 5
ZrCp2Cl
CO2CH3 C 4H 9
Br
CO2CH3
III.2.6 Pd-CATALYZED ALKENYL–ARYL
397
Yield (Selectivity) %
Reference
Pd(PPh3)4, NaOH
60
[257]
Pd(PPh3)4, THF
80
[258]
TABLE 14. (Continued ) R2 R1
Type of Alkenyl Electrophile X
M
Conditions
TMS C 3H 7
CH3 Br
BR2
CH3
TfO H
cis-α,βH3C
Cu
O O
a
See Table 10.
D.vii. trans- ,-Substituted Alkenylmetals Since most of the facile and general hydro- and carbometallation reactions involve synaddition, the preparation of trans-,-substituted alkenylmetals via syn-addition of alkynes would require carbometallation of terminal alkynes placing the metal in the internal position. Although such reactions exemplified by carbopalladation[259] are known, they are still more exceptional than normal. From the perspective of the current discussion, more commonly used are (i) some anti-hydrometallation reactions of proximally heterofunctional internal alkynes[260]–[263] and (ii) the hydroboration–migratory insertion tandem process of 1-haloalkynes.[135] Whereas the H migration produces (Z)-substituted alkenylboranes (Sect. D.iii), the corresponding C migration provides trans,-substituted alkenylmetals.[135] (See Table 15.) TABLE 15. Pd-Catalyzed Coupling of trans-,-Substituted alkenylmetals with Alkenyl Electrophiles a R2 R1
Type of Alkenyl Electrophile
M
(Z )-β-
CH3 C4H9
X
B(OiPr)
Br
C6H13
Br
C6H13
4H9
i
B(O Pr)2 CH3
C4H9
C4H9
Reference
Pd(PPh3)4, NaOH, H2O
70(>99)
[135]
Pd(PPh3)4, NaOH, H2O
66( 97)
[135]
Pd(PPh3)4, NaOH, H2O
70(>99)
[135]
Pd(PPh3)4, NaOH, H2O
59(>99)
[135]
2
CH3 tC
Conditions
Yield (Selectivity) %
i
B(O Pr)2 Ph B(OiPr)2
β, β-
CH3 Br
OH CH3
Br
CH3
(Continued )
398
III Pd-CATALYZED CROSS-COUPLING
TABLE 15. (Continued ) R2 R1
Type of Alkenyl Electrophile
M
X
Ph
CH3 Br
iPr)
C4H9
B(O 2 CF3
C2H5O
Reference
Pd(PPh3)4, NaOH, H2O
72(>99)
[135]
Pd(PPh3)4, THF
90
[267]
Pd(PPh3)4, THF
86
[267]
cis-α,β- Br
ZnBr CF3
C2H5O
CH3
Conditions
Yield (Selectivity) %
TfO
ZnBr
a
See Table 10.
Some trans-,-, along with cis-,-substituted alkenyltin compounds have been prepared and used in intramolecular coupling reactions to synthesize cyclic compounds,[264],[265] as shown in Scheme 69. The reaction could be mediated by stoichiometric CuCl instead of catalytic Pd complexes,[265] while the use of Cu(I) as a cocatalyst in Stille coupling has been demonstrated.[30]–[33],[266] SnMe3 R
Br
[264]
EtO2C SnMe3
I
70−95%
Pd(PPh3)4 DMF
R
CO2Et
CuCl DMF, 62 C
R = H, Me, (CH2)2OMe (CH2)3OTBS
89%
[265]
CO2Et
CO2Et Scheme 69
D.viii. Tetrasubstituted Alkenylmetals In a synthesis of nakienone A, tetrasubstituted alkenylzinc, in situ generated from the corresponding alkenyliodide, was successfully coupled with the dienyl iodide to give the desired coupling product in 95% NMR yield, which was further converted into nakienone A in three steps[268] (Scheme 70). OTMS
1. n -BuLi
5% Cl2Pd(TFP)2 10% n-BuLi 3. Replace THF TBDMSO I with DMF I
OTMS 2. ZnBr2
OTBDMS
O
OH
3 steps
95% by NMR
TBDMSO TBDMSO
HO nakineone A
Scheme 70
III.2.6 Pd-CATALYZED ALKENYL–ARYL
399
A number of fluorine-substituted alkenylzincs have been coupled successfully with alkenyl halides,[269],[270] and this reaction has been applied to the synthesis of fluorinated analogs of codlenone as shown in Scheme 71. The use of other tetrasubstituted alkenylmetals containing Zn, B, and Zr is shown in Table 16. F
F Me
I ZnBr + F
F Pd(PPh3)4
(CH2)7OAc
F
Me
OAc
THF
F
F F 91% 100% stereoisomeric purity Scheme 71
TABLE 16. Pd-Catalyzed Coupling of Tetrasubstituted alkenylmetals with Alkenyl Electrophiles a R2
R3
R1
M
Type of Alkenyl Electrophile
X
Conditions
Yield (Selectivity) Reference %
(E )-βI
C4H9
Pd(PPh3)4, THF
C6H13 Ph
ZnBr F
C4H9
I
F
BBu2
Br
F
[139]
Pd2dba3-PPh3, CuI, THF-HMPA
83−84
[271]
Pd2dba3-PPh3, CuI, THF-HMPA
82−86
[271]
Pd(PPh3)4, THF
78
[269]
Pd(PPh3)4, THF
83
[269]
Cl2Pd(PPh3)2 + DIBAH, CuI, THF, DMF
79
[99]
Pd(PPh3)4, THF
75
[269]
Cl2Pd(PPh3)2 + DIBAH, CuI, THF, DMF
81
[99]
Pd(PPh3)4, CuCl, THF
64
[272]
F I
C 4H 9 F
95(>97)
C6H13
ZnCl F I
F
C6H13
ZnCl C5H11
TMS I
()
ZnBr F
I
C5H11
C6H13
ZnCl TMS
I
() 4
ZnBr Et
4
(Z )-β-
F
C4H9
OtC4H9
Et ZrCp2Cl
α,β,β-
t
O C4H9
I Pr
Pr
(Continued )
400
III Pd-CATALYZED CROSS-COUPLING
TABLE 16. (Continued ) R2
R3
R1
M
Type of Alkenyl Electrophile
Et
X
Et
F C 4H 9
Conditions
I
ZrCp2Cl
Pr
F
I
C4H9
ZnCl
F
F
F
F
F
ZnCl
Yield (Selectivity) Reference %
I Cl
Pr
Pd(PPh3)4, CuCl, THF
90
[272]
Pd(PPh3)4, THF
78
[269]
Pd(PPh3)4, THF
80
[269]
F C5H11
a
See Table 10.
D.ix. Summary Since its discovery in the 1970s (Sect. A), Pd- and Ni-catalyzed alkenyl–alkenyl coupling, particularly the Pd version, has been developed into one of the most important modern methodologies for carbon–carbon bond formation. Alkenylmetals containing Li, Mg, Zn, B, Al, Si, Sn, Cu, Zr, and other metal counterions have been used in the coupling, and their merits and demerits depend on a number of factors, such as stereochemistry, regiochemistry, chemoselectivity, product yield, reagent accessibility, efficiency, operational simplicity, toxicity, and other environmental concerns. Consequently, it is difficult to compare them and rank their overall merits and demerits. Nonetheless, several of them highlighted in bold letter (i.e., Mg, Zn, B, Al, Sn, and Zr) in Scheme 72 have been more frequently used than the others.
Li Mg Cu Zr
Frequently used metal countercations: Mg, Zn, B, Al, Sn, and Zr (shown in bold)
B Al
Si
Zn
Generally satisfactory: Zn, B, Al, and Zr (circled)
Sn Scheme 72
The currently available data, especially those pertaining to comparison of metal countercations, suggest that the metal of choice in a given case may generally be found among Zn, B, Al, and Zr. In many cases, Pd-catalyzed reactions of alkenyl- and arylzincs have been shown to be more favorable than those of the corresponding organomagnesiums. Similarly, it has become increasingly clear that organozincs and organoborons are generally superior to organotins in many of the more demanding Pd-catalyzed cross-coupling reactions.
III.2.6 Pd-CATALYZED ALKENYL–ARYL
401
Although less frequently used than Zn, B, and Sn, the ability of Al and Zr to participate in stereo- and regioselective hydrometallation and carbometallation of alkynes coupled with their generally favorable Pd-catalyzed cross-coupling, especially in cases when Zn salts are used as cocatalysts, make them two generally favorable metals, and their use may be expected to increase in the future. Despite these comparisons, some merits of Sn, such as its generally high chemoselectivity and its ability to undergo Pd-catalyzed crosscoupling in tandem cyclization and other multistage cascade processes, are noteworthy. Alkenylcoppers have not been frequently used. However, generation of (Z)--substituted alkenylcoppers via carbocupration followed by their Pd-catalyzed cross-coupling appears to be the method of choice in the synthesis of 1,4-disubstituted (Z,Z)-conjugated dienes. It also nicely complements the synthesis of 1,4-disubstituted (E,Z)-conjugated dienes by the hydrometallation– cross-coupling tandem process involving B, Al, and Zr. The use of alkenylsilicons in Pd-catalyzed cross-coupling still largely remains as a scientific novelty. Its current main drawback is the low intrinsic reactivity of the C—Si bond, which must be activated with fluoride and other bases. Furthermore, there do not appear to be many persuasive examples where the superiority of Si is clearly demonstrated. Further investigation, especially critical comparison of Si with other widely used metals, would be necessary for an objective evaluation of Si relative to the others.
REFERENCES [1] M. S. Kharasch and O. Reinmuth, Grignard Reactions of Nonmetallic Substances, PrenticeHall, New York, 1954, Chap. 16, p.1046–1132. [2] M. Tamura and J. K. Kochi, J. Am. Chem. Soc., 1971, 93, 1483. [3] J. K. Kochi, Acc. Chem. Res., 1974, 7, 351–360. [4] M. Tamura and J. K. Kochi, J. Am. Chem. Soc., 1971, 93, 1487. [5] G. H. Posner, Org. React., 1975, 22, 253– 400. [6] O. P. Vig, J. C. Kapur, and S. D. Sharma, J. Indian Chem. Soc., 1968, 45, 734. [7] M. Nilsson and R. Wahren, J. Organomet. Chem., 1969, 16, 515. [8a] G. M. Whitesides, W. F. Fischer, Jr., J. San Filippo, Jr., R. W. Bashe, and H. O. House, J. Am. Chem. Soc., 1969, 91, 4871. [8b] A. T. Worm and J. H. Brewster, J. Org. Chem., 1970, 35, 1715. [9] J. Gasteiger, G. E. Gream, R. Huisgen, W. E. Konz, and U. Schnegg, Chem. Ber., 1971, 104, 2412. [10] O. P. Vig, S. D. Sharma, and J. C. Kapur, J. Indian Chem. Soc., 1969, 46, 167. [11] G. Büchi and J. A. Carlson, J. Am. Chem. Soc., 1969, 91, 6470. [12] K. Tamao, K. Sumitani, and M. Kumada, J. Am. Chem. Soc., 1972, 94, 4374. [13] R. J. P. Corriu and J. P. Masse, J. Chem. Soc. Chem. Commun., 1972, 144. [14] E. Negishi and S. Baba, J. Chem. Soc. Chem. Commun., 1976, 596. [15] S. Baba and E. Negishi, J. Am. Chem. Soc., 1976, 98, 6729. [16] E. Negishi and D. E. Van Horn, J. Am. Chem. Soc., 1977, 99, 3168. [17] N. Okukado, D. E. Van Horn, W. L. Klima, and E. Negishi, Tetrahedron Lett., 1978, 1027. [18] E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, and B. I. Spiegel, J. Am. Chem. Soc., 1978, 100, 2254. [19] M. Yamamura, I. Moritani, and S. I. Murahashi, J. Organomet. Chem., 1975, 91, C39.
402
III Pd-CATALYZED CROSS-COUPLING
[20] S. I. Murahashi, M. Yamamura, K. Yanagisawa, N. Mita, and K. Kondo, J. Org. Chem., 1979, 44, 2408. [21] K. Tamao, K. Sumitani, Y. Kiso, M. Zembayashi, A. Fujioka, S. Kodama, I. Nakajima, A. Minato, and M. Kumada, Bull. Chem. Soc. Jpn., 1976, 49, 1958. [22] H. P. Dang and G. Linstrumelle, Tetrahedron Lett., 1978, 191. [23] E. Negishi and F. Liu, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., VCH, Weinheim, 1998, 1–47. [24] N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483. [25] T. Hiyama and Y. Hatanaka, Pure Appl. Chem., 1994, 66, 471–1478. [26] J. K. Stille, Angew. Chem. Int. Ed. Engl., 1986, 25, 508–524. [27] V. Farina, V. Krishnamurthy, and W. J. Scott, Org. React., 1997, 50, 1–652. [28] J. F. Normant and A. Alexakis, in Current Trend in Organic Synthesis, H. Nozaki, Ed., Pergamon Press, New York, 1982, 291–302. [29] A. Alexakis, C. Chuit, M. Commercon-Bourgain, J. P. Foulon, N. Jabri, P. Mangeney, and J. F. Normant, Pure Appl. Chem.,1984, 56, 91–98. [30] J. P. Marino and J. K. Long, J. Am. Chem. Soc., 1988, 110, 7916. [31] L. S. Liebeskind and R. W. Fengl, J. Org. Chem., 1990, 55, 5359. [32] L. S. Liebeskind and J. Wang, Tetrahedron Lett., 1990, 31, 4293. [33] L. S. Liebeskind and S. W. Riesinger, J. Org. Chem., 1993, 58, 408. [34] V. Snieckus, Chem. Rev., 1990, 90, 879–933. [35] K. Ritter, Synthesis, 1993, 735–762. [36] E. Negishi, R. M. Williams, G. Lew, and T. Yoshida, J. Organomet. Chem., 1975, 92, C4. [37] J. B. Campbell and Jr. G. A. Molander, J. Organomet. Chem., 1978, 156, 71. [38] J. F. Normant and A. Alexakis, Synthesis, 1981, 841–870. [39] J. March, Advanced Organic Chemistry, 4th ed., Wiley, New York, 1992, 734. [40] E. Negishi, Pure Appl. Chem., 1981, 53, 2333–2356. [41] E. Negishi, Acc. Chem. Res., 1987, 20, 65–72. [42] E. Negishi and T. Takahashi, Aldrichimica Acta, 1985, 18, 31–48. [43] H. C. Brown, D. Basavaiah, and S. U. Kulkarni, J. Org. Chem., 1982, 47, 3808. [44] H. C. Brown, T. Imai, and N. G. Bhat, J. Org. Chem., 1986, 51, 5277. [45] N. A. Bumagin, N. L. Andryukhova, and I. P. Beletskaya, Dokl. Akad. Nauk SSSR, 1987, 297, 1126. [46] T. Jeffery, Tetrahedron Lett., 1999, 40, 1673. [47] V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585. [48] G. P. Roth and C. E. Fuller, J. Org. Chem., 1991, 56, 3493. [49] K. Kikukawa, K. Kono, F. Wada, and T. Matsuda, J. Org. Chem., 1983, 48, 1333. [50] Y. Hatanaka and T. Hiyama, J. Org. Chem., 1988, 53, 918. [51] N. A. Bumagin, N. P. Andryukhova, and I. P. Beletskaya, Dokl. Akad. Nauk SSSR, 1989, 307, 375. [52] N. A. Bumagin, I. G. Bumagina, and I. P. Beletskaya, Dokl. Akad. Nauk SSSR, 1984, 274, 818. [53] G. P. Roth, V. Farina, L. S. Liebeskind, and E. Peña-Cabrera, Tetrahedron Lett., 1995, 36, 2191. [54] D. R. Mckean, G. Parrinello, A. F. Renaldo, and J. K. Stille, J. Org. Chem., 1987, 52, 422. [55] E. Shirakawa, H. Yoshida, and H. Takaya, Tetrahedron Lett., 1997, 38, 3759. [56] S. Darses, J.-P. Genˆet, J.-L. Brayer, and J.-P. Demoute, Tetrahedron Lett., 1997, 38, 4393.
III.2.6 Pd-CATALYZED ALKENYL–ARYL
[57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96]
403
A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 1987, 109, 5478. D. Badone, R. Cecchi, and U. Guzzi, J. Org. Chem., 1992, 57, 6321. M. E. Krolski, A. F. Renaldo, D. E. Rudisill, and J. K. Stille, J. Org. Chem., 1988, 53, 1170. J. A. Stafford and N. L. Valvano, J. Org. Chem., 1994, 59, 4346. G. Martorell, A. García-Raso, and J. M. Saá, Tetrahedron Lett., 1990, 31, 2357. A. M. Gilbert and W. D. Wulff, J. Am. Chem. Soc., 1994, 116, 7449. G. Zweifel and J. A. Miller, Org. React., 1984, 32, 375 –517. J. Schwartz and J. A. Labinger, Angew. Chem. Int. Ed. Engl., 1976, 15, 333 – 340. H. C. Brown, Organic Synthesis via Boranes, Wiley, New York, 1975, 283p. N. Miyaura and A. Suzuki, J. Chem. Soc. Chem. Commun., 1979, 866. E. Negishi, in Aspects of Mechanism and Organometallic Chemistry, J. H. Brewster, Ed., Plenum Press, New York, 1978, 285–317. N. Miyaura and A. Suzuki, J. Organomet. Chem., 1981, 213, C53. A. Suzuki, Pure Appl. Chem., 1985, 57, 1749–1758. J. C. Colberg, A. Rane, J. Vaquer, and J. A. Soderquist, J. Am. Chem. Soc., 1993, 115, 6065. S. Hyuga, Y. Chiba, N. Yamashina, S. Hara, and A. Suzuki, Chem. Lett., 1987, 1757. S. Hyuga, N. Yamashina, S. Hara, and A. Suzuki, Chem. Lett., 1988, 809. F. Yin, Y. Xu, and B. Jiang, J. Fluorine Chem., 1993, 65, 111. J. W. Guiles, S. G. Johnson, and W. V. Murray, J. Org. Chem., 1996, 61, 5169. D. Badone, M. Baroni, R. Cardamone, A. Ielmini, and U. Guzzi, J. Org. Chem., 1997, 62, 7170. J.-L. Parrain, A. Ducheˆne, and J.-P. Quintard, Tetrahedron Lett., 1990, 31, 1857. J. Thibonnet, M. Abarbri, J.-L. Parrain, and A. Ducheˆne, Tetrahedron Lett., 1996, 37, 7507. A. Kalivretenos, J. K. Stille, and L. S. Hegedus, J. Org. Chem., 1991, 56, 2883. J. Yoshida, K. Tamao, H. Yamamoto, T. Kakui, T. Uchida, and M. Kumada, Organometallics, 1982, 1, 542. Y. Hatanaka and T. Hiyama, J. Org. Chem., 1989, 54, 268. K. Kikukawa, K. Ikenaga, F. Wada, and T. Matsuda, Chem. Lett., 1983, 1337. K. Tamao, K. Kobayashi, and Y. Ito, Tetrahedron Lett., 1989, 30, 6051. K. Gouda, E. Hagiwara, Y. Hatanaka, and T. Hiyama, J. Org. Chem., 1996, 61, 7232. S. E. Denmark and D. Wehrli, Org. Lett., 2000, 2, 565. K. Hirabayashi, J. Kawashima, Y. Nishihara, A. Mori, and T. Hiyama, Org. Lett., 1999, 1, 299. M. Portnoy and D. Milstein, Organometallics, 1993, 12, 1665. M. Huser, M. T. Youinou, and J. A. Osborn, Angew. Chem. Int. Ed. Engl., 1989, 28, 1386. E. Hagiwara, K. Gouda, Y. Hatanaka, and T. Hiyama, Tetrahedron Lett., 1997, 38, 439. K. Tamao, J. Yoshida, H. Yamamoto, T. Kakui, H. Matsumoto, M. Takahashi, A. Kurita, M. Murata, and M. Kumada, Organometallics, 1982, 1, 355. H. Matsumoto, S. Nagashima, T. Kato, and Y. Nagai, Angew. Chem. Int. Ed. Engl., 1978, 17, 279. T. Oh-e, N. Miyaura, and A. Suzuki, Synlett, 1990, 221. E. Negishi, T. Takahashi, S. Baba, D. E. Van Horn, and N. Okukado, J. Am. Chem. Soc., 1987, 109, 2393. J.-B. Verlhac, J.-P. Quintard, and M. Pereyre, J. Chem. Soc. Chem. Commun., 1988, 503. B. H. Lipshutz and R. Keil, Inorg. Chim. Acta, 1994, 220, 41. A. B. Smith and G. R. Ott, J. Am. Chem. Soc., 1996, 118, 13095. H. C. Brown and T. Imai, Organometallics, 1984, 3, 1392.
404 [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136]
III Pd-CATALYZED CROSS-COUPLING
H. C. Brown and V. Somayaji, Synthesis, 1984, 919. N. Miyaura, M. Satoh, and A. Suzuki, Tetrahedron Lett., 1986, 27, 3745. L. Labaudiniere and J. F. Normant, Tetrahedron Lett., 1992, 33, 6139. E. J. Corey and T. M. Eckrich, Tetrahedron Lett., 1984, 25, 2419. J. W. Labadie and J. K. Stille, J. Am. Chem. Soc., 1983, 105, 6129. M. Massol, J. Satge, and B. Bouyssieres, Synth. Inorg. Met.-Org. Chem., 1973, 3, 1. G. A. Kraus and B. M. Watson, Tetrahedron Lett., 1996, 37, 5287. Y. Hatanaka and T. Hiyama, Tetrahedron Lett., 1990, 31, 2719. S. Nunomoto and Y. Yamashita, J. Org. Chem., 1979, 44, 4788. S. Nunomoto, Y. Kawakami, and Y. Yamashita, Bull. Chem. Soc. Jpn., 1981, 54, 2831. S. Nunomoto, Y. Kawakami, and Y. Yamashita, J. Org. Chem., 1983, 48, 1912. B. Jiang and Y. Xu, J. Org. Chem., 1991, 56, 7336. R. Filler, S. Lin, and Z. Zhang, J. Fluorine Chem., 1995, 74, 69. P. A. Wender and T. E. Glass, Synlett, 1995, 516. H. C. Brown, A. B. Levy, and M. M. Midland, J. Am. Chem. Soc., 1975, 97, 5017. H. C. Brown and M. M. Midland J. Org. Chem., 1975, 40, 2845. R. Koster and L. A. Hagelee, Synthesis, 1976, 118. A. B. Levy, S. J. Schwartz, N. Wilson, and B. Christie, J. Organomet. Chem., 1978, 156, 123. J. A. Soderquist and I. Rivera, Tetrahedron Lett., 1989, 30, 3919. J. A. Soderquist and M. R. Najafi, J. Org. Chem., 1986, 51, 1330. I. Rivera and J. A. Soderquist, Tetrahedron Lett., 1991, 32, 2311. E. Negishi and F. T. Luo, J. Org. Chem., 1983, 48, 1560. T. Takahashi, M. Kotora, R. Fischer, Y. Nishihara, and K. Nakajima, J. Am. Chem. Soc., 1995, 117, 11039. E. Negishi, F. T. Luo, R. Frisbee, and H. Matsushita, Heterocycles, 1982, 18, 117. Y. Satoh, H. Serizawa, S. Hara, and A. Suzuki, Synth. Commun., 1984, 14, 313. Y. Satoh, H. Serizawa, N. Miyaura, S. Hara, and A. Suzuki, Tetrahedron Lett., 1988, 29, 1811. E. Negishi, F. E. Cederbaum, and T. Takahashi, Tetrahedron Lett., 1986, 27, 2829. G. Desurmont, S. Dalton, D. M. Giolando, and M. Srebnik, J. Org. Chem., 1996, 61, 7943. G. Desurmont, R. Klein, S. Uhlenbrock, E. Laloe¨, L. Deloux, D. M. Giolando, Y. W. Kim, S. Pereira, and M. Srebnik, Organometallics, 1996, 15, 3323. T. N. Mitchell and H. Killing, Organometallics, 1984, 3, 1318. T. N. Mitchell, H. Killing, and D. Rutschow, J. Organomet. Chem., 1986, 304, 257. T. N. Mitchell, K. Kwetkat, D. Rutschow, and U. Schneider, Tetrahedron, 1989, 45, 969. W. J. Scott, J. Chem. Soc. Chem. Commun., 1987, 1755. K. Tamao, K. Kobayashi, and Y. Ito, J. Am. Chem. Soc., 1989, 111, 6478. Y. Gao, K. Harada, T. Hata, H. Urabe, and F. Sato, J. Org. Chem., 1995, 60, 290. K. A. Agrios and M. Srebnik, J. Organomet. Chem., 1993, 444, 15. J. Terao, N. Kambe, and N. Sonoda, Tetrahedron Lett., 1996, 37, 4741. K. Tamao, K. Maeda, T. Tanaka, and Y. Ito, Tetrahedron Lett., 1988, 29, 6955. M. Satoh, N. Miyaura, and A. Suzuki, Chem. Lett., 1986, 1329. L. Deloux, E. Skrzypczak-Jankun, B. V. Cheesman, and M. Srebnik, J. Am. Chem. Soc., 1994, 116, 10302.
III.2.6 Pd-CATALYZED ALKENYL–ARYL
405
[137] A. Table and P. Kocienski, Tetrahedron Lett., 1989, 30, 1675. [138] T. Oh-e, N. Miyaura, and A. Suzuki, J. Org. Chem., 1993, 58, 2201. [139] E. Negishi, F. Liu, D. Choueiry, M. M. Mohamud, A. Silveira, Jr., and M. Reeves, J. Org. Chem., 1996, 61, 8325. [140] T. L. Gilchrist and R. J. Summersell, J. Chem. Soc. Perkin Trans. 1, 1988, 2595. [141] K. Kasai, Y. Liu, R. Hara, and T. Takahashi, Chem. Commun., 1998, 1989. [142] T. Ishiyama, N. Matsuda, N. Miyaura, and A. Suzuki, J. Am. Chem. Soc., 1993, 115, 11018. [143] S. D. Brown and R. W. Armstrong, J. Am. Chem. Soc., 1996, 118, 6331. [144] S. D. Brown and R. W. Armstrong, J. Org. Chem., 1997, 62, 7076. [145] R. S. Sorokina, L. F. Rybakova, I. O. Kalinovskii, and I. P. Beletskaya, Izv. Akad. Nauk SSSR Ser. Khim., 1985, 1647. [146] P. L. Heinze and D. J. Burton, J. Fluorine Chem., 1986, 31, 115. [147] P. L. Heinze and D. J. Burton, J. Org. Chem., 1988, 53, 2714. [148] F. Tellier, R. Sauveˆtre, J. F. Normant, Y. Dromzee, and Y. Jeannin, J. Organomet. Chem., 1987, 331, 281. [149] F. Tellier, R.Sauveˆtre, and J. F. Normant, J. Organomet. Chem., 1985, 292, 19. [150] P. A. Morken and D. J. Burton, J. Org. Chem., 1993, 58, 1167. [151] J. Ichikawa, T. Moriya, T. Sonoda, and H. Kobayashi, Chem. Lett., 1991, 961. [152] J. Ichikawa, T. Minami, T. Sonoda, and H. Kobayashi, Tetrahedron Lett., 1992, 33, 3779. [153] R. S. Sorokina, L. F. Rybakova, I. O. Kalinovskii, V. A. Chernoplekova, and I. P. Beletskaya, Zh. Org. Khim., 1982, 18, 2458. [154] L. Lu and D. J. Burton, Tetrahedron Lett., 1997, 38, 7671. [155] L. G. Sprague, A. W. Snow, and J. R. Griffith, J. Fluorine Chem., 1991, 52, 301. [156] E. Erdik, Organozinc Reagents in Organic Synthesis, CRC Press, Boca Raton, FL, 1996, 411pp. [157] H. Azizian, C. E. Eaborn, and A. Pidcock, J. Organomet. Chem., 1981, 215, 49. [158] A. N. Kashkin, I. G. Bumagina, N. A. Bumagin, V. N. Bakunin, and I. P. Beletskaya, J. Org. Chem. USSR, 1981, 17, 789. [159] N. A. Bumagin, I. G. Bumagina, and I. P. Belestskaya, Dokl. Akad. Nauk SSSR, 1984, 274, 1103. [160] T. Ishiyama, M. Murata, and N. Miyaura, J. Org. Chem., 1995, 60, 7508. [161] M. Murata, T. Oyama, S. Watanabe, and Y. Masuda, J. Org. Chem., 2000, 65, 164. [162] H. Matsumoto, M. Kasahara, M. Takahashi, T. Arai, T. Nakano, and Y. Nagai, J. Organomet. Chem., 1983, 250, 99. [163] A. Minato, K. Suzuki, and K. Tamao, J. Am. Chem. Soc., 1987, 109, 1257. [164] P. Ramiandrasoa, B. Bréhon, A. Thivet, M. Alami, and G. Cahiez, Tetrahedron Lett., 1997, 38, 2447. [165] B. Crousse, M. Alami, and G. Linstrumelle, Tetrahedron Lett., 1997, 38, 5297. [166] R. B. Miller and M. I. Al-Hassan, J. Org. Chem., 1985, 50, 2121. [167] G. A. Potter and R. McCague, J. Org. Chem., 1990, 55, 6184. [168] T. Studemann and P. Knochel, Angew. Chem. Int. Ed. Engl., 1997, 36, 93. [169] B. H. Lipshutz, B. Ullman, C. Lindsley, S. Pecchi, D. J. Buzard, and D. Dickson, J. Org. Chem., 1998, 63, 6092. [170] G. Stork and R. C. A. Isaacs, J. Am. Chem. Soc., 1990, 112, 7399. [171] J. P. Geneˆt, E. Blart, and M. Savignac, Synlett, 1992, 715.
406 [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198] [199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] [210] [211] [212] [213]
III Pd-CATALYZED CROSS-COUPLING
X. Yue, F.-L. Qing, H. Sun, and J. Fan, Tetrahedron Lett., 1996, 37, 8213. E. Negishi, Y. Noda, F. Lamaty, and E. J. Vawter, Tetrahedron Lett., 1990, 31, 4393. V. Farina, B. Krishnan, D. R. Marshall, and G. P. Roth, J. Org. Chem., 1993, 58, 5434. J. Srogl, G. D. Allred, and L. S. Liebeskind, J. Am. Chem. Soc., 1997, 119, 12376. E. Fouquet, M. Pereyre, and A. L. Rodriguez, J. Org. Chem., 1997, 62, 5242. A. Ducheˆne, M. Abarbri, J.-L. Parrain, M. Kitamura, and R. Noyori, Synlett, 1994, 524. P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1992, 33, 4815. F.-T. Luo and L.-C. Hsieh, J. Org. Chem., 1996, 61, 9060. E. Negishi, M. Ay, Yu. V. Gulevich, and Y. Noda, Tetrahedron Lett., 1993, 34, 1437. E. Morera and G. Ortar, Synlett, 1997, 1403. V. Farina and G. P. Roth, Tetrahedron Lett., 1991, 32, 4243. D. L. Comins and L. A. Morgan, Tetrahedron Lett., 1991, 32, 5919. J. K. Stille and B. L. Groh, J. Am. Chem. Soc., 1987, 109, 813. R. M. Moriarty and W. R. Epa, Tetrahedron Lett., 1992, 33, 4095. M. Gardette, N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron, 1984, 40, 2741. D. T. Hung, J. B. Nerenberg, and S. L. Schreiber, J. Am. Chem. Soc., 1996, 118, 11054. W. J. Scott, G. T. Crisp, and J. K. Stille, J. Am. Chem. Soc., 1984, 106, 4630. W. J. Scott and J. K. Stille, J. Am. Chem. Soc., 1986, 108, 3033. M. R. Attwood, T. M. Raynham, D. G. Smyth, and G. R. Stephenson, Tetrahedron Lett., 1996, 37, 2731. R. Rossi, A. Carpita, and M. G. Quirici, Tetrahedron, 1981, 37, 2617. L. Zhu, R. M. Wehmeyer, and R. D. Rieke, J. Org. Chem., 1991, 56, 1445. F. Bjorkling, T. Norin, C. R. Unelius, and R. B. Miller, J. Org. Chem., 1987, 52, 292. N. Miyaura, K. Yamada, and A. Suzuki, Tetrahedron Lett., 1979, 20, 3437. N. Miyaura, H. Suginome, and A. Suzuki, Tetrahedron Lett., 1981, 22, 127. N. Miyaura, K. Yamada, H. Suginome, and A. Suzuki, J. Am. Chem. Soc., 1985, 107, 972. J.-M. Duffault, J. Einhorn, and A. Alexakis, Tetrahedron Lett., 1991, 32, 3701. V. Ratovelomanana and G. Linstrumelle, Tetrahedron Lett., 1984, 25, 6001. G. Cassani, P. Massardo, and P. Piccardi, Tetrahedron Lett., 1983, 24, 2513. N. Miyaura, H. Suginome, and A. Suzuki, Tetrahedron Lett., 1983, 24, 1527. W. R. Roush, J. S. Warmus, and A. B. Works, Tetrahedron Lett., 1993, 34, 4427. A. Carpita, D. Neri, and R. Rossi, Gazz. Chim. Ital., 1987, 117, 503. S. W. Djuric, R. A. Haack, and S. S. Yu, J. Chem. Soc. Perkin Trans. 1, 1989, 2133. Y. Kobayashi, S. Okamoto, T. Shimazaki, Y. Ochiai, and F. Sato, Tetrahedron Lett., 1987, 28, 3959. J. Uenishi, R. Kawahama, O. Yonemitsu, and J. Tsuji, J. Org. Chem., 1996, 61, 5716. Y. Naruse, T. Esaki, and H. Yamamoto, Tetrahedron, 1988, 44, 4747. N. Miyaura, H. Suginome, and A. Suzuki, Bull. Chem. Soc. Jpn., 1982, 55, 2221. N. Miyaura, Y. Satoh, S. Hara, and A. Suzuki, Bull. Chem. Soc. Jpn., 1986, 59, 2029. P. M. Pihko and A. M. P. Koskinen, Synlett, 1999, 1966. R. J. Boyce and G. Pattenden, Tetrahedron Lett., 1996, 37, 3501. A. G. M. Barrett, M. Pe˜na, and J. A. Willardsen, J. Org. Chem., 1996, 61, 1082. M. A. J. Duncton and G. Pattenden, J. Chem. Soc. Perkin Trans. 1, 1999, 1235–1246. B. H. Lipshutz and C. Lindsley, J. Am. Chem. Soc., 1997, 119, 4555.
III.2.6 Pd-CATALYZED ALKENYL–ARYL
407
[214] Y. Kobayashi, T. Shimazaki, H. Taguchi, and F. Sato, J. Org. Chem., 1990, 55, 5324. [215] J. Uenishi, J.-M. Beau, R. W. Armstrong, and Y. Kishi, J. Am. Chem. Soc., 1987, 109, 4756. [216] W. R. Roush and R. Riva, J. Org. Chem., 1988, 53, 710. [217] M. Avignon-Tropis, M. Treilhou, J. Lebreton, J. R. Pougny, I. Fre´chard-Ortuno, C. Huynh, and G. Linstrumelle, Tetrahedron Lett., 1989, 30, 6335. [218] K. C. Nicolaou, J. Y. Ramphal, J. M. Palazon, and R. A. Spanevello, Angew. Chem. Int. Ed. Engl., 1989, 28, 587. [219] K. C. Nicolaou, J. Y. Ramphal, and Y. Abe, Synthesis, 1989, 898. [220] W. R. Roush and R. J. Sciotti, J. Am. Chem. Soc., 1994, 116, 6457. [221] D. M. Hodgson, L. T. Boulton, and G. N. Maw, Synlett, 1995, 267. [222] J. K. Stille and M. Tanaka, J. Am. Chem. Soc., 1987, 109, 3785. [223] E. Negishi, A. Alimardanov, and C. Xu, Org. Lett., 2000, 2, 65. [224] D. R. Swanson, T. Nguyen, Y. Noda, and E. Negishi, J. Org. Chem., 1991, 56, 2590. [225] C. Xu and E. Negishi, Tetrahedron Lett., 1999, 40, 431. [226] N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1981, 22, 959. [227] N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1982, 23, 1589. [228] E. Negishi unpublished results [229] F. Ramiandrasoa and F. Tellier, Synth. Commun., 1990, 20, 333. [230] S. R. Baker, G. P. Roth, and C. Sapino, Synth. Commun., 1990, 20, 2185. [231] P. I. Svirskaya, C. C. Leznoff, and W. L. Roelofs, Synth. Commun., 1980, 10, 391. [232] A. Commercon, J. F. Normant, and J. Villieras, Tetrahedron, 1980, 36, 1215. [233] B. Jiang and Y. Xu, Tetrahedron Lett., 1992, 33, 511. [234] E. Piers, R. W. Friesen, and B. A. Keay, Tetrahedron, 1991, 47, 4555. [235] P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1990, 31, 1889. [236] D. E. Van Horn and E. Negishi, J. Am. Chem. Soc., 1978, 100, 2252. [237] E. Negishi, D. E. Van Horn, and T. Yoshida, J. Am. Chem. Soc., 1985, 107, 6639. [238] A. Marfat, P. R. McQuirk, and P. Helquist, Tetrahedron Lett., 1978, 19, 1363. [239] E. Negishi and Z. Owczarczyk, Tetrahedron Lett., 1991, 32, 6683. [240] F. Zeng and E. Negishi, Org. Lett., 2001, 3, 719. [241] K. C. Nicolaou, T. K. Chakraborty, A. D. Piscopio, N. Minowa, and P. Bertinato, J. Am. Chem. Soc., 1993, 115, 4419. [242] K. C. Nicolaou, A. D. Piscopio, P. Bertinato, T. K. Chakraborty, N. Minowa, and K. Koide, Chem. Eur. J., 1995, 1, 318. [243] F. Yokokawa, Y. Hamada, and T. Shiori, Tetrahedron Lett., 1993, 34, 6559. [244] N. Tanimoto, S. W. Gerritz, A. Sawabe, T. Noda, S. A. Filla, and S. Masamune, Angew. Chem. Int. Ed. Engl., 1994, 33, 673. [245] A. G. M. Barrett, J. J. Edmunds, J. A. Hendrix, K. Horita, and C. J. Parkinson, J. Chem. Soc. Chem. Commun., 1992, 1238. [246] S. D. Burke, A. D. Piscopio, M. E. Kort, M. A. Matulenko, M. H. Parker, D. M. Armistead, and K. Shankaran, J. Org. Chem., 1994, 59, 332. [247] K. C. Nicolaou, J. Xu, F. Murphy, S. Barluenga, O. Baudoin, H. Wei, D. L. F. Gray, and T. Ohshima, Angew. Chem. Int. Ed. Engl., 1999, 38, 2447. [248] B. Dom´ınguez, B. Iglesias, and A. R. de Lera, Tetrahedron, 1999, 55, 15071. [249] A. G. M. Barrett, A. J. Bennett, S. Menzer, M. L. Smith, A. J. P. White, and D. J. Williams, J. Org. Chem., 1999, 64, 162.
408
III Pd-CATALYZED CROSS-COUPLING
[250] A. M. Garc´ıa, J. L. Mascare˜nas, L. Castedo, and A. Mouri˜no, Tetrahedron Lett., 1995, 36, 5413. [251] P. A. Wender and M. L. Snapper, Tetrahedron Lett., 1987, 28, 2221. [252] D. W. Hart, T. F. Blackburn, and J. Schwartz, J. Am. Chem. Soc., 1975, 97, 679. [253] J. S. Panek and T. Hu, J. Org. Chem., 1997, 62, 4912. [254] K. E. Drouet and E. A. Theodorakis, J. Am. Chem. Soc., 1999, 121, 456. [255] J. S. Panek and T. Hu, J. Org. Chem., 1997, 62, 4914. [256] A. Pimm, P. Kocienski, and S. D. A. Street, Synlett, 1992, 886. [257] J. A. Soderquist and G. Leo´n-Colo´n, Tetrahedron Lett., 1991, 32, 43. [258] E. J. Corey and H. Kigoshi, Tetrahedron Lett., 1991, 32, 5025. [259] E. Negishi, M. Ay, and T. Sugihara, Tetrahedron, 1993, 49, 5471. [260] E. J. Corey, J. A. Katzenellenbogen, and G. H. Posner, J. Am. Chem. Soc., 1967, 89, 4245. [261] B. Jousseaume and J. G. Duboudin, J. Organomet. Chem., 1975, 91, C1. [262] J. G. Duboudin and B. Jousseaume, J. Organomet. Chem., 1979, 168, 1. [263] S. Ma, F. Liu, and E. Negishi, Tetrahedron Lett., 1997, 38, 3829. [264] E. Piers and Y.-F. Lu, J. Org. Chem., 1988, 53, 926. [265] E. Piers and T. Wong, J. Org. Chem., 1993, 58, 3609. [266] V. Farina, S. Kapadia, B. Krishnan, C. Wang, and L. S. Liebeskind, J. Org. Chem., 1994, 59, 5905. [267] G. Shi, X. Huang, and F. Hong, J. Org. Chem., 1996, 61, 3200. [268] M. Pour and E. Negishi, Tetrahedron Lett., 1997, 38, 525. [269] F. Tellier, R. Sauveˆ tre, and J. F. Normant, J. Organomet. Chem., 1986, 303, 309. [270] F. Tellier, R. Sauveˆ tre, and J. F. Normant, J. Organomet. Chem., 1989, 364, 17. [271] J. Ichikawa, C. Ikeura, and T. Minami, Synlett, 1992, 739. [272] R. Hara, Y. Nishihara, P. D. Landre´, and T. Takahashi, Tetrahedron Lett., 1997, 38, 447.
HetAr–X(M) + R–M(X)
III.2.7 Heteroaromatics via PalladiumCatalyzed Cross-Coupling KJELL UNDHEIM
A. INTRODUCTION Heterocyclic aromatic chemistry is a large and important part of organic Chemistry. A great number of reports deal with transition-metal-catalyzed cross-coupling reactions in heteroarenes. A review from 1991 deals with carbon – carbon bond-forming reactions using nickel and palladium catalysis in heterocycles.[1] A comprehensive review over transition metal catalysis in cross-coupling reactions in -deficient heteroarenes covered the literature up to 1995.[2] Coupling reactions in pyrimidines and benzopyrimidines were summarized in 1996.[3]* This work deals with Pd-catalyzed coupling reactions in the fiveand six-membered heteroaromatic ring systems. Other heterocyclic systems assigned aromatic character are normally charged and unstable. Any works with such peripheral structures are not included. Substrates for cross-coupling of simple heteroaromatics are either commercially accessible or are in most cases readily prepared. Before reviewing cross-coupling reactions, a brief summary of the characteristics of heteroaromatic systems and substitution modes may be useful. The heteroarenes can broadly be divided into three major groups for the purpose of rationalizing the substitution behavior and characteristics of these systems. 1. The -excessive heteroaromatics are five-membered rings containing one heteroatom. 2. The -deficient heteroaromatics, the azines, are six-membered ring systems containing one or more nitrogen atoms. 3. The third group, the azoles, are five-membered ring systems containing one or more heteroatoms in addition to a nitrogen heteroatom. In the main, the reactivity patterns for groups (1) and (2) can readily be rationalized, whereas the characteristics of azoles can be regarded as arising from a combination of the *
A book on palladium in heterocyclic chemistry has been published very recently. See J. J. Li and G. W. Gribble, Palladium in Heterocyclic Chemistry, Pergamon, Oxford, 2000.
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
409
410
III Pd-CATALYZED CROSS-COUPLING
properties of the first two groups. In addition, the nature of the heteroatoms and their relative positions in the azole will affect the properties. Benzannulation in either series leads to slight changes of character, but the principal characteristics of the systems are retained although the relative preference for regiosubstitution may be affected. The annulated systems may perhaps be compared to naphthalene, but the preference for reaction in the benzene or the heterocyclic ring will largely be controlled by the -excessive or -deficient nature of the annulated heterocycle. Not unexpectedly, the presence of strongly electronaffecting substituents in the ring may override the usual characteristics of a heterocyclic system. In the -excessive systems, an iodo, bromo, or triflyloxy substituent in either position in the substrate is appropriate for cross-coupling reactions. Other useful leaving groups such as phosphoroxy groups have received little attention. Sometimes an -chloro substituent next to the ring heteroatom can be substituted, but normally coupling at the chloro carbon occurs less readily. The halogen substituents can be introduced into the excessive heterocycle by electrophilic substitutions; initial electrophilic substitution is in a vacant -position to the heteroatom, then in -positions. Alternatively, halogenation is effected via a metallated species. Metallation generally, and lithiation in particular, takes place in an -position to the heteroatom using either a lithium amide or an alkyllithium reagent for the H – Li exchange. Halogen – metal exchange can be effected in either positions. Activated metals will insert directly into a carbon – halogen bond. More frequently, the desired metallation is via a metal – metal exchange with the lithiated species in the usual manner. In the annulated systems the carbocycle has largely retained the benzenoid properties. In the -deficient systems, metallation is generally more difficult to effect except by halogen – metal exchange in the benzenoid positions, for example, the 3,5-positions in pyridine or the 5-position in pyrimidine. Competitive reactions are frequently observed between lithium – hydrogen or lithium – halogen exchange and nucleophilic addition of the organometallic reagent to the electrophilic positions in these systems. In azines, the -positions are electrophilic sites, for example, the 2,4,6-positions in pyridine and pyrimidine. The electrophilic character increases with the number of heteroatoms in the ring and varies with the relative locations of the heteroatoms. In most cases a chlorine substituent will be exchanged equally readily as a bromine or iodine substituent in crosscoupling reactions involving electrophilic positions. Relative reactivity, however, may allow for regioselective substitutions. The reactivity is comparable to that of chlorobenzenes substituted by strongly electron-withdrawing groups, or somewhat less reactive than an acid chloride. In most cases, therefore, there is no need for an exchange of a chloro substituent with a bromo or iodo substituent in the electrophilic positions unless it is desirable to change the order of selectivity. Readily available heterocycles often carry hydroxy groups in electrophilic positions and are easily converted into chloro derivatives using simple, common methodology. Bromo or iodo derivatives are less readily available and are most often prepared by a halogen – halogen exchange reaction from the chloro derivatives. Triflates of hydroxy groups in all positions can be prepared. In the azoles, the coupling characteristics very much follow the pattern from the -excessive systems. Normally bromo, iodo, or triflyloxy groups are displaced in any position. The halogens are introduced by electrophilic substitutions along the lines outlined for the -excessive systems, but the regiochemistry depends among other things on the relative position of the annular heteroatoms. Hydroxy groups are replaced by a chlorine substituent in electrophilic positions as in the -deficient series. Metallated species are commonly
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
411
prepared by hydrogen–metal exchange reactions, commonly by lithiation. The lithiated species may subsequently be subjected to a metal – metal exchange operation. The preferential regiochemistry pattern from metallation in the -excessive systems may be overcome by initial metallation between two heteroatoms in a 1,3-relationship. B. CROSS-COUPLING IN -EXCESSIVE RING SYSTEMS B.i. Metallated Five-Membered Ring Systems B.i.a. Arylation Tin Derivatives. -Metallation followed by electrophilic trapping has become a powerful method in regioselective functionalization of five-membered heteroaromatics. The Stille organotin methodology will provide 2-indolyl-stannanes intermediates for the synthesis of 2-substituted indoles (Scheme 1). N-Metallation of indole and N-carboxylation before a subsequent lithiation and metal – metal exchange can be used for stannylation in the 2position. The stannane reagent 1 can be prepared on a multigram scale and has been stored for one month at 20 °C.[4] More common protecting groups are often used. An example is provided by the protection of indole with the trimethylsilylethoxymethyl group. The resultant indole derivative 2 undergoes Stille-type couplings with an aryl, a heteroaryl, or vinyl bromides or iodides.[5] A bromo or triflyloxy substituent in the -position of the indole can be replaced by stannylation after initial lithiation (Scheme 2) . The N1-silyl-protected 3-bromo-7-azain-
[I]
ArX
Sn(n-Bu)3 N H
N 1
Ar
[II]
N COOH
COOH 70−92%
Ar = ph, 1-naphthyl, 2- and 5-indolyl, 2-pyridinyl, 5-isoquinolinyl, 2-benzo[b]thiophenyl and -furyl, 2-thienyl, β-styryl [III]
2
Sn(n-Bu)3
RBr (III) [IV] or [V]
N
N
CH2OCH2CH2SiMe3
CH2OCH2CH2SiMe3 R N 42−97%
CH2OCH2CH2SiMe3
R = Ar, HetAr [I] (i) n-BuLi, THF, −68 °C, CO2, (ii) t-BuLi, (iii) (n-Bu)3SnCl; [II] 5 mol % Cl2Pd(PPh3)2, EtOH, rfx, 24−48 h; [III] (i) n-BuLi, THF, −10 °C, (ii) (n-Bu)3SnCl, THF, −20 °C; [IV] 10 mol % Pd(PPh3)4, DMF, 110 °C, 1−72 h; [V] 5 mol % Pd2(dba)3, P(2-furyl)3, THF, 60 °C, 2−76 h. Scheme 1
412
III Pd-CATALYZED CROSS-COUPLING
dole 3 was lithiated and converted to the corresponding 3-stannane with trimethylstannyl chloride for coupling with aryl and heteroaryl bromides.[6] Zinc Derivatives. Furan and N-methylpyrrole are lithiated in an -position (Scheme 3). Subsequent zincation by treatment with anhydrous zinc chloride or bromide gives the substrates 4 and 5 for mono- or dicoupling with thiophenes under Negishi conditions.[7] Br
N
N
N
[III]
[II]
N
N
N H
N
TBDMS
TBDMS 45−74%
TBDMS
3
R
RBr
[I]
N
R
SnMe3
38−57%
R = 2-pyridinyl R = C6H4-4-MeO, -4-NO2 R = 5-pyrimidinyl R = 3-thienyl [I] (i) t-BuLi, THF, −90 °C, (ii) Me3SnCl; [II] 20 mol % Pd(PPh3)4, LiCl, THF, rfx, 48 h; [III] 10% aq. HCl, r.t. Scheme 2
Br
[I]
O
O
Br
S [II]
ZnCl
O
S
O
High yield
4
[III]
S
N
N
Me
Me
ZnCl
Br
[IV]
N 70%
S
Me
5 [I] (i) n-BuLi, THF, 0 to r.t., (ii) ZnCl 2, − 40 to r.t. [II] 3 mol % Cl2Pd(dppb), THF, rfx, 2 h; [III] (i) n-BuLi, hexane, TMEDA, rfx, 20 min, (ii) ZnCl 2, THF, r.t.; [IV] 3 mol % Cl2Pd(dppb), THF, rfx, 6 h. Scheme 3
In a comparative study (Scheme 4) of different methods for the preparation of 2arylthieno[3,2-b]thiophenes 7, the lithiated species 6 was treated with zinc chloride to effect zincation, tributyl borate to effect boronation, and tri(n-butyl)stannyl chloride to effect stannylation. Aryl bromides or iodides were used. The yields of the 2-aryl product 7 depend on the substituents in the benzene ring, the metallated species, and the palladium catalyst.[8] 1-(Benzenesulfonyl)-2-indolylzinc chloride 8, prepared by metathesis of 1-(benzenesulfonyl)-2-lithioindole with ZnCl2, will couple with 2-halogenopyridines to give 2-(2pyridinyl)indoles (Scheme 5). A number of substituted 2-chloro- or 2-bromopyridines were reacted. In the electrophilic pyridine 2-position, the chloro- and bromopyridines react equally well with formation of coupling products. Homocoupled indole was a minor product. Pyrazine as the electrophilic partner with a chloro substituent in the electrophilic
413
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
2-position also reacts well. -Excessive heterocycles used as electrophiles under these conditions give low or moderate yields.[9] In the zincated indole 9 a variety of protecting groups were present in the substrates for the coupling with phenyl iodide.[10] S
ZnCl
S
[II]
[V]
C6H4R S
S
[I]
S
S
Li [III]
B(OH)2 [VI]
S
S 6
R
S
[IV] [VII]
S
Sn(n-Bu)3
RC6H4Br
S 7
[V] R = NO2, CN; COOMe; 10−85% [VI] R = NO2, CN, COOMe, H; 40−65% [VII] R = COOMe; 60%
S
[I] n-BuLi, THF, 0 °C to r.t., 1 h; [II] ZnCl 2, 0 °C, 30 min; [III] (i)B[O(M-Bu)]3,(ii) aq. NaOH; [IV] (n-Bu)3SnCl, THF, r.t., 1 h; [V] 2 mol % Pd(dba) 2 or 4 mol % PPh3, DMF, 80 °C, 1 h; [VI] 5 mol % Pd(PPh3)4, Ba(OH)2, DME, H2O, rfx, 16−24 h; [VII] 10 mol % Pd(PPh3)4, dioxane, rfx, 18−36 h. Scheme 4
R2 R3
R1 R1 N
[I]
ZnCl
N
N
SO2Ph
SO2Ph
R
N 9
R3
[II]
ZnCl
[III]
N
X N
X = Br, Cl 40−95%
8
N
SO2Ph
PhI
Ph
[IV]
R
R2
N 0−68%
R
R = CH2OMe, CH2NMe2, COO(t-Bu), SO2Ph [I] (i) LDA, THF, 0 °C, (ii) ZnCl2, THF, 25 °C; [II] 2 mol % Cl2Pd(PPh3)2, DIBAH, THF, rfx, 4 h; [III] ( i) n-BuLi, THF, −78 °C, (ii) ZnCl2, THF, −78 °C to r.t.; [IV] 5 mol % Pd(PPh3)4, THF, rfx, 14−18 h. Scheme 5
414
III Pd-CATALYZED CROSS-COUPLING
Carbamate protection can also be used in zincation in the indole 2-position for the subsequent coupling (Scheme 6). The 1-lithio-oxycarbonyl group also serves as a directing group for vicinal lithiation. Subsequent transmetallation with zinc chloride gives the corresponding lithio-oxycarbonylindolylzinc chloride 10 for coupling with aryl bromides or iodides.[10]
[I]
ArI
ZnCl
N COOH
Ar
[II]
N COOZnCl (Li)
N 29−75%
10
COOH
Ar = Ph; 4-NO2-, 4-COOEt, 4-MeO-, 3-COOEt, and 3-Me2NCO-C6H4; 2-thienyl 2-pyridinyl, 6-Me2NCO-2-pyridinyl, 4-Me2NCO-6-Me-2-pyrimidinyl [I] (i) t-BuLi, THF, −70 °C, (ii) ZnCl2, THF, −70 °C to r.t.; [II] 5 mol % Pd(PPh 3)4, THF, rfx, 11−18 h. Scheme 6
(1-TBDMS-3-indolyl)zinc chloride 11 has been coupled with 2-halogenopyridines carrying alkyl, methoxy, methoxycarbonyl, nitro, and hydroxy groups to yield the corresponding 3-(2-pyridinyl)indoles (Scheme 7). Another series of 3-(heteroaryl)indoles (pyrazinyl, furyl, thienyl, indolyl) has similarly been prepared from the indolylzinc substrate 11. When the indole is N-protected as a sulfonyl derivative, the intermediate 1-(benzenesulfonyl)-3-lithioindole easily suffers rearrangement to the 2-lithio isomer. The 1-TBDMS-3-lithioindole is stable toward this rearrangement. The TBDMS-protecting group has therefore been recommended for use in cross-coupling reactions with metaloindoles. The silyl group is removed after the reaction by fluoride salts in the usual manner or under acidic conditions.[9] R2
R2
ZnCl
Br
R
R1
3
N
[I]
N
N
TBDMS
TBDMS 11
R3
R1
X
N
[II]
42−95% X = Br, Cl
N TBDMS
R1, R2, R3 = H, Me, Et, OMe, OH, COOMe, NO2 [I] (i) t-BuLi, THF, −78 °C, (ii) ZnCl2, THF, 25 °C; [II] 2 mol % Cl2Pd(PPh3)2, DIBAH, THF, rfx, 4 h. Scheme 7
Basic lithium species as intermediates are avoided by direct zincation of an organo halide. It has been claimed that metallation in the 3-position in indoles is best effected by oxidative addition of zinc to a 3-iodide (Scheme 8). In the formation of the metallated species 12 from 3-iodo-N-benzenesulfonylindole, no rearrangement to the 2-isomer was
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
415
observed. The 2-iodo isomer reacts similarly, but the yield of coupled product was slightly lower. With a strongly directing metallation group in the 3-position, initial metallation is in the peri-vicinal position in the phenyl ring, that is, in the 4-position. The zincated intermediate 13 is subsequently coupled with aryl halides.[10]
I
ZnI
[I]
N
N
SO2Ph
SO2Ph
ZnCl
TIPS
SO2Ph
Ar
CH2NMe2
CH2NMe2
ArI
[III]
N
N
72−83% 3-Ar: Ar = Ph, 2- and 3-pyridinyl, 2-thiazolyl; X = Br, I 57%, 45% 2-Ar: Ar = Ph, 2-pyridinyl
12
CH2NMe2
Ar
ArX [II]
N TIPS
[IV]
50−58%
13
N TIPS Ar = Ph, 3-pyridinyl
[I] Zn*, THF, r.t., 1−2 h; [II] 5 mol % Pd(PPh3)4, THF, r.t., 18 h; [III] (i) t-BuLi, −70 °C, (ii) ZnCl2, −70 °C; [IV] 5 mol % Pd(PPh3)4, THF, rfx, 24 h. Scheme 8
Boron Derivatives. Lithiation and metal – metal exchange in thiophene or furan give 2-boronic acids 14 for coupling with bromobenzenes (Scheme 9).[7] 2- or 3-Furanboronic acids 15 can be coupled with 5-bromonicotinic acid methyl ester.[11] 2- or 3-Thiopheneboronic acids have been coupled to 5-bromothiophene to yield the corresponding bithienyls in good yields.[12] 2-Formyl-3-furanboronic acid 16 under Suzuki conditions was coupled to bromobenzenes carrying an o-nitro or o-acetamido substituent.[13] The reaction proceeds equally well for the regioisomeric 3-formylthiophene 17.[14] 3-Arylpyrroles are available from 3-iodopyrroles (Scheme 10). Lithiation in the 3position in 1-(triisopropylsilyl)-3-iodopyrrole followed by reaction of the lithio species with trimethyl borate and hydrolysis of the product gives the boronic acid. Coupling of the crude boronic acid with aryl halides under Suzuki conditions leads to the formation of 3-arylpyrroles 18. Stannyl derivatives of pyrrole, prepared in a similar manner, gave comparable yields. The silyl deprotection was by tetrabutylammonium fluoride in THF.[15] N-Protection of 3-bromoindole, lithiation, and subsequent boronation gave boronic acid substrates 19 for cross-coupling with substituted 5-bromo- or 5-iodoimidazole.[16] In the 2-position, the Suzuki coupling of N-Boc-pyrrole-2-boronic acid with phenyl iodide gave a moderate yield of the 2-phenyl product 20 (Scheme 11). With bromobenzene the yield was low. The best results were obtained with -deficient arenes. The same coupling with indole derivatives gave even lower yields of arylated products. Homocoupling of the heterocycle is responsible for the major by-product. The boronic acid group
416
III Pd-CATALYZED CROSS-COUPLING [II]
[I]
B(OMe)2
Z
Z Z = O, S
B(OH)2
Z
ca, 90%
14 R
R Br Z = S [III] Br
COOMe
B(OH)3
S R = NO2 80% R = CHO 100%
N
N
O
[IV]
15
Br
COOMe O
2–isomer 86% 3–isomer 83%
O 2N
B(OH)2 NO2
CHO
O
[V]
85%
16
CHO
O
Br
OHC
OHC
B(OH)3 NO2
NO2 [V] S S 83% 17 [I] (i) n-BuLi, THF, −10 °C to r.t., (ii) B(OMe) 3, −90 to −10 °C; [II] 30% HCl, THF, H2O, −30 °C, 30 min; [III] 3 mol % Pd(PPh3)4, K2CO3, DME, H2O, rfx, 30−45 min; [IV] 3 mol % Pd(OAc)2 P(o-tol)3, NEt3, DMF, 100 °C, 2-3h; [V] 3 mol % Pd(PPh3)4, DME, H2 O, NaHCO3 , rfx, 1 h. Scheme 9 B(OH)2
N I
Li [I]
[II]
TIPS
ArX [IV]
[III]
N
N
TIPS
TIPS
Sn(n-Bu)3
59–90%
ArX
N
[V]
X = Br, I N TIPS
Scheme 10
R
69–89%
TIPS 18
R = Ph; C6H4-4-Me, -MeO, -AcNH, -Cl, -NO2, -COOMe, -CHO, -CN; C6H4-2-Me and 3-Me; 3-pyridinyl
417
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
N
B(OH)2 X
Br
N
[VI]
N
SPh
SEM
N
N
TBDMS
TBDMS
SPh
N
[VII]
N
SEM
TBDMS X = Br, I 79% 19 [I] t-BuLi, THF, −78 °C; [II] (i) B(OMe)3, THF, −78 °C, (ii) MeOH, H2O, −78 °C to r.t.; [III] (n-Bu)3SnCl, THF, −78 °C to r.t.; [IV] 5−10 mol % Pd(PPh3)4, benzene, MeOH, 2 M aq. Na2CO3, rfx, 10−48 h; [V] 10−17 mol % Pd(PPh 3)4, dioxane, rfx, 24−40 h; [VI] (i) n-BuLi, THF, −78 °C, (ii) B(OMe) 3, (iii) MeOH-H2O; [VII] 10 mol % Pd(PPh3)4, Na2CO3, MeOH, benzene, rfx, 15 h. Scheme 10 (Continued) RBr
N
B(OH)2
[I]
Boc
Ar = Ph 15%; (for PhI 55%) R = 2-thienyl 35% , 3-pyridinyl 72% R = C6H3-2-MeO-5-EtSO2 98%
R
N Boc 20
[II]
B(OH)2
N
N
Boc
Boc
ArX
Ar
[I]
N Boc
Ar = Ph, X = I 52% Ar = 3-pyridinyl, X = Br 66%
[III]
BEt3
N
R1
R2 N
[IV]
N
R1
R2X
Li
15–80%
R1
21
R1 = Me, Boc, SO2Ph, MOM, SEM, OMe R2 = Ph, C6H4-4-COOEt, β-styryl, 2-pyridinyl, 4-t-Bu-cyclohexen-1-yl [I] 5 mol % Pd(PPh 3)4, Na2CO3, H2O, DME, rfx, 0.5−18 h; [II] (i) LiTMP, THF, −78 °C, (ii) B[O(i-Pr)]3, (iii) H +, H2O; [III] (i) n- or t-BuLi, THF, −78 °C, (ii) BEt 3; [IV] 5 mol % Cl2Pd(PPh3)2, THF, 60 °C, 0.5−2 h. Scheme 11
is introduced by lithiation of N-protected indole, which is subsequently reacted with triisopropyl borate.[17] Lithiation and treatment of N-protected indoles with triethylboron gave N-substituted triethyl(2-indolyl)borates 21 for Suzuki coupling with aryl halides. Methoxymethyl (MOM) as N-protecting group suffered reduction. The benzenesulfonyl group was inferior for N-protection.[18] The Diels – Alder reaction of equimolar quantities of bis(trimethylsilyl)acetylene and 4-phenyloxazole gives ready access to 3,4-bis(trimethylsilyl)furan, which undergoes ipso monosubstitution when treated with boron trichloride (Scheme 12). Hydrolysis of the
418
III Pd-CATALYZED CROSS-COUPLING
product gives the trimeric anhydride of the boronic acid, a boroxine 22. The boroxine smoothly undergoes coupling reactions under Suzuki conditions to furnish the arylated product. A phenyl bridged dimeric product 23 is formed with 1,4-dibromobenzene.[19] SiMe3
SiMe3
O
O 1,4-Br2C6H4
SiMe3 Me3Si
SiMe3
O B
[I]
O O
O B
O
90%
[II]
B O
23
SiMe3
ArX
Me3Si
Ar
[II]
X = Br, I
Me3Si O
97–98%
O
Ar = Ph, p-tolyl, 1-naphthyl
22 [I] (i) BCl3, CH2Cl2, −78 to 0 °C, (ii) 1 M aq. Na2CO3; [II] 10 mol % Pd(PPh3)4, Na2CO3, MeOH/toluene, rfx, 3−6 h. Scheme 12
Magnesium Derivatives. Lithiation and metal – metal exchange with a magnesium halide in either N-methylpyrrole, furan, or thiophene give the organomagnesium substrates 24 and 25 for Pd-catalyzed cross-coupling (Scheme 13).[7] The method has been adapted for the preparation of the alternating thiophene–pyridine chain 26.[20] B.i.b. Alkenylation Tin Derivatives. Indole, N-protected by the (trimethylsilyl)ethoxymethyl group, is alkenylated as a 2-stannane 27 with vinyl bromides (Scheme 14). The coupling also proceeds readily with complex heterocycles as exemplified with the structures 28 and 29.[5] 3,4-Bis(tri-n-butyl)stannylfuran or the 3-monostannyl derivative is available by a Diels – Alder reaction between bis(tri-n-butylstannyl)acetylene and 4-phenyloxazole. Either substrate, 30 or 31, undergoes alkenylation when reacted with trans--bromostyrene (Scheme 15).[21] B.i.c. Alkynylation: Allenes Boron Derivatives. Alkynylation is commonly effected between a metallated terminal alkyne and a halogeno- or triflyloxyheterocycle. In the present case it is the heterocycle that is metallated. The coupling leads to allene derivatives 32 (Scheme 16).[22] B.i.d. Alkylation Tin Derivatives. A regiocontrolled method for construction of substituted benzofurans, dibenzofurans, benzothiophenes, and dibenzothiophenes uses 4-chloro-2,3-disubstituted2-cyclobutenones as reactants together with a heterocycle (Scheme 17). In the construction
419
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
[I]
Br
O
N Me
[II]
MgBr
N
N
Me
O
75%
Me
O
O
24 Br
MgCl
O
O
Br
[II]
O
25
High yield
N
N S
S
[III]
S
S
MgBr N
Br
[IV]
82% [I] (i) n-BuLi, TMEDA, hexane, rfx, 20 min, (ii) THF, MgBr2·Et2O, 0 to 20 °C; [II] 2.5 mol % Cl2Pd(dppb), THF, rfx, 2.5 h; [III] (i) THF, −40 °C to r.t., 30 min, (ii) MgBr, − 60 °C to r.t.; [IV] 0.7 mol % Cl 2Pd(dppb), THF, rfx, 4 h.
Br
N S
S
N
N S
S
26 Scheme 13
[I]
RBr
Sn(n-Bu)3
[II]
N
N
CH2OCH2CH2SiMe3
CH2OCH2CH2SiMe3 27
R N CH2OCH2CH2SiMe3 42−97% R = alkenyl Scheme 14 (Continued )
420
III Pd-CATALYZED CROSS-COUPLING y O
MeOOC N
Me
OEt Ind-2
HN
H O O
H Ind-2
O
O
92%
Ind-2 O Me
N H
42% 94%
O
Ind-2
N
O
O
85% (I) 28 29 [I] (i) n-BuLi, THF, −10 °C, (ii) (n-Bu)3SnCl, THF, − 20 °C; [II] 10 mol % Pd(PPh3)4 DMF, 110 °C, 1−72 h. Scheme 14 (Continued) Ph
R
Sn(n-Bu)3
R
β-Br-styrene
O
[I]
30
R = H 80% R = PhCO 82%
O
Ph (M-Bu)3 Sn
Ph
Sn(n-Bu)3 β-Br-styrene [II]
O 31
O 69%
[I] 5 mol % [(C3H5)PdCl]2, HMPA, 60 °C, 23 h (R = PhCO, 2 h); [II] 4 mol % [(C3H5)PdCl]2, HMPA, r.t., 1 h. Scheme 15 R4 R2 [I]
BEt3 N
N
R3 OAc [II]
R4
Li
1
R1
R
C N
R3
R2
1
16−74% R1
R
32
R2
= Me, Boc, OMe; = H, Me, Ph, COOMe, TMS, CH2OTHP; R3R4 = (CH2)5, (CH2)2N(Boc)(CH2)2; R3, R4 = Me, (CH2)2CH CH2, (CH2)3Cl [I] (i) n- or t-BuLi, −78 °C to 0 °C, (ii) BEt3, −78 °C to 0 °C; [II] 10 mol % Pd(PPh3)4, Cl2Pd(PPh3)2, Pd2(dba)3·CHCl3/PPh3, Pd2(dba)3·CHCl3, Pd(OAc) 2, Cl2Pd(MeCN)2, THF, 60 °C, 30 min.
Scheme 16
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
O
R1 R2
(n-Bu)3Sn
Cl
R3
Z (50 °C)
[I]
H OAc O
R1
R1
100 °C
R2
H
R3
R3
Z
Z
R2
58−71% (R 3 = H 37%) 34
33
R1, R2 = Me, Et, n-Bu, Ph, i-PrO R3 = TMS, (H) Z = O, S R3
O
R1
Sn(n-Bu)3
OAc
R1
R3
Z
R2
Cl
R2
[I]
H
Z 35
51−94%
R1, R2 = Me, Et, n-Bu, Ph, i-PrO R3 = H, Me Z = O, S R1
O
S
R1
Sn(n-Bu)3
O S
N
Cl R2
[II]
R2
H
N
H R2
S
[III]
N R1 O 34−54%
36 R1 = Me, Et R2 = Et, Ph, i-PrO
[I] (i) 5 mol % Cl2Pd(PhCN)2, 10 mol % TFP, dioxane, 50 °C (4−12 h), 100 °C (4 h), (ii) Ac 2O, pyridine; [II] 2.5 mol % Pd2(dba)3, 10 mol % TFP, toluene, 60 °C, 3−8 h; [III] rfx, 5–14 h. Scheme 17
421
422
III Pd-CATALYZED CROSS-COUPLING
of substituted benzothiophenes or benzofurans, the initial reaction is a Pd-catalyzed coupling between 4-chloro-2,3-disubstituted-2-cyclobutenones and a 2-stannylthiophene or -furan. The product from the Stille cross-coupling with 4-chlorocyclobutenones is an alkylated heterocycle 33, which is not isolated, but the reaction mixture is heated to 100 °C when a rearrangement takes place with formation of the benzannulated heterocycle 34, presumably via a ketene-like intermediate. Relying on the control inherent in the construction of 4-chloro-2,3-disubstituted-2-cyclobutenones, regioisomeric substituted heteroarenes can be prepared. Several annulated heterocyclic systems including 35 and 36 have been prepared by this methodology.[23],[24] B.i.e. Carbonylation and Acylations Tin Derivatives. 3-(Tri-n-butylstannyl)furan can be converted into a 3-furyl ketone 37 either by a Stille-type coupling under CO pressure or by acylation with an acid chloride (Scheme 18).[25] When 3-(phenylethyl)-4-(tri-n-butylstannyl)thiophene was allowed to react with benzyl bromide under an atmosphere of CO, formation of the carbonylated product 38 was accompanied by 13% yield of the symmetrical ketone, bis[4-(phenylethyl)thiophen3-yl] ketone.[26] In 3,4-bis(tri-n-butylstannyl)furan 39 selective monoacylation can be achieved with acid chlorides. The ketones can subsequently be further carbonylated.[25]
O
O Sn(n-Bu)3 R
RX [I]
O 37
Ph
PhCOCl [II]
O
O 80%
40−82% R = Ph, n-Bu, PhCH=CH, n-hexCH=CH
Bn
Bn
O
Sn(n-Bu)3 Bn
BnBr [III]
S
50%
S 38 O
(n-Bu)3Sn
Sn(n-Bu)3
(n-Bu)3Sn
R
RCOCl
O
[IV]
O
39 [I] 4 mol % Cl2Pd(PPh3)2 or 7 mol % Pd(PPh3)4, THF, CO (30 psi), 50 °C, 2 d; [II] 4 mol % Pd(PPh3) THF, 60 °C, 2 h; [III] 10 mol % Pd(PPh3)4, CO (25−30 psi), THF, 50−60 °C, 2 d; [IV] 4 mol % Cl2Pd(PPh3)2, THF, 65−80 °C, 8−24 h. Scheme 18
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
423
Zinc Derivatives. 3-Acylindoles are formed by Pd-catalyzed coupling of a 1,2disubstituted 3-indolylzinc chloride 40 with a number of acid chlorides to give the corresponding ketones (Scheme 19). The method is recommended for the preparation of acid-sensitive 3-acylindoles. The 3-lithio compound was prepared from the 3-bromide and zincated by means of zinc chloride. The palladium catalyst was prepared in situ by treating a suspension of palladium dichloride with n-BuLi.[27] Cl
Cl
Br ZnCl O
[I]
O
N
N
Me
Me 40
Cl O R
RCOCl
O
[II]
N Me 61−74% R = Me, Bn, n-Pr, Ph 33% for R = CH2Cl [I] (i) t-BuLi, THF, −78 °C, (ii) ZnCl2, THF, −78 °C to r.t.; [II] (i) 10 mol % Cl2Pd(PPh3)2, n-BuLi, r.t.,10 min, (ii) add RCOCl, −35 °C to 0 °C, 2 h. Scheme 19
B.ii. Halogeno- or Triflyloxy-Substituted Five-Membered Ring Systems B.ii.a. Arylation Tin Reagents. The N-protected triflyloxy derivative 41 of pyrrolo[2,3-d]pyrimidine when reacted with an arylstannane affords 5-aryl derivatives (Scheme 20).[28] A closely related reaction has been used in the preparation of the 5-substituted -2-deoxyribosylpyrrolo[2,3-d]pyrimidines 42 from the corresponding C-5 triflate.[29] Stille couplings involving heterocycles have been effected in aqueous solution using a water-soluble catalyst, which was generated in situ from PdCl2 and KOH (Scheme 21). Whereas halogen substituents on tin strongly retard the Stille reaction in organic media, the opposite effect was seen in aqueous media. It would appear that hydrolysis of the RSnCl3 reagent facilitates both solubilization and C — Sn bond activation. Coupling was reported into the 5-position in furan-2-carboxylic acid as well as into the 4-position in pyridine 43.[30] Zinc Reagents. Negishi coupling between 2-iodofuran and phenylzinc chloride is a good reaction but the same reaction appears to fail when 2-bromofuran is used as reagent (Scheme 22).[31] Coupling between 2,5-dibromothiophene and 2-furylzinc chloride provides the dicoupled product 44 in high yield.[7]
424
III Pd-CATALYZED CROSS-COUPLING OBn OBn
BnO
BnO O
O
OTf
N O
N Sn(n-Bu)3
N
N
O
[I]
2
N
N
R2
R
76% 41
OBn
OBn
OBn
OBn
O MOM
O
OTf MOM
N
O TolO
Sn(n-Bu)3
N
N
[II]
BOM O
71%
N
O
N
TolO
BOM O
N
OTol 42 OTol [I] 4.5 mol % Pd2(dba)3 · CHCl 3, 9 mol % P(2-furyl)3, ZnCl2, NMP, 55 °C, 24 h; [II] 10 mol % Pd2dba3, P(2-furyl)3, NMP, 55 °C, 16 h. Scheme 20 Ph PhSnCl3
Br
[I]
COOH
O
Ph
O
COOH
N 81% 96% 43 [I] 0.5−3 mol % PdCl2, 2−12 mol % PhPdP(m-C6H4SO3Na)2, 10% KOH, 90 °C, 3 h. Scheme 21 PhZnCl
I
O
[I]
O 91%
O
Br
S
Br
ZnCl [II]
O S O 44 High yield [I] 5 mol % Pd(PPh3)4, THF, N.t., 5 h; [II] 3 mol % Cl2Pd·dppb, THF, rfx, 2 h. Scheme 22
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
425
Boron Reagents. Iodination of 3,4-bis(trimethylsilyl)thiophene followed by a Suzuki phenylation gives the monophenylated product 3-phenyl-4-trimethylsilylthiophene 45 (Scheme 23). After another ipso-iodination using iodine and silver trifluoroactetate and Suzuki coupling at the iodo carbon, 3,4-diarylated thiophenes are produced.[26] The same reactions have been effected in furans.[32] TMS
I
Ph
Ar
Ph
Ph
ArB(OH)2
[I]
[II]
S
76−90% S
67%
Ar = 4-MeC6H4, 4-MeOC6H4, 2-naphthyl
S 45
Ph
Br B(OH)2 [III]
S
S
P(t-Bu)2
98% 46
(A)
Ph BEt2 N
S
Br
[IV]
75%
S
N
47 [I] I2, CF3COOAg, THF, −78 °C to r.t.; [II] 5 mol % Pd(PPh 3)4, Na2CO3, MeOH-PhMe (1:1), rfx, 5 h; [III] 1 mol % Pd(OAc) 2, 1 mol % (A), KF, THF, r.t., 17 h; [IV] 5 mol % Pd(PPh3)4, KOH, (n-Bu)4NBr, THF, rfx, 8 h. Scheme 23
A highly active palladium catalyst for Suzuki coupling reactions can be generated from palladium diacetate and 2-(di-tert-butylphosphino)biphenyl. Potassium fluoride is the preferred base for this system. The coupling of both bromides and chlorides proceeds at room temperature in excellent yields as exemplified by the preparation of 3-phenylthiophene 46.[33] Cross-coupling between 2-bromothiophene and diethyl(3-pyridinyl)borane gives a pyridinyl 2-substituted thiopene 47.[34] Magnesium Reagents. Nickel catalysis is commonly used for cross-coupling reactions involving organomagnesium reagents. Palladium catalysis is often less efficient but more selective. In 2,3-dibromothiophene selective reaction in the 2-position gives the monocoupled product 48 (Scheme 24). Selectivity is rationalized by activation of the 2-position by the annular heteroatom. Monosubstitution can also be effected in 2,5dibromothiophene to yield the bithienyl 49.[7] Homocoupling. Homocoupling corresponds to an arylation reaction with formation of symmetrical biheteroaryls from the same substrate. Homocoupling is frequently a side
426
III Pd-CATALYZED CROSS-COUPLING
reaction when heterocouplings are desired. Conditions can be chosen for exclusive homocoupling as for the preparation of bithienyls 50.[35] Br
Br Br
S
MgBr
S [I]
S
S
80% MgBr
S
Br
Br
S
48
[I]
S
Br
S
49 50% [I] 1.5 mol % Cl2Pd(dppf), Et 2O, 25 °C, 1.5 h. Scheme 24 R
R
R [I]
X
S S R = 5-CHO, -MeCO, -NO2, Cl; 2-Me X = Cl, Br, I 50 [I] 5 mol % Pd(OAc) 2, NEt(i-Pr)2, (n-Bu)4 NBr, toluene, 105 °C, 4−24 h (2-Cl, 106 h). S
58−92%
Scheme 25
B.ii.b. Alkenylation Tin Reagents. In the -excessive systems alkenylation has often been carried out with the metallated heterocycle (vide supra). Also widely used are Heck alkenylations (vide infra). Coupling of vinylstannanes with 3-iodoindoles was used in the preparation of 3alkenylindoles 51 (Scheme 26).[36] B.ii.c. Alkynylation Copper Reactants. Application of the Pd/Cu-catalyzed cross-coupling, the Sonogashira reaction, with monosubstituted or protected acetylene gives rise to a variety of ethynylheteroarenes (Scheme 27). Reactions with trimethylsilylacetylene or phenylacetylene in R2 I
Sn(n-Bu)3
CHO N R1
R2
CHO [I]
N
67−89% 51
R1
R1 = SO2Ph, MOM, R2 = H, OEt [I] 5 mol % Cl2Pd(PPh3)2, Et4NCl, DMF, 80 °C, 2 h. Scheme 26
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
TMS [I] or [II]
Br
Z
Z TMS
52 [I] Z = S 75% [I] Z = O 74% [II] Z = NMe 79%
R
Br R [III] or [IV]
S
S 53 [III] R = TMS 88% [IV] R = Ph 65% R I R [V]
Z
Z
58−96%
54
Z = S, NMs R = TMS, Ph, n-Bu, CH2OH
Me HO Me
Br
Z
Me
[VI]
OH
Z Me
Z = O 84% Z = S 95%
55 Me
Me
Br
OH Me
HO Me [VII]
O
O 77% 56
S
I
[VIII]
83%
S
S 57
Scheme 27 (Continued )
427
428
III Pd-CATALYZED CROSS-COUPLING I [VIII]
S
S
89%
S 58
[I] 2.5 mol % Cl2Pd(PPh3)2, PPh3, CuBr, LiBr, NEt 3, rfx, 1−2 h; [II] 2.5 mol % Cl2Pd(PPh3)2, CuBr, NEt 3, 75 °C, 3 h; [III] 2.5 mol % Pd(PPh3)4, PPh3, CuBr, LiBr, piperidine, rfx, 20 min; [IV] 2.5 mol % Pd(PPh 3)4, PPh3, CuI, Et2NH, EtOH, benzene, 45 °C, 30 min; [V] 4.5 mol % Cl2Pd(PPh3)2, CuI, NEt3, DMF, 25 °C; [VI] 10 mol % Pd(PPh3)4, PPh3, CuBr, NEt 3, 90 °C (rfx), 40−60 min; [VII] 10 mol % Pd(PPh3)4, PPh3, CuBr, LiBr, (i-Pr)2NH, piperidine, rfx, 5 h; [VIII] 3 mol % Cl2Pd(PPh3)2, PPh3, CuI, Et2NH, rfx, 2−4 h. Scheme 27 (Continued)
both the 2- and 3-positions of the -excessive heterocycles furnish the ethynyl derivatives 52 and 53 in high yields.[37] 3-Iodobenzo[b]thiophene and N-protected indole 54 react similarly.[38] Acetylene is frequently protected as a monosilylated derivative. The monoadduct between acetylene and acetone can also be used for coupling of acetylene into -excessive five-membered rings in either the 2- or the 3-position as in the preparation of the products 55 and 56, respectively. Removal of the protecting group furnishes a monosubstituted acetylene. With free acetylene, dicoupling can be effected in excellent yields to give products with two thiophene units symmetrically bridged in the 2or the 3-position, structures 57 and 58, respectively.[37] Unsymmetrically bridged structures are best obtained in a two-step process starting from monoprotected acetylene. Regioselectivity can be achieved in coupling reactions with 2,3-dibromothiophene or 2,3-dibromofuran (Scheme 28). The halogen next to the heteroatom is the more reactive. With silyl-protected acetylene, selective reaction in the 2-position in either heterocyclic system gives the coupling products 59. The acetone-protected acetylene gave 72% of the 2-ethynylthiophene 60. The reactivity is lowered after introduction of the first acetylene substituent. Therefore, the monocoupled silyl-protected acetylenic product 61 is accessible from 3,4-dibromothiophene.[37] In tetraiodothiophene the halogens in the -positions are the more reactive in Sonogashira coupling. Thus, TMS-protected acetylene gave the 2,5diethynyl product 62 in high yield. The latter can be further ethynylated in a second reaction step under similar conditions. The reaction with acetone-protected acetylene, that is, with 2-methyl-3-butyl-2-ol, proceeds even better (84%) in the tetraethynylation than with the silyl-protected reagent. The silyl groups are removed under mild alkaline conditions to furnish tetraethynylthiophene. Acetonyl deprotection requires more vigorous conditions.[39] The Sonogashira coupling procedure is a high yielding process also in structurally complicated molecules (Scheme 29). Reaction between fully protected 5-triflyloxy -2deoxyribosylpyrrolo[2,3-d]pyrimidines and N-(propargyl)trifluoroacetamide was used to prepare the alkynylated product 63.[29] Tin Reagents. ipso-Monoiodination of 3,4-bis(trimethylsilyl)thiophene followed by Pdcatalyzed cross-coupling with stannylated acetylene gives the monalkyne 64. Distannylated acetylene will give the alkyne substituted at both termini 65 (Scheme 30).[26] Zinc Reagents. Coupling of heteroaryl iodides or bromides with ethynylzinc halides yields alkynylated heterocycles (Scheme 31). The ethynylzinc reagent can be prepared in situ by addition of a zinc halide to the ethynylmagnesium halide, which is either
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
Br
Br TMS
Br [I] or [II]
Z
Z
TMS
[I] Z = O 60% [II] Z = S 50%
59
Me
Me
Me [III]
Br
S
Br
OH
Br
OH S
Me
72%
Br
60
TMS
Br
Br
TMS [IV]
S
S
75%
R
61 I
I
I
I R
TMS
[VI]
[V]
I
S
I TMS
S
R
TMS TMS
84%
S
TMS
62
R = TMS 45% R = Me2COH 86% [I] 3 mol % Pd(PPh3)4, PPh3, CuBr, LiBr, NEt 3, rfx, 1.5 h; [II] 3 mol % Cl2Pd(PPh3)2, PPh3,Cu (i-Pr)2NH, rfx, 2 h; [III] 3 mol % Cl2Pd(PPh3)2, PPh3, CuI, NEt3, 50−80 °C, 3 h, [IV] 3 mol % Cl2Pd(PPh3)2, PPh3, CuI, Et2NH, rfx, 3 h; [V] 5 mol % Cl2Pd(PhCN)2, PPh3, CuI, (i-Pr)2NH, r.t. (12 h), rfx, 1 h; [VI] 10 mol % Cl 2 Pd(PhCN) 2 , PPh 3, CuI, (i-Pr)2NH, N.t. (4−12 h), rfx. Scheme 28 NHCOCF3 O MOM
O
OTf MOM
N
O
N
N
TolO
BOM O
CH2NHCOCF3
N
91%
N
O
N
TolO
BOM O
[I]
OTol
63
[I] 10 mol % Pd(PPh3)4, CuI, NEt3, DMF, r.t., 4 h Scheme 29
OTol
429
430
III Pd-CATALYZED CROSS-COUPLING
TMS Sn(n-Bu)3
TMS
TMS
TMS
I
90%
[II]
S
[I]
64 (n-Bu)3Sn
S
Sn(n-Bu)3
S
96%
TMS TMS
[III]
56%
S
S
[I] I2, CF3COOAg, THF, −78 °C, 6 h; [II] Pd(PPh3)4, dioxane, rfx, 6 h; [III] Pd(PPh3)4, dioxane, Et3N, 90 °C, 8 h.
65
Scheme 30 ZnBr
R
I
Z
R
[I]
Z
Z = O, S, NMe 76−92% R = H, Me ZnBr
I Z
[I]
Z = O, S 78%, 92%
Z 66
[I] 5 mol % Pd(PPh3)4, THF, 22 °C, 1−4 h. Scheme 31
commercially available or readily prepared. Since Sonogashira coupling does not permit direct cross-coupling of acetylene itself in a selective manner, mainly due to competitive dicoupling, the Zn – Pd procedure offers a distinct advantage in the synthesis of terminal alkynes. Arenes containing an electron-rich aryl group are known to be less reactive in Pdcatalyzed coupling than those containing an electron-withdrawing group due to slower rates of oxidative addition. Using ethynylzinc halides, synthesis of arylethynes containing a -excessive heteroaryl group proceeds exceptionally well. A variety of furan, thiophene, and benzannulated derivatives 66 have been prepared.[40] B.ii.d. Alkylation Boron Reagents. The transfer of an alkyl group from a stannane to a Pd(II) complex in the catalytic cycle normally requires vigorous conditions unless the alkyl group is specially activated. Alkyl groups are transferred more easily from an alkylzinc halide. Alkyl groups can also be transferred from boranes (Scheme 32). In carbazoles there is no heterocyclic ring position available for substitution. Carbosubstitutions are in a benzene ring and cross-coupling will therefore proceed in the same manner and under the same conditions as in other phenyl derivatives. When the triflate 67 was subjected to Suzuki coupling with 9-alkyl-9-BBN reagents, 1-alkylcarbazoles were formed.[36]
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
R1
R1
B R2
Me
Me N H
431
[I]
OTf
76−96%
67
N H
R2
R1 = H, OEt R2 = n-Hept, (CH2)nCHMe2, n = 4−6
[I] 5−8 mol % Cl2Pd(dppf), NaOH, THF, 80 °C, 1.5−3 h; [II] 4 mol % Pd(PPh3)4 Na2CO3, DME, 100 °C, 1 h. Scheme 32
Aluminum Reagents. Simple aluminum derivatives are good reagents for alkylations because the alkyl groups are readily transferable from alanes to the Pd(II) complexes in the catalytic cycle. This methodology has been used for the synthesis of C-alkylated purine nucleosides from halogenopurine nucleosides and trialkylalanes (Scheme 33). The coupling reaction for 8-bromoadenosine 68 itself failed. Reaction with TMS-protected NH2
NH2 N
N HO
Br N
N
N
N
R
AlR3 [I]
O
HO
N
68 NH2
R HO
N
N O
HO OH 69
R
O N
N
O R = Me, Et, n-Pr, i-Bu; 42−95% HO X R = H; 21−34% Al(i-Bu)3: R = i-Bu; 13%; R = H; 59%
X = H, OH
HO X
N
N
HN H2N HO
R N
N O
N
N H2N HO
N
N O
HO OH
HO OH
70
71
R = Br R = Br R = Me, Et, n-Pr R = Me 83% (24 h) Al(i-Bu)3: R = i-Bu; 34%; R = H; 43% [I] (i) HMDS, (ii) 5 mol % PdCl2, PPh3, THF, rfx, 2 h. Scheme 33
R = Cl R = Me 70% (70 h)
432
III Pd-CATALYZED CROSS-COUPLING
8-bromoadenosine, however, led to the alkylated product when trimethylalane was the reagent. Excess of the alane was used. Other trialkylalanes reacted similarly to furnish the corrresponding 8-alkylpurine nucleosides. Debromination may lead to a side reaction. Debromination was especially pronounced in reactions with the bulky triisopropylalane. 2-Bromoadenosine and 8-bromoguanosine also gave the corresponding alkylated products, 69 and 70. For alkylation in the electrophilic 6-position, the substrate was 2-amino-6-chloro-9--D-ribofuranosylpurine 71.[41] B.ii.e Carbonylation and Acylation. The keto function in pyrrolo[3,2-c]pyridin-4-ones and pyrido[3,4-b]pyrrolizidin-1-ones can be enolized and triflated to yield the substrates 72 and 73, respectively (Scheme 34). Replacement of the triflyloxy group by carbonylation is effected with palladium catalysis. Reaction of the pyrido[3,4-b]pyrrolizidin-1-ones 73 was complicated by formation of a by-product, namely, the 2-methoxy adduct 74. In the latter case competitive palladium-assisted elimination of the triflyloxy group leads to an imminium intermediate, which adds a methoxy group as a O Bn
O
OTf Bn
[I]
N N
N N
80%
Bn
Bn
72 O Bn
COOMe
O
R Bn
N
O OMe
N
N
N
73
60%
74
R = OTf R = COOMe O MOM O
OTf
O MOM
N N
N
BOM TolO O
COOMe
N
[II]
N
O
N
TolO
BOM O
83% OTol
OTol
75 [I] 3 mol % Pd(OAc) 2, PPh3 (2:9), NEt3, CO (1 atm), DMF, MeOH, 65 °C; [II] 10 mol % Pd(OAc) 2, PPh3, NEt3, CO (1 atm), DMF, MeOH, 68 °C, 2 h. Scheme 34
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
433
nucleophile to form the by-product 74.[42] Similarly, the triflated deazapurine nucleoside analog 75 can be carbonylated and esterified.[29] Carbonylation of a 2-iodoindole in the presence of an amine provides a method for the preparation of indole-2-carboxamides 76 (Scheme 35). Unprotected indole was a better substrate than its Boc-protected derivative in this reaction. The methodology can also be used to construct more complex carbamates 77.[43] NHR1R2
I
CONR1R2
[I]
N H
N H
33−90%
76
NHR1R2 = BuNH2, glycine, BnNHMe, PhNH2, 4-NH2C6H4Ac, PhNHMe
S N
I N
HN
Cl
N
[I]
COOR
S
NH2
R = H 85% R = t-Bu 33%
O
N Cl
COOR 77
[I] 5 mol % Cl2Pd(PPh3)2, N(n-Bu)3, CO (1 atm), DMA, 115 °C, 10 min. Scheme 35
B.ii.f. Heck Reaction Addition into the Heterocycle. The regiochemistry in Heck-type arylation of 2- and 3-substituted thiophenes is affected by the nature of the thiophene substituent and its relative position (Scheme 36). Regiospecific substitution occurs in the 5-position when the heterocycle is -substituted with an electron-withdrawing group 78. An electronwithdrawing group in the thiophene 3-position largely directs the Heck substitution into the 2-position 79. By-products result from substitution in the 4- and the 2,4-positions.[44] A number of Heck couplings into -excessive heterocycles 80 have been effected using the -deficient pyrazine ring substituted by a chlorine. Since all pyrazine positions are electrophilic, a chloro rather than a bromo or iodo derivative can be used for the coupling. Under the conditions of the reaction, some disubstitution into the furan, thiophene, or pyrrole may result 81. Pyrrole and its N-methyl derivative behaved similarly, furnishing the monocoupled product in moderate yields; furan and thiophene reacted well. In all these cases the regiospecificity was such that the carbosubstitution was in the 2-position, next to the heteroatom as commonly seen in Heck reactions with a vinyl ether. Benzo[b]furan and benzo[b]thiophene behaved in the same manner with regioselective substitution into the 2-position 82. With pyrrole N-acylated by the strongly electronwithdrawing benzenesulfonyl group 83, however, the product was a mixture of the two regioisomers.[45] 5-Iodo- and 5-bromo-2,4-dimethoxypyrimidine also undergo the Heck substitution into thiophene. The reaction was effected under heterogeneous conditions in
434
III Pd-CATALYZED CROSS-COUPLING
aqueous media by heating the reactants in aqueous solution containing (n-Bu)4NHSO4 and potassium carbonate. The yield of the Heck product 84 was 50% from the iodopyrimidine and 37% from the bromopyrimidine. When the iodopyrimidine and thiophene were heated at 150 °C in a pressure reactor (50 psi), the reaction took another course in that the thienylation was in the pyrimidine 6-position, the product being 6-(2thienyl)-2,4-dimethoxypyrimidine 85.[46] R
Br [I]
EWG
S
EWG
S R
30−81%
78
R = H, 4-MeO, 2- and 4-CF3, and C6H4R = 1-naphthyl R
EWG
EWG Br [I]
S
S
R
79 R = H, EWG = CHO 35% R = OMe, EWG = CN 30% N R
R
N R
[II]
N
N
R
N
Cl
R
N
R
N
Z R
N
80 Z = O, S 55− 82% Z = NH, NMe 25− 29%
R = Me, Et, i-Bu
R
N +
Z
Cl
N
Z
R
N
R
81 0−22% 14−27%
R Z
[II]
Z
R
N
R = Me, Et, i-Bu Z = O, S 45−72% N
R
N
Cl
N R
N SO2Ph 83
[II]
R = Me, Et, i-Bu
R
R
82 N
SO2Ph + N R
N R = Me, Et, i-Bu Scheme 36
N
R N
40−44% (1:1−2:5)
SO2Ph
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
OMe
OMe N MeO
MeO
S
OMe X
N
X
N N
MeO
OMe N
N
[IV]
S
[III]
N
435
MeO
N
S X = I 50% X = I 23% 85 X = Br 37% [I] 5 mol % Pd(OAc) 2, K2CO3, (n-Bu)4NBr, MeCN, H 2O, 80 °C, 3−7 h (NO2; 54 h); [II] 5 mol % Pd(PPh3)4, AcOK, DMA, rfx, 6 h; [III] 7 mol % Pd(OAc) 2, PPh3, K2CO3, (n-Bu)4NHSO4, H2O, 95 °C, 24 h; [IV] 7 mol % Pd(OAc)2, PPh3, K2CO3 (n-Bu)4NHSO4, H2O, 150 °C, 50 psi, 24 h. 84
Scheme 36 (Continued )
Addition by the Heterocycle. Under Heck conditions, 3-phenyl-4-vinylthiophenes 86 were formed from 3-iodo-4-phenylthiophene and ethyl vinyl ketone, methyl acrylate, and m-nitrostyrene (Scheme 37)[26] 4-Iodo-3-trimethylsilylfuran under similar Heck conditions with alkenes reacted in two regioselective manners. Alkenes with electron- withdrawing groups, such as methyl vinyl ketone and ethyl acrylate, gave exclusively trans-substituted alkenes 87. Allyl alcohol, styrene, and 4-methylstyrene gave ,-disubstituted products 88.[47] 1-(Phenylsulfonyl)indol-3-yl trifluoromethanesulfonate under Heck conditions provides 3-vinylindoles 89.[48] An excellent yield was reported for the reaction between the triflated deaza nucleoside 90 and ethyl acrylate.[29] B.ii.g. Annulation Heck Annulation. Intramolecular Heck reactions are useful for annulation in heterocyclic structures. N-(2-Iodobenzoyl)indoles or -pyrrole undergo Pd-catalyzed annulation to furnish R TMS
I
Ph
Ph
S
67%
Ph
R
[I] [II]
S
50−65%
S 86
R = COEt, COOMe, 3-NO2C6H4 R TMS R
O 87
[III]
I
R
TMS
O
[III]
61−75%
62−78%
R = CN, COMe, COOEt
TMS
R
O 88
R = CH2OH, Ph, C6H4-4-Me
Scheme 37 (Continued )
436
III Pd-CATALYZED CROSS-COUPLING R OTf R [IV]
N
N
61−93%
SO2Ph
SO2Ph 89
R = COOMe, COOEt, COEt, CHO, Ph, H, O MOM
MOM
N
O TolO
COOEt
N
N BOM O
COOEt
O
OTf N
N
O
N
TolO
BOM O
[V]
82% OTol
OTol
90 [I] I2, CF3COOAg, THF, −78 °C to r.t.; [II] Pd(OAc)2, K2CO3, (n-Bu)4NI, DMF, 90 °C, 8 h; [III] 5 mol % Pd(OAc) 2, NEt3, rfx, 28 h; [IV] 3 mol % Cl2Pd(Ph3)2 (i-Pr)2NEt, DMF, 70−80 °C, 12−36 h; [V] 10 mol % Cl2Pd(PPh3)2, PPh3, NEt3, DMF, MeOH, 90 °C, 17 h.
Scheme 37 (Continued)
the corresponding Heck products 91 and 92 (Scheme 38).[49] N-Alkarylindoles and 7azaindole analogs furnish cyclic compounds under Heck conditions with the new carbon – carbon bond in the indole 2-position 93. When the 2-position in the indole is blocked by methyl substitution, cyclization occurs into the 7-position in the benzene ring 94.[50] Indole-3-acetic acid derivatives can be prepared by the Heck cyclization of N-allyl substituted o-halogenoanilines.[51] – [53] The same concept has been used in the preparation of seleno- and thienopyrroles (Scheme 39). In this reaction N-Boc-protected oiodoheteroarylamines were N-allylated with ethyl 4-bromocrotonate to form the substrate 95. Pd-catalyzed ring closure in a one-pot reaction yielded N-Boc-protected thienopyrroles and selenopyrrole. The Boc group was readily removed thermally after adsorption on silica. Oxothienopyrroles were similarly prepared from appropriate carbamoyl derivatives 96.[54] Alkylpalladium(II) species 97, generated via initial palladium cyclization of an aryl iodide onto a proximate alkene, are highly reactive and will attack proximate aromatic or heteroaromatic rings, both electron rich and electron poor, leading to spirocycles 98 (Scheme 40). The second cyclization step onto the aromatic ring is expected to occur with cis-stereochemistry. The -hydride elimination step normally occurs with cis-stereochemistry. This process is not possible in the present case. Similarly, formally forbidden eliminations are not uncommon especially when the Pd(II) species is located at a benzylic position and may involve prior stereomutation of the Pd(II) moiety or a slower trans-elimination.[55]
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
R
R [I]
I N
N 63−80%
O R = H, Me
O
1
91
N
I
[I]
N
O 80%
O 92 R1
R1
R2
437
R2 [II]
Br Z
N
N
Z 25−87%
n
n
93
n = 1−3; Z = CH, N; R1 = CHO, CN; R2 = H, OMe, Br CHO
CHO
Me N
[II]
N
Me
Br 97%
94 [I] 10 mol % Pd(OAc) 2, PPh3, K2CO3, Et4NCl, MeCN, rfx, 4−12 h; [II] 6 mol % Pd(PPh3)4, KOAc, DMF, 110 °C, 1.5−10 h. Scheme 38
Annulation Via Heterosubstituent. Several applications of the Larock synthesis of indoles have been published where heterocycles are used as substrate. In the Larock method for indol construction, Pd-catalyzed heteroannulation of internal alkynes using orthoiodoaniline and its derivatives were used.[56] The methodology is well suited for adaption to heterocyclic systems (Scheme 41). Larock in his method for indole formation uses acetylenes with large protecting groups at the one terminus. A sterically demanding silyl group ends up adjacent to the nitrogen in the indole. The same methodology and findings were observed in the reaction between 3-amino-2-iodothiophenes and terminally silylated propargyl alcohol in the preparation of heteroannulated pyrroles 99.[57]
438
III Pd-CATALYZED CROSS-COUPLING COOEt
Boc N
COOEt
COOEt I
S
[I]
S N
Z
Z
COOEt
95
Boc Z = S, Se
NHBoc I
N
N
Boc
Boc
59−72%
Z EtOOC
EtOOC
EtOOC
O
H
H
Boc N
COOEt I
S
H S
O
[II]
96
O
S
O N
N
N
S
Boc Boc Boc 21−54% [I] 5 mol % Pd(OAc) 2, PPh3, K2CO3, DMF, r.t. −65 °C; [II] 5 mol % Pd(OAc) 2, PPh3, DMAP, TEA, THF, rfx, 5 h (40 °C, 50 h; r.t., 96 h). Scheme 39
R
N I
PdX
R
N
N H
PdX
[I]
N
N
SO2Ph
SO2Ph
97
R
N 74−91% SO2Ph
R
N
N
SO2Ph 98 R = H, Me, CHO O O
R R N
N
N
N
N
N
SO2Ph
SO2Ph
N I [I]
N SO2Ph
R = H 59% R = CHO 81%
[II] 75% Me N
O
N
O
Me
I N SO2Ph
[III]
N 68%
Scheme 40
SO2Ph
SO2Ph [II] 80%
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
SO2Ph
SO2Ph
N
N
439
Z
I
Z
[IV]
PdI
N
N
SO2Ph
SO2Ph
Z PhO2S
Z = O 64% Z = S 41%
N
N
SO2Ph [I] 10 mol % Pd(OAc) 2, 20 mol % PPh3, KOAc or K 2CO3, MeCN or anisole, 60 or 130 °C, 15−24 h; [II] 10 mol % Pd(OAc) 2, 20 mol % PPh3, Et4NCl, K2CO3, MeCN, rfx, 3−3.5 h; [III] 10 mol % Pd(OAc) 2, 20 mol % PPh3, Et4NCl, K2CO3, MeCN, rfx, 17 h; [IV] 10 mol % Pd(OAc) 2, 20 mol % PPh3, TlOAc, Et 4NCl, MeCN, rfx, 15 h; or DMF, 100 °C, 9 h. Scheme 40 (Continued) TBDMS
S
NHR
OH
HO I S
TBDMS N
[I]
22% R = Ac 67% R = BOc
R 99
[I] 5 mol % Pd(OAc) 2, (n-Bu)4 NCl, 90−100 °C, Na2 CO3 , or KOAc, 3−22 h. Scheme 41
C. CROSS-COUPLING IN AZOLES C.i. Metallated Azoles C.i.a. Arylation Tin Derivatives A convenient and direct method for the preparation of metallated species in the azole series starts with lithiation, as in the case of -excessive systems. In thiazoles the initial lithiation is in the 2-position. Subsequent quenching with a stannyl halide will furnish a stannane substrate 100 to be used for Stille couplings with aryl or heteroaryl halides, in the present case with a bromide[7] (Scheme 42). Stannylated oxazoles are similarly prepared and react in the same manner.[58] The same applies to their benzannulated analogs 101.[59] Isoxazoles are initially metallated in the 5-position. The 5-stannyl derivatives 102 (Scheme 43) could be cross-coupled with hydroxy- and methoxy-substituted 2-iodophenols
440
III Pd-CATALYZED CROSS-COUPLING
Me
Me
Me
Me N
N
[I]
S
N
[II]
Sn(n-Bu)3
S
Li
S
100%
S
Ar
N
ArBr [IV]
O
[III]
Ar = 3-pyridinyl 83% Ar = 2-thienyl 80%
100
Me N
N
ArBr
Ar
O
Sn(n-Bu)3 80−100%
Ar = C6H4-4-Ac, 2-pyridinyl Z
S Sn(n-Bu)3
PhBr
N
Ph N
[V]
101
Z = O 75% Z = S 56%
[I] n-BuLi, THF-hexane, −80 to −65 °C, 15 min; [II] (n-Bu)3SnCl, THF, −70 °C, 15 min; [III] 2 mol % Pd(PPh3)4, benzene, DMF, rfx, 5 h; [IV] 5 mol % Pd(PPh 3)4, benzene, rfx, 12−24 h; [V] 1 mol % Cl2Pd(PPh3)2, xylene, 120 °C, 20 h. Scheme 42
R1
OH
R1
R2
I
R2 6
N O
N
R5
R3 (n-Bu)3Sn
R3
OH
R6
R
O
[I] or [II]
R6
102
R6 5
R R1, R2, R3, R4, R5, R6 = H, OH, OMe [I] 35−81% R1, R3, R4, R5, R6 = H, R2 = OH [II] 95% R1, R3, R4, R5 = H, R 2, R6 = OH [II] 78%
Me3Sn
Me3Sn
Me N O
Me3Sn [III]
R
Me N O
[IV]
Me
O
N R = Ph 62% R = 3-pyridinyl 74%
103 [I] 5 mol % PdCl2, dioxane, rfx, 5 h; [II] 5 mol % Pd2(dba)3, 20 mol % AsPh 3, dioxane, 45 °C, 48 h; [III] NH4OH, EtOH-H2O, 150 °C, 15 h; [IV] 2−5 mol % Cl2Pd(PPh3)2, dioxane, rfx, 24−36 h (PhCO, 3 h). Scheme 43
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
441
to yield 3-aryl-5-(2-hydroxyaryl)isoxazoles. Triphenylphosphine was the preferred ligand except when the substrates were rich in hydroxy groups, in which case triphenylarsine as ligand gave the higher yields of the coupling product.[60] 4-Stannylisoxazoles 103 can be prepared by a 1,3-dipolar cycloaddition reaction of bis(tributylstannyl)acetylene with nitrile oxides, followed by treatment with aqueous ammonia in ethanol in a sealed tube to remove selectively the stannyl group at the more acidic 5-position. The product in the present case is 4-(ntributyl)stannyl-3-methylisoxazole. Pd-catalyzed cross-coupling with iodobenzene or 3bromopyridine leads to the corresponding aryl- and heteroaryl-substituted derivative.[61] N-Trityl-4-iodopyrazole 104 can be coupled with stannylbenzenes using PdC/CuI/AsPh3 as the catalyst system (Scheme 44). The 4-anisylstannane gave the coupling product in good yield. Lower yields were obtained from the 4-phenol and 4-anilino analogs, and the reaction failed for the 4-nitro derivative. Better results were obtained when the polarization of the reactants was reversed, that is, in the coupling between 4-stannylpyrazoles 105 and phenyl iodides. The stannyl substrate is available from 4-halogenopyrazole by lithiation with t-butyllithium and subsequent treatment with the stannyl chloride.[62] I
(n-Bu)3Sn
Ar N N
ArSn(n-Bu)3
N
[I]
N
Tr 104
Tr 83%
I
ArI
N
[I]
55−90%
[II]
N
N
N
Tr
Tr
105
Ar = C6H4-4-OMe 79% Ar = C6H4-4-OH, 4-NH2 11−27% [I] 1.3 mol % Pd-C (10%), AsPh 3, CuI, MeCN, rfx, 48 h; [II] (i) t-BuLi, THF-Et2O, −78 °C, (ii) (n-Bu)3SnCl. Scheme 44
Zinc Derivatives Oxazoles and benzoxazoles can be lithiated in the 2-position by alkyllithium. In transmetallation of lithiated oxazole excess zinc dichloride gave the highest yield. The zincated substrates 106 and 107 were used in Negishi-type coupling (Scheme 45). Reactions of zincated oxazoles and benzoxazole with aryl halides all proceed well.[63] A similar reaction sequence was used in the preparation of a 2-oxazolylsubstituted tricyclic structure 108.[64] 1,2,3-Triazoles are lithiated next to the N-substituted nitrogen 109 by analogy to metallation in N-substituted pyrrole and pyrazole (Scheme 46). Alternatively, directed orthometallation (DOM) can be used to explain metallation in the 5-position. Zincation is effected by quenching with zinc iodide. Stannylation is effected similarly with a stannyl chloride. The zincated substrate readily undergoes the Negishi reaction with aryl iodides. The cross-coupling was less effective with stannanes as substrates. In the case of 2fluoro-1-iodobenzene, the coupling reaction proceeded more readily than for the corresponding bromide and chloride. In general, iodo derivatives of the heterocycle reagent were used in the heteroarylation.[65]
442
III Pd-CATALYZED CROSS-COUPLING R2 N
R1
N
R2ArX [I]
ZnCl
O
R1
O
56−68%
106
R1 = H, Ph, R2 = C6H4-4-Ac, 2-Me, 4-OMe, 4-NO2 O ZnCl
O
Naph-I
(1-naphthyl)
[III]
N
N
78%
107
I N(n-Pr)2
N
N
[II]
O
O
N N(n-Pr)2
HN
ZnCl
O
[I]
54% HN
[I] (i) 5 mol % Cl2Pd(PPh3)2, 10 mol % n-BuLi, THF, rfx, 1−2 h; [II] (i) n-BuLi, −70 °C, THF, (ii) ZnCl 2, Et2O, −78 °C to r.t.
108
Scheme 45
R
[I] N
N
[III]
[II]
N
N OBn N OBn N N N
N
ArI
ZnI
Li N
N OBn
71−87%
N OBn
R = H, 2-F, 4-NO 2, 4-OMe, 2-NH2, 4-OH
109
HetArI [III]
HetAr N
HetAr = N
S
N
N OBn N
63%
N
N OBn
80% 49% Failure [I] n-BuLi, THF, −78 °C; [II] ZnI2; [III] 2−5 mol % Pd(PPh3)4, THF, −78 °C to r.t., 30 min. Scheme 46
N
N OBn
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
443
C.i.b. Alkenylation Tin Derivatives Treatment of N-protected 4-iodoimidazole with ethylmagnesium bromide in anhydrous dichloromethane followed by quenching with trimethyltin chloride will give the 4-stannylated imidazole 110 (Scheme 47). Subsequent Stille coupling has been effected with -bromostyrene or the bromovinyl-dioxole 111.[66] Ph Br Ph (E/Z = 10:1)
Me3Sn
I N
N
trans 68%, cis 12%
[II]
N
[I]
N
N
Et
Et
O
O
N [III]
66%
OEt
OEt
OEt 110
Br
N
O O Et
Et
(E/Z = 9:1)
N
trans 60%, cis 13%
111
OEt [I] (i) EtMgBr, CH 2Cl2-Et2O, r.t., 30 min; (ii) Me 3SnCl, 0 °C to r.t., 2 h; [II] 5 mol % Pd2(dba)3, 10 mol % AsPh 3, 10 mol % CuI, DMF, 80 °C, 3 h; [III] 5 mol % Cl2Pd(PPh3)2, DMF, 80 °C, 8 h. Scheme 47
Zinc Derivatives Oxazole and 5-substituted oxazoles are lithiated in the 2-position. Subsequent zincation gives the corresponding 2-oxazolylzinc chloride 112 for alkenylation (Scheme 48). Excess of zinc chloride was used in the zincation. Subsequent cross-coupling with a 1-butenyl iodide yields 2-alkenyl derivatives. The Pd-catalyst was pregenerated by reduction with DIBALH.[67] The alkenylated oxazole 113 was formed in a corresponding coupling reaction with a cyclic vinyl triflate.[63] C.i.c. Carbonylation and Acylation Tin Derivatives. 5-Stannylated or 5-zincated 1-benzyloxy-1,2,3-triazole, 114 and 115, respectively, is available from the 5-lithiated species by quenching with the respective metal halide (Scheme 49). Either metal complex is a good substrate for ketone formation 116 in the 5-position with acid chloride reagents.[65] C.i.d. Heck Reaction. -Deficient chloropyrazines can be Heck-coupled into 1,3-azoles (Scheme 50). It will be recalled that the same methodology was used to couple into the -excessive furan, thiophene, and pyrrole heterocycles and their benzo derivatives (vide supra). The Heck reaction in oxazole and thiazole proceeds in a regiospecific manner. The new carbon – carbon bond is formed in the 5-position 117 next to the “ether” heteroatom as commonly observed in vinyl ethers and strongly favored in furan and thiophene. In benzoxazole and benzothiazole the only vacant position is between the two heteroatoms, and the Heck coupling results in substitution into the 2-position 118.[45]
444
III Pd-CATALYZED CROSS-COUPLING I
N R1
N ZnCl
O
[I]
R1
O
53−78%
112
R1 = H, Ph, 3-methylisoxazol-5-yl
COOEt
COOEt OTf
N ZnCl
O
Ph
[II]
N
Ph
O
84%
113
[I] (i) 10 mol % Cl2Pd(PPh3)2, 20 mol % DIBALH, THF, (ii) r.t., 1−6 h; [II] (i) 5 mol % Cl2Pd(PPh3)2, 10 mol % n-BuLi, THF, (ii) rfx, 1−2 h. Scheme 48
Sn(n-Bu)3 [II]
N N
Li
N
R
[IV]
114
[I]
N
O
RCOCl
N OBn
N OBn
N N
N OBn
N [III]
RCOCl
ZnI
[V]
N
N
N OBn
59–93% 116
N OBn R = Me, n-C11H23, t-Bu, Ph N 115
[I] n-BuLi, THF, −78 °C; [II] (n-Bu)3SnCl; [III] ZnI2; [IV] 2−5 mol % Pd(PPh3)4, THF, − 78 °C to r.t., 30 min; [V] as [IV] except for 2 h reaction time. Scheme 49
N
R
N
Cl
N N Z
R
R Z
[I]
R
N
61−80%
N 117
R = Me, Et, iso-Bu
Z = O, S Scheme 50
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
N Z
R
N
R
N
Cl
N
445
R Z
[I]
R
N N
43−83% 118 R = Me, Et, i-Bu
Z = O, S
[I] 5 mol % Pd(PPh3)4, AcOK, DMA, rfx, 6 h. Scheme 50 (Continued)
C.ii. Halogeno- or Triflyloxy-Substituted Azoles C.ii.a. Arylation Tin Reagents. Stille coupling in the 2-position in the 2-bromoimidazole 119 gives the 2-phenyl derivative (Scheme 51). In the 2,4-dibromoimidazole 120 regioselective monocoupling in the more electrophilic 2-position gives the 2-phenylated product. A stepwise coupling would allow for differential substitution in 2,4-dibromoimidazoles.[68] Stille coupling between trimethylsilyl-protected 9-(-D-ribofuranosyl)-2,6-diamino-8bromopurine 121 and 2- or 3-tri(n-butyl)stannylthiophene proceeds well. Similar couplings are effected with 2- or 3-tri(n-butyl)stannylfuran. The catalyst system was Cl2Pd(dppp) with cupric oxide as cocatalyst. Excess of the 2- and 3-tri(nbutyl)stannylthiophene and -furan reagents had to be used.[69] 4-Substituted 3-halogenoand 3-triflyloxy-1,2,5-thiadiazoles 122 can be arylated in reactions with appropriate stannanes. In reactions of 1,2,5-thiadiazoles with organometallic reagents, Grignard reagents, and alkyllithium reagents, reductive cleavage of a nitrogen – sulfur bond to form ring-opened products is a complicating factor. This is avoided in Pd-mediated carbosubstitution reactions. 1,2,5-Thiadiazole is a -deficient heterocycle. In many cases coupling can therefore be effected with a chloro substituent in the electrophilic 3-position 122. In this case, however, the bromo derivative was the more active. Triflates are highly reactive when the reaction is carried out in the presence of lithium chloride.[70] The bromide 123 is a useful substrate for the coupling of aryl- and heteroarylstannanes into the 5-position in 3-amino-4-arylisothiazole 1,1-dioxides. In general, the best results were obtained using benzyl chlorobis(triphenylphosphine)palladium as catalyst.[71] Boron Derivatives. A 5-substituted imidazole can be selectively brominated in the 4-position (Scheme 52). Suzuki coupling conditions for the 4-bromo imidazole with phenylboronic acid gives the 4-phenylimidazole 124.[68] 2-Bromothiazole reacts similarly with phenylboronic acid carrying an o-carbamoyl group 125.[72] The Suzuki type coupling between 6-substituted 1-benzyl-2-iodo-1H-benzimidazoles 126 and aryl boronic acids can be used for the preparation of the corresponding 2-aryl-1H-benzimidazoles 127. The reaction series is initiated by regioselective lithiation in the 2-position. Subsequent treatment with NIS furnished the 2-iodo derivative. Phenylboronic acids, substituted in the ortho positions, required more vigorous reaction conditions than those substituted elsewhere.[73]
446
III Pd-CATALYZED CROSS-COUPLING
Ph
Ph N
Me
Br
Br [I] Me
N
N Ph Me
N
60%
Bn 119
Br
N
PhSnMe3
Br [II] Me
N
Bn
N
PhSnMe3
58%
Bn 120
N
Ph
Bn
NH2
H2N HO
NH2
N
N
Br N
N
5 × ArSn(n-Bu)3 [III]
O
N
N H2N HO
N
N O
81−84% HO OH 121
Z 2-, 3- ; Z = O, S
HO OH 2
R
R1
X
R1 4-R2
-C6H4Sn(n-Bu)3
N
N
N [IV], [V], or [VI] N S S 122 [IV] 51−92% X = Br, R1 = Ph, 2,6-Cl2C6H3, tert-Bu, R2 = H, Cl, MeO, Me; [V] 90% X = Br, R 1 = Ph, R2 = Cl; [VI] 83% X = OTf, R 1 = Ph, R2 = Cl MeO MeO
NEt2
NEt2
RSn(n-Bu)3 [VII]
Br
N S O2 123
R 60−70%
N S O2
R = Ph, 2-pyridinyl, 3(1-ethoxycarbonyl)indolyl
[I] 2 mol % Cl2Pd(PPh3)2, toluene, rfx, 12 h; [II] 10 mol % Cl2Pd(PPh3)2, toluene, rfx, 12 h; [III] (i) HMDS, pyridine, (NH4)2SO4, (ii) Cl2Pd(dppb), CuO, DMF, 110 °C, 2−3.5 h; [IV] 5 mol % Pd(PPh3)4, toluene, 120 °C, 12 h; [V] 5 mol % Cl2Pd(PPh3)2, toluene, 120 °C, 12 h; [VI] 5 mol % Pd(PPh3)4, LiCl, toluene, 120 °C, 12 h; [VII] 10 mol % PhCH2ClPd(PPh3)2, toluene, rfx, 1 h. Scheme 51
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
Br N Me
Ph N
[I]
Me
N
95%
Bn
447
N
PhB(OH)2 [II]
N
Me
N
93%
Bn
Bn 124
B(OH)2
N S
[III]
Br
CON(i-Pr)2
N
CON(i-Pr)2
S 87%
125 N
N
[IV]
I N
O
N
(CH2)2NMe2
Bn
O (CH2)2NMe2 Bn 81%
126
R
R B(OH)2 [V]
45−78%
O
N N
(CH2)2NMe2 Bn 127
R = 4-Me, 3,5-t-Bu2, 3,5-Ph2, and 2-naphthyl [I] NBS, MeCN; [II] 5 mol % Pd(PPh3)4, Na2CO3, toluene, dil EtOH, rfx, 24 h; [III] 3 mol % Pd(PPh3)4, aq. Na2CO3, toluene, rfx, 6 h; [IV] (i) n-BuLi, THF, −78 °C, (ii) NIS; [V] 5 mol % Pd(PPh3)4, Na2CO3, toluene-EtOH (20:1), rfx, 24 h. Scheme 52
Bromination in N-benzyltetrazole can be effected by initial lithiation in the 5-position follwed by addition of bromine (Scheme 53). The bromo substrate 128 can be phenylated by coupling with phenyl(tri-n-butyl)stannane for the preparation of the 5-phenyl derivative. A better process, however, was to carry out the coupling with phenylboronic acids under Suzuki conditions.[74] Homocoupling. Homocoupling of heteroarenes leads to symmetrical coupling products as described for thiophenes (vide supra). The catalyst system can be generated from palladium diacetate and an amine base. 2-Bromothiazole is converted to the 2,2’biheteroarene 129 in high yield under these conditions (Scheme 54).[35] Similarly, N-tritylated 4-iodoimidazoles can be homocoupled to give 4,4´-bis(imidazoles).[75]
448
III Pd-CATALYZED CROSS-COUPLING R
N N N N N
N N
[I]
[II]
N
Bn
N N
N
Br
N
R
B(OH)3
Bn 88−96%
Bn
R = H, 4-Me, 4-F, 4-OMe, 2-OMe, 2-CH2OBn, 2-CON(i-Pr)2
128
[I] (i) n-BuLi, THF, −78 °C, (ii) Br2; [II] 3 mol % Pd(PPh3)4, Na2CO3, toluene-H2O-EtOH (8:1:1), 110 °C, 20 h. Scheme 53 N S
N
[I]
Br
N
S
86%
S 129
TrN R
TrN
[II]
N
I
R
NTr N N R = H 69% R = Me 63%
R
[I] 5 mol % Pd(OAc) 2, NEt(i-Pr)2, (n-Bu)4 NBr, toluene, 105 °C, 23 h; [II] 5 mol % Pd(PPh3)4, NEt 3, DMF, 110 °C, 24−48 h. Scheme 54
C.ii.b. Alkenylation Tin Reagents. Vinyltrialkyltin reagents can be used for introduction of alkenyl substituents into the 4-position in N-protected imidazoles 130 (Scheme 55). In this particular case alkenylation reaction under Heck conditions was unsatisfactory due to facile homocoupling of the heterocycle.[66] A related series of reactions has been used for introduction of an allylic alcohol substituent into the imidazole 4-position in a ribosylimidazole nucleoside 131.[76] Vinylation of 5-bromo-3-diethylamino-4-(4methoxyphenyl)isothiazole 1,1-dioxide 132 with vinylstannane reagents can be used for the preparation of 5-alkenylated isothiazole 1,1-dioxides.[71] Boron Reagents. Tetrazole can be lithiated in the 5-position and brominated to yield a 5-bromo substrate that reacts with a vinylboronic acid to furnish the corresponding vinyltetrazole 133 (Scheme 56).[74] C.ii.c. Alkynylation Copper Reactants. 4-Alkynyl imidazoles are available from N-protected 4-iodoimidazoles and alkynes or alkynyltrialkyltin derivatives (Scheme 57). Reactions under Sonogashira conditions can be used to prepare the cross-coupled products 134. The same
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
Et
Et Et O
I
O
Et
O
O
N
N
R3Sn [I] or [II]
N
N
R = Bu [I] 45% R = Me [II] 83%
OEt
OEt 130
I
TBDMSO N N
N
OTBDMS
Bu3Sn
N
(E:Z = 9:1)
Ts
[III]
trans 55%, cis 10%
HO
CONH2
CONH2
N
N Sn(n-Bu)3
I
N
AcO
Ts
O
N
AcO
[IV]
O
OH
68% AcO OAc 131
MeO
AcO OAc MeO
R
NEt2
Sn(n-Bu)3
NEt2
[V]
Br
N
N
S O2
35−70%
R
S O2
R = H, OEt, COOMe
132 [I] 5 mol % Pd2(dba)3, 10 mol % AsPh 3, 10 mol % CuI, DMF, 80 °C, 24 h; [II] 5 mol % Pd(PPh3)4, DMF, 80 °C, 24 h; [III] 5 mol % Pd2(dba)3, 10 mol % AsPh 3, 10 mol % CuI, DMF, 80 °C, 3 h; [IV] 10 mol % Cl2Pd(PhCN)2, MeCN, 100 °C, 12 h; [V] 10 mol % PhCH2ClPd(PPh3)2, toluene, rfx, 0.25−4 h. Scheme 55
N N N N Bn
N N
[I]
Br
N N Bn
N N
B(OH)2
Ph
Ph
[II]
91%
[I] (i) n-BuLi, THF, −78 °C; (ii) Br2; [II] 3 mol % Pd(PPh3)4, Na2CO3, toluene-H2O-EtOH (8:1:1), 110 °C, 20 h. Scheme 56
N N Bn 133
449
450
III Pd-CATALYZED CROSS-COUPLING
products were formed under Stille conditions using alkynylstannanes for the coupling reaction.[66] A number of 4- and 5-bromo- and iodo-oxazoles, -thiazoles, and N-methylimidazoles 135 have been alkynylated under Sonogashira conditions. Alkynylation reactions in the 2-position were less successful.[77] Isoxazoles 136 have been alkynylated in a similar manner.[78] Aminopyrazoles react similarly to furnish the alkynylated products 137 and 138.[79] The same methodology has been applied for the preparation of pyrazolo[3,4-d]pyrimidine derivatives 139 by coupling of the 3-iodo or 3-bromo heterocycle with dimethyl 4-ethynylbenzoyl-L-glutamate.[80] C.ii.d. Alkylation Sodium Salts of Stabilized Carbanions. The carbosubstitution in 4- and 5-bromo-2,4- or 5,6-diphenyl-1,3-azoles 140 (oxazoles, thiazoles, and imidazoles) with phenylsulfonylacetonitrile in the presence of a strong base is promoted by palladium catalysis R2 I N
N
R2 [I]
N
N 42−89%
R1
R1
134 R1 = Ts, PhSO2, EtOCH2 R2 = Ph, CH2OTBDMS, (CH 2)2OTBDMS R2
N
R2
R3
X
R3
[II]
R1
Z
R1
Z
25−83%
135
R1 = Me, Ph R2 = H, Me
Z = O, S, NMe X = Br, I
R1
R1 R2
R2
R3
X
N
N
O
44−85%
X = Br, I H2N
N
R3
[III]
O 136
R1 = H, Me, R2 = H, Me, Ph R3 = Ph, n-Bu
Ar
H2N
Me
Me
H2N
Ar
I
N N Me
N
[IV]
N Me
Ar 137 Ar = Ph 86% Ar = C6H4-4-NO2 71% Scheme 57
Me
N N Me 138
Ar = Ph 36% Ar = C6H4-4-NO2 73%
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
451
O NH
R1
X
N R
2
COOMe COOMe
N N H
N
[V]
43−73%
X = Br, I
O NH R1
COOMe
N R
2
COOMe
N N H
N 139
R1 = OH, NH2; R2 = H, Me, NH2 [I] 5 mol % Pd(PPh 3)4, 10 mol % CuI, Et3 N, DMF, 80 °C, 3 h; [II] 4 mol % Cl2 Pd(PPh3)2, CuI, Et3N, 80−100 °C, 3−15 h; [III] 2 mol % Cl 2Pd2(PPh3)2, PPh3, CuI, NEt 3, rfx, 10−124 h; [IV] 1.2 mol % Cl 2Pd(PPh3)2, CuI, Et 3N, 80 °C, 0.5−8 h; [V] 8 mol % Pd(PPh3)4, CuI, NEt3, DMF, 85 −105 °C, 3−18 h.
Scheme 57 (Continued)
(Scheme 58). 2-Chloro-oxazole or -thiazole substrates 141 were used for substitution in the electrophilic 2-position. The 2-chloro-N-methylimidazole, however, showed low reactivity, and therefore the iodo analog was used in the coupling. A similar series of reactions was run for carbosubstitution in the 4-position in 1,2-azoles.[81] SO2Ph Ph
Ph NC
N Br
Ph
Z
SO2Ph
NaH, [I]
42−85% 140
NC
N Ph
Z PhO2S
Z = O, S, NMe
Ph 75−88%
Z
Ph
Z = O, S, NMe
Ph
Ph NC
N Ph
NC
N
Z
X
N
SO2Ph
NaH, [I]
Ph
SO2Ph
Z CN
141 [I] 4 mol % Pd(PPh3)4, (MeOCH2)2, rfx, 1.5−24 h.
Scheme 58
Z = O, S; X = Cl 63−88% Z = NMe; X = Br 70%
452
III Pd-CATALYZED CROSS-COUPLING
C.ii.e. Heck Reaction The cross-coupling between 5-iodoimidazoles and methyl acrylate has been applied to complex structures as depicted for the preparation of (E)-5(2-carbomethoxyvinyl)-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)imidazole-4-carboxamide 142 from the corresponding 5-iodoimidazole (Scheme 59). Acrylonitrile reacts in the same manner under Heck conditions to provide the (E)-5-cyanovinyl derivative.[76] The C-glycosyl bond formation in the Heck coupling between the 3-iodopyrazolo[4,3d]pyrimidine 143 and the ribofuranoid glycal 144 was regio- and stereospecific. The iodo substituent in the substrate was introduced by a simple electrophilic substitution.[82] CONH2
CONH2 N
N AcO
O
AcO
R
I
N
AcO
O
[I]
59−65%
OAc
N
AcO
R OAc R = COOMe, CN
142 HO
O
THPO THP
THPO THP N
N
TBDPSO
N [II]
N I 143
N
N
144
HO 62%
N N O
OSPDBT [I] 10 mol % Cl2Pd(PhCN)2, NEt3, MeCN 100 °C; [II] 10 mol % Pd(dba), 20 mol % AsPh 3, N(n-Bu)3, MeCN, 80 °C, 20 h. Scheme 59
CROSS-COUPLING IN -DEFICIENT RING SYSTEMS D.i. Metallated Six-Membered Ring Systems D.i.a. Arylation Tin Derivatives. Most stannanes are stable compounds that can be isolated and purified in the normal manner for organic compounds. Generally, stannylation is effected by a transmetallation reaction between an organostannyl chloride and a lithiated species. This method works well in the benzenoid position in pyrimidines. Stannylation in the 4position can be effected on 4-iodo derivatives 145 (Scheme 60) using hexaalkyldistannanes in the presence of fluoride ions.[83] The same product is obtained when the stannylation is effected by tri(n-butyl)stannylcopper in THF at 78 °C. Bis(-allyl)palladium chloride is the recommended catalyst for the coupling of 5-bromopyrimidines 146 with hexaalkyldistannanes to form 5-stannanes. The presence of halide ions promotes the reaction, especially fluoride ions.[84] The promoting effect is ascribed to the high affinity of fluoride ions for tin. Stannylation in the 5-position can also be effected by a
453
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
I X
SnR3
N
SMe
[I]
N
54%, 56%
rfx
SMe
N
N
Z
N
Z
72−74%
Sn(n-Bu)3 X
N N
SMe
R = Me, n-Bu
Z = MeS, MeSO2
Sn(n-Bu)3
COOSn(n-Bu)3 Cl
SMe
70−73%
[IV]
N
[III]
N
R3Sn
146 R = Me, n-Bu
COO Sn(n-Bu)3 N
R6Sn2
N
N
[II]
145 X = H, Cl
X
Br
X
R6Sn2
N
N
O
Cl
N N
O
66−71%
R R 148 R = Me, Bn [I] 3 mol % (AcO)2Pd(PPh3)2, (n-Bu)4NF, THF, r.t., 6 h; [II] 3 mol % Cl 2Pd2(π-allyl)2, (n-Bu)4NF, THF, rfx, 9 h; [III] 3 mol % Cl 2 Pd(MeCN)2, anisole, rfx, 4−6 h; [IV] anisole, rfx, 45 min. 147 X = Cl, Br
Scheme 60
metal – metal exchange with trialkylstannylcopper or -sodium reagents. Thermal decarboxylation of a stannyl carboxylate 147 can be used for stannylation in the electrophilic 4-position. The reaction is promoted by Pd catalysis.[83] In the more -electron-deficient 2-pyrimidinone carboxylic ester 148, decarboxylation with concurrent stannylation in the 4-position takes place without palladium catalysis. Stannylated azines have been widely used for cross-coupling. N-Oxides of tri(nbutyl)stannylated pyridine, quinoline, and isoquinoline and tri(n-butyl)stannylated Nmethiodides of pyridine and quinoline have been coupled with heteroaryl halides (Scheme 61). The use of tosylate as a counterion for the quaternized salts 149 and 150 minimized decomposition of the stannane whereas iodide anion promotes destannylation.[85] The yield of coupling products from 5-stannylated pyrimidines 151 is normally high (Scheme 62).[84] Pyrimidines with the stannyl group in the electrophilic 4-position 152 also react well.[83] Carbosubstitution in the 4-position in the 2-pyrimidinone 153 proceeds under similar conditions. In the pyridine series, the coupling reaction is exemplified by the reaction of a 4-stannyl derivative with a triflate of a benzonaphthyridine for the preparation of a pyridinylbenzonaphthyridine 154.[86] Zinc Derivatives. Zincated and N-protected 6-iodouracil 155 can be used under Negishi conditions for the preparation of 6-arylated uracil derivatives (Scheme 63). The conversion of the 6-iodouracil derivative is best performed using highly active zinc dust in DMAC.[87] The oxidative addition of active zinc has also been applied to a number of other iodo- and bromo-substituted -deficient heteroarenes such as pyridine, pyrimidine, and quinoline, giving the corresponding heteroarylzinc halides 156, which are transformed to arylated derivatives by palladium catalysis.[88] Magnesium Derivatives. Iodopyridines undergo iodine – magnesium exchange when treated with alkyl- or phenylmagnesium halides. The more readily available bromo- and
454
III Pd-CATALYZED CROSS-COUPLING R R
R
+ N
+ N
+ N
O− R = Sn(n-Bu)3
43−66% O − 51% HetAr-Br R = Sn(n-Bu)3 [I] R = 3-quinolinyl, 3-isoquinolinyl, 5-pyrimidinyl
O−
58% HetAr-Br R = Sn(n-Bu)3 [I]
R = 5-pyrimidinyl
R = 5-pyrimidinyl
R
R + N
54−74%
70−87% Me
Me
149 R = Sn(n-Bu)3
HetAr [II]
TsO−
+ N
TsO−
150 R = Sn(n-Bu)3
R = 3-quinolinyl, R = 3-quinolinyl, 4-isoquinolinyl, 5-pyrimidinyl, 2-pyrazinyl (2-Cl) 3-pyridinyl (3-I) [I] 10 mol % Pd(PPh3)4, THF or DMF, rfx, 12 −24 h; [II] 10 mol % Cl2Pd(dppe)2, toluene, rfx, 20−30 h. Scheme 61 (n-Bu)3Sn
N
N SMe 151 Sn(n-Bu)3 X
PhI
N
R
RBr
N
[I]
N
68−95% Ph X
Cl
N
[II]
N
N
SMe
152
R = 2- and 3-furyl, 2- and 3-thienyl, 5-(2-formyl)furyl and -thienyl, 2-, 3-, and 4SMe pyridinyl, 2-thiazolyl Sn(n-Bu)3 Ph
SMe
Cl
N N
O
[III]
N O 1 65−69% R R1 = Bn, Me
R1
X = H, Cl, Br 55−65%
N
PhI
153
X = H, Cl,Br N OTf
Sn(n-Bu)3
N
OMe
N [IV]
N 79%
OMe 154 [I] 3 mol % Cl2Pd(PPh3)2, THF, DCE or DMF, 80 °C, to-rfx, 5−24 h; r.t., 6 h; [II] 3 mol % Cl2Pd(PPh3)2, DCE, rfx, 4 h; [III] 3 mol % Cl2Pd(MeCN)2, DCE, rfx, 5 h; [IV] 3 mol % Pd(PPh3)4, LiCl, dioxane, rfx, 36 h. N
Scheme 62
N
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
O Bn
O
N
O
I
N
O
R
Bn
I
Bn
[I]
N
O
ZnI
N
Bn
O
Bn
70−76% ZnX
[III]
N
N
Bn R = H, 4-Cl, 3-COOEt Ph N
Me I
I
R N
N
PhI [IV]
156
N R
[II]
155 X
455
N N
X
Me
N
N
I
X = I, Br R = H 76%, 77% 75% 96% 26% X = I, R = COOEt 82% [I] Zn, DMAC, 25 °C, 1 h; [II] 1 mol % Pd(dba)2, 4 mol % P(2-furyl)3, DMAC, 0 °C to r.t., 4 h; [III] Zn*, THF, r.t., 1.5−6 h; [VI] 0.5 mol % Pd(PPh3)4, THF, r.t., 41–47 h. Scheme 63
chloropyridines are converted into corresponding magnesium chlorides when treated with isopropylmagnesium chloride in THF at room temperature.[89] By analogy to the findings in the five-membered heterocyclic series, azine magnesium halides are expected to become useful substrates for cross-coupling reactions. Boron Derivatives. Coupling of diethyl(3-pyridinyl)borane with 2-chloropyridine, 2chloropyrimidine, and 3-bromoquinoline under Suzuki conditions gives the corresponding 3-heteroarylpyridine 157 (Scheme 64).[34] The 4-pyridinylborane 158 can be prepared by
BEt2
Ar
ArX [I]
N
47−82%
N
Ar = 2-pyridinyl, 3-quinolinyl, 2-pyrimidinyl
157 NH2
B CON(i-Pr)2
[II]
NH2 I
CON(i-Pr)2
CON(i-Pr)2
[III]
OMe N 61% OMe N 62% 158 [I] 5 mol % Pd(PPh3)4, THF, KOH, ( n-Bu)4NBr, rfx, 8 h; [II] (i) n-BuLi, THF, −10 °C, (ii) 9-MeO-BBN; [III] 3.5 mol % Pd(PPh3)4, NaOH, THF, H 2O, rfx, 24 h. N
OMe
Scheme 64
456
III Pd-CATALYZED CROSS-COUPLING
directed ortho-metallation chemistry of a nicotinamide leading to the lithiated species, which was quenched with 9-MeO-BBN. The Suzuki coupling was effected with 2iodoaniline.[86] D.i.b. Alkenylation Tin Derivatives. Alkenylation by the Stille methodology using 4-pyrimidinylstannanes furnishes the 4-alkenylated pyrimidines 159 and 160 in good yields (Scheme 65).[83] Ph
Ph
Ph
Sn(n-Bu)3
Sn(n-Bu)3 Cl
I
N
Cl
N
Cl
SMe
N
73%
Cl
N
[I]
N
Ph
N
SMe
O
R1
159
N
I [II]
N 67%
[I] 3 mol % Cl2Pd(PPh3)2, DMF, rfx, 3 h; [II] 3 mol % Cl2Pd(MeCN)2, DCE, rfx, 4 h.
O
Bn 160
Scheme 65
Zinc Derivatives. 2-(Benzopyran-4-yl)pyridine N-oxide has been prepared from 2chlorozinciopyridine N-oxide and benzopyran-4-yl triflate in a Negishi-type coupling from 2-chlorozinciopyridine N-oxide (Scheme 66). A five-fold excess of the the zincated pyridine N-oxide had to be used for optimal formation of the cross-coupled product 161.[90] Boron Derivatives. Diethyl(3-pyridinyl)borane 162 can be alkenylated under Suzuki conditions (Scheme 67).[91] OTf
+ N
O2N F
+ N O−
O
[I]
+ N
Br
F
O2N F
[II]
ZnCl
64%
O−
O
F
161
[I] (i) n-BuLi, THF, −78 °C, (ii) ZnCl2, −78 to 0 °C; [II] 1.2 mol % Pd(PPh 3)4, THF, r.t., 21 h. Scheme 66 Br EtO
OEt N
O−
Br
BEt2
Ph
Ph [I]
[I]
N 162
[I] mol % Pd(PPh3)4, THF, KOH, (n-Bu)4 NBr, rfx, 1 h. Scheme 67
N
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
457
D.i.c. Alkynylation Tin Derivatives. 5-Alkynylpyridines can be prepared by a Stille-type reaction between a 1-bromoalkyne and a 5-trimethylstannylpyridine 163 (Scheme 68).[92]
Et Me3Sn
Et
Br
COO-(t-Bu)
N 163
84%
COO-(t-Bu)
N
[I] 5 mol % Pd(PPh3)4, benzene, rfx, 48 h. Scheme 68
D.i.d. Alkylation Zinc Derivatives. Direct zincation of 6-bromoxazolo[4,5-b]pyridines can be effected using activated zinc (Scheme 69). The zincated species 164 and 165 from oxazolo[4,5b]pyridin-2(3H)-ones or 2-phenyl- or 2-benzyloxyoxazolo[4,5-b]pyridines were used in Negishi-type coupling in a one-pot reaction with benzyl bromide for the preparation of 6-benzyl derivatives.[93] Br
BrZn
O O N
N
Bn
O
[I]
O N
Me
O
[II]
N
O
BnBr
Me
N
N Me
91%
164 Br
Br-Zn
O N
N
N
O
BnBr
R
R N
Bn
O
[I]
[II]
56, 65% 165
R N
N
R = OBn, Ph
[I] Zn*, (CH2Br)2, TMSCl, THF; [II] 1 mol % Pd(PPh 4)2, THF, 50 °C, 20 min. Scheme 69
D.i.e. Carbonylation and Acylation Tin Derivatives. 4-Stannylpyrimidines are highly active in coupling reactions at low temperature and will couple with an acid chloride to form ketones 166 in the absence of a catalyst (Scheme 70). 2-Stannylpyrimidines also react rapidly with acid chlorides to form ketones 167 in the absence of a catalyst.[94] Alkyl, aryl, and heteroaryl ketones in the benzenoid 5-position 168 are available from 5-stannylpyrimidines and carbonyl chlorides. The trimethylstannyl derivatives gave consistently slightly higher yields than the tri(nbutyl)stannyl pyrimidines. The reaction with pyrroles was run on N-alkylated or N-acylated
458
III Pd-CATALYZED CROSS-COUPLING
O
(n-Bu)3Sn COCl
S
N
S N
[I]
N
SMe
N 166
64 %
COCl
Z
N
SMe
N
[I]
N
N
Sn(n-Bu)3
Z O 167
Z = O 52% Z = S 56%
O Me3Sn N
R
RCOCl
S(O)n
N
N
[II]
71−97%
Me n = 0, 2
N
S(O)n
168
Me
R = Me, Ph, 2-furyl COCl
O
N
(n-Bu)3Sn N N
R
S
N N
[III]
N
R
Me
169
S Me
72% R = Me, 2–isomer 61% R = PhSo2, 3–isomer
O Me3Sn N N
RCOCl
O
R
[IV]
N N H
TBDMS 170 Scheme 70
O
R = Ph 47% R = 2-furyl 36%
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
SnMe3
SnMe3 ( t-BuO)2CO
SnMe3
171
COR RCOCl [VI]
[V]
N
459
N
COO(t-Bu)
75−92% 3-, 4-, 5-, 6-
N 51−91%
COO(t-Bu)
R = Ph, cyclohex
[I] THF, −78 °C, 0−5 min; [II] 7 mol % Cl2Pd(PPh3)2, DCE or THF, rfx, 2−6 h; [III] 4 mol % Cl2Pd(PPh3)2, THF, rfx, 6 h; [IV] 4 mol % Cl 2Pd(PPh3)2, DCE, rfx, 20 h; [V] benzene , rfx, 12−48 h; [VI] 5 mol % Pd(OAc) 2 or Pd(PPh3)4, benzene, rfx, 8 h. Scheme 70 (Continued)
pyrrolocarbonyl chlorides to furnish the corresponding ketones 169.[95] 2-Pyrimidinones are protected and solubilized as a t-butyldimethylsilyl ether 170 before coupling. During the reaction the silyl group is cleaved off. The products were isolated as pyrimidinones. The silyl function in the 5-acylated pyrimidine product is sensitive to cleavage because of the electron-withdrawing properties of the acyl group.[96] A method for the introduction of different carbon functional groups, acyl and tertbutoxycarbonyl groups, in the pyridine ring has been described. The substrate is a bis(trimethylstannyl)pyridine 171. The stannyl group in the electrophilic 2-position is replaced directly by an electrophile such as a t-butyloxycarbonyl group by heating the distannane with di-t-butyl dicarbonate. The remaining stannyl group is subjected to Stilletype coupling with an acid chloride to furnish the corresponding ketone. Alternatively, the 6-isomer, which has the stannyl group in the electrophilic 6-position, can be converted to the 6-ketone by heating with the acid chloride in the absence of a Pd catalyst.[92] D.ii. Halogeno- or Triflyloxy-Substituted Six-Membered Ring Systems D.ii.a. Arylation Tin Reagents. Modest yields of coupling products were obtained from reactions of 2-thienyl- and 2-selenylstannanes with unprotected iodouracil. Silyl protected 5-bromouracil 172 reacts with formation of a number of biheteroaryl derivatives (Scheme 71).[97] In the preparation of 5-(2-indolyl)pyridin-2-ones 173 by Pd-catalyzed cross-coupling of 5bromopyridin-2-ones, SEM-protected 2-indolylstannanes are better reagents than the corresponding 2-indolylzinc halides.[98] Coupling into pyridazines using 3-iodo derivatives and stannyl-thiopenes or -furan gives disubstituted pyridazines 174.[99] Coupling between silyl-protected 5-bromouridine and arylstannanes containing a boronic acid substituent in the aryl group proceeds chemoselectively at the C —Sn bond rather than at the C —B bond to give boron-containing nucleosides 175. The methodology was developed to provide boron-10 containing nucleosides for neutron-capture therapy. The same conditions can be used to introduce the benzeneboronic acid moiety into the 5-position of O-benzyl-protected 5-iodouracil 176, and into the 6-position in O-benzylprotected 6-bromouracil.[100] The 6-position in N9-substituted purines is more electrophilic than the 8-position. Hence, the 6,8-dichloropurines 177 can be selectively monoarylated in the 6-position under Stille conditions, the product being 178. In the 6chloro-8-iodo derivative the regioselectivity for monoarylation is reversed, and the 8-aryl derivatives 179 are obtained in a monosubstitution reaction.[101]
460
III Pd-CATALYZED CROSS-COUPLING
O
OTMS Br
N HetArSn(n–Bu)3
Het
NH HetAr = 2-thienyl, 2-selenyl, 2-thiazolyl, O N-Me-2-pyrrolyl, 2-, 3-pyridinyl
[I]
N
OTMS
N H
28−44%
172 Sn(n-Bu)3 N
Br
SEM
N
[II]
O
N Bn
I R1
N
HetArSn(n-Bu)3
N
[III]
Z
R1 75−93%
N
N
SEM 173
71%
N
O
Bn R2 R1 = OMe, SMe, NMe2 R2 = H, Z = S; R2 = 1,3-dioxolan-2-yl, Z = O
174 O
O Br TMSO
O
NH O
N
O
B
O
O
B
O
C6H4-4-Sn(n-Bu)3
N
[IV]
TMSO
O
N
O
79% TMSO OTMS
TMSO OTMS 175 OBn O
N BnO
B O
N 5-, 6176
Scheme 71
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
R2
Cl N
N
R2SnR33
Cl N
R1
Cl N
N
[V] X = Cl
N
X
R2Sn(n-Bu)3
N
N
N
R2
[VI] X = I
N
64−75%
R1
177
R3 = Me, n-Bu
179 R2 = Ph, 2-thienyl
R1 = THP, Bn
R2 = Ph, 2-thienyl
N
N
R1
41−63%
178
461
[I] 5 mol % Cl2Pd(PPh3)2, THF, rfx, 20 h; [II] 5 mol % Pd(PPh 3)4, DMF, 110 °C; [III] 5 mol % Cl2Pd(PPh3)2, DMF, 80 °C, 2 h; [IV] 5 mol % Pd(PPh3)4, toluene, rfx, 24 h; [V] 5 + 2.5 mol % Pd(PPh3)4, DCE, 60 °C to rfx, 24 −30 h; [VI] 5 mol % Pd[P(2-furyl])3]4, DMF, 60−85 °C, 2.5−18 h. Scheme 71 (Continued)
Pyrimidine has been triflated in the 2- and in the 4-position, and in both the 4/6positions.[102] Pyrimidinyl triflates show reactivity comparable to chlorides in electrophilic positions with stepwise coupling. Thus, the ditriflate 182 (Scheme 72) can be monocoupled to the 4-thienyl derivative 183, which reacts further to the dithienyl derivative. The higher reactivity in the 4-position as compared with the 2-position is also seen in the time required for completion of the coupling reactions by the two isomers. It is recommended that the triflation of pyrimidinones is carried out at low temperature (78 °C). Thereafter
R1
R1 Sn(n-Bu)3
S
N
N [I], 10 h
R2
R2
OTf
N
N
67%
180 R1, R2 = H, Me R1
R1 Sn(n-Bu)3
S
N
N
[I] 1 h
TfO
N
S
SMe
N
181 R1 = H, Me
OTf RSn(n-Bu)3
N
R RSn(n-Bu)3
N
182
SMe
N
[I]
[I], 10 h
N
SMe
88%
OTf
TfO
S
R
N
SMe
183 R = 2-thienyl
[I] 3 mol % Pd(PPh3)4, LiCl, dioxane, rfx. Scheme 72
R 73%
N
SMe
462
III Pd-CATALYZED CROSS-COUPLING
the temperature is raised slowly to room temperature. Triflation carried out in this manner gives products stable for purification by preparative chromatography.[102] Zinc Reagents. The pyrimidinyl triflates show comparable reactivity to the chloropyrimidines in Pd-catalyzed reactions with organozinc reagents. High yields result from coupling reactions with 2-triflyloxypyrimidines 184 and 4-triflyloxypyrimidines 185 (Scheme 73). 2-Methylthiopyrimidinyl 4,6-ditriflate 187 reacts with arylzinc reagents to give dicoupled products.[102] In the reaction between 4-anisylzinc bromide and 2,4dichloropyrimidine, it is the 4-position that is the more reactive, and the monoarylated 4anisyl derivative 186 is formed using 1 equiv of the zinc reagent.[103] The regioselectivity is the same as observed for the corresponding triflates and for Pd-catalyzed reactions of the dichloride with stannanes.[104] The chlorine in the 2-position can also be replaced by an excess of reagent. Another zinc or tin reagent would give a pyrimidine product with two different carbosubstituents. In the 2,4-ditriflate 188, the initial reaction is at the more electrophilic 4-position, as for the corresponding 2,4-dichloride. With excess p-anisylzinc bromide the disubstituted product is formed. The intermediate monoarylated product has
R N R
Me
R
N
OTf
[I]
N
N
RZnBr
R
TfO
N
R = H 86% R = Me 96%
184
Me
N
OMe
N
RZnBr
SMe
185
[I]
R
N
SMe
R = Ph 73% R = p-anisyl 76%
OMe
Cl N N
R
OTf
[II]
Cl
R = p-anisyl
N
N
RZnCl
N 65%
TfO
Cl
N
SMe
[I]
R
N
SMe
R = Ph 82% R = p-anisyl 89% OMe
187
186
N
RZnBr
OMe
OTf RZnCl
N N 188
OTf
Me R = p-anisyl 80%
N
N [II]
[I]
Me
Sn(n-Bu)3
S
N OTf
61%
S Me
N
[I] 3 mol % Pd(PPh3)4, LiCl, dioxane, rfx, 2 h; [II] 2 mol % Pd(PPh3)4, THF, rfx, 1−2 h. Scheme 73
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
463
been reacted further under Stille conditions with 2-tri(n-butyl)stannylthiophene under Pd catalysis and gives the 2-thienyl derivative.[103] Boron Reagents. Cross-coupling reactions between organoboranes and simple pyrimidines are illustrated by the reaction between 2-chloropyrimidine and 2- or 3-thiopheneand selenophene-boronic acids, which gives the corresponding 2-substituted pyrimidines 189 (Scheme 74). In 2,4-dichloro- or 2,4-dibromopyrimidine it is the 4-halogeno substituent that is the more reactive, 2-chloro- or 2-bromo-4-(2-thienyl)pyrimidine 190 being the product from the coupling with thiophene-2-boronic acid.[105] It was necessary to protect 5-bromo- or 5-iodouracil before coupling; t-butyl and benzyl derivatives of the uracils were used in the preparation of the biheteroaryls.[97] 2-Amino-3-benzoyl-5bromopyrazine gives excellent yields of cross-coupled product 191 with arylboronic acids.[106] Symmetrically and unsymmetrically 2-substituted 4,6-diphenyl-1,3,5-triazines 192 have been prepared by the Suzuki reaction from 2-substituted 4,6-dichloro-1,3,5position using benzeneboronic acid.[107] 3-Iodopyridazines 193 are coupled in the same manner.[99] Arylation in 2-chloroquinolines 194 proceeds well because the chlorine substituent is located in an electrophilic quinoline position.[108] Benzeneboronic acid has been coupled with 2-chloro- and 6-bromo derivatives of 1- and 3-methylimidazo[4,5b]pyridines to furnish the corresponding 2-phenyl and 6-phenyl derivatives 195. The halogen in the 6-position should be a bromine or iodine for an easy coupling. The 6bromo-2-chloro substrate gave 2,6-diphenylimidazo[4,5-b]pyridines 196 when an excess of benzeneboronic acid was used. If not, mixtures of monophenylated and diphenylated products were obtained. The imidazo[4,5-b]pyridine substrate had to be N-protected for the coupling reactions to proceed.[109] Couplings in 5-bromo-2-chloropyrimidine would be expected to proceed preferentially in the 5-bromo position (Scheme 75). This order of preference has been changed by an initial exchange of the chloro with an iodo substituent. The product from the halogen exchange, 5-bromo-2-iodopyrimidine, is selectively coupled in the 2-position with a wide
S X
B(OH)2
N N
N
Z
Cl
[I]
N
43−62 % N 189
Z
N
B(OH)2
S
N
[I]
X
N X 190
X = Cl 59% X = Br 50%
Z = S, Se; 2-, 3-
Cl N
NH2 ArB(OH) 2 [II]
Br
N
COPh
N
NH2
Ph N PhB(OH)2
N
N
N
[III]
Ar
N
COPh R
191 82−96% Ar = Ph; C6H4-4-OMe, F, CF 3; 2-naphthyl; 2-thienyl
N
Cl R Ph N 82−91% 192 R = MeO, n-PrO, PhO, Ph
Scheme 74 (Continued )
464
III Pd-CATALYZED CROSS-COUPLING
I
Ph
PhB(OH) 2
R
N 193
N
[IV]
R
R
N
N R
R = H 67% R = Me 81%
PhB(OH)2 [V]
N
R = OMe 76% R = NMe2 58%
N
Cl
Ph
194 Br
Ph
N R N
N
PhB(OH)2
R
[VI]
N
N
N
Me
195
R = H 70% R = OMe 66% R = NH2 20%
Me R1, R2 = H, F; R3 = F, CF 3, n-OctO
Br
Ph
N Cl N
N Me
N
PhB(OH)2
Ph
[VI]
70%
N
N
196
Me
[I] 3 mol% Pd(PPh3)4, 1 M Na2CO3, glyme, rfx, 14; [II] (i) 5 mol % Cl2 Pd(PhCN)2, dppb, toluene, r.t, 30 min, (ii) EtOH, H 2O, Na2CO3, toluene, rfx, 7 h; [III] 5 mol % Pd(PPh3)4, Na2CO3, H2O, toluene, rfx, 48 h; [IV] 3 mol % Pd(PPh3)4, Na2CO3, H2O, toluene, rfx, 12 h; [V] 2 mol % Pd(PPh3)4, BHT, Ba(OH) 2, THF, 75 °C, 1.5−2 h; [VI] 3 mol % Pd(PPh3)4, Na2CO3, DME, H2O, rfx, 2−5 h. Scheme 74 (Continued)
range of arylboronic acids to provide substituted 2-pyrimidines 197.[110] A catalyst system generated from palladium diacetate and 2-(di-tert-butylphosphino)biphenyl efficiently promotes Suzuki coupling at or close to room temperature of both -electron-rich or electron-poor aryl bromides and chlorides with potassium fluoride as the base. Even a chlorine in the benzenoid 3-position in pyridine is replaced with high yield of the crosscoupled product 198.[33] Selective N-quaternization or N-oxidation in a dipyridine system can be achieved indirectly by a cross-coupling between the two differently functionalized pyridine components as illustrated by the coupling reaction leading to the products 199.[111] 4-Arylated -carbolines 200 are generated from the corresponding triflate under Suzuki conditions.[112] Homocoupling. In cross-coupling reactions a major by-product may arise from homocoupling. Homocoupling is effected in the absence of a second reaction partner. In the reactions of 3-bromoquinoline or 2-chloroquinoline under conditions for homocoupling, the products 201 are formed (Scheme 76).[113]
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
R2
Br
[I]
N N
Br
N
3
Br
R1
N
B(OH)2
R2
N [II]
I
N
Cl
R
R1
High yields
R3
197
R1, R2 = H, F; R3 = F, CF 3, n-OctO MeOC
B(OH)2
Cl COMe [III]
N
94% P(t-Bu)2
N 198
A= Ph N
BF2
X N
N [IV]
R
N 63, 43%
R = O− (X = Br); Me (X = I)
R 199
Ar
TfO Ar(BOH)2 [V]
N
N 53−86%
SEM
SEM 200
Ar = Ph, C6H4-3-Me, C6H4-3-Cl, 2-naphthyl = C6H4-4-OMe, P(PPh3)4 was used. [I] 57% HI, CH2Cl2, 0 °C, 5 h; [II] Pd(PPh3)4, Na2CO3, DME, H2O; [III] 1 mol % Pd(OAc), 2 mol % A, KF, THF, 50 °C, 9 h; [IV] 5 mol % Pd(Ph3)4, THF, H 2O, NaHCO3, rfx, 8−36 h; [V] 5 mol % Cl2Pd(dppf), THF/dioxane, K3PO4, heat. Scheme 75
465
466
III Pd-CATALYZED CROSS-COUPLING [I]
X
N
N
N
2,2′- 62% 201 3,3 ′ 79% [I] 5 mol % Pd(OAc) 2, i-PrOH, (n-Bu)4NBr, K2CO3 , DMF, 135 °C, 22 h (3-isomer), 96 h (2-isomer). X = 2-Cl, 3-Br
Scheme 76
D.ii.b. Alkenylation Tin Reagents. The presence of a 3-methyl group in the 2-chloroquinoline 202 has a beneficial effect on reaction rates and efficiency in Stille-type alkenylations with terminal stannyl alkenes (Scheme 77). This was attributed to steric acceleration in the reductive elimination of Pd(0) from a Pd(II) complex.[108] The purine 6-position is highly electrophilic. A chloro substituent is readily replaced under Stille conditions using tri(nbutyl)vinylstannane. The 6-vinylpurine product 203 from the coupling is reacted further in situ in Heck couplings. These reactions proceed readily because of the electronwithdrawing effect from the -deficient pyrimidine moiety of the heterocycle.[114] R1 N
1 3 R1 R = H, R = n-Bu 48% R1 = Me, R3 = Ph 75%
Sn(n-Bu)3
R3
[I]
Cl
R3
N
R
202 Cl N
N N
N
Sn(n-Bu)3
N
N [II]
N
N
RI
N
N
[III]
N
N
55−82% overall
THP THP 203 R = Ph; C6H4-4-Cl and OMe, 2-OH; 3-iodo- and 5-iodo-2-thienyl; 5-iodo-2-furyl; trans-CHC(Me)CO2Me, trans-CHC(Me)CH2OH [I] 4 mol % Pd(OAc) 2, dppp, BHT, NEt 3, DMF, 80 °C, 24−36 h; [II] 5 mol % Cl 2Pd(PPh3)2, DCE, rfx, 5.5 h; [III] 5 mol % Pd(OAc)2, EtN(i-Pr)2, DMF, 55−85 °C, 3.5−24 h. THP
Scheme 77
Both 2- and 4-pyrimidinyl triflates yield the respective coupling products 204 and 205 with vinylstannanes under Stille conditions (Scheme 78).[102] Another example is provided by Stille coupling between 6-triflyloxy-4(3H)-pyrimidinones and tri(nbutyl)vinyltin with formation of the 6-substituted-4(3H)-pyrimidinone 206.[115] 5-Bromopyrimidines give 5-alkenyl derivatives when coupled with alkenylstannanes.[116] A chlorine in an electrophilic azine position, but not in a benzenoid position, can be replaced by a carbosubstituent (Scheme 79). The reaction between 2,5-dichloropyrimidine and styryltributylstannane occurs at the activated 2-position with formation of 208.
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
R1
R1 (n-Bu)3SnR3
N
N
[I]
R2
R2
OTf
N
57−68%
R1, R2 = H, Me
R3
204 CH2, CH CHPh R1
= CH
R1
(n-Bu)3SnR
N
[I]
TfO
N
2
N
R2
SMe
SMe
N 205
60−93%
R1 = H, Me
R3
N
R2 = CH CH2, CH CHPh OTf Et O
N
Et
Sn(n-Bu)3
N
[II]
Ph
O
N Ph
N
82% TMS TMS 206 [I] 3 mol % Pd(PPh3)4, LiCl, dioxane, rfx, 1−2 h (vinyl 14 h); [II] Pd(PPh3)4, LiCl, dioxane, rfx. Scheme 78 Ph
Ph
X
Ph
N N 207
[I], 70 °C, 6 h
Cl 73%
Cl
N
Sn(n-Bu)3
N
Cl
[I], 100 °C, 7 h
X = Cl
X = Br
70%
R1
Cl R1Sn(n-Bu)3
N
N
Cl
Cl
R
Cl RSn(n-Bu)3
N
Cl
[I], 70−80 °C, 3−10 h
[I] 2 mol % Cl2Pd(PPh3)2, DMF.
N N
R2
54−68% 209 R1 = Ph, β-styryl
N
Ph
208 R1
[I], 100−130 °C, 10 −15 h
60−77%
Cl
N
R2Sn(n-Bu)3
N
[I], 70−80 °C, 7−10 h
N
N
Sn(n-Bu)3
Cl
R1 = β-styryl, R2 = Ph R1 = Ph, R2 = β-styryl
N
69−71%
N 210
Scheme 79
Cl R = Ph, β-styryl
467
468
III Pd-CATALYZED CROSS-COUPLING
5-Bromo-2-chloropyrimidine, however, is coupled selectively at the 5-position to form the product 207. Phenylation by phenylstannanes takes place in the same regioselective manner (vide supra). In reactions of 2,4-dichloropyrimidine with -styryl- or phenyl(tri-nbutyl)stannane, the carbosubstituent goes selectively into the 4-position 209.[117] A second carbosubstituent can subsequently be introduced into the 2-position. The regioselectivity corresponds to the relative reactivity of pyrimidine toward heteronucleophiles. In 2,4,6trichloropyrimidine one chlorine in the 4/6-position is replaced selectively 210 under conditions for monocoupling. A good demonstration of the regio- and chemoselectivity in these reactions is provided by the stepwise introduction of three different carbosubstituents into 5-bromo-2,4dichloropyrimidine (Scheme 80). Initial styrylation is in the 4-position 211, subsequent phenylation is in the 5-position 212, and finally thienylation is in the 2-position 213.[117]
Ph
Ph Ph
Cl Br
Sn(n-Bu)3
N
Br
PhSn(n-Bu)3
N
[I], 70 °C, 6 h
N
Cl
N 73%
Cl
Ph
N
[I], 80 °C, 50 h
N
70%
211 S
Cl 212
[I], 100 °C, 15 h
Sn(n-Bu)3 Ph
82%
Ph
N N
[I] 2 mol % Cl2Pd(PPh3)2, DMF.
S
213 Scheme 80
Zinc Reagents. Negishi coupling of -zincated vinyltrimethylsilanes with 2-bromopyridine yields 2-vinylpyridine functionalized by a silyl substituent at the -carbon of the vinyl group 214 (Scheme 81).[118] Similarly, the trifluoroethenyl group has been substituted into the 2-position in pyridine 215 using zincated trifluoroethene and 2-iodopyridine.[119] Aluminum Reagents. Alkenylaluminum compounds can also be used as reagents for alkenylation in reactions promoted by palladium. Formation of a 2-alkenylpyridine 216 is shown (Scheme 82).[120] Zirconium Reagents. Ethenylation can be effected via hydrozirconated terminal alkynes (Scheme 83). The alkenylzirconocene gives the E-alkenyl product. The reaction is carried out in the presence of zinc chloride. Presumably metal metathesis occurs before the palladium-mediated coupling takes place. The coupling is regiospecific with initial
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
F
SiMe3 ZnCl
Me3Si
F
F
[I]
N
ZnCl
F
N
[II]
X
N
F
F
64%
76%
469
X = Br, I
215
214
[I] 0.5 mol % Cl2Pd(dppb), THF, rfx, 2 h; [II] 3 mol % Pd(PPh 3)4,THF-Et2O, r. t. Scheme 81 Me
AlMe2
n-Hex
N
Me [III]
Br
N n-Hex
[I] 5 mol % Pd(PPh3)4, THF, 25 °C, 5 h.
216
Scheme 82 (n-Bu)
(n-Bu) (n-Bu)
Cl N
(n-Bu)
Cl
Cp2ZrCl
N
N
Cp2 ZrCl
[I]
N
Cl
N
[I]
70%
N
Cl
N
Cl
78%
N
Cl
218
217
[I] (i) 1-Hexyne, Cp2Zr(Cl)H, benzene, r.t., 2 h, (ii) 5 mol % Pd(PPh 3)4, 5 mol % ZnCl2; THF, rfx, 20 h. Scheme 83
carbosubstitution in the more electrophilic 4-position in 2,4-dichloropyrimidine and 2,4dichloroquinazoline with formation of the alkenylated products 217 and 218, respectively.[121] D.ii.c. Alkynylation Tin and Zinc Reagents. Coupling under Sonogashira conditions is commonly used for ethynylation. Other methodologies are less popular but useful (Scheme 84). Under Stille conditions, a 3-pyridinyl triflate was coupled with 1-stannylalkynes to form the ethynyl derivatives 219.[122] Under Negishi conditions, a monoprotected ethynylzinc reagent was used for the preparation of ethynylpyridines 220 by coupling with the respective bromopyridines.[40] Copper Reactants. Sonogashira coupling of vicinal halogenopyridine-carbonitriles can be used for preparation of the corresponding alkynylated pyridines (Scheme 85). The products
470
III Pd-CATALYZED CROSS-COUPLING R
R
OTf (n-Bu)3Sn
N
[I]
COOMe
N 219
COOMe R = TMS 83% R = Ph 80%
Me BrZnO
Br N
ZnBr
Me
Me
OH
[II]
76−83%
N
Me
220
2-, 3-
[I] 5 mol % Pd(PPh3)4, LiCl, dioxane, 80 °C, 2−14 h; [II] 5 mol % Pd(PPh3)4, THF, DMF, 50 °C, 5−24 h. Scheme 84
221 are generally formed in high yields.[123] 3-Bromopyridine is ethynylated in the benzenoid 3-position 222.[37] 3,6-Dialkyl-2-chloropyrazines form the cross-coupled products 223. Their N-oxides were coupled under similar conditions.[124] 3-Iodopyridazines were used as substrate for the preparation of 3-ethynylated pyridazines 224.[99] Treatment of 5-iodo-1-methyluracil with terminal alkynes under Sonogashira conditions results in the formation of 5-alkynyl derivatives 225. This reaction easily proceeds further with cyclization to 6-substituted 3-methylfurano[2,3-d]pyrimidin-2-ones (vide infra).[125] The ethynylation methodology has also been used for the preparation of C-2 alkynylated adenosine 226 from the 2-iodo derivative. The reaction with monosilylated acetylene was run without protection of the functional groups in the nucleoside.[126] In the 4-chloro-5-iodopyrimidine 227 the iodine in the 5-position is selectively displaced in the alkynylation, and in the 5-chloro-4-iodo isomer coupling is in the 4-position (Scheme 86).[127] In silyl-protected 5-chloro-4-iodopyrimidin-2-one 228 hydrolysis of the silyl ether function during the alkynylation reaction was prevented by the use of hexamethyldisilazane as a trapping agent for adventitious water.[128] In the quinazoline series, at room temperature, selective alkynylation can be effected in the more reactive 4-position in 2,4-dichloroquinazoline to provide the product 229. The second alkynyl group is substituted into the 2-position on slight warming of the reaction mixture. The same regioselectivity for alkynylation is achieved in 2,4-dichloropyrimidine. In 6-bromo-2,4dichloroquinazoline competitive reactions between the 4-chloro position and the 6-bromo position led to a mixture of the corresponding hexynynyl derivatives 230. Either product is a substrate for the introduction of two additional alkynyl groups to furnish the trialkynylated quinazoline 231.[121] Vicinal diynes have been prepared as intermediates for subsequent cyclization studies (Scheme 87). Monoprotected acetylene was used. Coupling with 2,3-dichloroquinoxaline gave the dialkyne 232. The vicinal pair in the pyridine 233 was a bromo and a triflyloxy substituent, and in the pyrimidine 234 a chloro and an iodo substituent. The dialkynylated products were obtained in modest to good yields.[129] With free acetylene, coupling at both termini is readily achieved as illustrated by the preparation of ethynyl-bridged bipyridine 235 (Scheme 88).[37]. This is an example of a
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
TMS
R CN N
Br
R
Cl
TMS
[I]
CN
N
68−93%
[II]
N
N
94%
221 R = n-Pent, Ph
R1
N
N
N
N
[IV] or [V]
R1
N
N
224
R1 =
Me, Et, i-Pr, i-Bu R2 = n-Bu, Ph, CH2OH
R1 = OMe, F, NMe 2 [IV] R2 = CH2OH; [V] R2 = Ph
O
R
I
HN
HN
R VI
N
O
R2
64−93%
R2
223
O
R2
I R1
R1
Cl 61−84%
N
222
R1
N
R2 [III]
R1
471
N
O 84, 85%
Me
Me 225 R = n-Bu, CH2CH2OC6H4-4-Me NH2
NH2 N
N I
HO
N
N TMS
N
N O
[VII]
HO
N
N O
64%
HO OH HO OH 226 Cl2 [I] 2.5 mol % Cl2Pd2 (PPh3)2, CuI, NEt3 , 10 °C, 4−6 h; [II] 4 mol % Cl2 Pd 2 (PPh3)2, CuBr, NEt 3, rfx, 1 h; [III] 5 mol % Pd(PPh3)4, DMF, AcOK, 100 °C, 2 h; [IV] 3 mol % Pd(PPh3)2, CuI, NEt3, THF, r.t., 8 h; [V] 5 mol % Cl2Pd(PPh3)2, CuI, NEt3, DMF, r.t., 8 h; [VI] 1 mol % Cl 2 Pd 2 (PPh3)2, CuI, NEt3, 50 °C, 1.5, 2 h; [VII] 8 mol % Pd(PPh3)4, CuI, TEA, DMF, 80 °C, 70 min. Scheme 85
general reaction for disubstitution. With metallated free acetylene a mixture from monoarylation and diarylation is normally the case unless conditions have been chosen for diarylation. A recent study shows that the metal in the metaloacetylene as well as the nature of the heterocyclic substituent are important for the control of the two reaction modes, which lead to the products 236 and 237.[40]
472
III Pd-CATALYZED CROSS-COUPLING Me I Cl
Me
Ph N
Ph
Me
N
N
[I]
66%
Cl
N
227
Me
R
I Cl
Cl
N N
N
R
OTMS
228
[II]
N
OTMS
80−85%
R = Ph, n-Bu, CH2OTHP, TMS (n-Bu)
Cl (n-Bu)
N
N
[III], N.t.
Cl
N
Cl
N
55%
(n-Bu)
229
(n-Bu)
N
[III], 65 °C
N 66%
Cl Br
R2 N
(n-Bu)
N N
(n-Bu)
R1
Cl
[III], 20 °C
R1 = 1-hexynyl, R 2 = Br; 67% R1 = Cl, R2 = 1-hexynyl; 22%
Cl
N 230
(n-Bu) (n-Bu) N
(n-Bu) [III], 65 °C
54%
N
231 [I] 2 mol % Cl2Pd(PPh3)2, CuI, NEt3, N.t.; [II] 1 mol % Cl2Pd(PPh3)2, CuI, NEt3, HMDS, 20 °C; [III] 2 mol % Cl2Pd(PPh3)2, CuI, NEt3, 20 h. Scheme 86
(n-Bu)
III.2.7 HETEROAROMATICS VIA PALLADIUM-CATALYZED CROSS-COUPLING
TMS N
Cl
N
Cl
N TMS [I]
N TMS
232
H N
[II]
N H TMS OTf
TMS [IV]
Br
N
71%
N
47%
TMS
233 OMe
OMe
TMS
I
N
TMS
MeO
Cl
N
N
[IV]
MeO
234
N 61%
TMS
[I] 10 mol % Cl2Pd(PPh3)2, CuI, NEt3, 100 °C, 10 h; [II] HF-NaF buffer pH 5.5, H2O, r.t., 14 h; [III] 10 mol % Pd(PPh 3)4, CuI (i-Pr)2NH, 100 °C, 13 h; [IV] as Scheme 87
[I]
N
N
N
Br 80%
M
Br [I]
N 2-, 3-
235
+ N
N
N 237
236 M = MgBr < 2% M = ZnBr 21−30% 2-I; M = ZnBr 70%
2-, 64%; 3-, 65% 44−47% 95
4-MeC6H4
PhCH2
H
90
>95
[I] Trimethylsilylacetylene (7 equiv)/CuI (10 mol %)/Pd(PPh3)4 (10 mol %)/THF/Et3N (1/1), r.t., 40 h. [II] TBAF, 1.0 M solution in THF, 5 h, r.t. [III] Aldehyde (4 equiv)/piperidine (4 equiv)/CuCl (10 mol %)/dioxane, 90 °C, 36 h. [IV] TFA/H2O (9:1), r.t., 0.5 h. Scheme 30
D.iii. Aryl Bromides Aromatic bromides react much less readily than the corresponding iodides and generally require solvents at reflux in order to effect the reaction. Whereas with iodides no special care is needed to ensure useful conversions of starting materials to products, the lower reactivity of the bromides requires a more careful choice of reaction conditions. It is advisable in this case to use a high-quality amine solvent (triethylamine most commonly), although vigorous drying is necessary. An important requirement, however, is to deoxygenate the reaction mixture prior to addition of the copper catalysts. It is useful to prevent the decomposition of the Pd catalyst and the oxidative coupling of the acetylenes. Reliable and practical procedures for the synthesis of arylacetylenes by Pd-catalyzed cross-coupling of aryl bromides with terminal acetylenes have been developed, which
III.2.8.1 Pd-CATALYZED ALKYNYLATION
513
involve the use of THF as solvent.[47] By careful choice of the reaction mixture and the mode of addition of the reactants, even unreactive substrates are converted into the products with good yields at room temperature as shown in Scheme 31.
Br + HC C R2
R1
Cl2Pd(PPh3)2/CuI
C C R2
1.5 equiv Et3N in THF, 25 °C
R1
R2
Method
Yield (%)
4-CHO
Me3Si
A
99
4-COMe
Me3Si
A
92
2-CO2Me
Me3Si
B
88
3-CO2Me
Me3Si
B
87
Bu
B
91
Ph
B
n
4-COMe 4-COMe
R1
A: Cl2Pd(PPh3)2 (4 mol %)/CuI (2 mol%) 1h B: Cl2Pd(PPh3)2 (5 mol %)/ PPh3 (2.5 mol %)/CuI (3 mol %) 16 h
87 Scheme 31
D.iv. Aryl or Vinyl Triflates Aryl or vinyl triflates, which can easily be prepared from the less expensive and readily available hydroxyl, aldehyde, or ketone derivatives, can undergo Pd-catalyzed crosscoupling reactions with terminal acetylenes. Facile Pd/Cu coupling of vinyl triflates with terminal acetylenes was reported by Cacchi.[48] The cross-coupling of enol triflate with phenyl acetylene proceeds easily under normal conditions (Scheme 32).[49] In view of the importance of C5-alkynyl uridine nucleosides as anticancer agents, Pd-catalyzed couplings of terminal acetylenes with 5-(trifluoromethanesulfonyloxy)pyrimidine nucleosides have been investigated. In most cases coupling is observed at room temperature but it is often very slow; slight elevation(55 °C) in the reaction temperature leads to a dramatic increase in the rate of coupling (Scheme 33).[50] For the double cross-coupling of aromatic 1,2-bistriflates with trimethylsilylacetylene, the addition of nBu4NI accelerates enediyne formation. Enediyne formation with catechol ditriflate and trimethylsilylacetylene are shown in Scheme 34.[51] The coupling under standard conditions gives a 29:71 ratio of 48/49. Iodide salts (300 mol % of either KI or nBu4NI) greatly accelerate the Pd-catalyzed coupling reaction. Bromide, chloride, or triflate salts do not show the same enhancement. Ph OTf + CO2Et
Cl2Pd(PPh3)2/CuI
PhC CH 2,6-lutidine 88%
78
CO2Et 79
Scheme 32
514
III Pd-CATALYZED CROSS-COUPLING
O HN O R1
R3
O OTf HN
N
O
[I]
O R1
N 81
80
R1 R2
O
R1 R2
[I] R3-C CH (1.5 equiv)/Pd(PPh3)4 (5%)/CuI (10%)/Et3N (1.5 equiv)/DMF Temperature (°C)
R3
Time (h)
TMS
2.5
50
85
HOMe2C
0.5
55
90
Ph
2.0
55
93
Yield (%)
Scheme 33
TMS R R
OH
Tf2O
R
OTf
OH
TMS (3 equiv) Cl2Pd(PPh3)2/CuI/ Additive/Et 3N/DMF (1:5), 70 °C
OTf
82
83
TMS
84 +
TMS
R Cl2Pd(PPh3)2 (mol %) 10 5 10
CuI 30 20 25
Time (h)
Additive
Additive (mol %)
Product (%)
OTf
44
none
none
84/85
29:71
20
nBu NBr 4
300
85
38
18
nBu NBr 4
300
84
52
300
84
91
300
84
91
10
30
3
nBu NBr 4
10
30
4
KI
85
Scheme 34
D.v. Aryl Chlorides Aryl chlorides are both more readily available and less expensive than aryl bromides or iodides. A few existing methods for the Pd-catalyzed coupling of aryl chloride substrates usually only function well for electron-deficient substrates such as 86 and 87
III.2.8.1 Pd-CATALYZED ALKYNYLATION
515
(Scheme 35).[2],[44],[52] Many heteroaromatic chlorides such as 88 can, however, react quite readily. This situation has changed rapidly in the past few years. For example, in the case of the Heck reaction, noteworthy advances in the use of aryl chlorides have been described by Ohff et al.,[53] Herrmann et al.,[54] and Shaw et al.[55] Recent work by Littke and Fu[56] has established that certain Pd-catalyzed coupling reactions of aryl chlorides can be accomplished efficiently in the presence of sterically hindered, electron-rich phosphines such as PtBu3. However, there are no examples of utilization for the coupling reaction of chloroarene with terminal acetylenes.
Pd(PPh3)4/MeONa
Cl + H
NC
DMF, 80 °C, 8 h
NC 86
NO2
NO2
Cl + H
O2N
Cl + H
C5H11
TMS
N
Pd(PPh3)4/ CuBr Et3N, reflux, 10 min
O2N
C5H11 87
Cl2Pd(PPh3)2/CuI Et3N, 120 °C, 12 h
yield 64%
yield 87% TMS
N
yield 80%
88
Scheme 35
On the other hand, even the recently prepared Herrmann–Beller catalyst[34],[57] still requires higher temperatures for efficient coupling rates of the Heck reaction. Interestingly, the complexation of chloroarenes with the Cr(CO)3 fragment activates the arene–chlorine bond considerably toward the oxidative addition. Thus, Cr(CO)3 complexed chloroarenes react about 15 times faster than iodoarenes in Pd-catalyzed cross-coupling reactions under mild conditions, in particular in Pd/Cu-catalyzed cross-couplings with terminal acetylenes in refluxing THF and/or tertiary amines (Scheme 36).[57]
Cl OC
Cr
CO CO 89
SiMe3
Cl2Pd(PPh3)2 (5%)/CuI (5%) THF/Et3N, reflux, 6 h yield 90%
OC
Cr CO CO
90
Scheme 36
E. APPLICATIONS E.i. Synthesis of Terminal Acetylenes A conjugated terminal acetylene is an important intermediate in organic synthesis. The reaction of acetylene gas with organic halides preferentially gives only internal acetylenes because of the higher reactivity of monosubstituted acetylenes than that of acetylene gas.
516
III Pd-CATALYZED CROSS-COUPLING
The most commonly used protecting group for acetylenes is the trimethylsilyl (TMS) group.[58] Thus, commercially available trimethylsilylacetylene provides an excellent starting material for the synthesis of aryl and alkenyl acetylenes. Triisopropylsilyl groups are also useful for the step wise deprotection with TMS groups (Scheme 37). Cross-coupling of aryl or alkenyl halides with trimethylsilylacetylene proceeds in the presence of a Pd catalyst and CuI, followed by treatment with dilute aqueous KOH[58] or K2CO3[6],[60] in MeOH or a source of fluorine, such as KF, KF-crown ether, TASF, or nBu4NF[66],[78] to give terminal acetylenes. This protocol is applied to the synthesis of the starting monomers for acetylenic nanoarchitectures, such as ring and dendrimer molecules. Br
O
TMS
iPr
91
Br
CBr4/PPh3
Pd(PPh3)4/CuI
yield 66%
n
TMS
TMS
92
iPr Si 3
SiiPr3
3Si
BuNH2 in Et3N 25 °C TMS yield 65%
SiiPr3
K2CO3 (cat.) yield 99%
TMS
93
H
TMS
94
H
Scheme 37
Recently, direct synthesis of terminal acetylenes via Pd-catalyzed cross-coupling of aryl or alkenyl halides with ethynylmetals was developed by Negishi and co-workers (Section III.2.8.2).[59] A combination of selective and stepwise cross-couplings of polyhalides with protected acetylenes and deprotections under various conditions leads to the synthesis of unsymmetrically substituted polyethynylated arenes or olefins as shown in Schemes 37,[60] 38,[61]and 39.[62] SiiPr3
SiiPr3
I [I], [II]
R
CN
R
CN
[III]
Br
R
CN 95
TMS [I] HC CSiiPr3/[Pd2(dba)3]CHCl3/CuI/PPh3/Et3N, 70 °C. [II] HC CTMS/[Pd2(dba)3]CHCl3/CuI/PPh3/Et3N, 70 °C. [III] LiOH/THF/H 2O, r.t. Scheme 38
H
517
III.2.8.1 Pd-CATALYZED ALKYNYLATION
TMS Br
Br [I]
I
[II]
iPr Si 3
yield 90%
yield 100%
96
iPr Si 3
Br
Br
TMS [III] yield 95%
[I] HC CSiiPr3/Cl2Pd(PPh3)2/CuI/Et2NH, r.t. [II] HC CTMS/Cl2Pd(PPh3)2/CuI/Et3N/benzene, reflux. [III] aq. K2CO3/acetone, reflux.
H
iPr Si 3
97
H Scheme 39
A relatively inexpensive 2-methyl-3-butyn-2-ol 98 is also a useful protecting reagent for stable and volatile arylalkynes. Base-catalyzed “retro-Favorsky” elimination of acetone from alcohols RC# CC(CH3)2OH 99 can successfully be applied to prepare terminal acetylenes (Scheme 40).[63],[64] Treatment with KOH at elevated temperatures is required for elimination of acetone. Many procedures are reported.
[I]
ArX +
[II] Ar
OH
OH 98
Ar
+ CH3COCH3
99
[I] Pd(PPh3)4 /CuBr in Et3N or piperidine. [II] KOH(cat.)/paraffin oil, heat. Scheme 40
By utilization of this methodology, dehydro[12]annulenes were prepared in two steps (Scheme 41).[65] By the in situ desilylation/alkynylation reaction diiodoveratrole 104 reacts with trimethylsilylbutadiyne derivative 105 to afford silylated , -polyyne 106, which is further desilylated by nBu4NF in THF/ethanol solution (Scheme 42).[66]
518
III Pd-CATALYZED CROSS-COUPLING
OH
Br
OH [I]
Br
100
63%
[II]
Br 101
Br 102
36% 103
[I]
Pd(PPh3)4 /CuI in Et3N, 60 °C, 5 h.
[II] 5N aq. KOH/Pd(PPh 3)4 /CuI/BnNEt3Cl/benzene, 85 °C, 22 h. Scheme 41
TMS
i
Pr3Si NO2
105 O2N I
MeO
[I]
MeO
I
SiiPr3 MeO
82%
SiiPr3
MeO
104
106
NO2
[I] Cl2Pd(PPh3)2 (5 mol %)/CuI (6%)/ KOH (10 equiv per Si)/ H2O/THF/Et3N (0.01:1:5), 50 °C, 12−24 h. [II] nBu4NF/EtOH/THF. [III] Pd(OAc)2/CuCl/Py. MeO
OMe
[II] , [III] 97%
O2N
107
NO2 Scheme 42
519
III.2.8.1 Pd-CATALYZED ALKYNYLATION
The cross-coupling of the poorly reactive aryl bromides 108 with sensitive alkynes 109 (R H) do not proceed under standard conditions. The one-pot desilylation of TMSprotected alkynes 109 (R TMS) followed by the cross-coupling with a brominated complex allows the use of sensitive diynes and provides an easy access to models of wires (Scheme 43).[67]
+
N 2
N
N Ru
Br + R
C
Ar
[I]
R
109 N
N 108
2+
N N
N
N Ru
N
Ar
C
C
Ru N
N
N N N
110 [I] NaOH/CuI (3%)/Pd(PPh3)4 (5%)/DMF, 80 °C, 16 h.
Yields (%) :
Ar
=
(34) ,
(39) ,
S
(60)
Scheme 43
Alkynylsilanes 111 react with aryl or alkynyl triflates 112 by the Pd–Cu catalyst in DMF to give the cross-coupling, namely, “sila”-Sonogashira–Hagihara coupling, products in good to excellent yields (Scheme 44 and Table 1).[68] The Si—C bond may be cleaved by Cu in a polar solvent. As as application of the coupling, desired unsymmetrical diaylacetylenes 115 starting with trimethylsilylacetylene can be synthesized without isolation of 114 (Scheme 44).
520
III Pd-CATALYZED CROSS-COUPLING
TABLE 1. Cross-Coupling Reaction a of (Phenylethynyl)trimethylsilane 111 with 4-Acetyl-phenyl Triflate 112 (Scheme 44) Pd(PPh3)4 (mol %)
CuCl (mol %)
Time (h)
Yield b (%) 113
5 1 5c 0 5
10 2 5 10 0
12 24 12 12 12
97 97 93 0 0
a Reactions were carried out using Pd(PPh3)4 (1.0 mmol) and 4-acetylphenyl triflate (112) (1.2 mmol) in DMF (5 mL). b GC yield based on (phenylethynyl)trimethylsilane. c Cl2Pd(PPh3)2 was used.
R1
TMS + TfOR2 111 112
Pd(PPh3)4 (5 mol %)/CuCl (10 mol %) DMF, 80 °C, 12−24 h
R2
R1 113
R1 = C6H5, 4-NCC6H4, 4-MeOC6H4, 2-thieny; R2 = 4-MeCOC6H4, 4-NCC6H4, 4-Me3CC6H4
H
TMS
TfOR1
R1
Pd(PPh3)4 (10 mol %) Et3N/DMF, 60 °C, 6 h
TMS 114
TfOR2 CuCl (10 mol %) 80 °C, 12 h
R2
R1 115
Scheme 44
E.ii. Synthesis of Alkynyl Ketones
, -Acetylenic ketones have attracted considerable biological interest because of their utility as synthetic intermediates, particularly for the synthesis of heterocyclic systems. A common route to , -acetylenic ketones involves the acylation of metal acetylide. The direct Pd-catalyzed coupling of acyl chloride with terminal acetylenes[69],[70] or (alk-1-ynyl)tributylstannanes[71] to give , -acetylenic ketones was reported (Schemes 45 and 46). Alkynyltributylstannanes provide a convenient and mild method for synthesizing alkynyl ketones that is complementary to or, when sensitive functional groups such as TMS group are present, superior to the corresponding terminal acetylenes. Alternatively, acetylenic ketones can also be obtained via one-pot formation of two carbon–carbon bonds under Pd-catalyzed carbonylative conditions by reaction of alk-1-ynes with aryl or vinyl halides and vinyl triflates (Scheme 47).[72] E.iii. Synthesis of Enediyne Macrocycles Enediynes have attracted attention as substrates for the Bergman cyclization, and as a structural motif found in a variety of DNA-cleaving antitumor antibiotics, such as
521
III.2.8.1 Pd-CATALYZED ALKYNYLATION
O
O R1
+ 116
Cl2Pd(PPh3)2,/CuI
Cl
R1
117
R2
R2
in Et3N, r.t., 15 h
R2
R1
Yield (%)
Reference
96
[69]
75
[69]
Ph
tBu
79
[69]
Ph
Ph
Ph
PhCH
CH
Me
o-BrC6H4
33
[70]
nBu
o-BrC6H4
71
[70]
Ph
o-BrC6H4
89
[70]
118
Scheme 45
O
O R1
Cl2Pd(PPh3)2, 84 °C, 2 h
SnBu3 + Cl
119
R2
in ClCH2CH2Cl
120
1
R2
Yield (%)
Ph
Ph
94
Ph
iPr
69
TMS
Ph
64
TMS
iPr
71
R
R2 R1
121
Scheme 46
OTf R1
O
[I]
+
R1
Enol Triflate
Yield (%)
C 8 H 17 83 TfO
H
OMe 80
"
[I] : Pd(OAc) 3, dppp,Et 3 N, CO(1 atm), 60 °C, 2.5 h Scheme 47
R1
522
III Pd-CATALYZED CROSS-COUPLING
esperamisins and dynemicins. Conjugated polyeneyne 126 is a model precursor for the intramolecular Diels–Alder cyclization in a biomimetic pathway to the esperamicins 127 (Scheme 48-1). This model compound is synthesized via 122–123 from cis-dichloroethylene by regiocontrolled sequential coupling of three different alkynes using two kinds of appropriate Pd catalysts.[73] Interestingly, the novel intramolecular reaction of the alkenyl bromide with the terminal acetylene in 128, followed by intramolecular Diels–Alder reaction, affords the highly strained dynemicin A skelton 130 in one step (Scheme 48-2).[73],[74]
Cl
SitBuPh2
SitBuPh2 Pd(PPh3)4/CuI
122
PrNH2
Cl
SitBuPh2
CH(OEt)2 Pd(PPh3)4/ CuI
123
PrNH2
Cl
CH(OEt)2 124 Br
OMe TFA/H 2O nBuLi
SitBuPh2 125
OMe OH O
n
1. Bu4NF
MeO2C
CO2Me I 2. Pd(PPh3)4 /CuI
OSitBuMe2
H H
Et3N
CO2Me
127
126
OMe OH
Scheme 48-1
III.2.8.1 Pd-CATALYZED ALKYNYLATION
523
CO2Me
CO2Me
O
N Br
O
O
OMe
OMe
130
O 128 CO2Me Pd(PPh3)4
N
CuI, r.t.
O
25%
OMe
O 129 Scheme 48-2
E.iv. Polymer Synthesis by Cross-Coupling Since the yield of the Pd-catalyzed cross-coupling of aryl iodides with terminal acetylenes is practically quantitatve, the cross-coupling of , -diethynyl would be expected to yield linear aryleneethynylene-conjugated polymers. Polymers such as polyphenyleneethynylene 131 can be synthesized via polymerization of aryl iodides with acetylene gas in aqueous medium (Scheme 49).[75]
I
I + H
H
Pd(OAc) 2 (5%) /PPh3 (10%)/CuI (5%) Et3N (5 equiv), r.t., 3 days, in MeCN/H2O (3:1)
n 131 Scheme 49
However, the coupling reaction of 132 with terminal acetylenes 134 using a Cl2Pd(PPh3)2/CuI catalyst system in amine gives only a complex mixture. Diethynylsilole-based -conjugated polymers 135 are prepared by the Stille coupling reaction of 2,5-dibromosiloles 132 with bis(stannylethynyl)arenes 133, as shown in Scheme 50. When the phenylene and thienylene derivatives, 133a and 133b, are employed, the coupling reaction smoothly proceeds to give a red polymer 135a and deep violet polymer 135b in 92% and 68% yields, respectively.[76]
524
III Pd-CATALYZED CROSS-COUPLING
Bu3Sn
SnBu3
Ar 133
Ph
Ph
Pd(dba)2/P(2-furyl)3
Ph
Ph
Ar
THF, reflux, 12 h
Si n
C6H13
C6H13 Br
Br Si C6H13 C6H13
135 H
Ar 134
132
H
Cl2Pd(PPh3)2/CuI, amine
S Ar
=
, a
,
N b
C6H13
c
C6H13
Scheme 50
Currently, increasing interest is being paid to monodisperse, well-defined oligomers as models for polymers. Besides this, the oligomers themselves can be used as modules for nanoscopic architectures, like rings and dendrimers, for example. For this purpose, shapepersistent oligomers like oligo(phenyleneethynylene)s and oligo(phenylenevinylene)s appear especially attractive. Oligo(phenyleneethynylene)s with hexyl or isopentoxy substituents have been prepared in a stepwise manner by Tours as shown in Scheme 51.[77] The iterative divergent/convergent binominal strategy is based on the bromine– iodine selectivity of the Pd-catalyzed cross-coupling, the conversion of a bromine substituent into an iodine substituent via halogen metal exchange, and the trimethylsilyl as an acetylene-protecting group. The synthesis is efficient and gives gram amounts of octamers 143. Another synthetic approach to the well-defined -conjugated oligomers is a reported solid-phase strategy, which is illustrated in Scheme 52 for the synthesis of the 120-nm long heptadecameric oligo( p-phenyleneethynylene) rod 152. The iterative divergent/convergent synthetic approach is applicable to protocols for solid-phase synthesis. The starting monomer 144 is anchored through the hydroxy group using PPTS in dichloroethane to the dihydropyran-modified Merrifield’s resin and is followed by the two steps of cross-coupling to give the extended resin-bound pentamer 149. Attempts to generate 148 (R H) directly from 147 and 1,4-diehynylbenzene fail, possibly due to rapid homocoupling of 1,4-diehynylbenzene with trace oxygen present. Compound 148 (R H) is prepared by the Pd/Cu-catalyzed cross-coupling of 147 with monomer 145 followed by deprotection. Polymer-supported trimer 148 (R H) is then coupled with 146 {5–6 mol of 146 per mol of 148 (R—H)} to afford polymersupported pentamer 149. Excess 146 is easily recovered by filtration. One portion of 149 is coupled with 145 to produce the polymer -supported heptamer 150 (R TMS). The remaining portion of 149 is treated with acid to liberate pentamer 151. The
III.2.8.1 Pd-CATALYZED ALKYNYLATION
525
Pd/Cu-catalyzed coupling of 150 with excess of the liberated pentamer 151 affords the polymer supported 17-mer. Directly heating the mixture of 150 and 151 causes a much lower yield, possibly due to decomposition of the , -diyne 150 (R H). Recovery of excess 151 is simply achieved by filtration from the beads, followed by passage through silica gel. Finally, treatment of anchored 152 with acid liberates the free 120nm long 17-mer 152.[78]
R c
R
88%
TMS
Br
TMS
Br
137
R
b 96%
R 136
R
a 95%
I
TMS 138
R R = hexyl
R TMS
Br
2
R
139
R
95%
TMS
Br
R
b
140
2
R
58%
a
4
R
TMS
I
142
R R TMS
Br R
c
H
Br R
8
143
a: (1) nBuLi, (2) ICH2CH2I; b:Cl2Pd(PPh3)2/CuI/Et2NH; c: NaOH/MeOH/THF. Scheme 51
141
2
90%
526
I
C12H25
C12H25
R = TMS
R
144
20% from 147
2) [III]
1) [I]
I
I
R=H
I
C12H25
C12H25
(CH2)5OH
(CH2)5OH
(CH2)5OH
148
145
TMS
[I] Pd2(dba)3/CuI/PPh3/Et2NH/THF;
[III]
[I]
R
[II]
(CH2)5OH
(CH2)5OH
C12H25
146
152
C12H25
C12H25
I
C12H25
C12H25
R
C12H25
I
150
P
C12H25
(CH2)5OH
[II] nBu4NF/THF;
Scheme 52
C12H25
O
R = TMS
O
C12H25
(CH2)5OH
(CH2)5OH
I
C12H25
120 nm
151
[I]
145
=
R=H
147
(CH2)5OH
(CH2)5OH
C12H25
I
C12H25
(CH2)5OH
I
[III] PPTS/nBuOH/ClCH2CH2Cl.
2
C12H25
[II]
C12H25
149
O(CH2)5 [I]
145
R
I C12H25
I C12H25
[III]
[I]
144
C12H25
C12H25
(CH2)5OH
I
III.2.8.1 Pd-CATALYZED ALKYNYLATION
527
F. SUMMARY 1. Pd/Cu-catalyzed cross-coupling reactions of sp2-C halides with terminal acetylenes have been shown to be highly useful and established reactions for the synthesis of eneyne compounds. 2. Recent developments of Pd/Cu-catalyzed cross-coupling such as low-temperature coupling, use of long-lived palladacycle catalysts, and coupling reactions in aqueous media were described. Although there have been tremendous developments in Pdcatalyzed systems for Heck-type reactions in the last decade, successful approaches toward the cross-coupling reaction with terminal acetylenes are rare. 3. Several examples of the application of Pd/Cu-catalyzed cross-coupling for synthesis of alkynyl ketones, terminal acetylenes, enediyne macrocycles, and enediyne polymers are given. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
H. A. Dieck and F. R. Heck, J. Organomet. Chem., 1975, 93, 259. L. Cassar, J. Organomet. Chem., 1975, 93, 253. K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 1975, 4467. K. Sonogashira, T. Yatake, Y. Tohda, S. Takahashi, and N. Hagihara, J. Chem. Soc. Chem. Commun., 1977, 291. C. E. Castro and R. D. Stephens, J. Org. Chem., 1963, 28, 2163. W. B. Austin, N. Bilow, W. J. Kelleghan, and K. S. Y. Lau, J. Org. Chem., 1981, 46, 2280. M. Alami, F. Ferri, and G. Linstrumelle, Tetrahedron Lett., 1993, 34, 6403. J. P. Genêt, E. Blart, and M. Savignac, Synlett, 1992, 715. J.-F. Nguefack, V. Bolitt, and D. Sinou, Tetrahedron Lett., 1996, 37, 5527. R. W. Wagner, T. E. Johnson, F. Li, and J. S. Lindsey, J. Org. Chem., 1995, 60, 5266. R. W. Wagner, J. Seth, S. I. Yang, D. Kim, D. F. Bocian, D. Holten, and J. S. Lindsey, J. Org. Chem., 1998, 63, 5042. J.-P. Strachan, S. Gentemann, J. Seth, W. A. Kalsbeck, J. S. Lindsey, D. Holten, and D. F. Bocian, Inorg. Chem., 1998, 37, 1191. J. Li, A. Ambroise, S. I. Yang, J. R. Diers, J. Seth, C. R. Wack, D. F. Bocian, D. Holten, and J. S. Lindsey, J. Am. Chem. Soc., 1999, 121, 8927. J. Kajanus, S. B. van Berlekom, B. Albinsson, and J. Mårtensson, Synthesis, 1999, 1155. F. M. Romero and R. Ziessel, Tetrahedron Lett., 1999, 40, 1895. S. Bräse, S. Dahmen, and J. Heuts, Tetrahedron Lett., 1999, 40, 6201. A. Khatyr and R. Ziessel, Tetrahedron Lett., 1999, 40, 5515. R. Ziessel, J. Suffert, and M.-T. Youinou, J. Org. Chem., 1996, 61, 6535. L. J. Silverberg, G. Wu, A. L. Rheingold, and R. F. Heck, J. Organomet. Chem. 1991, 409, 411. G. H. Posner, Org. React., 1975, 22, 253 – 400. G. H. Posner, An Introduction to Synthesis Using Organocopper Reagents, Wiley, New York, 1980, 140 pp. K. Okuro, M. Furuune, M. Miura, and M. Nomura, Tetrahedron Lett., 1992, 33, 5363. K. Okuro, M. Furuune, M. Enna, M. Miura, and M. Nomura, J. Org. Chem., 1993, 58, 4716. V. Grosshenny, F. M. Romero, and R. Ziessel, J. Org. Chem., 1997, 62, 1491.
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[25] M. A. De la Rosa, E. Velarde, and A. Guzmán, Synth. Commun., 1990, 20, 2059. [26] F. Paul, J. Patt, and J. F. Hartwig, J. Am. Chem. Soc., 1994, 116, 5969. [27] A. L. Casalnuobo and J. C. Calabrese, J. Am. Chem. Soc., 1990, 112, 4324. [28] M. Alami and G. Linstrumelle, Tetrahedron Lett., 1991, 32, 6109. [29] V. N. Kalinin, Synthesis, 1992, 413 – 432. [30] P. Bertus and P. Pale, Tetrahedron Lett., 1996, 37, 2019. [31] K. Nakamura, H. Okubo, and M. Yamaguchi, Synlett, 1999, 549. [32] G. B. Kauffman and L. Y. Fang, Inorg. Synth., 1983, 22, 101. [33] J. P. Wolfe, R. A. Singer, B. H. Yang, and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 9550. [34] W. A. Herrmann, V. P. W. Böhm, and C.-P. Reisinger, J. Organomet. Chem. 1999, 576, 23. [35] C.-J. Li, Chem. Rev., 1993, 93, 2023 – 2035. [36] H. Dibowski and F. P. Schmidtchen, Tetrahedron Lett., 1998, 39, 525. [37] C.-J. Li, W. T. Slaven IV, Y.-P. Chen, V. T. John, and S. H. Rachakonda, J. Chem. Soc. Chem. Commun., 1998, 1351. [38] M. Bujard, F. Ferri, and M. Alami,. Tetrahedron Lett., 1998, 39, 4243. [39] P. Magnus and S. M. Fortt, J. Chem. Soc. Chem. Commun., 1991, 544. [40] G. Hynd, G. B. Jones, G. W. Plourde II, and J. M. Wright, Tetrahedron Lett., 1999, 40, 4481. [41] M. W. Miller and C. R. Johnson, J. Org. Chem., 1997, 62, 1582. [42] W.-M. Dai and J. Wu, Tetrahedron, 1997, 53, 9107. [43] J. Uenishi, R. Kawahama, O. Yonemitsu, and J. Tsuji, J. Org. Chem., 1998, 63, 8965. [44] R. Singh and G. Just, J. Org. Chem., 1989, 54, 4453. [45] O. Mongin, C. Papamicaël, N. Hoyler, and A. Gossauer, J. Org. Chem., 1998, 63, 5568. [46] A. B. Dyatkin and R. A. Rivero, Tetrahedron Lett., 1998, 39, 3647. [47] S. Thorand and N. Krause, J. Org. Chem., 1998, 63, 8551. [48] S. Cacchi, Synthesis, 1986, 320. [49] K. Nakatani, S. Isoe, S. Maekawa, and I. Saito, Tetrahedron Lett., 1994, 35, 605. [50] G. T. Crisp and B. L. Flynn, J. Org. Chem., 1993, 58, 6614. [51] N. A. Powell and S. D. Rychnovsky, Tetrahedron Lett., 1996, 37, 7901. [52] H. Yamanaka, T. Sakamoto, M. Shiraiwa, and Y. Kondo, Synthesis, 1983, 312. [53] M. Ohff, A. Ohff, M. E. van der Boom, and D. Milstein, J. Am. Chem. Soc., 1997, 119, 11687. [54] W. A. Herrmann, C. Brossmer, K. Öfele, C.-P. Reisinger, T. Priermeier, M. Beller, and H. Fischer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1844. [55] B. L. Shaw, S. D. Perera, and E. A. Staley, J. Chem. Soc. Chem. Commun., 1998, 1361. [56] A. F. Littke and G. C. Fu, J. Org. Chem., 1999, 64, 10. [57] T. J. J. Müller and H. J. Lindner, Chem. Ber., 1996, 129, 607. [58] S. Takahashi, Y. Kuroyama, K. Sonogashira, and N. Hagihara, Synthesis, 1980, 627. [59] E. Negishi, M. Kotora, and C. Xu, J. Org. Chem., 1997, 62, 8957. [60] Y. Rubin, C. B. Knobler, and F. Diederich, Angew. Chem. Int. Ed. Engl., 1991, 30, 698. [61] Y. Tobe, N. Utsumi, A. Nagano, and K. Naemura, Angew. Chem. Int. Ed. Engl., 1998, 37, 1285. [62] K. Onitsuka, M. Fujimoto, N. Oshiro, and S. Takahashi, Angew. Chem. Int. Ed. Engl., 1999, 38, 689. [63] S. H. Havens and P. M. Hergenrother, J. Org. Chem., 1985, 50, 1763. [64] A. G. Mal’kina, L. Brandsma, S. F. Vasilevsky, and B. A. Trofimov, Synthesis, 1996, 589.
III.2.8.1 Pd-CATALYZED ALKYNYLATION
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[65] C. Huynh and G. Linstrumelle, Tetrahedron, 1988, 44, 6337. [66] J. J. Pak, T. J. R. Weakley, and M. H. Haley, J. Am. Chem. Soc., 1999, 121, 8182. [67] S. Fraysse, C. Coudret, and J.-P. Launay, Tetrahedron Lett., 1998, 39, 7873. [68] Y. Nishihara, K. Ikegashira, A. Mori, and T. Hiyama, Chem. Lett., 1997, 1233. [69] Y. Tohda, K. Sonogashira, and N. Hagihara, Synthesis, 1977, 777. [70] H. Sashida, Synthesis, 1998, 745. [71] M. W. Logue and K. Teng, J. Org. Chem., 1982, 47, 2549. [72] P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1991, 32, 6449. [73] S. L. Schreiber and L. L. Kiessling, J. Am. Chem. Soc., 1988, 110, 631. [74] J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, and S. L. Schreiber, J. Am. Chem. Soc., 1990, 112, 7410. [75] C.-J. Li, W. T. Slaven IV, V. T. John, and S. J. Banerjee, J. Chem. Soc. Chem. Commun., 1997, 1569. [76] S. Yamaguchi, K. Iimura, and K. Tamao, Chem. Lett., 1998, 89. [77] U. Ziener and A. Godt, J. Org. Chem., 1997, 62, 6137. [78] S. Huang and J. M. Tour, J. Am. Chem. Soc., 1999, 121, 4908.
III.2.8.2 Palladium-Catalyzed Alkynylation with Alkynylmetals and Alkynyl Electrophiles EI-ICHI NEGISHI and CAIDING XU
A. INTRODUCTION AND GENERAL DISCUSSION A.i. Scope of the Pd-Catalyzed Alkynylation with Respect to Metal Countercations As discussed in Sect. III.2.8.1, the Sonogashira alkyne synthesis[1],[2] and related Hecktype alkynylation[3] using terminal alkynes as reagents collectively offer widely applicable and generally satisfactory procedures for Pd-catalyzed alkynylation. Even so, various limitations and difficulties associated with the Sonogashira and related reactions have also been noted, as detailed later. There are a group of Pd-catalyzed cross-coupling reactions that are also generally satisfactory, and their overall scope, especially that with alkynylzincs, appears to be considerably broader than that of the Sonogashira alkyne synthesis. Highly satisfactory Pd-catalyzed alkynylation with discrete alkynylmetals was developed during the course of a systematic investigation of the scope of Pd-catalyzed cross-coupling with respect to metal countercations.[4] To this end, a series of 1-heptynylmetals containing a wide variety of metals including Li, Mg, Zn, Hg, B, Al, Si, Sn, and Zr were reacted with o-tolyl iodide in the presence of a Pd catalyst. o-Tolyl iodide was chosen to probe both regiospecificity and possible steric influences, but no regioisomerization was observed. As shown in Table 1, a wide variety of metal countercations have been shown to participate in this reaction. Under the same reaction conditions, alkynylmetals containing Zn exhibit the highest reactivity (Entry 6), which is followed by those of Mg (Entries 4 and 5), Al (Entries 12 – 14), and Sn (Entries 16 and 17). Although the product yield observed with 1-heptynylmagnesium bromide was modest (49%), alkynylmagnesium reagents have since been shown to be very satisfactory in many cases.[5],[6] The reaction of 1-heptynyltributyltin represents one of the prototypical examples of the Pd-catalyzed cross-coupling reactions of organotins and the first of the Pd-catalyzed alkynylation with alkynyltins. The 1-heptynylboron derivative generated by the treatment of 1-heptynyllithium with (n-Bu)3B is relatively unreactive at room temperature (Entry 10), but it reacts readily under reflux (THF) to give the desired product in 92% yield (Entry 11). This reaction represents the first example of the Pd-catalyzed reaction of
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
531
532
III Pd-CATALYZED CROSS-COUPLING
TABLE 1. Effects of Countercations in the Pd-Catalyzed Reaction of 1-Heptynylmetals with o-Tolyl Iodide [4] cat.PdL n n-PentC#CM o-TolI n-PentC # CTol-o THF Entry
M of n-PentC#CM
1 2 3 4 5
Li Li Na(NaOMe) MgBr MgBr
6 7
ZnCl ZnCl
8 9 10
Reaction Conditions a Temperature (C) Time (h)
Product Yield (%)
Residual o-TolI (%)
22 22 Reflux 22 22
1 24 24 1 24
Trace 30 58 29 49
88 80 41 55 33
22 22
1 3
91 88
8 2
HgCl HgCl BBu3Li
22 Reflux 22
1 6 3
Trace Trace 10
92 88 76
11
BBu3Li
Reflux
1
92
5
12 13 14 15
AlBu3Li AlBu3Li AlBu2 SiMe3
22 Reflux 22 Reflux
3 1 3 1
4 38 49 Trace
80 10 46 94
16 17
SnBu3 SnBu3
22 22
1 6
75 83
14 6
18
ZrCp2Cl
Reflux
3
0
80
a
In all cases except Entry 3,5 mol % of Cl2Pd(PPh3)2 treated with 10 mol % of i-Bu2AlH was used as the catalyst. In Entry 3,5 mol % of Pd(PPh3)4 was used as the catalyst, and the reaction was run as reported in cassar.[7]
organoboron compounds. It is striking that three metals most widely used in Pd-catalyzed cross-coupling today—Zn, B, and Sn—led to the highest product yields despite major differences in their intrinsic reactivities. Despite its high intrinsic reactivity toward a wide variety of compounds including organic halides, the reaction of 1-heptynyllithium leads to a very low yield of the desired product (Entries 1 and 2). Although equilibrium mixtures of terminal alkynes and sodium alkoxides were reported to produce arylalkynes in good yields,[7] alkynylmetals containing alkali metals appear to be generally inferior to several other metals, one of the general problems being their low chemoselectivity. The unexpectedly low reactivity of alkynyllithiums appears to stem from their intrinsically high chemical reactivity leading to catalyst poisoning. Under stoichiometric conditions, alkynyllithiums are at least as reactive and effective as the corresponding alkynylzincs. And yet, under catalytic conditions, they are ineffective[8] (Scheme 1). There are indications that Pd catalysts are irreversibly transformed into inert complexes by the action of alkynyllithiums. Thus, for example, treatment of Cl2Pd(PPh3)2 with an excess of LiC#CBu-t produces Li2Pd(C#CBu-t)4, which is catalytically inactive (Scheme 2).[8]
III.2.8.2 PALLADIUM-CATALYZED ALKYNYLATION WITH ALKYNYLMETALS
1. Pd(PPh3)4 (1 equiv) 2. LiC CBu-t (1 equiv)
PhI
LiC CBu-t (1 equiv) 5 mol % Pd(PPh3)4
533
PhC CBu-t >95%
PhC CBu-t + PhI 10% 90% remaining unreacted
ClZnC CBu-t (1 equiv) 5 mol % Pd(PPh3)4
PhC CBu-t 90%
Scheme 1
2 LiC CBu-t
>95%
+ (LiCl)nPd(PPh3)4 (n = 1 or 2)
Li2Pd(C CBu-t)4 >95%
+ 4 LiC CBu-t + 2 PPh3 + 2 LiCl
t-BuC C C CBu-t
Cl2Pd(PPh3)2 8 LiC CBu-t
Scheme 2
Finally, Hg (Entries 8 and 9), Si (Entry 15), and Zr (Entry 18) appear to be essentially ineffective probably for different reasons. In short, the countercation survey reported in 1978[4] clearly indicated that, besides Cu used in the Sonogashira reaction (Sect. III.2.8.1), Zn, Mg, B, Al, and Sn showed promising results. Those alkynylmetals that contain Zn, B, Al, and Sn are usually generated from alkynylmagnesium derivatives or alkynyllithiums. So, in cases where alkynylmagnesium reagents are very satisfactory, there would be no need for any of the other metals. In reality, however, there are a number of limitations associated with alkynylmagnesium derivatives. In such cases, Zn, B, Al, and Sn may then be considered. In view of the relative ease of generation, low cost, and the highest intrinsic reactivity observed, Zn should be considered first among them. On the other hand, the usefulness of Al appears to be more limited than the other three metals. The lower intrinsic reactivities and significantly higher costs of B and Sn compounds as compared with alkynylzincs would have to be offset by some distinct advantages that B or Sn might offer. The generally high toxicity associated with organotins is another factor in the selection of a suitable countercation. In some cases, however, the high intrinsic reactivity of alkynylzincs has some undesirable effects, and Sn has been shown to be superior to Zn, as discussed later. Despite the initial promising results observed with alkynylboron derivatives,[4] B had not been used further as the metal component of alkynylmetals until recently.[9]–[11] In view of various factors including intrinsic reactivity and cost, it would be desirable to justify the use of B with some distinct advantages that B might offer.
534
III Pd-CATALYZED CROSS-COUPLING
A.ii. Sonogashira Alkyne Synthesis versus Pd-Catalyzed Alkynylation with Preformed Alkynylmetals Since Pd-catalyzed alkynylation with preformed alkynylmetals is generally somewhat more involved than the Sonogashira alkynylation, the use of the former protocol has to be duly justified. The following differences between the two protocols are worth noting. A.ii.a. Synthesis of Terminal Alkynes. The synthesis of terminal alkynes by the Sonogashira reaction using acetylene itself is known not to produce the desired product in satisfactory yields,[1],[2],[6] disubstitution at both ends of acetylene being the major side reaction. Consequently, a three-step alternative involving (i) protection of one end of acetylene, usually in the form of trimethylsilylacetylene, (ii) cross-coupling, and (iii) deprotection is generally employed. On the other hand, the synthesis of terminal alkynes from acetylene without its protection and deprotection was achieved using ethylnylzinc chlorides and bromides as early as 1977.[12] The required ethynylzinc haldies can readily be generated in situ from commercially available HC#CMgX(XBr or Cl). In fact, ethynylmagnesium halides themselves have been shown to be as satisfactory as any other alkynylmetals in many cases.[6] So, it is advisable to consider first the use of HC#CMgX for Pd-catalyzed ethynylation. In cases where they are unsatisfactory, however, ethynylzinc halides should prove to be superior alternatives in most cases, as detailed below. Puzzlingly, ethynylboron derivatives have failed to give the desired terminal alkynes.[6] Some side reactions, such as 1,2-migration, may be suspected. A.ii.b. Electronic and Steric Impedance in the Sonogashira Alkyne Synthesis. There have been ample indications that terminal alkynes containing electron-withdrawing substituents either fail or are sluggish to undergo the Sonogashira alkynylation. Those that essentially fail to undergo the reaction include F3CC#CH[13] and EtOOCC#CH.[14] A striking difference between the Sonogashira and Negishi protocols is shown in Scheme 3.[13] Although rigorous comparisons of steric and other electronic effects on the Sonogashira and Negishi alkyne syntheses are essentially unknown, a detailed investigation of the electronic and steric effects for comparing Mg, Zn, and Sn has clearly established that the Zn protocol not only is compatible with both electron-withdrawing and electron-donating substituents but also best tolerates steric hindrance, as detailed below.[6]
F3CC CH + PhI
cat. Pd(PPh3)4, Et2NH
F3C F3CC CPh 0%
1. n-BuLi 2. ZnCl2 F3CC CZnCl
+ PhI
cat. Pd(PPh3)4
F3CC CPh 96%
Scheme 3
+ 25%
NEt2
III.2.8.2 PALLADIUM-CATALYZED ALKYNYLATION WITH ALKYNYLMETALS
535
A.ii.c. Other Limitations and Difficulties Associated with the Sonogashira Alkyne Synthesis. Other limitations and difficulties observed with the Sonogashira alkyne synthesis include (i) alkyne dimerization, which appears to be induced by radicals, and (ii) addition of amines to alkynes as exemplified in Scheme 3.[13] A.ii.d. Comparison of Operational Simplicity. As mentioned earlier, the Sonogashira protocol is operationally somewhat simpler than the use of preformed alkynylmetals. This indeed is the main reason for considering first the Sonogashira protocol in cases where it is very satisfactory. When the starting terminal alkynes are prepared via alkynylmetal intermediates, however, the direct use of alkynylmetals would be more convenient, as demonstrated in a recent synthesis of xerulin[15] (Scheme 4).
I Br cat. Pd(PPh3)4
ZnBr
Br I
1. LDA 2. ZnBr2
Br cat. Pd(PPh3)4
ZnBr
Br steps
O
xerulin
O
Scheme 4
A.ii.e. Distinct Reaction Paths for the Sonogashira Reaction and the Negishi Alkyne Synthesis. The Sonogashira and Negishi protocols can follow two distinct reaction paths to give much different products. For example, the reaction of terminal alkynes with (Z )--iodoacrylic acid under Sonogashira conditions leads to the formation of (Z )-alkylidenebutenolides via a cross-coupling–lactonization tandem process.[15]–[18] On the other hand, the corresponding reaction of alkynylzinc bromides provides the crosscoupling products without inducing lactonization[19] (Scheme 5).
RC CH
+
I
COOH
1. R1MgBr 2. ZnBr2
RC CZnBr
+
I
COOH
cat. PdLn CuI, NEt3 [15], [16]−[18] 1. cat. PdLn 2. H3O+ [19]
Scheme 5
R
RC C
O
O
COOH
536
III Pd-CATALYZED CROSS-COUPLING
B. Pd-CATALYZED ALKYNYLATION WITH ALKYNYLMETALS CONTAINING Mg, Zn, AND Al B.i. Alkynylaluminums Alkynylmetals containing Mg, Zn, and Al have been shown to be effective among those containing relatively electropositive metals.[4] However, alkynylaluminum derivatives have rarely been used.[4],[20],[21] Enol phosphates derived from ketones readily react with PhC#CAlEt2 and n-BuC#CAlEt2 in the presence of 1 mol % of Pd(PPh3)4 in 57 – 83% yields.[20],[21] As the use of organoaluminums is somewhat more involved than those containing Mg or even Zn, it should be reserved for those cases in which the use of Al leads to more favorable results than other more convenient options. B.ii. Synthesis of Terminal Alkynes with Ethynylmetals Containing Mg and Zn Because of the highest reactivity and the seemingly broadest scope that alkynylzincs display, they have been most extensively investigated and used among preformed alkynylmetals. With respect to ethynylation to produce terminal alkynes, a detailed comparison of Mg, Zn, and Sn was made.[6],[22],[23] The results summarized in Table 2 indicate that all three metals are satisfactory in less demanding cases but that the lower catalytic reactivity of Mg and Sn as well as a significantly higher tendency of Mg to undergo disubstitution are clearly seen in sterically and electronically more demanding cases. Even so, the direct use of commercially available and economical HC#CMgX (X Cl or Br) should be considered, when they are effective, while the use of more expensive and toxic Sn reagents should be reserved for those cases where neither Mg nor Zn is effective for chemoselectivity or other reasons. B.iii. Scope of Pd-Catalyzed Alkynylation with Alkynylmetals Containing Mg and Zn with Respect to the Alkynyl Groups and Organic Electrophiles Some additional representative examples of Pd-catalyzed alkynylation with alkynylmetals containing Mg and Zn are summarized in Table 3.[5],[24]–[39] The results indicate that the scope of the reaction with respect to the alkynyl groups is indeed very broad. In addition to the parent ethynyl group (Sect. B.ii.) and electron-withdrawing carbon groups (Scheme 3), a wide variety of other carbon groups including alkyl, alkenyl, aryl, and alkynyl (Scheme 4) groups of various steric and electronic requirements can be accommodated. Heteroatom groups containing Si (Entries 9 – 13), N (Entry 14), and O (Entry 15) can also be accommodated. The scope with respect to organic electrophiles has been largely limited to alkenyl, aryl, and acyl derivatives containing I, Br, OPO(OPh)2,[20],[21] and OSO2CF3.[27] In the cases of acyl derivatives, acyl chlorides have mostly been used.[24] Alkynylation of alkyl electrophiles including allyl, propargyl, and benzyl derivatives is usually better accomplished by some known methods involving Li, Mg, and Cu. Moreover, Pd catalysis appears to be largely ineffective in most of these cases. The Pd-catalyzed reaction of alkynylmetals containing Mg and Zn with alkynyl iodides and bromides proceeds readily but leads to the mixtures of the desired conjugated diynes and the two possible homodimers[40] except in some favorable combinations. For strictly “pair-selective” synthesis of unsymmetrically substituted conjugated diynes by Pd-catalyzed cross-coupling, an alternate approach involving Pd-catalyzed alkynyl – alkenyl coupling with 1,2-dihaloethylene discussed in Sect. III.2.14.2 and later in this section should be considered.
III.2.8.2 PALLADIUM-CATALYZED ALKYNYLATION WITH ALKYNYLMETALS
537
TABLE 2. Comparison of Metal Countercations in the Direct Synthesis of Terminal Alkynes by Pd-Catalyzed Ethynylation with Ethynylmetals Containing Mg, Zn, and Sn 5% Pd(PPh3)4
HC# CM RI
HC#CR THF Time b
RI
M
n-Hex
H
H
I
a
(h)
Product Yield c (%) HC#CR
RC#CR
Residual RI c (%)
MgBr
1
95
d
d
ZnBr
1
96
d
d
SnBu3
6
95
d
d
ZnCl
d
83 (65)
d
d
H
H
n-Bu
I
n-Hex
H
MgBr
1
94
d
d
Me
I
ZnBr
1
94
d
d
Pr-n
MgBr
24e
82
d
d
Reference
[6]
[12]
[6]
n-Pr
[6] Me
I
e
ZnBr
3
95
d
d
ZnCl
3
71
d
d
MgBr
1
95
d
0
ZnBr
1
95
d
0
MgBr
1
97 (72)
d
0
1
94
d
0
12
0
d
d
Me I
MeO
F
I
[6]
I
ZnBr MgBr ON2
MeOOC
I
I
[22]
ZnBr
3
93 (89)
d
0
ZnBr
1
92 (86)
d
0
[6]
[6]
[6]
(Continued )
538
III Pd-CATALYZED CROSS-COUPLING
TABLE 2. (Continued ) Time b RI
M Me
a
(h)
Product Yield c (%) Residual HC#CR
RC#CR RI c (%)
MgBr
48
60 (56)
24
14
ZnBr
3
92 (85)
4
0
SnBu3
24
73
6
15
OMe
MgBr
20
51
36
d
I
ZnBr
2
77
Trace
d
MgBr
48
28
12
66
MgBr
24
d
95
10
d
I
Reference
[6]
Me
Me Me
f
g
1
I
ZnBr Me
Me
[6]
S
S
S
O
N Me
18
g
74 (68)
[6]
SnBu3
72
36
8
52
MgBr
d
35
24
d
ZnBr
d
87
0
0
ZnBr
1
85 (71)
d
d
[23]
ZnBr
1
92 (71)
d
d
[23]
I
ZnBr
1
92
d
d
[23]
I
ZnBr
4
76
d
d
[23]
70
96% E R1
R2
n-Bu
n-Hex
100
n-Bu
Ph
72
Ph
n-Hex
95
Me
Ph
91
Yield (%)
Scheme 11
E. SUMMARY 1. Pd-Catalyzed alkynylation with alkynylmetals can be achieved with a wide variety of metals. Alkynylzincs display the highest intrinsic reactivity and the currently broadest scope. 2. In less demanding cases where various metals and protocols are comparably satisfactory, the inherent operational simplicity and economy should favor the Sonogashira reaction and the alkynylmagnesium reaction. In many more demanding cases where these reactions show some difficulties, the organozinc reaction should be considered. 3. The relatively low reactivity, high cost, and toxicity are some of the concerns associated with Sn, even though the low intrinsic reactivity and high chemoselectivity make Sn a metal of choice in some cases. 4. Although promising, alkynylaluminums and alkylborons have not been extensively used, and their unique advantages, if any, are essentially unknown. 5. For a variety of different reasons, other metals tested in Pd-catalyzed alkynylation including Li, Hg, Si, and Zr appear to be unsatisfactory at least in a comparative sense. 6. Pd-catalyzed alkynylation with 1-haloalkynes has not been extensively investigated. In cases where organometals are readily obtainable via hydrometallation or carbometallation, Pd-catalyzed alkenyl – alkynyl coupling may prove to be more advantageous than the corresponding reaction of alkynylmetals with alkenyl halides.
548
III Pd-CATALYZED CROSS-COUPLING
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40]
K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 1975, 4467. S. Takahashi, Y. Kuroyama, K. Sonogashira, and N. Hagihara, Synthesis, 1980, 627. H. A. Dieck and R. F. Heck, J. Organomet. Chem., 1975, 93, 259. E. Negishi, in Aspects of Mechanism and Organometallic Chemistry, J. H. Brewster, Ed., Plenum Press, New York, 1978, 285 – 317. H. P. Dang and G. Linstrumelle, Tetrahedron Lett., 1978, 191. E. Negishi, M. Kotora, and C. Xu, J. Org. Chem., 1997, 62, 8957. L. Cassar, J. Organomet. Chem., 1975, 93, 253. E. Negishi, K. Akiyoshi, and T. Takahashi, J. Chem. Soc. Chem. Commun., 1987, 477. J. A. Soderquist, K. Matos, A. Rane, and J. Ramos, Tetrahedron Lett., 1995, 36, 2401. J. A. Soderquist, A. M. Rane, K. Matos, and J. Ramos, Tetrahedron Lett., 1995, 36, 6847. J. W. Guiles, S. G. Johnson, and W. V. Murray, J. Org. Chem., 1996, 61, 5169. A. O. King, N. Okukado, and E. Negishi, J. Chem. Soc. Chem. Commun., 1977, 683. N. Yoneda, S. Matsuoka, N. Miyaura, T. Fukuhara, and A. Suzuki, Bull. Chem. Soc. Jpn., 1990, 63, 2124. M. Kotora and E. Negishi, Synthesis, 1997, 121. E. Negishi, A. Alimardanov, and C. Xu, Org. Lett., 2000, 2, 65. X. Lu, X. Huang, and S. Ma, Tetrahedron Lett., 1993, 34, 5963. E. Negishi and M. Kotora, Tetrahedron, 1997, 53, 6707. F. Liu and E. Negishi, J. Org. Chem., 1997, 62, 8591. M. Abarbri, J. L. Parain, J. C. Cintrat, and A. Duchêne, Synthesis, 1996, 82. K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1980, 21, 2531. M. Sato, K. Takai, K. Oshima, and H. Nozaki, Tetrahedron Lett., 1981, 22, 1609. A. O. King, E. Negishi, F. J. Villani, Jr., and A. Silveira, Jr., J. Org. Chem., 1978, 43, 358. E. Negishi, C. Xu, Z. Tan, and M. Kotora, Heterocycles, 1997, 209. E. Negishi, V. Bagheri, S. Chatterjee, and F.-T. Luo, Tetrahedron Lett., 1983, 24, 5181. F. Tellier, R. Sauvêtre, and J. F. Normant, Tetrahedron Lett., 1986, 27, 3147. F. Tellier, R. Sauvêtre, and J.-F. Normant, J. Organomet. Chem., 1987, 328, 1 Q. Y. Chen and Y. B. He, Tetrahedron Lett., 1987, 28, 2387. A. Carpita and R. Rossi, Tetrahedron Lett., 1986, 27, 4351. B. P. Andreini, M. Benetti, A. Carpita, and R. Rossi, Tetrahedron, 1987, 43, 4591. B. P. Andreini, A. Carpita, and R. Rossi, Tetrahedron Lett., 1988, 29, 2239. B. P. Andreini, A. Carpita, R. Rossi, and B. Scamussi, Tetrahedron, 1989, 45, 5621. R. Rossi, F. Bellina, and L. Mannina, Tetrahedron Lett., 1998, 39, 3017. P. Vincent, J.-P. Beaucourt, and L. Pichat, Tetrahedron Lett., 1981, 22, 945. B. P. Andreini, A. Carpita, and R. Rossi, Tetrahedron Lett., 1986, 27, 5533. R. Rossi, F. Bellina, A. Carpita, and R. Gori, Synlett, 1995, 344. R. Rossi, A. Carpita, and A. Lezzi, Tetrahedron, 1984, 40, 2773. K. Ruitenberg, H. Kleijn, H. Westmijze, J Meier, and P. Vermeer, Rec. J. R. Netherlands Chem. Soc., 1982, 405. A. Bartlome, U. Stampfli, and M. Neuenschwander, Chimia, 1991, 45, 346. A. Loffler and G. Himbert, Synthesis, 1992, 495. E. Negishi, unpublished results.
III.2.8.2 PALLADIUM-CATALYZED ALKYNYLATION WITH ALKYNYLMETALS
[41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65]
549
P. Cadiot and W. Chodkiewicz, in Chemistry of Acetylenes, H. G. Viehe, Ed., Marcel Dekker, New York, 1969, 597 – 647. E. Negishi, N. Okukado, S. F. Lovich, and F. T. Luo, J. Org. Chem., 1984, 49, 2629. V. Ratovelomanana and G. Linstrumelle, Tetrahedron Lett., 1981, 22, 315. A. S. Kende and C. A. Smith, J. Org. Chem., 1988, 53, 2655. E. Negishi, M. Hata, and C. Xu, Org. Lett., 2000, 2, 3687. E. Negishi, Y. Noda, F. Lamaty, and E. J. Vawter, Tetrahedron Lett., 1990, 31, 4393. J. M. Nuss, B. H. Levine, R. A. Rennels, and M. M. Heravi, Tetrahedron Lett., 1991, 32, 5243. J. M. Nuss, R. A. Rennels, and B. H. Levine, J. Am. Chem. Soc., 1993, 115, 6991. S. Torii, H. Okumoto, T. Tadokoro, A. Nishimura, and A. Rashid, Tetrahedron Lett., 1993, 34, 2139. J. K. Stille and J. H. Simpson, J. Am. Chem. Soc., 1987, 109, 2138. U. H. F. Bunz, V. Enkelmann, and J. Rader, Organometallics, 1993, 12, 4745. D. E. Rudisill and J. K. Stille, J. Org. Chem., 1989, 54, 5856. Y. Ito, M. Inouye, and M. Murakami, Tetrahedron Lett., 1988, 29, 5379. Y. Ito, M. Inouye, and M. Murakami, Chem. Lett., 1989, 1261. D. E. Rudisill, L. A. Castonguay, and J. K. Stille, Tetrahedron Lett., 1988, 29, 1509. M. Hirama and K. Fujiwara, J. Am. Chem. Soc., 1989, 111, 4120. T. Kobayashi, T. Sakakura, and M. Tanaka, Tetrahedron Lett., 1985, 26, 3463. R. J. Hinkle, G. T. Poulter, and P. J. Stang, J. Am. Chem. Soc., 1993, 115, 11626. W. J. Scott, G. T. Crisp, and J. K. Stille, J. Am. Chem. Soc., 1984, 106, 4630. T. Sakamoto, A. Yasuhara, Y. Kondo, and H. Yamanaka, Synlett, 1992, 502. D. A. Siesel and S. W. Staley, Tetrahedron Lett., 1993, 34, 3679. E. Negishi, N. Okumoto, A. O. King, D. E. Van Horn, and B. I. Spiegel, J. Am. Chem. Soc., 1978, 100, 2254. N. Miyaura, K. Yamada, and A. Suzuki, Tetrahedron Lett., 1979, 3437. W. Graaf, A. Smits, J. Boersma, K. Koten, and W. P. M. Hoekstra, Tetrahedron, 1988, 44, 6699. D. L. J. Clive, Y. Bo, Y. Tao, S. Daigneulat, Y.-J. Wu, and G. Meignan, J. Am. Chem. Soc., 1998, 120, 10332.
RM +
Pd
X X
Ar
III.2.9 Palladium-Catalyzed Cross-Coupling between Allyl, Benzyl, or Propargyl Groups and Unsaturated Groups EI-ICHI NEGISHI and FANG LIU
A. INTRODUCTION In 1977 Kosugi et al.[1] reported the Pd-catalyzed allylation with allyltins, which most probably is the first Pd-catalyzed allylation reaction and the first Pd-catalyzed crosscoupling with organotins, while Negishi et al.[2] reported what appears to be the first Pd-catalyzed benzylation with benzylzinc halides. So, Pd-catalyzed allylation and benzylation began in 1977 (Scheme 1). The related propargylation most probably was reported first in 1980.[3] Prior to these developments, the stoichiometric reaction of arylmercuric halides with allyl halides and Pd complexes was reported by Heck.[4] The catalytic version of this and related reactions was later developed as the Heck reaction, as discussed in Part IV. Curiously, both of the prototypical reactions shown in Scheme 1 involve the use of allyl- or benzylmetals. Their charge affinity-inverted versions, which are currently much more commonly employed, were reported by Tamao et al.[5] in 1978 on allylation and by Milstein and Stille[6] in 1979 on benzylation (Scheme 2). Thus, the foundation of Pdcatalyzed allylation and benzylation was laid in the late 1970s. Of Pd-catalyzed allylation, benzylation, and propargylation, allylation has been most extensively investigated by far.
B. Pd-CATALYZED ALLYLATION B.i. Background Traditionally, allylation of organometals has been achieved mainly with organometals containing relatively electropositive metals, such as Mg. Catalysis with Cu compounds, such as Li2CuCl4, along with the stoichiometric organocopper reactions has significantly expanded the synthetic scope of allylation. In many instances, these conventional reactions provide some of the most satisfactory procedures for allylation. So, the use of expensive Pd catalysts has to be amply justified and reserved for those cases that do require catalysis by Pd complexes. There are indeed many such cases and many different reasons for the use of Pd catalysts. Generation of alkenyl- and alkylmetals via
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
551
552
III Pd-CATALYZED CROSS-COUPLING
hydrometallation and carbometallation followed by direct cross-coupling has often required catalysis with Pd and other metals. Use of allylic acetates, carbonates, and other less reactive allylic electrophiles has also mandated the use of catalysts.
SnBu3
ZnBr
cat. Pd(PPh3)4
+ Br
[1]
96%
cat. Cl2Pd(pph3)2 DIBAH
I +
[2]
NO2
88%
NO2 Scheme 1
1. HSiCl3, cat. H2PtCl2 2. KF, H 2O
n-BuC CH
[5]
Cl
H
(2 equiv)
cat. Pd(OAc) 2
n-Bu
K2 n-Bu
SiF5
60%
H
Ph4Sn + BrCH2Ph
cat. PhCH2PdCl(PPh3)2 [6]
PhCH2Ph 91%
Scheme 2
Pd-catalyzed allylation is closely related to the Tsuji–Trost reaction involving allylation of enolates. Interestingly, enolates and “harder” organometals have been shown to follow different reaction courses, as discussed later in this section. Mechanistically and historically, the Tsuji–Trost reaction has been viewed as a process involving nucleophilic attack on coordinated -allyl ligands, and it is therefore discussed in Part V. However, it is not unreasonable to view it as a group of Pd-catalyzed cross-coupling reactions. Remember that the term “cross-coupling” does not imply any particular mechanism, as it only pertains to a certain starting material–product relationship. It is striking that, despite the pioneering investigation of Pd-catalyzed allylation with allyltins,[1] subsequent investigations have been almost totally dominated by Pd-catalyzed allylation with allylic electrophiles, as can be gleaned from the discussions presented below. In this connection, it should be clearly recognized that the Pd-catalyzed reaction of allylmetals can be and has, in some cases, been shown to be significantly different from that of allylic electrophiles, even though many of these reactions may be expected to converge at the intermediary stage of allyl(organyl)palladium(II) derivatives. Although mechanistic details have not yet been well clarified, it is entirely conceivable that allylmetals, especially those containing more electropositive metals, can strongly interfere with Pdcontaining species generated in a catalytic cycle. Because of their tendency to serve as bidentate 3 ligands, interaction of allylmetals with Pd species can be more intense than other organometals, such as those containing alkyl, aryl, and alkenyl groups. Since allyl electrophiles are not expected to readily react with Pd(II) intermediates, their catalyst
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
553
poisoning effects must be less serious. Also expected are much less intense effects exerted by benzylmetals. Indeed, benzylmetals resemble in many ways saturated alkylmetals more than allylmetals. Whatever the true reason for the general difficulties associated with the use of allylmetals in Pd-catalyzed allylation, it is to be generally avoided provided that allylation with allyl electrophiles is a viable option. In allyl–allyl cross-coupling, however, the use of allylmetals is unavoidable. In reality, only those allylmetals containing electronegative metals, mostly allyltins, have been used as discussed in Sect. III.2.10. With the notable exceptions of allyl–allyl coupling (Sect. III.2.10) and enolate allylation (Sect. V.2.1.4), Pd-catalyzed allylation has been achieved mostly with alkenylmetals (alkenyl–allyl coupling) and arylmetals (aryl–allyl coupling). The use of alkylmetals and alkynylmetals has been rare perhaps because their allylation can be performed satisfactorily with appropriate Grignard reagents, whose reactivity can be modified favorably with either stoichiometric or catalytic amounts of Cu compounds, as needed. B.ii. Scope B.ii.a. Metal Countercations. Although Pd-catalyzed allylation can be complicated by a number of side reactions and undesirable processes as detailed below, it is nonetheless a fundamentally favorable transformation that can be achieved with a wide variety of allyl derivatives containing a bewilderingly wide array of heteroatom groups in the allylic position, as discussed later. It has also been observed with a wide range of organometals, especially aryl- and alkenylmetals containing a number of main group metals, such as Mg, Zn, Cd, Hg, B, Al, Si, and Sn, as well as transition metals including Ti and Zr. Some prototypical examples of Pd-catalyzed allylation with various organometals mentioned above are shown in Scheme 3. With most of these metals, the earliest examples were reported in the early 1980s. The general trends observed with various metals in Pd-catalyzed cross-coupling in general are also seen in allylation. Thus, the highest reactivity under catalytic conditions is observed with metals of intermediate electronegativity, that is, Zn Al Zr, the relative intrinsic reactivity order among them being as shown above. Even though objective comparative studies are relatively scarce, the superior intrinsic reactivity of Zn has been clearly indicated by the results shown in Schemes 4[8] and 5.[17] Those metals that readily participate in hydrometallation, that is, B, Al, and Zr, have provided particularly attractive synthetic procedures. Hydrostannylation and recently developed hydro- and carbozincation reactions have also been profitably combined with Pdcatalyzed allylation. Despite a concern about toxicity, Sn has been used extensively. The available literature information indicates that Al, B, Mg, Sn, Zn, and Zr are the six metals that have been most widely used, even though their relative merits and demerits are often not very clear (Scheme 6). The generally low chemoselectivity associated with Mg is a limiting factor. However, as organometals containing other metals, such as Zn and Sn, are often prepared from the corresponding Grignard reagents, it is advisable to test the usefulness of Grignard reagents before converting them into other organometals. Facile and undesirable redox processes that would interfere with the desired Pd-catalyzed reaction can take place with heavy metals, such as Cd and Hg. These metals as well as Sn are also associated with toxicity problems that can be a serious concern. The intrinsic reactivity of organosilanes, which must generally be activated by added reagents for Pd-catalyzed cross-coupling vis-à-vis the availability of several satisfactory metals, mandates justification of the use of Si with some unique advantages it might offer.
554
III Pd-CATALYZED CROSS-COUPLING
Me
Mg (1981): Hayashi et al. [7] cat. Cl2Pd(dppf)
PhMgBr + X
Me
Zn (1981): Negishi et al. [8] PhZnCl + AcO
Ph Me + Ph 96% (96% E ) 4% Me
Me
5% Pd(PPh3)4
Me + Ph 100% (77:23)
Ph
Me
Cd (1981): Negishi et al. [8] PhCdCl + AcO
Me
Hg (1986): Larock and
Ilkka [9]
Me + Ph 96% (77:23)
Ph
cf. Ref. [4] 10% Li2PdCl4 5% NH4Cl
O
PhHgCl + B (1980): Yatagai
5% Pd(PPh3)4
OH
Ph
89% (E / Z = 86:14)
[10]
, Miyaura et al. [11]
R R
R +
B
cat. Pd(OAc) 2
Cl
H (R = n-Bu) Al (1981): Negishi et al. [8] RC CH Me2Al Cl2ZrCp2
R
R
[10]
geranyl acetate 5% Pd(PPh3)4
H
70%
R 82% (>98% E,E)
AlMe2
neryl acetate 5% Pd(PPh3)4
R
90% (>98% Z,E)
Si (1978): Tamao et al.[5] cf. Scheme 2 Sn (1981): Beletskaya et al. [12] RSnMe3 + AcOCH2CH CH2 (R = Ar, vinyl)
cat. Pd(PPh3)4 THF or HMPA
RCH2CH CH2 59−100%
Ti (1984): Tolstikov and Kasatkin [13] Cl 5%
Pd)
2
PhCH2CH CHPh 98% Zr (1981): Schwartz et al. [14] cf. Refs. [15] and [16] for the stoichiometric version (EtO)3TiPh + BrCH2CH CHPh
COOEt t-Bu
Br ZrCp2Cl + Scheme 3
1% PdLn
COOEt t-Bu
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
PhM + AcO
5% Pd(PPh3)4 22 °C
Me
M
Me Ph
Me + Ph (I)
(II)
Reaction Time (h)
Total Yield (%)
(I)/(II)
3 3 12 3 24
15 100 96 55 25
48:52 77:23 77:23 62:38 46:54
MgBr ZnCl CdCl AlPh2 ZrPh3
555
Scheme 4
R1
M
+ Cl
SnBu3
cat. PdLn
R1
SnBu3
R2
R2
M
React. Cond.
Yield (%)
Li[9-MeO-9-BBN] ZrCp2Cl AlEt2 ZnBr
60 C, 3h 60 C, 3h 50 C, 2h r.t., 0.5 h
5 4 42 80
Scheme 5
B Mg Six most widely used metals in Pd-catalyzed allylation
Al
Zn Zr
Sn
Scheme 6
B.ii.b. Allylic Electrophiles. Pd-catalyzed allylation can take place with a wide variety of allylic electrophiles. A systematic study of the scope with respect to the leaving group in the reaction of alkenylalanes with geranyl derivatives summarized in Table 1 has indicated that not only Cl and OAc, but also other oxy groups such as OAlMe2, OPO(OEt)2, and even OSiR3 including OSiMe3 and OSiMe2Bu-t participate in the reaction at room temperature.[8] Allylic iodides may be too reactive and, more significantly, too unstable to be useful. Even allylic bromides have rarely been used and are generally unnecessary. On the other hand, many other intrinsically less reactive allylic derivatives have been used satisfactorily. They include allylic carbonates,[18] epoxides,[19] acetals,[20] sulfones,[21] 2-alkoxyallyl derivatives,[22] and even 2-azaallyl derivatives,[23] and some representative examples are shown in Scheme 7.
556
III Pd-CATALYZED CROSS-COUPLING
TABLE 1. The Effect of Leaving Groups in the Pd-Catalyzed Reaction of Geranyl Derivatives with (E)-2-Methyl-1-hexenyldimethylalane (at 22 C) Product Yield (%) Leaving Group Cl OAc OAlMe2 OPO(OEt)2 OSiMe3 OSiMe2Bu-t
+ O
EtO2CO
Ph
1h
6h
48 h
100 100 43 33 18 Trace
– – – 93 41 37
– – – 100 94 46
5% Pd2(dba)3 DMF, 23 °C, 3h [18]
SnBu3
cat. Cl2Pd(MeCN)2 DMF, 23 °C
Ph Ph
SnMe3
+
[19]
O
CH(OMe)2 cat. Pd(PPh3)4
AlMe2 Me (R = n-C5H11)
Ph
PhZnBr
+
H3O+
OMOM PhSnBu3 + Cl
Me
69% (E/Z = 2/1)
Me
50%
C(OEt)2
Ph 5% Pd(PPh3)4
Ph
[21]
Ph
OMe
R
[20]
SO2Ph
Ph 55% (98% 1,4-, 90% E)
R
C(OEt)3 cat. Pd(PPh3)4, ZnCl2
92%
OH
[20]
R
Ph
O
80%
OMOM
1% Pd(PPh3)4
Ph
[22]
79%
H R
AlMe2 + Me (R = n-Hex)
Ph2C NCHCOOMe
cat. Pd(PPh3)4 [23]
OAc
Ph2C NCHCOOMe Me
H R
Scheme 7
68%
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
557
B.iii. Regiochemistry, Stereochemistry, and Mechanism B.iii.a. Regiochemistry. Pd-catalyzed allylation of organometals containing Zn, B, Sn, and other metal countercations can proceed with retention of regiochemistry of allylic electrophiles, as exemplified by the reaction of geranyl and neryl acetates shown in Scheme 3 and the results summarized in Scheme 5. The extent of retention of the allyl regiochemistry depends on the relative rates of the - and -allylation of organometals. In allylic electrophiles, either - or -position of allylic electrophiles may be substituted with 0, 1, or 2 substituents. In cases where the -position is unsubstituted and the -position is disubstituted, complete or nearly complete retention of regiochemistry may be and has indeed been observed in many cases. Conversely, if the - and -positions are substituted with 2 and 0 substituents, respectively, an extensive allylic rearrangement may be observed. The other cases are expected to lie between these two extreme cases, and the currently available data indeed support this generalization. In general, allylic rearrange-ment occurring at least to minor extents should be anticipated in cases where the difference in the extents of substitution in the - and -positions is 0 or 1, as exemplified by the first four entries in Scheme 3. It should also be noted that allylic rearrangement is usually accompanied by stereoisomerization to varying degrees. Any predictions beyond these useful but somewhat vague generalizations are difficult, and experiments are needed to find the extents of regioselectivity except in the favorable cases of ,-disubstituted allylic derivatives. The capricious nature of the regiochemistry of Pd- or Ni-catalyzed allylation of organometals is amply demonstrated by the results summarized in Schemes 8–10.
R
R
X
Ph 3
1
cat.
+ PhMgBr X R
R
2
4
Allyl Ether Me
OSiEt3
OSiEt3 Me
Ph
Catalyst
Total Yield (%)
Cl2Pd(dppf) Cl2Pd(dppp) Pd(PPh3)4
100 68 52
96 (92/4) 93 (80/14) 90 (85/5)
7 7 10
Cl2Ni(dppf)
100
12
(11/1)
88
Cl2Pd(dppf) Cl2Pd(dppp)
83 60
91 (75/16) 88 (80/8)
9 12
Cl2Ni(dppf)
91
19
81
Scheme 8
3 (E/Z)
(10/9)
4
558
III Pd-CATALYZED CROSS-COUPLING
R R
DIBAH (5×) Pd(PPh3)4 (1×)
PdLn R Me
1
Cl R = n-Pent
Me
+ R
+ R
2
3
R PdLn
Temperature (C)
Total Yield (%)
1
Composition (%) 2 3
78
100
100
0
0
45 0 r.t.
87 76 69
70 26 34
6 18 14
24 56 52
Scheme 9
Et OAc
A
+ 0.5 NaBPh4
Ph
Et
+
E
Ph 70% (1E/1Z/3 = 66:5:29) Ph A
OAc + 0.5 NaBPh3
Ph
+ 3-Ph isomer
+
82% (1E/1Z/3 = 72:12:16) Ph
OAc A
Ph
+ 0.5 NaBPh 4
+ 3-Ph isomer
+
87% (1E/1Z/3 = 17:70:13) Ph A
OAc
Ph
+ 0.5 NaBPh 4
A = 2% Pd(dba) 2 + 4% PPh3
+
+ 3-Ph isomer
81% (1E/1Z/3 = 56:25:19) Scheme 10
The results summarized in Scheme 8[7] indicate that, under the same conditions using the same catalysts and other reagents and solvents, these allylation reactions tend to be regioconvergent, leading to similar regioisomeric ratios whether the starting allylic electrophiles are - or -substituted. It is interesting to note that the diametrically opposed regiochemical outcomes are observed with Pd and Ni catalysts. The results of the reaction of (Z )-2-octenyl chloride with 5 equiv of DIBAH and 1 equiv of Pd(PPh3)4 summarized in Scheme 9[24] indicate that the regio- and stereochemistry of allylation can significantly be influenced by the reaction temperature.
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
559
The results summarized in Scheme 10[24a] provide further useful information about the regiochemistry of Pd-catalyzed allylation of organometals. Even in cases where the and -positions are maximally differentiated as in the cases of the second through fourth entries, regiochemical scrambling accompanied by stereoisomerization can occur to significant extents. The significantly lower levels of stereospecificity relative to those observed with organoaluminum compounds (Scheme 3) must be a consequence of lower rates of the desired allylation relative to stereoisomerization (and regioisomerization) in the reaction of NaBPh4. Strong effects on regiochemistry exerted by the Ph group shown in Scheme 11 are also noteworthy, and they must be attributable to electronic effects. In such cases, nearly 100% regioselectivity may be observed, even when regiochemical scrambling might otherwise be expected.[25] Strong electronic effects are also evident in the reaction of allylic acetates containing an allenyl group.[26] Ph
R
+ NaBPh4
OAc
2% PdLn
Ph
R
[25]
Ph
99% (R = Me), 94% (R = Et), 81% (R = i-Pr) OMe + RZnCl
H2C C C
2% PdLn
R
OMe
CR'2OAc R H2CRCH9 Me3SiC#C9 Ph9 t-BuCHRCRCH9 H2CRC(Me)C#C9
CR'2 R
Yield (%)
H H Me Me Me
50 85 95 90 80
Scheme 11
B.iii.b. Stereochemistry. The stereochemistry of Pd-catalyzed allylation of organometals is considerably more complicated than the regiochemistry discussed above, since it involves both E,Z stereochemistry of the C"C bond and R,S-configuration of the allylic Csp3 center. The extents of E,Z stereochemical retention or scrambling are intimately coupled with the retention or scrambling of the regiochemistry of the allylic electrophiles, as amply indicated in the previous subsections. Specifically, those reactions that proceed with retention of regiochemistry, such as the alkenylalane reaction in Scheme 3, the reaction in Scheme 5, the reaction run at 78 °C in Scheme 9, and the first reaction in Scheme 11, also retain the E or Z stereochemistry, suggesting that these two phenomena must be mechanistically linked to each other, as discussed below. The stereochemistry at the allylic Csp3 center is also a very intricate issue. In the 1970s it was demonstrated that Pd-catalyzed allylation of doubly stabilized enolates, that is, the Tsuji–Trost reaction, proceeded with retention at that Csp3 center, resulting from double
560
III Pd-CATALYZED CROSS-COUPLING
inversions, first in oxidative addition and then in C—C bond formation via attack of -allylpalladium intermediates by nucleophiles on the side opposite to Pd.[27],[28] The same stereochemistry was also observed later even with “ordinary” enolates.[29] In the early 1980s the opposite stereochemistry, that is, overall inversion, was demonstrated first in the stoichiometric reaction of allylpalladium derivatives with organozirconiums by Schwartz and co-workers[15],[16] and then in the catalytic reactions of an alkenylalane and a phenylzinc derivative by Matsushita and Negishi[31] (Scheme 12). The same stereochemistry has since been repeatedly observed with organozinc.[30],[32] Similar experiments with organotins pointing to the same conclusion were also reported later by Stille and coworkers.[33],[34] All of these investigations relied on diastereochemical relationships. The retention of configuration in the C—C bond-forming step was also confirmed subsequently by the determination of absolute configurations, as shown in Scheme 13.[35]
R
R
H
Me
AlMe2
H
Me
cat. Pd(PPh3)4
90%
[31]
O
HOOC Ph PhZnCl cat. Pd(PPh3)4
O
94%
[31]
OAc PhZnCl (2 equiv) Pd(0)Ln [30],[32]
HOOC OAc Catalyst Pd(PPh3)4 Pd(PPh3)4/dba Pd2(dba)3/dppe
OAc
Ph Scheme 12
Me
Ph
PhMgBr (4 equiv) PPh3 (2 equiv)
Me
Ph Ph
PdCl 2
(S) 59% ee
(−)-(1S,2R,3R) 85% ee MgCl (5 equiv)
Me
Ph
PPh3 (2 equiv)
Me
Ph
PdCl 2 (S) 57% ee
(−)-(1R,2S,3S) 70% ee Scheme 13
Yield (%) 85 75 0
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
561
All of the conclusions in the investigations discussed above are predicated on an earlier conclusion that the oxidative addition reaction of allylic electrophiles with Pd complexes proceeds with inversion at the allylic Csp3 center,[36] and these conclusions appear to be still valid in many of the synthetically important Pd-catalyzed allylation reactions. However, more recent studies spearheaded by Kocˇovsky´ [37],[38] and Kurosawa[39],[40] have indicated that the stereochemistry of the oxidative addition of allylic electrophiles to Pd complexes can be much more complicated and dependent on solvents and other factors, covering the entire stereoselectivity range, that is, from 100% R to 100% S. Some noteworthy results are shown in Scheme 14.
Pd(0)Ln
PhZnCl [37]
LnPd+
Ph2PCH2COO
COOMe
Ph
COOMe
COOMe
Pd2(dba)3
+
[39]
Cl PdLn
COOMe + Cl
RM
PdLn
Solvent
trans (%)
cis (%)
Benzene THF CH2Cl2 Acetone DMF MeCN DMSO
100 95 94 75 29 5 3
0 5 6 25 71 95 97
C3H5PdCl olefin benzene [39]
COOMe
R
R = Ph (80%, trans/cis = 98:2), R = vinyl (92%, trans/cis = 92:8) Scheme 14
B.iii.c. Mechanism. The currently available data indicate that both oxidative addition of allylic electrophiles with Pd complexes and the subsequent C—C bond formation can proceed with either inversion or retention of configuration at the allylic Csp3 center, pointing
562
III Pd-CATALYZED CROSS-COUPLING
to the diverse nature of the mechanism of Pd-catalyzed allylation of organometals. It is nonetheless reasonable to state that the predominant course of the C—C bond formation reaction of allylpalladium intermediates with organometals appears to proceed with retention, strongly suggesting that organometals most likely attack Pd to produce diorganylpalladium intermediates, which would then reductively eliminate to produce the observed products (Scheme 15). This then is in sharp contrast with the corresponding reactions of “softer” nucleophiles, such as enolates (the Tsuji–Trost reaction) and amines.
ZOOC
RM
ZOOC
ZOOC red. elim.
PdLn
PdXLn
R
R retention of configuration
Scheme 15
B.iv. Other Noteworthy Aspects of Pd-Catalyzed Allylation B.iv.a. Pd-Catalyzed Cyclic Allylation. The fact that a wide range of allylic electrophiles including not only halides and sulfonates but also phosphates and even silyl ethers that are normally poor and unreactive electrophiles can be used as electrophiles in Pdcatalyzed allylation[8] can be exploited in generating organometals containing relatively inert allylic electrophiles for the preparation of cyclic compounds via Pd-triggered cyclic allylation. As might be expected, it is advantageous to use organometals of relatively low intrinsic reactivity, such as B,[41] Al,[42] and Sn.[43],[44] However, even Zn[45],[46] has been shown to satisfactorily participate in Pd-catalyzed cyclic allylation. Some representative examples are shown in Scheme 16.
B [41] Pd(PPh3)4, NaOH benzene, reflux
HBSia2 X = Cl, Br
X
X
BSia2 humulene (32%)
Al [42]
SiR3 OH
1. Me3Al 2. DIBAH
SiR3 AlBu2 1. ZnCl2 2. cat. Pd(PPh3)4 OAlMe 2
SiR3
R = Me or Et
54% (R = Me) Scheme 16
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
O
Sn
563
O Pd2(dba)3 AsPh3
O
O
[43]
Cl
SnBu3
38% O
HO
O
O
HO HO OH E
SnBu3
E
amphidinolide A
1. ClCOOEt, Py DMAP 2. Pd2(dba)3, DMF [44]
E E 81%
OH Zn [45],[46] R R
SiMe3
SiMe3
R
SiMe3
ZnBr
+ ZnBr R1O
cat. Pd(PPh3)4 THF, 65 °C
R1O R
R1
MeOCH29 Me3SiOCH2CH29 HOCH2CH29 Cl(CH2)49
Ph Ph PhCH2 PhCH2
Yield (%) 51 78 67 75
Scheme 16 (Continued)
B.iv.b. Regioselective Synthesis of Benzene Derivatives via Pd-Catalyzed CrossCoupling of 4-Halo-2-cyclobuten-1-ones. The Pd-catalyzed reaction of 4-chloro-2cyclobuten-1-ones with alkenylzirconium derivatives or alkenyltins and heteroaryltins followed by thermolysis at 100 °C has regioselectively (95%) produced multiply substituted benzene[47] (Scheme 17) and heteroarene-fused benzene derivatives[48] (Scheme 18), respectively.
564
III Pd-CATALYZED CROSS-COUPLING
R
ClCp2Zr Pd
Me
O
Cl ) , PPh3
OH Me
2
O R
PrO
PrO
O
Me
100 °C Me
R
PrO
H
H
H 66% (R = n-Bu)
O Cl
PrO
H
OH
R
ClCp2Zr
H
O
Pd(PPh3)4, PPh3
R PrO
H
R
PrO
H
100 °C
Me
Me 41% (R = n-Bu), 58% (R = Ph)
Scheme 17
Me
OAc
O Me Cl + Bu3Sn
PrO
SiMe3
O
H
A
SiMe3 O
PrO
78%
H OAc Ph
O Cl
Me
H
Me
A
Ph
Me
+ Bu3Sn S
Me
S H
A: (1) 5% Cl2Pd(PhCN)2, 10%
P O
3
63%
; (2) 100 °C; (3) Ac 2O, Py.
Scheme 18
B.iv.c. Stereospecific Synthesis of C-Arylglycosides. The Pd- or Ni-catalyzed reaction of -O- 2-glycopyranoside (1) with arylmagnesium bromides has provided - or -Caryl- 2-glycopyranosides, respectively, exhibiting 100% stereospecificity in each case[49] –[51] (Scheme 19). A related study with aryltins and arylsilicates has also been published.[52]
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
BnO
ArMgBr Cl2Pd(dppf)
BnO
O 70−95%
25 °C
O
BnO OC6H4Bu-t
BnO
565
Ar
BnO
ArMgBr Cl2Ni(dppe)
O Ar 65−85%
−40 °C
BnO
Ar = Ph, 2- or 4-MeOC6H4, 3,4-(CH2O2)C6H3, 2- or 4-tolyl, 4-ClC6H4, PhCH2, 2-thienyl Scheme 19
B.v. Survey of Other Pd-Catalyzed Allylation In this subsection, additional results of Pd-catalyzed allylation that are not discussed in the preceding subsections are summarized in the following order: aryl–allyl coupling (Table 2), allyl–aryl coupling (Table 3), alkenyl–allyl coupling with monometallated alkenes (Table 4) and alkenyl–allyl coupling with dimetallated alkenes (Table 5). The entries in each table are arranged according to the metal countercations in the order: Li, Mg, Zn, B, Al, Si, Sn, Cu, Ti, and Zr. The Pt- or Pd-catalyzed metallometallation (Sect. VII.4) of alkynes with metal – metal bond-containing reagents shown in Scheme 20 provides a novel, if rather expensive, route to cis-1,2-dimetalloalkenes. Their Pd-catalyzed cross-coupling produces regioselectively trisubstituted alkenes containing one metal group (Table 5).
O
O B B
R1C CH
R 1C
R1 O B O
O O cat. Pt(PPh3)4 [68]
Me3Si SnMe3 cat. Pd(PPh3)4 CR2 [69]
R1 Me3Si
H O
R2X cat. PdLn base
R1 O B O
B O R2 SnMe3
R3X cat. PdLn [70]
R1
R2
Me3Si
R3
H R2
Scheme 20
B.vi. Synthesis of Natural Products via Pd-Catalyzed Allylation Although still small in number, Pd-catalyzed allylation has successfully been employed in more than a dozen natural product syntheses, and the number of its applications is expected to grow in the future. In this section, some noteworthy and prototypical examples not discussed earlier are highlighted. The structures of the natural products and crosscoupling partners are also listed in Table 7 of Sect. III.2.18.
566
III Pd-CATALYZED CROSS-COUPLING
TABLE 2. Pd-Catalyzed Aryl–Allyl Coupling
ArM M
Allyl Electrophile
= Zn
Other Conditions
Catalyst
OTs
Product Yield Refer(%) ences
Pd(dba)2
dppe
66
[53]
Pd(dba)2
dppe
75
[54]
OAc
Pd(OAc) 2
P(o-Tol) 3
68
[55]
OAc
Pd(OAc) 2
P(o-Tol) 3
75
[55]
79
[56]
PhZnCl PhZnCl
OAc COOMe ZnBr
O
OTHP CH2OAc
ZnBr
O
OTHP ZnBr Br Me 3Si M
Pd(PPh3)4
N
O O
=B
Br R1
M
B(OH)2
= Si PhSiEtF2
Pd(dba)2
K2CO3
[57]
R2
Ph
PhSiEtF2
R1
R2
Yield (%)
H MeO Cl H Br H Cl Br MeO
H H H Cl H Br Cl Cl Cl
72 58 78 77 87 91 78 73 83
OCOOEt OCOOEt
Pd2(dba)3 · CHCl3,
PPh3
84
[58]
Pd2(dba)3 · CHCl3,
PPh3
52
[58]
PhSiEtF2
OCOOEt
Pd2(dba)3 · CHCl3,
PPh3
33
[58]
PhSiEtF2
OCOOEt
Pd2(dba)3 · CHCl3,
PPh3
40
[58]
Ph
OCOOEt
Pd2(dba)3 · CHCl3,
PPh3
97
[58]
Ph
OCOOEt
Pd2(dba)3· CHCl3,
PPh3
97
[58]
S
SiEtF2 OMe
MeO
SiEtF2
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
567
TABLE 2. (Continued )
ArM M
Allyl Electrophile
Other Conditions
Catalyst
Product Yield Refer(%) ences
= Sn PhSnMe3
Ph
PhSnMe3
Ph
OAc
Pd(dba)2
PPh3
57
[59]
Pd(dba)2
PPh3
32
[59]
Pd(dba)2
PPh3
65
[59]
Pd(dba)2
PPh3
69
[59]
Pd(dba)2
PPh3
81
[59]
Pd(dba)2
PPh3
76
[59]
Pd(dba)2
PPh3
50
[59]
Cl2Pd(MeCN)2
DMF 83 [60] (88% 1,4-, E/Z = 18)
Cl2Pd(MeCN)2
DMF
85 [60] (88% 1,4-)
Cl2Pd(MeCN)2
DMF
75
OAc
PhSnMe3 OAc
PhSnMe3 OAc OAc
PhSnMe3
OAc
PhSnMe3 MeO
SnMe3 OAc
PhSnMe3
O
PhSnMe3
O
PhSnMe3
O
Ph
[60]
Aside from the stoichiometric construction of steroidal side chains by the reaction of alkenylzirconium derivatives with steroidal -allylpalladiums,[15] a one-pot synthesis of -farnesene and its 6Z-isomer from generanyl and neryl chlorides, respectively, reported in 1981[73] appears to be the first example of natural product syntheses via Pd-catalyzed allylation (Scheme 21).
Cl 5% Pd(PPh3)4 Me3Al, Cl2ZrCp2
AlMe2
86%, ≥98% E,E α-farnesene
Cl
5% Pd(PPh3)4
77%, ≥98% E,Z Scheme 21
568
III Pd-CATALYZED CROSS-COUPLING
TABLE 3. Pd-Catalyzed Allyl–Aryl Coupling with Allyltributylstannane
Ar
Catalyst
Other Conditions
Product Yield (%)
References
Me OTf
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
62
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
98
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
97
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
84
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
78
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
41
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
63 (Cl) 67 (Br)
[61]
Me OMe OTf OMe OMe OTf COOMe OMe OTf OMe OMe OHC
OTf OMe Br OTf
HO OMe X
OMe OTf
MeO OMe (X = Cl or Br)
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
569
TABLE 3. (Continued )
Ar
Catalyst
Other Conditions
Product Yield (%)
References
OMe
Cl
OTf
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
28
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
34
[61]
Cl2Pd(PPh3)2
PPh3, LiCl, DMF
0
[61]
Pd(PPh3)4
toluene, 100°
85
[62]
MeO OMe
Cl O
OMe O OTf OMe O OMe O OTf Cl
OMe Br
N
Another noteworthy earlier example is the synthesis of humulene, albeit in 32% yield, via Pd-catalyzed intramolecular alkenyl–allyl coupling shown in Scheme 16.[41] In the earlier examples discussed above, those metals that readily participate in selective hydro- and carbometallation reactions of alkynes, that is, B, Al, and Zr, were used to develop efficient synthetic protocols. Puzzlingly, more recent examples reported mostly in the 1990s have heavily relied on the use of organotins, the use of which in the natural product synthesis was probably reported, for the first time, in 1983 in the synthesis of vitamin K.[74] Pd-catalyzed intramolecular alkenyl–allyl coupling with alkenyltins to produce a large ring in the synthesis of amphidinolide A[43] shown in Scheme 16 is another example along with the synthesis of humulene, pointing to the advantage of the use of relatively electronegative metals, such as B and Sn. Despite the heavy use of Sn in recent years, its choice appears to have been made without rigorous metal countercation screening in most cases. In the synthesis of -bisabolene shown in Scheme 22,[75] for example, the required alkenylstannane was prepared by Zr-catalyzed carboalumination–ate complexation–transmetallation procedure. Comparison of Schemes 21 and 22 strongly suggests that the direct allylation of the alkenylalane intermediate would have provided a much simpler route.
570
III Pd-CATALYZED CROSS-COUPLING
TABLE 4. Pd-Catalyzed Alkenyl–Allyl Coupling with Monometallated Alkenes
Alkenylmetal M
Product Yield (%)
References
Catalyst
Other Conditions
Pd(OAc) 2
TFP
81
[63]
Pd(OAc) 2
TFP
73
[63]
Pd(OAc) 2
TFP
67
[63]
Pd(OAc) 2
TFP
88
[63]
Cl
Pd(PPh3)4
TFP-Hexane
75
[64]
Cl
Pd(PPh3)4
TFP-ClCH2CH2Cl 86
[64]
Pd(OAc) 2
PPh3, DMF
Pd(OAc) 2
PPh3, DMF
76 [58],[65] (α/γ = 62:14)
Pd(OAc) 2
PPh3, DMF
90 [58],[65] (α/γ = 70:20)
Allyl Electrophile
= Zn ZnBr
OAc
COOEt ZnBr
Ph
OAc
Me
OAc
COOEt ZnBr COOEt
Me OAc
ZnBr COOEt M
= Al
n-Hex
AlBu2
n-Hex
AlMe2 Me
M
= Si n-Hex
Ph
SiMeF2
Ph
OCO2Et
SiMeF2 OCO2Et
Ph
SiMeF2
Ph
73
[58],[65]
OCO2Et
M = Sn OAc
SnBu3
LiCl DMF
68
[59]
Pd(dba)2
LiCl DMF
40
[59]
Pd(dba)2
LiCl DMF
80
[59]
Pd(dba)2 OAc
SnBu3
SnBu3
Ph
OAc
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
571
TABLE 4. (Continued ) Allyl Electrophile
Alkenylmetal M
Other Conditions
Catalyst
Product Yield (%)
References
= Sn
HO
SnBu3
Ph
OAc
Pd(dba)2
LiCl DMF
69
[59]
Ph
OAc
Pd(dba)2
LiCl DMF
64
[59]
Ph
OAc
Pd(dba)2
LiCl DMF
88
[59]
Cl2Pd(MeCN)2 PPh3
70
[66]
Cl2Pd(MeCN)2 PPh3
30
[66]
Cl2Pd(MeCN)2 PPh3
60
[66]
OTBS
SnBu3 OEt SnBu3
O
OH PhO
SnBu3
Br O
SnBu3 PhO
OH
Br O
PhO
SnBu3
Br
OH SnBu3 Ph
Bu
SnBu3
M
DMF
Cl2Pd(MeCN)2
DMF
O
SnBu3
O
65
[60]
Cl2Pd(MeCN)2
DMF
63
[60]
Cl2Pd(MeCN)2
DMF
72
[60]
Ph
Cl2Pd(MeCN)2
DMF
55
[60]
Br
Pd )
70
[67]
O
SnBu3
77 [60] (87% 1,4, E/Z = 10)
(82% 1,4, E/Z = 13)
O
SnBu3 Ph
Cl2Pd(MeCN)2 O
= Ti Ti(NEt 2)3
Ph
Cl 2
572
n-Bu
Me3Sn
Me
Me3Sn
H
Me3Sn
Ph
R3Sn
SiMe3
SiMe3
B(O2C2Me4)
B(O2C2Me4)
R = Me R = Bu
SiMe2Bu-t
OEt
SiMe2Bu-t
OEt
H
H
= Sn (Si)
R
H
R = Ph, Et
(Me4C2O2)B
R
(Me4C2O2)B
=B
Ph
M
M
Alkenylmetal
Br
Br
Br
Br
Ph
Ph
AcO
X
Ph
Ph
Br
Cl
Allyl Electrophile
Cl2Pd(PPh3)2
Cl2Pd(dppf)
Catalyst
PhCH2Pd(PPh3)2Cl
PhCH2Pd(PPh3)2Cl
PhCH2Pd(PPh3)2Cl
PhCH2Pd(PPh3)2Cl
TABLE 5. Pd-Catalyzed Alkenyl–Allyl Coupling with 1,2-Dimetallated Alkenes
KOH
K3PO4
Other Conditions
97
95
49
75
51
>95
62
56
67
Product Yield (%)
[72]
[72]
[70]
[70]
[71]
[68]
References
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
573
AcO
1. Me3Al, Cp2ZrCl2 2. MeLi 3. Me3SnCl
Pd(dba)
2 SnMe3 LiCl, DMF
96%, 97% E (E)-α-bisabolene Scheme 22
In addition to the several examples mentioned above, the syntheses of the following natural products and related compounds via Pd-catalyzed allylation have been reported, and they are summarized in Sect. III.2.18: (E)-neomanoalide,[76] vineomycinone B2 methyl ester,[77] cephalosporin analogs,[78] hennoxazole A,[79] stypoldione,[80] 6-ketoprostanoids,[81] constanolactones A and B,[82] lurlene,[83] lurlenic acid,[84] and lurlenol.[84]
C. Pd-CATALYZED BENZYLATION C.i. Background Pd-catalyzed benzylation shares some fundamental features with Pd-catalyzed allylation. However, it is less complicated and generally more favorable than allylation, even though oxidative addition of benzylic electrophiles with Pd is kinetically less favorable than that of allylic electrophiles.[85] Much of these differences between benzyl and allyl may be attributable to the fact that the , -bond in benzyl is part of an aromatic ring system and is hence less reactive toward Pd than that in allyl. Some fundamental features of the benzylic reagents in Pd-catalyzed cross-coupling are summarized in Table 6. TABLE 6. Some Fundamental Features of the Benzylic Reagents in Pd-Catalyzed Cross-Coupling Feature
Benzylic Reagents (Versus Allylic Reagents)
Oxidative addition with Pd
• Generally favorable but kinetically less facile than that
Stereochemistry
• Generally react with inversion of the -Csp3 center
Regiochemistry
• No complication due to E-Z isomerization • No complication due to allylic rearrangement • No complication due to -dehydrometallation
of allylic reagents (similar to the cases of allylic reagents)
Dehydrometallation
observable with ordinary alkyl reagents Use of benzylic electrophiles Use of benzylic organometals
• Generally favorable and free of serious complications • Generation of benzylzinc derivatives by direct metallation is often facile, high-yielding, free of serious complications, and generally more favorable than that with other metals, including Li, Mg, B, Al, Si, and Sn • Use of benzylic organometals is generally much more favorable than that of allylic organometals
574
III Pd-CATALYZED CROSS-COUPLING
The synthesis of any given diarylmethanes (Ar1CH2Ar2) via Pd-catalyzed crosscoupling can, in principle, be achieved by any of the four transformations shown in Scheme 23. It should also be noted that the corresponding Ni-catalyzed reactions have been highly competitive in many cases and that they should be considered and compared with the Pd-catalyzed counterparts. Although Ni-catalyzed benzylation is not systematically surveyed and discussed here, some of the results are included for comparison. Aryl−benzyl coupling Ar1M + XCH2Ar2 Ar1CH2X
+
MAr2
cat. PdLn or NiLn
cat. PdLn or NiLn
Ar1CH2Ar2
Benzyl−aryl coupling Ar1CH2M + XAr2 Ar1X + MCH2Ar2
cat. PdLn or NiLn cat. PdLn or NiLn
Ar1CH2Ar2
Scheme 23
In the other Pd- or Ni-catalyzed benzylation reactions, the number of synthetic options is reduced to the two processes shown in Scheme 24. Moreover, one of the two options shown in Scheme 24 is often not available. Thus, for example, cross-coupling between benzyl and alkyl groups should be achieved primarily by alkyl–benzyl coupling using benzyl electrophiles rather than benzyl–alkyl coupling. On the other hand, benzylation of acyl derivatives should generally be achieved by benzyl–acyl coupling using benzylmetals. Since the Pd-catalyzed benzylation of alkyl (Sect. III.2.11), acyl (Sect. III.2.12.1), and other proximally heterosubstituted organic groups (Sects. III.2.12–III.2.15) is to be discussed later in the sections indicated in parentheses, attention in this subsection is focused on the Pd-catalyzed benzylation of aryl and alkenyl derivatives. Use of benzyl electrophiles RM + XCH2Ar
cat. PdLn or NiLn
RCH2Ar
Use of benzylmetals RX + MCH2Ar
cat. PdLn or NiLn
RCH2Ar
Scheme 24
Benzylic Electrophiles. Benzylic chlorides and bromides are widely and readily available. They are therefore the reagents of choice in most cases. Less readily available benzylic iodides and fluorides have hardly been used. More recently, the use of benzylsulfonium salts in Pd- or Ni-catalyzed cross-coupling has been reported.[86],[87] These results are interesting in view of the fact that metal-mediated cleavage of the C—S bond has been shown to be an important biological process. It is not clear, however, in what cases this reaction would turn out to be the synthetic method of choice in preference to the corresponding reactions of benzyl chlorides and bromides.
575
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
Benzylmetals. As indicated in Table 6, benzylic organometals are readily, generally, and cleanly preparable by the treatment of benzylic bromides with Zn metal.[88] This reaction is distinctly cleaner than the corresponding reaction with Mg, which tends to produce bibenzyls to varying extents, typically 5–15%, as by-products. Coupled with the superior reactivity of benzylzinc bromides in Pd- or Ni-catalyzed cross-coupling,[2] Zn has proved to be by far the most favorable metal countercation in cases where the use of benzylmetals is called for. Although Mg has also been used as part of the benzylmetal reagents since the original investigation of Pd- or Ni-catalyzed benzylation with benzylmetals,[2] its reaction with benzyl halides is plagued with (i) competitive formation of bibenzyls, (ii) cross-homo scrambling most probably due to Mg–halogen exchange, (iii) lower reactivity in Pd- or Nicatalyzed cross-coupling, and (iv) lower chemoselec-tivity in the conventional sense. As is well known, these difficulties are substantially magnified with Li and other alkali metals. On the other side of the spectrum, benzylmetals containing more electronegative metals including B, Al, Si, and Sn are less readily available than benzylzinc derivatives. They have, in fact, been rarely used. In a rare example of the use of a benzyltin derivative, 3,4dichlorobenzyltributylstannane was generated via the corresponding benzylzinc derivative only in 19% yield and used in the reaction with 2-methyl-3,4-dichlorophenyl triflate in the presence of Pd(PPh3)4, LiCl, and DMF to give the desired diarylmethane in 22% yield.[89] Although no comparative data for this particular case were reported, it would be difficult to consider this procedure as a viable alternative. All in all, benzylzinc derivatives appear to be by far the most favorable benzylmetals in essentially all respects. Catalysts. In the original study of benzylation, both Pd and Ni complexes were shown to be satisfactory catalysts.[2],[90] In the synthesis of benzylated alkenes, however, the Nicatalyzed reaction shown in Scheme 25 provided the desired product in 46% yield along with a double bond isomer formed in 15% yield, while the corresponding Pd-catalyzed reaction cleanly produced the desired product in 86% yield.[90]
Et cat. Ni(PPh3)4
Ph
Et Ph +
Et Et
PhCH2ZnBr + I H
46% cat. Cl2Pd(PPh3)4 DIBAH
Et
H
Et H
15%
Et Ph
Et 86% H
Scheme 25
In contrast, the reaction of alkenylalanes with benzylic chlorides was reported to proceed faster and in higher yields in the presence of a Ni catalyst than in the presence of a Pd catalyst,[91] as detailed later in the discussion of natural products synthesis. However, a more recent investigation has indicated that, aside from the rate of cross-coupling, the Pdcatalyzed reaction can proceed very satisfactorily in 90% yields in the same and closely related cases.[92] It is therefore advisable to consider and compare Pd and Ni catalysts for a given case of benzylation.
576
III Pd-CATALYZED CROSS-COUPLING
C.ii. Scope of Pd-Catalyzed Benzylation Some representative examples of Pd-catalyzed benzylation along with those of Nicatalyzed benzylation are presented according to the following order mainly in the form of tables. In some cases, they are highlighted in schemes: (a) Benzyl–aryl coupling (Table 7) (b) Aryl–benzyl coupling (Schemes 26 and 27) (c) Benzyl–alkenyl coupling (Table 8) (d) Alkenyl–benzyl coupling (Table 9) For the other types of Pd-catalyzed benzylation reactions, readers are referred to those sections mentioned in Sect. C.i. C.ii.a. Benzyl – Aryl Coupling. As indicated by the results shown in Table 7, Pd- or Nicatalyzed benzyl – aryl coupling has been carried out by using benzylmetals containing Mg, Zn, and Sn. In those cases where these metals were compared (as in the highlighted examples), however, Zn was shown to be superior to either Mg or Sn. The level of chemoselectivity displayed by benzylzincs is noteworthy. C.ii.b. Aryl – Benzyl Coupling. In contrast with the corresponding Pd- or Ni-catalyzed benzyl – aryl coupling, the range of satisfactory metals in the arylmetals is broader, and Zn, Sn, and B have been successfully used. The absence of comparative data does not permit their objective comparisons. Specifically, diphenylmethane was prepared in 90% yield by the reaction of either Ph4Sn or Ph3SnMe with BrCH2Ph in the presence of PhCH2Pd(PPh3)2Cl.[6] The synthesis of polychlorinated diarylmethanes shown in Scheme 26 is noteworthy despite the modest product yields.[89] Most of the other currently known examples of Pd-catalyzed aryl – benzyl coupling pertain to the synthesis of heteroarenes (Scheme 27).
Me
cat. Pd(PPh3)4
Cl
ZnCl + BrCH2
Cl
Cl
36% Cl
Me
Cl
Cl
CH2 Cl
Cl Me
Cl
Me
Cl
cat. Pd(PPh3)4
Cl
ZnCl + BrCH2
Cl
Cl
Cl
Cl
41% Cl
Cl Cl
OTf + Bu3SnCH2 Cl
Cl
CH2
Cl
cat. Pd(PPh3)4
Cl
CH2 Cl
Me
Me 22%
Scheme 26
Cl
577
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
X
OMe
OAc AcO
Br
OAc
X
Pd(PPh3)4, K2CO3 AcO
O
O
[96]
AcO OAc
OMe
AcO OAc
SnBu3 OMe
OMe Yield (%)
X N N N
COOZnCl
H Me CN NO2
Ph N
69 80 81 79
Pd(PPh3)4
ZnCl + BrCH2
[97]
N Bn
N N N
COOH
Ph N
CH2 N Bn
80−90%
ZnBr Me3Si
CH2Ph N
Pd(PPh3)4
+ BrCH2Ph
O
[56]
N
Me3Si
O
O 73%
O
Br SiMe3 O
Pd(PPh3)4 Na2CO3
+ B
O
Me3Si
[98]
O
3
55%
Br PdLn
cyclic trimer Me3Si
Me3Si
PdLn
O
O Pd Br Cl Pd(PhCN)
2 2 Me L + S [86],[87] S _ S PF6 L = none (46%), (o-Tol) 3P (78%), Ph3P (0%), (o-Furyl)3P (78%), Ph3As (54%), (C6F5)3P (100%), (PhO)3P (84−97%)
Me
SnBu3 +
Scheme 27
578
III Pd-CATALYZED CROSS-COUPLING
TABLE 7. Pd-Catalyzed Benzyl–Aryl Coupling ArX
Benzylmetal
Catalyst
Other Conditions
Yield (%)
Reference
PhCH2MgCl
Br
Ni(acac)2
DIBAH
80
[2]
PhCH2MgCl
Br
Cl2Pd(PPh3)2
DIBAH
86
[2]
PhCH2MgCl
Br
COOMe
Ni(acac)2
PPh3, DIBAH
12
[2]
PhCH2ZnCl
Br
COOMe
Ni(acac)2
PPh3, DIBAH
85
[2]
PhCH2MgCl
Br
CN
Ni(acac)2
PPh3, DIBAH
50
[2]
PhCH2ZnCl
Br
CN
Ni(acac)2
PPh3, DIBAH
92
[2]
PhCH2ZnCl
I
Cl2Pd(PPh3)2
DIBAH
88
[2]
NO2
Recovered Starting Mono Material
Br
PhCH2MgCl
Di
Pd(PPh3)4
79
20
0
[93]
Pd(PPh3)4
9
68
12
[93]
Pd(PPh3)4
20
52
6
[93]
Pd(PPh3)4
15
56
13
[93]
Pd(PPh3)4
13
60
15
[93]
Pd(PPh3)4
THF
82
[94]
Cl2Pd(PPh3)2
DMF
62
[94]
N
Pd(PPh3)4
THF
91
[94]
N
Cl2Pd(PPh3)2
DMF
48
[94]
Br Br
PhCH2ZnCl
Br Br
PhCH2ZnCl
S Br
PhCH2ZnCl
Cl
N
Cl
Br
N
Br
PhCH2ZnCl
PhCH2SnBu3
Ph
Cl
PhCH2ZnBr
N
N N
N
Cl
PhCH2ZnBr PhCH2SnBu3
N N
Ph
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
579
TABLE 7. (Countinued) Benzylmetal
ArX
Catalyst
Other Conditions
Yield (%)
Reference
Pd(dba)2
TFP
82–93
[95]
Pd(dba)2
TFP
74–85
[95]
Pd(dba)2
TFP
90–92
[95]
Pd(dba)2
TFP
84
[95]
Pd(dba)2
TFP
79–82
[95]
OTf CH2ZnBr
I
X
X = COOEt, NO2, OAc, Cl
TfO CH2ZnBr
I
X
X = COOEt, NO2, OTf, Cl TfO
CH2ZnBr
I
X
X = COOEt, NO2 TfO
CH2ZnBr
I MeO
Br
CH2ZnBr
I
X
X = OMe, Cl
C.ii.c. Benzyl–Alkenyl Coupling. As in the cases of benzyl – aryl coupling, benzylzincs appear to be the reagents of choice, although comparative data are virtually absent. Some representative results are shown in Table 8. C.ii.d. Alkenyl – Benzyl Coupling. Alkenylmetals containing B, Al, and Sn have been employed in Pd- or Ni-catalyzed alkenyl – benzyl coupling. Somewhat surprisingly, Zn does not appear to have been used in this reaction. Puzzlingly, even an inhibitory effect of ZnCl2 in the reaction of alkenylalanes with benzyl halides has been observed[90] (Table 9). The overall usefulness of Zn in alkenyl – benzyl coupling is therefore yet to be clarified. An unsettled issue of Pd versus Ni in alkenyl – benzyl coupling was discussed in Sect.C.i. An interesting, if rather expensive, protocol for stereoselective syntheses of alkenylmetals containing two substituents is to achieve syn-metallometallation of alkynes involving B, Si, and Sn (Scheme 28). C.ii.e. Pd-Catalyzed Asymmetric Benzylation. This topic has been investigated extensively by Hayashi et al.[99] –[101] and Cross et al.[102] For this topic, however, readers are referred to Sect. III.2.16. C.iii. Applications to Natural Products Synthesis Only a small number of examples of the application of Pd- or Ni-catalyzed benzylation to the synthesis of natural products are known. Nonetheless, the examples shown in Scheme 29 clearly point to the potentially high synthetic utility of Pd- or Ni-catalyzed benzylation.
580
III Pd-CATALYZED CROSS-COUPLING
TABLE 8. Pd- or Ni-Catalyzed Benzyl–Alkenyl Coupling Benzylmetal
Alkenyl Halides
PhCH2ZnBr
I
PhCH2ZnBr
I
PhCH2ZnBr
I
PhCH2ZnBr
I
Catalyst
Bu
Other Conditions
Yield (%)
References
Ni(PPh3)4
73
[90]
Pd(PPh3)4
78
[90]
Ni(PPh3)4
46a
[90]
Me Hex
Et Et Et
Cl2Pd(PPh3)2
DIBAH
86
[90]
Cl2Pd(PPh3)2
DIBAH
76
[90]
65
[90]
75
[90]
Et
PhCH2ZnBr
Br
Et Et Me
Br
PhCH2ZnBr
COOMe
Ni(PPh3)4
Me Br
PhCH2ZnBr a
COOMe
Cl2Pd(PPh3)2
DIBAH
A styrene derivative was formed as a by-product in 15% yield (cf. Scheme 25).
TABLE 9. Pd- or Ni-Catalyzed Alkenyl–Benzyl Coupling Alkenylmetal SnBu3 Ph
Benzyl Halide
Catalyst
BrCH2Ph
PhCH2Pd(PPh3)2Cl
+
SnBu3
S
N Boc
n-Hex
AlMe2 Me
References
100
[6]
P(OPh)3 CuI
97
[87]
Pd2(dba)3· CHCl3
P(OPh)3 CuI
78
[87]
PF6
S
N Boc
Yield (%)
Pd2(dba)3· CHCl3
_
+
SnBu3
Other Conditions
_ PF6
ClCH2Ph
Pd(PPh3)4
92
[90]
BrCH2Ph
Pd(PPh3)4
93
[90]
BrCH2Ph
Pd(PPh3)4
10% ZnCl2
70
[90]
Pd(PPh3)4
100% ZnCl2
45
[90]
BrCH2Ph
581
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
n-BuC CH Y2B BY2, Pt(PPh3)4 O BY2 B
n-Bu
O
XCH2Ph Cl2Pd(dppf), K2CO3
H
Y2B
[68]
BY2
n-Bu
H
Y 2B
CH2Ph
X = Cl (82%), Br (32%) Cl2Pd(PPh3)2 KOH, DME
R
R
+ XCH2Ph
[71]
BY2
Y2B
R
R
CH2Ph
Y2B
R = Et (83%), Ph (>95%) Scheme 28 COOMe Br
O
COOMe + Me3Sn
OTHP
OTHP
O
Pd(PPh3)4
OSiPh2Bu-t
OSiPh2Bu-t
[103]
O
O COOMe
O
O
O
steps
O O
acerosolide O
MeO MeO
H
Me Me2Al
n−1
[91],[104]
MeO MeO
PdLn
NiLn
MeO MeO
Me nH
MeO MeO
Cl
n
Catalyst
Temperature (C)
5 5 5
Pd(PPh3)4 Pd(PPh3)4 Cl2Ni(PPh3)2 DIBAH
r.t. THF reflux r.t. —
3
Cl2Ni(PPh3)2 DIBAH
r.t. Scheme 29
Time (h)
Yield (%)
4 12 0.25
3 68 87
0.25
89
582
III Pd-CATALYZED CROSS-COUPLING
D. Pd-CATALYZED ALLENYLATION AND PROPARGYLATION Pd-catalyzed allenylation and propargylation of organometals has been much less extensively investigated than the corresponding allylation. The first report on the Pd-catalyzed reaction of organometals with propargylic electrophiles is most probably a paper reported in 1980 by Jeffery-Luong and Linstrumelle on the reaction of n-octylmagnesium chloride and tolylmagnesium bromide with propargyl and allenyl halides in the presence of a Pd catalyst generated in situ from PdCl2, PPh3 (2 equiv), and DIBAH[3] (Scheme 30). Regardless of whether propargylic chlorides or allenyl bromides were used, allenes were produced to the extent of 99% except in a couple of cases where the regioselectivity was 90 – 93%.
Me R
Cl
R1MgX Cl2Pd(PPh3)2, DIBAH
or
Me R1
R Me R
R = H or Me R1 = n-Oct or Tol
Br
48−98% (90−99% regioselective)
Scheme 30
This was soon followed by a series of detailed studies by Vermeer and co-workers on similar reactions of organometals containing Li, Mg, Zn, Cu, and Ag.[26],[105] –[108] A systematic screening of metal countercations summarized in Tables 10 and 11[106] indicate the following. (i) Both allenyl and propargyl electrophiles selectively produce allenes rather than alkynes. (ii) In the reaction of allenyl electrophiles, only the bromide, but not the acetate, gives satisfactory results. In sharp contrast, a variety of propargylic electrophiles, such as those containing Br, OAc, OSOMe, and OPO(OEt)2, can provide the desired allenyne in excellent yields. (iii) Alkynylmetals containing Mg, Zn, Cu, and Ag, but not Li, can produce the desired allenyne in excellent yields. However, Zn along with (CuLi)1/2 has consistently led to the highest product yields except with the allenyl acetate. Although somewhat inferior, Mg and Ag can lead to very satisfactory results in some cases. However, the results obtained with the Li reagents are uniformly poor. TABLE 10. Pd-Catalyzed Reaction of 3-Methyl-1,2-butadienyl Electrophiles with Trimethylsilylethynylmetals 4% Pd(PPh3)4
+
M
SiMe3
X
X Br OAc
SiMe3
M Li
M MgCl
3 0
80 34
Product Yield (%) M ZnCl M Cu 100 7
33 4
M (CuLi)1/2
M Ag
100 —
23 —
583
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
TABLE 11. Pd-Catalyzed Reaction of 2-Methyl-3-butyn-2-yl Electrophiles with Trimethylsilylethynylmetals 4% Pd(PPh3)4
M
+
SiMe3 SiMe3
X Product Yield (%) M MgCl M ZnCl
M Li
X Br OAc OSOMe OPO(OEt)2
0 0 — 20
70 75 90 98
M Cu
M Ag
— 98 98 —
98 86 5 80
98 98 98 98
The scope of these reactions has been further probed with various organozincs, and some representative results are shown in Scheme 31.[106]
Br +
SiMe3
2% Pd(PPh3)4
SiMe3
ClZn
90%
2% Pd(PPh3)4
+ Ph
ClZn Ph
Br ClZn +
Me
Br
Br
Bu-t
Me 1% Pd(PPh3)4
Me
100%
Bu-t 4% Pd(PPh3)4
+ ClZn
85% Me
80%
ClZnC CPh 0.4% Pd(PPh3)4
Ph 95%
Br
ClZn Bu-t 0.4% Pd(PPh3)4
70%
Bu-t
Me
Me Br
ClZn Me 0.4% Pd(PPh3)4
Me
Me 80%
ClZn 2% Pd(PPh3)4
n-Pent
n-Pent MsO
ClZn 2% Pd(PPh3)4
Scheme 31
n-Pent
95%
95%
Me
584
III Pd-CATALYZED CROSS-COUPLING
Later studies have indicated that, in addition to Zn along with Cu, Mg, and Ag discussed above, Al,[109] Sn,[109] and B[110] are effective in some Pd-catalyzed allenylation – propargylation reactions (Scheme 32). So, essentially all of the nine or ten metals used in Pd-catalyzed cross-coupling with the exception of Si and Zr may be used in this reaction. Among them, organozincs have been most extensively and successfully used, and they appear to be the reagents of choice in a general sense. As in many other Pd-catalyzed cross-coupling reactions, however, the selection of the optimal metal countercation must take into consideration various other factors and parameters as well in each given case.
Et3Al cat. PdLn
Ph Me
Ph
Me
[109]
AcO
Et2Al
Ph
Pent-n
cat. PdLn
Me
Ph
Me
[109]
AcO
Bu3Sn cat. PdLn
Ph
Et 68%
Pent-n
Ph Me
[109]
Ph +
H3C3
Me AcO
Me 73% (80:20)
Sn cat. PdLn
4
Ph
Me
+
Ph
[109]
n-Hex Me C OCO2R
O Bu + PhB O
3% Pd(PPh3 )4 THF, reflux [110]
75% (64:36) n-Hex Bu
Me
Me Ph R = Me (78%), t-Bu (47%), Ph (12%)
Scheme 32
Interesting variations of potential synthetic utility include the use of -acetylenic epoxides[106] and -allenic alcohol derivatives.[26],[111] The latter, which can be obtained from the former, have been converted to conjugated dienes for use in the Diels–Alder and other reactions (Scheme 33). As might be expected in analogy with Pd-catalyzed allylation, the overall inversion of configuration at the propargylic carbon center has been shown to be predominant[108],[112] (Scheme 34). This is in accordance with a sequence consisting of oxidative addition with inversion, transmetallation, and reductive elimination with retention. As indicated by the results shown in Schemes 31–34 and Tables 10 and 11, Pd-catalyzed allenylation has been achieved mostly by using allenyl and propargyl electrophiles. Because of the predominant or even exclusive formation of allenes in these reactions, incorporation of a propargyl group has rarely been observed in these reactions. Only within the past few years has the use of allenyl- or propargylmetals been investigated, and a propargyl moiety has been incorporated in the products of Pd-catalyzed allenyl(propargyl)–alkenyl coupling (Scheme 35).[113] This reaction clearly deserves further investigation.
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
RZnCl cat. Pd(PPh3)4
R1
R1C C C CH2 O 1,
R
R2 =
R = H2C CH
C C C
CR1OAc 2
R1 = H or Me
R1 R1
C C CHCH2OCO2Me H or Me
, Ph, t-BuCH C CH R1
R3BX2 3% Pd(PPh3)4
R2
[111]
R2
OMe
R2
R2 = H2C CH , Me3SiC C
R3
R2
C C C n-Bu CH2OH
[26]
R1
(>98%) CH2OH
, t-BuCH C CH
R1
R2ZnCl 2% Pd(PPh3)4
OMe
R2 =
, Me3SiC C
n-BuZnCl cat. Pd(PPh3)4
H or Me
H 2C C C
R1,
R2
R
R2
585
R3
31−92%
= alkyl, alkenyl, aryl Scheme 33
Ph C
H
PhZnCl 3% Pd(PPh3)4
Ph
Ph
H (R)-(−)
(R)-(−) X
H
X = AcO, CF 3CO2, MeSO2 Scheme 34
PhC CCH3 1. BuLi 2. ZnBr2
I
COOEt 5% Pd(PPh3)4
Ph 88%
[PhC C CH2]ZnBr
COOEt
X COOEt 5% Pd(PPh3)4 1.5% HgCl2
Ph
COOEt
X = I (60%), Br (69%), Cl (0%) Scheme 35
Pd-catalyzed allenylation–propargylation has hardly been applied to natural products synthesis. To date, the synthesis of ( )-2,3-octadiene-5,7-diyn-1-ol, a metabolite from fungus Cortinellus berkeleyanus shown in Scheme 36,[106] may well be the only example.
586
III Pd-CATALYZED CROSS-COUPLING
Although the products are not natural, the synthesis of indole derivatives shown in Scheme 37 is noteworthy.[114]–[116] Interestingly, -allenylation and -propargylation with concomitant -ethylation have been observed. The ethyl group is derived from Et3B used as a boron reagent. 1. HC C HC
CH2 O
cat. Pd(PPh3)4
Me3Si(C C)2ZnCl 1. AgNO 3 2. NaCN
Me3Si(C C)2CH C CHCH2OH
2. H3O+
H(C C)2CH
C CHCH2OH
a metabolite of Cortinellus berkeleyames Scheme 36
R1
R 1. t-BuLi 2. BEt3
N Z
N Z
Li+ _ BEt3
1
cat. PdLn
R2 C R3 OCOOMe
R3 N Z
R2 +
Et R2
N Z
R3 R1
Scheme 37
REFERENCES [1] [2] [3] [4] [5] [6] [7]
[8] [9] [10]
M. Kosugi, K. Sasazawa, Y. Shimizu, and T. Migita, Chem. Lett., 1977, 301. E. Negishi, A. O. King, and N. Okukado, J. Org. Chem., 1977, 42, 1821. T. Jeffery-Luong and G. Linstrumelle, Tetrahedron Lett., 1980, 21, 5019. R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5531. K. Tamao, J. Yoshida, M. Takahashi, and M. Kumada, Tetrahedron Lett., 1978, 2161. D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1979, 101, 4992. (a) T. Hayashi, M. Konishi, K. Yokota, and M. Kumada, J. Chem. Soc. Chem. Commun., 1981, 313. (b) T. Hayashi, M. Konishi, K. Yokota, and M. Kumada, J. Organomet. Chem., 1985, 285, 359. E. Negishi, S. Chatterjee, and H. Matsushita, Tetrahedron Lett., 1981, 22, 3737. R. C. Larock and S. J. Ilkka, Tetrahedron Lett., 1986, 27, 2211. H. Yatagai, Bull. Chem. Soc. Jpn., 1980, 53, 1670.
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [24a] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47]
587
N. Miyaura, T. Yano, and A. Suzuki, Tetrahedron Lett., 1980, 21, 2865. I. P. Beletskaya, A. N. Kashin, S. A. Lebedev, and N. A. Bumagin, Izv. Akad. Nauk SSSR Ser. Khim., 1981, 2414. G. A. Tolstikov and A. N. Kasatkin, Izv. Akad. Nauk SSSR Ser. Khim., 1984, 2835. J. Schwartz, Y. Hayashi, M. Riediker, and J. S. Temple, Tetrahedron Lett., 1981, 22, 2629. J. S. Temple and J. Schwartz, J. Am. Chem. Soc., 1980, 102, 7381. J. S. Temple, M. Riediker, and J. Schwartz, J. Am. Chem. Soc., 1982, 104, 1310. M. W. Hutzinger and A. C. Oehlschlager, J. Org. Chem., 1995, 60, 4595. A. M. Castaña and A. M. Echavarren, Tetrahedron Lett., 1996, 37, 6587. D. R. Tueting, A. M. Echavarren, and J. K. Stille, Tetrahedron, 1989, 45, 979. S. Chatterjee and E. Negishi, J. Org. Chem., 1985, 50, 3406. A. Orita, A. Watanabe, H. Tsuchiya, and J. Otera, Tetrahedron, 1999, 55, 2889. M. Kosugi, Y. Miyajima, H. Nakanishi, H. Sano, and T. Migita, Bull. Chem. Soc. Jpn., 1989, 62, 3383. M. J. O’Donnell, M. Li, W. D. Bennett, and T. Grote, Tetrahedron Lett., 1994, 35, 9383. M. W. Hutzinger and A. C. Oehlschlager, J. Org. Chem., 1991, 56, 2918. J. Y. Legros and J. C. Fiaud, Tetrahedron Lett., 1990, 31, 7453. Y. Uozumi, H. Danjo, and T. Hayashi, J. Org. Chem., 1999, 64, 3384. H. Kleijn, H. Westmijze, J. Meijer, and P. Vermeer, Recl. Trav. Chim. Pays-Bas, 1983, 102, 378. B. M. Trost and T. R. Verhoeven, J. Org. Chem., 1976, 41, 3215. B. M. Trost and P. E. Strege, J. Am. Chem. Soc., 1977, 99, 1649. E. Negishi and R. A. John, J. Org. Chem., 1983, 48, 4098. E. Keinan and Z. Roth, J. Org. Chem., 1983, 48, 1769. H. Matsushita and E. Negishi, J. Chem. Soc. Chem. Commun., 1982, 160. E. Keinan and Z. Roth, Israel J. Chem., 1990, 30, 305. F. K. Sheffy and J. K. Stille, J. Am. Chem. Soc., 1983, 105, 7173. F. K. Sheffy, J. P. Godschalx, and J. K. Stille, J. Am. Chem. Soc., 1984, 106, 4833. T. Hayashi, M. Konishi, and M. Kumada, J. Chem. Soc. Chem. Commun., 1984, 107. B. M. Trost, Acc. Chem. Res., 1980, 13, 385 – 393. I. Stary´ and P. Kocˇovsky´, J. Am. Chem. Soc., 1989, 111, 4981. I. Stary´, J. Zajicˇek, and P. Kocˇovsky´, Tetrahedron, 1992, 48, 7229. H. Kurosawa, S. Ogoshi, Y. Kawasaki, S. Murai, M. Miyoshi, and I. Ikeda, J. Am. Chem. Soc., 1990, 112, 2813. H. Kurosawa, H. Kajimaru, S. Ogoshi, H. Yoneda, K. Miki, N. Kasai, S. Murai, and I. Ikeda, J. Am. Chem. Soc., 1992, 114, 8417. N. Miyaura, H. Suginome, and A. Suzuki, Tetrahedron Lett., 1984, 25, 761. S. Chatterjee and E. Negishi, J. Organomet. Chem., 1985, 285, C1. C. Boden and G. Pattenden, Synlett, 1994, 181. A. M. Castaño, M. Ruano, and A. M. Echavarren, Tetrahedron Lett., 1996, 37, 6591. J. van der Louw, J. L. van der Baan, F. Bickelhaupt, and G. W. Klumpp, Tetrahedron Lett., 1987, 28, 2889. J. van der Louw, J. L. van der Baan, F. J. de Kanter, F. Bickelhaupt, and G. W. Klumpp, Tetrahedron, 1992, 48, 6087. D. J. Krysan, A. Gurski, and L. S. Liebeskind, J. Am. Chem. Soc., 1992, 114, 1412.
588 [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81]
III Pd-CATALYZED CROSS-COUPLING
L. S. Liebeskind and J. Wang, J. Org. Chem., 1993, 58, 3550. C. Moineau, V. Bolitt, and D. Sinou, J. Chem. Soc. Chem. Commun., 1995, 1103. C. Moineau, V. Bolitt, and D. Sinou, J. Organomet. Chem., 1998, 567, 157. C. Moineau, V. Bolitt, and D. Sinou, J. Org. Chem., 1998, 63, 582. M. R. Brescia and P. DeShong, J. Org. Chem., 1998, 63, 3156. A. Stolle, J. Salau¨n, and A. de Meijere, Synlett, 1991, 327. A. Stolle, J. Ollivier, P. P. Piras, J. Salau¨n, and A. de Meijere, J. Am. Chem. Soc., 1992, 114, 4051. R. J. Alabaster, J. F. Cottrell, D. Hands, G. R. Humphrey, D. J. Kennedy, and S. H. B. Wright, Synthesis, 1989, 598. D. S. Ennis and T. L. Gilchrist, Tetrahedron, 1990, 46, 2623. M. Moreno-Mañas, F. Pajuelo, and R. Pleixats, J. Org. Chem., 1995, 60, 2396. H. Matsuhashi, S. Asai, K. Hirabayashi, Y. Hatanaka, A. Mori, and T. Hiyama, Bull. Chem. Soc. Jpn., 1997, 70, 1943. L. Del Valle, J. K. Stille, and L. S. Hegedus, J. Org. Chem., 1990, 55, 3019. A. M. Echavarren, D. R. Tueting, and J. K. Stille, J. Am. Chem. Soc., 1988, 110, 4039. J. M. Saá, G. Martorell, and A. García-Raso, J. Org. Chem., 1992, 57, 678. B. E. Blough, S. W. Mascarella, R. B. Rothman, and F. I. Carroll, J. Chem. Soc. Chem. Commun., 1993, 758. H. Doucet and J. M. Brown, Bull. Soc. Chim. Fr., 1997, 134, 995. E. Negishi and S. Huo, unpublished results. H. Matsuhashi, Y. Hatanaka, M. Kuroboshi, and T. Hiyama, Tetrahedron Lett., 1995, 36, 1539. G. A. Tolstikov, M. S. Miftakhov, N. A. Banilova, Ya. L. Vel’der, and L. V. Spirikhin, Synthesis, 1989, 625. A. N. Kasatkin, A. N. Kulak, and G. A. Tolstikov, Izv. Akad. Nauk SSSR Ser. Khim., 1987, 391. T. Ishiyama, M. Yamamoto, and N. Miyaura, Chem. Lett., 1996, 1117. T. N. Mitchell, H. Killing, R. Dicke, and R. Wickenkamp, J. Chem. Soc. Chem. Commun., 1985, 354. T. N. Mitchell, R. Wickenkamp, A. Amamria, R. Dicke, and U. Schneider, J. Org. Chem., 1987, 52, 4868. S. D. Brown and R. W. Armstrong, J. Am. Chem. Soc., 1996, 118, 6331. M. Murakami, H. Amii, N. Takizawa, and Y. Ito, Organometallics, 1993, 12, 4223. H. Matsushita and E. Negishi, J. Am. Chem. Soc., 1981, 103, 2882. J. P. Goschalx and J. K. Stille, Tetrahedron Lett., 1983, 24, 1905. L. Argenti, F. Bellina, A. Carpita, N. Dell’Amico, and R. Rossi, Synth. Commun., 1994, 24, 3167. S. Katsumura, S. Fujiwara, and S. Isoe, Tetrahedron Lett., 1987, 28, 1191. M. A. Tius, X. Gu, and J. Gomez-Galeno, J. Am. Chem. Soc., 1990, 112, 8188. V. Farina, S. R. Baker, D. A. Benigni, S. I. Hauck, and C. Sapino, Jr., J. Org. Chem., 1990, 55, 5833. P. Wipf and S. Lim, J. Am. Chem. Soc., 1995, 117, 558. K. Mori and Y. Koga, Liebigs Ann. Chem., 1995, 1755. Y. Kawanaka, N. Ono, Y. Yoshida, S. Okamoto, and F. Sato, J. Chem. Soc. Perkin Trans. 1, 1996, 715.
III.2.9 COUPLING OF ALLYL, BENZYL, OR PROPARGYL WITH UNSATURATED GROUPS
[82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116]
589
J. D. White and M. S. Jensen, Synlett, 1996, 31. K. Mori and S. Takanashi, Tetrahedron Lett., 1996, 37, 1821 S. Takanashi and K. Mori, Liebigs Ann. Chem., 1997, 825. J. K. Stille and K. S. Y. Lau, Acc. Chem. Res., 1977, 10, 434 – 442. J. Srogl, G. D. Allred, and L. S. Liebeskind, J. Am. Chem. Soc., 1997, 119, 12376. S. Zhang, D. Marshall, and L. S. Liebeskind, J. Org. Chem., 1999, 64, 2796. M. Gaudemar, Bull. Soc. Chim. Fr., 1962, 974. R.-J. de Lang, M. J. C. M. van Hooijdonk, L. Brandsma, H. Kramer, and W. Seinen, Tetrahedron, 1998, 54, 2953. E. Negishi, H. Matsushita, and N. Okukado, Tetrahedron Lett., 1981, 22, 2715. B. H. Lipshutz, G. Bulow, R. F. Lowe, and K. L. Stevens, J. Am. Chem. Soc., 1996, 118, 5512. E. Negishi and C. Xu, unpublished results. A. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett., 1980, 21, 845. L.-L. Gundersen, A. K. Bakkestuen, A. J. Aasen, H. Øverås, and F. Rise, Tetrahedron, 1994, 50, 9743. M. Rottländer and P. Knochel, Tetrahedron Lett., 1997, 38, 1749. T. Kuribayashi, S. Gohya, Y. Mizuno, and S. Satoh, J. Carbohydr. Chem., 1999, 18, 393. L. E. Fisher, S. S. Labadie, D. C. Reuter, and R. D. Clark, J. Org. Chem., 1995, 60, 6224. Z. Z. Song and H. N. C. Wong, J. Org. Chem., 1994, 59, 33. T. Hayashi, M. Konishi, H. Ito, and M. Kumada, J. Am. Chem. Soc., 1982, 104, 4962. T. Hayashi, M. Konishi, Y. Okamoto, K. Kabeta, and M. Kumada, J. Org. Chem., 1986, 51, 3772. T. Hayashi, A. Yamamoto, M. Hojo, and Y. Ito, J. Chem. Soc. Chem. Commun., 1989, 495. G. Cross, B. K. Vriesema, G. Boven, R. M. Kellogg, and F. van Bolhuis, J. Organomet. Chem., 1989, 370, 357. P. C. Aslles and L. A. Paquette, Synlett, 1992, 444. B. H. Lipshutz, S.-K. Kim, P. Mollard, and K. L. Stevens, Tetrahedron, 1998, 54, 1241. K. Ruitenberg, H. Kleijn, C. J. Elsevier, J. Meijer, and P. Vermeer, Tetrahedron Lett., 1981, 22, 1451. H. Kleijn, J. Meijer, G. C. Overbeek, and P. Vermeer, Recl. Trav. Chim. Pays-Bas, 1982, 101, 97. K. Ruitenberg, H. Kleijn, H. Westmijze, J. Meijer, and P. Vermeer, Recl. Trav. Chim. PaysBas, 1982, 101, 405. C. J. Elsevier, P. M. Stehouwer, H. Westmijze, and P. Vermeer, J. Org. Chem., 1983, 48, 1103. E. Keinan and E. Bosch, J. Org. Chem., 1986, 51, 4006. T. Moriya, N. Miyaura, and A. Suzuki, Synlett, 1994, 149. T. Moriya, T. Furuuchi, N. Miyaura, and A. Suzuki, Tetrahedron, 1994, 50, 7961. C. J. Elsevier, H. Kleijn, J. Boersma, and P. Vermeer, Organometallics, 1986, 5, 716. S. Ma, A. Zhang, Y. Yu, and W. Xia, J. Org. Chem., 2000, 65, 2287. M. Ishikura and I. Agata, Heterocycles, 1996, 43, 1591. M. Ishikura, Y. Matsuzaki, and I. Agata, Heterocycles, 1997, 45, 2309. M. Ishikura, Y. Matsuzaki, I. Agata, and N. Katagiri, Tetrahedron, 1998, 54, 13929.
M Ar
M
+X X
Pd Ar
III.2.10 Palladium-Catalyzed CrossCoupling between Allyl-, Benzyl-, or Propargylmetals and Allyl, Benzyl, or Propargyl Electrophiles EI-ICHI NEGISHI and BAIQIAO LIAO
A. INTRODUCTION Cross-coupling between allyl-, benzyl-, or propargylmetals and allyl, benzyl, or propargyl electrophiles is a potentially important synthetic operation. 1,5-Dienes, 1,5-enynes, and other related compounds obtainable by this process represent many natural products and related biologically important compounds. Unfortunately, this synthetic operation commonly performed with organometals containing Li and Mg has been plagued with various difficulties including regiochemical, stereochemical, and cross-homo scramblings, even though some moderately satisfactory procedures for allyl–allyl coupling[1],[2] and propargyl–allyl coupling[3]–[5] have been devised. In view of some highly satisfactory Pd-catalyzed cross-coupling reactions between alkenyl-, aryl-, or alkynylmetals and allyl, benzyl, or propargyl electrophiles discussed in Sects. III.2.8.2 and III.2.9, it is not unreasonable to explore related Pd-catalyzed allyl– allyl, benzyl–allyl, propargyl (or allenyl)–allyl coupling and related reactions. Most of the efforts have been focused on the Pd-catalyzed allyl–allyl coupling involving Sn.
B. Pd-CATALYZED ALLYL–ALLYL COUPLING The Pd-catalyzed reaction of allyltins with allyl electrophiles was independently reported by Trost and Keinan[6] and Godschalx and Stille[7] in 1980. Some representative results are summarized in Table 1. Although some high product yields have been observed, they often are disappointingly low. The regio- and stereochemistry of the allylic electrophiles can be maintained in many cases. On the other hand, allyltin reagents largely undergo an allylic rearrangement, but the regiospecificity has not generally been very high. In some cases, ZnCl2 was used as a cocatalyst.[7] However, the reaction of allyltins and allyl bromides can proceed using just ZnCl2 as a catalyst without resorting
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
591
592
III Pd-CATALYZED CROSS-COUPLING
TABLE 1. Pd-Catalyzed Reaction of Allyltins with Allyl Electrophiles Allyl Electrophile
Allyltin
Pd Catalyst a
Product
Yield (%) Ref.
SnBu3
Ph
OAc
A
Ph
69
[6]
Sn
Ph
OAc
A
Ph
71
[6]
Ph
OAc
A
Ph
32
[6]
Ph
OAc
A
Ph
4
[6]
58
[7]
4
SnBu3
SnBu3
SnBu3
Br
B and
20
Br
Sn
50–70
B
[7]
4
and
Sn
Br C
4
SnBu3
Br
B
10
only
81
[7]
48
[7]
3
a
A Pd(PPh3)4; B Cl(PhCH2)Pd(PPh3)2; C B ZnCl2.
to Pd complexes.[8] So, the roles of Pd complexes in the reactions involving both Pd and Zn are not very clear. Along with the development of the stoichiometric reactions of preformed -allylpalladium derivatives with allylic Grignard reagents and allylic organotins,[9]–[11] a Pd-catalyzed version of the allyltin reaction was developed using maleic anhydride as an added ligand.[10],[11] In contrast with the results discussed above, retention of the regioand stereochemistry of both allyltins and allyl electrophiles to the extents of 90% was observed. However, the yields of the desired products were only poor to modest due to the formation of the two possible homocoupled products to significant extents, as indicated by the results shown in Table 2. Some additional results of Pd-catalyzed allyl–allyl coupling are summarized in Table 3. In cases where regioisomerization, stereoisomerization, and/or cross-homo scrambling are
III.2.10 CROSS-COUPLING BETWEEN ALLYL, BENZYL, AND PROPARGYL GROUPS
593
TABLE 2. Pd-Catalyzed Reaction of allyltins with Allyl Halides in the Presence of Maleic Anhydride a Allyltin
Product b
Allyl Halide
Br SnBu3 Cl SnBu3
Cl SnBu3
c
Br
EtOOC
Yield (%) Ref.
40
[10]
38
[10]
68
[10]
36
[10]
a The reaction is carried out in THF at 50 C using -allylpalladium chloride (1–2%) in the presence of maleic anhydride. b Greater than 90% E,E, where appropriate. Significant amounts (12–37%) of the two possible homocoupling products are observed. c
EtOOC
SnMe2.
possible, they occur to considerable extents, and significant improvements would be necessary before these reactions can be of high value in the synthesis of stereo- and regiodefined 1,5-dienes. Little is known about the use of allylmetals containing metals other than Sn in this reaction. There has been just one report on the Pd-catalyzed cross-coupling of allylzinc bromide with allyl acetate in 54% yield.[16]
C. OTHER Pd-CATALYZED ALLYLATION REACTIONS USING BENZYLAND ALLENYLMETALS AND RELATED CROSS-COUPLING REACTIONS The current scope of other Pd-catalyzed allylation reactions using benzyl- and allenylmetals and their synthetic values are very limited. Even more limited is the scope of related benzylation and propragylation (or allenylation) with benzyl and propropargyl electrophiles. Some of the results in the literature are shown in Scheme 1.
D. SUMMARY The Pd-catalyzed cross-coupling reactions of allyl-, benzyl-, or propargyl (or allenyl) metals with allyl, benzyl, or propargyl electrophiles appear to be intrinsically prone to various side reactions including regio- and stereoisomerization as well as cross-homo scrambling. Although the yields of the desired compounds can be high, in some cases, they tend to be rather modest, in part, as a consequence of isomerization and scrambling processes.
594
SnMe3
(Z/E = 87:13)
COOEt
SnBu 3
SnBu3
Ph Cl (Bu3SnCl + 2e−)
Ph
Allyltin
N
Ph
Ph
O
OAc
NHBOC
COOR2
S
(X = Br, OAc)
X
R2 = CHPh2
R1 = HO
O
R1HN
Cl
Br
Allyl Electrophile
Pd(PPh3)4
Pd(dba)2 TFP
Cl2Pd(PPh3)2
Pd(PPh3)4
Pd Catalyst
O
and R1HN
O
R1HN
Ph
Ph
COOEt
N
N COOR2
Ph
COOR2
S
S
Ph
Product
TABLE 3. Additional Examples of the Pd-Catalyzed Allyl–Allyl Coupling Using Organotins
70−80
10
47
89
85
Yield (%)
[15]
[14]
[13]
[12]
Ref
595
III.2.10 CROSS-COUPLING BETWEEN ALLYL, BENZYL, AND PROPARGYL GROUPS
PhCH2ZnBr
cat. PdLn [16]
+ AcO
cat. PdLn [16]
PhCH2ZnBr + AcOCH 2Ph
+ AcO SnBu3
·
Ph
Ph 60%
PhCH2CH2Ph 44%
cat. PdLn [17]
Ph +
Ph
·
37%
25%
OAr ·
+ SnBu3
cat. PdLn [17]
Ar2
Ar1
+ Ar1
Ar2
(I)
Ar1
Ar2
Ph Ph Ph
4-FC6H4 4-BrC6H4 4-MeC6H4
Ar1
(I) (%) 52 42 47
(II)
(II) (%) 41 38 47
Me ·
Me cat. PdLn [17]
AcO
+
Ar2
SnBu3 CN
33%
CN OAc
·
+ SnBu3
cat. PdLn [17]
Ph
Ph 65%
Me
Me
· +
+ Ph
Ph 19%
Me
13%
Me
OAc Sn 4
+
Ph
cat. PdLn [17]
Me +
Ph 66% Scheme 1
Ph
Me
30%
Me
596
III Pd-CATALYZED CROSS-COUPLING
In this connection, it should be recalled that, whereas those Pd-catalyzed crosscoupling reactions involving allylic electrophiles tend to be facile and satisfactory, the use of allylmetals containing the same allyl moiety, especially those containing relatively electropositive metals, in Pd-catalyzed cross-coupling has been generally much less favorable. In Pd-catalyzed allyl–allyl coupling, the use of allylmetals is unavoidable. Consequently, it may suffer from problems associated with allylmetals. From the viewpoint of the selective and satisfactory synthesis of stereo- and regiodefined 1,5-dienes, 1,5-enynes, and related compounds, Pd-catalyzed allyl–allyl, propargyl–allyl, and related reactions must be judged to be generally unsatisfactory, even though future developments may alleviate various difficulties associated with them. Much more satisfactory has been the use of homoallyl-, homobenzyl-, and homopropargylmetals, especially those containing Zn and Mg in their Pd- or Ni-catalyzed cross-coupling with alkenyl and aryl electrophiles, as discussed in Sect. III.2.11.2.
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
J. F. Biellmann and J. B. Ducep, Tetrahedron Lett., 1969, 3707. N. Ya. Grigorieva, O. A. Pinsker, and A. M. Moiseenkov, Mendeleev Commun., 1994, 129. E. J. Corey and H. A. Kirst, Tetrahedron Lett., 1968, 5041. R. E. Ireland, M. J. Dawson, and C. A. Lipinski, Tetrahedron Lett., 1970, 2247. E. Negishi, C. L. Rand, and K. P. Jadhav, J. Org. Chem., 1981, 46, 5041. B. M. Trost and E. Keinan, Tetrahedron Lett., 1980, 21, 2595. J. Godschalx and J. K. Stille, Tetrahedron Lett., 1980, 21, 2599. J. P. Godschalx and J. K. Stille, Tetrahedron Lett., 1983, 24, 1905. A. Goliaszewski and J. Schwartz, J. Am. Chem. Soc., 1984, 106, 5028. A. Goliaszewski and J. Schwartz, Organometallics, 1985, 4, 417. A. Goliaszewski and J. Schwartz, Tetrahedron, 1985, 41, 5779. N. A. Bumagin, A. N. Kasatkin, and I. P. Beletskaya, Izv. Akad. Nauk SSSR Ser. Khim., 1984, 588. J. Yoshida, H. Funahashi, H. Iwasaki, and N. Kawabata, Tetrahedron Lett., 1986, 27, 4469. V. Farina, S. R. Baker, D. A. Benigni, and C. Sapino, Jr., Tetrahedron Lett., 1988, 29, 5739. Y. Yamamoto, S. Hatsuya, and J. Yamada, J. Org. Chem., 1990, 55, 3118. D. L. Minsker, A. G. Ibragimov, and U. M. Dzhemilev, Zh. Org. Khim., 1984, 20, 873. E. Keinan and M. Peretz, J. Org. Chem., 1983, 48, 5302.
Alkyl-M + RX
Pd
III.2.11 Palladium-Catalyzed Cross-Coupling Involving Alkylmetals or Alkyl Electrophiles III.2.11.1 Palladium-Catalyzed Cross-Coupling Involving Saturated Alkylmetals EI-ICHI NEGISHI and SEBASTIEN GAGNEUR
A. INTRODUCTION In Sects. III.2.9 and III.2.10, Pd-catalyzed cross-coupling reactions involving allylic, benzylic, and propargylic organometals and organic electrophiles are discussed. Pd complexes readily undergo oxidative addition with organic electrophiles containing ,unsaturated alkyl groups, allowing their Pd-catalyzed cross-coupling to proceed readily. In sharp contrast with these ,-unsaturated alkyl electrophiles, alkyl electrophiles either without an unsaturated carbon–carbon bond or with only a ,- or more remote unsaturated group are much more reluctant to undergo oxidative addition with Pd (Sect. I.2). Furthermore, even if alkylpalladium derivatives are formed by oxidative addition, those that contain one or more -H atoms are prone to -dehydropalladation to give alkenes and H – Pd derivatives. These two factors make it generally difficult to achieve Pdcatalyzed cross-coupling with alkyl electrophiles without ,-unsaturation. Although the Pd-catalyzed cross coupling reaction of MeMgX was reported as early as 1975,[1] the use of alkylmetals containing -H atoms was not reported until 1978.[2] Although the initial attempts to use alkyllithiums were unsuccessful,[1] a later investigation reported moderately satisfactory results for the Pd-catalyzed reaction of -bromostyrene with n-BuLi.[3] The fact that the reaction can take place via Li– Br exchange without a catalyst makes the interpretation of the observed results difficult, and further clarification of this point may be desirable. In fact, there have been very few studies reporting successful uses of organolithiums in Pd-catalyzed cross-coupling. A few independent reports published in the following couple of years[4]–[6] have established that higher primary normal alkyland isoalkyl-containing Grignard reagents and alkylzincs readily participate in Pdcatalyzed cross-coupling reactions with alkenyl and aryl halides containing I and Br. Even secondary and tertiary alkylmetals containing Mg and Zn[4]–[6] can be used, although
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
597
598
III Pd-CATALYZED CROSS-COUPLING
alkyl group isomerization, that is, s-alkyl to n-alkyl and t-alkyl to isoalkyl, and reduction of organic electrophiles are two serious side reactions associated with Pd-catalyzed alkylation. The mechanistic courses of these two side reactions and their relationships with the desired cross-coupling reaction can readily be rationalized by Scheme 1.[6] Although it is generally no more than a reasonable working hypothesis, it does suggest that the extent of reduction of organic electrophiles, that is, dehalogenation and related processes, and of the alkyl group isomerization should critically depend on the relative rates of three processes — reductive elimination, dehydropalladation, and rehydropalladation. If this analysis is indeed reasonable, it would be desirable to slow down dehydropalladation relative to the desired reductive elimination. This mechanism also suggests that, after the putative oxidative addition and transmetallation steps, the metal countercations may not exert significant influences. In reality, however, the mechanism of the reaction most probably is much more complicated by other processes involving some resting states.
R X
PdLn oxid. add.
R PdLnX
R = alkenyl, aryl, etc. X = I, Br, OTf, etc. trans-
H
metallation
M C
C R2
R1
R PdLn H C R
C
red. elim.
1
R C
dehydropalladation
R PdLn
H
C R2
C
dehydropalladation
red. elim.
rehydropalladation
R desired product
R H
H
PdLn
C
C R2
red. elim.
+ R1
C
C R2
reduction product
R R1
C R2
1
rehydropalladation
R1
H R2
R1
H
R
C
C R2
isomerized product Scheme 1
In this section, those Pd-catalyzed alkylation reactions that involve the use of either saturated or remotely unsaturated (i.e., -, -, and beyond) alkylmetals will be reviewed, with focus on their reactions with alkenyl and aryl electrophiles. For other Pd-catalyzed reactions of alkylmetals, readers are referred to the sections indicated below. Pd-catalyzed alkylation reactions of homoallyl-, homopropargyl-, or homobenzylmetals with alkenyl and aryl electrophiles possess a special synthetic significance in that they offer alternative
III.2.11.1 Pd-CATALYZED CROSS-COUPLING INVOLVING ALKYLMETALS
599
and generally superior and highly satisfactory routes to 1,5-dienes, 1,5-enynes, and related compounds of natural origin and/or of medicinal significance that are difficult to access. For this reason, these reactions are discussed separately in Sect. III.2.11.2. Related Topics
Section Number
Alkyl-M + heteroaryl-X
III.2.7
Alkyl-M + alkynyl-X
III.2.8.2
X ,
Alkyl-M +
Ar
X
, or
III.2.9 X
Alkyl-M + RCOX
III.2.12.1
Alkyl-M + RCHX (Z = heteroatom)
III.2.12.2
Z
Use of β-heterosubstituted electrophiles
III.2.14.2
Alkyl-M + XC
O
III.2.15
Asymmetric cross-coupling
III.2.16
Synthesis of natural products
III.2.18
C
C
B. Pd-CATALYZED ALKYLATION WITH ALKYLMETALS CONTAINING Li, Al, AND Sn As in some other cases of Pd-catalyzed cross-coupling, nearly ten or a dozen metals including Li, Cu, Mg, Zn, B, Al, and Sn have been used as the metal countercations, and trends similar to several other cases have been observed. 1. Li. Despite some early successful results with alkyllithiums,[3] they have scarcely been used in Pd-catalyzed alkylation. This must, in part, be due to their inability to tolerate many conventional polar functional groups. As discussed earlier, however, the high intrinsic reactivity of alkyllithiums appears to be responsible for some of the difficulties observed with alkyllithiums. In any event, it may be stated that the current scope of Pd-catalyzed alkylation with alkyllithiums is rather limited. In cases where alkylmetals containing other metals are prepared via alkyllithiums, however, it would be desirable and advisable to examine the reaction of alkyllithiums themselves to justify the use of other metals. Some of the favorable results observed with alkyllithiums[3] are summarized in Scheme 2. 2. Cu and Zr. Little is known about the use of Si, Zr, and even Cu in Pd-catalyzed alkylation with alkylmetals. It should be recalled, however, that Cu-promoted or -catalyzed alkylation without the involvement of Pd or other transition metal complexes is a widely applicable and generally satisfactory synthetic methodology. 3. Al and Sn. Both trialkylalanes[7]–[14] and tetraalkyltins[15]–[31] have been used successfully in Pd-catalyzed alkylation. Even so, the current scope with respect to
600
III Pd-CATALYZED CROSS-COUPLING
=
PhCH CHBr + LiR
cat. PdLn
=
PhCH CHR
E or Z
R
PdLn
Yield (%)
Z Z E Z Z Z E
Me Me Me Bu Bu Bu Bu
Pd(PPh3)4 Cl2Pd(PPh3)2 Pd(PPh3)4 Ph(PPh3)4 Cl2Pd(PPh3)2 Cl2Pd(PBu3)2 Pd(PPh3)4
90 95 88 62 73 14 46
Scheme 2
alkylalanes is mostly limited to Me3Al, Et3Al, Pr3Al, and (i-Bu)3Al, the only exception being Me3SiCH2AlR2, where R is Me3SiCH2 or Me.[9] One practical difficulty is that only one of the three alkyl groups in R3Al can be used in this reaction, which can be a serious limitation in cases where more elaborate and expensive alkyl groups are involved. Alkyltins are generally even less reactive. In many cases, Me4Sn appears to be satisfactory. On the other hand, (n-Bu)4Sn appears to be significantly less reactive. In general, the scope with respect to alkyltins is almost as limited as in the cases of alkylalanes. Typically, only one out of four alkyl groups is utilized in the reaction. More recently, however, the use of RSnX3, where X is a halogen, in Pd-catalyzed alkylation has been reported.[30],[31] The use of HO2CCH2CH2SnCl3 to achieve alkylation in 71% yield is noteworthy and promising[30] (Scheme 3). In most cases, however, Pd-catalyzed alkylation with alkylmetals containing Al and Sn may also be achieved with those containing Mg, Zn, and B. Collectively, these three metals provide satisfactory procedures of significantly wider scope. Consequently, the use of other metals, such as Al and Sn, will have to be well justified. Some representative results observed with alkylalanes[7]–[14] and alkylstannanes[15]–[29] are shown in Tables 1 and 2, respectively.
SO3Na Cl2Pd Ph2P
2
cat.
HO2CCH2CH2SnCl3 + I
H2O, 100 °C
COOH
HO2CH2CH2C COOH 71% Scheme 3
601
III.2.11.1 Pd-CATALYZED CROSS-COUPLING INVOLVING ALKYLMETALS
TABLE 1. Pd-Catalyzed Cross-Coupling Reactions of Alkylaluminums with Alkenyl and Aryl Electrophiles Catalyst
R′X
RM
Solvent
Yield (%) Reference
n-Dec
Me3Al
Pd(PPh3)4
DCE
91
[7]
Pd(PPh3)4
DCE
72
[7]
Pd(PPh3)4
Benzene
83
[8]
Cl2Pd(PPh3)2
THF
53
[11]
Pd(PPh3)4
THF
53
[10]
Pd(PPh3)4
THF
97
[10]
PdCl2-PPh3
THF
95
[12]
Pd(PPh3)4
THF
71−86
[13]
Pd(PPh3)4
DCE
80
[7]
Pd(PPh3)4
Benzene
82
[8]
Pd(PPh3)4
Benzene
55
[8]
Pd(PPh3)4
THF
24
[14]
OP(O)(OPh)2
Me3Al Me3Al
OP(O)(OPh)2
t-Bu n-Pr
OP(O)(OPh)2 SPh
Me3Al
BnO
CO2Me
3
_
OP(O)(OPh)2
Me3Al
2-MePhOTf
Me3Al
4-ClPhOTf
NH2 N
Me3Al
N
Br
HO
N
O
DIBAH
N (1)
OH
OH NH2 Br (or I)
HN
Me3Al
HO
O N O R OH
R′
Ph
Et3Al OP(O)(OPh)2 n-Pr
OP(O)(OPh)2
Et3Al SPh Ph
OP(O)(OPh)2
Et3Al SPh Br
CO2CH3
Et3Al N
Pr3Al Pr3Al
PhOTf (1)
Pd(PPh3)4 PdCl2-PPh3
THF THF
97 53
[10] [12]
i-Bu3Al i-Bu3Al
(1) PhOTf
PdCl2-PPh3 Pd(PPh3)4
THF THF
13 52
[12] [10]
602
III Pd-CATALYZED CROSS-COUPLING
TABLE 2. Pd-Catalyzed Cross-Coupling Reactions of Alkyltins with Alkenyl and Aryl Electrophiles R′X
RM RCONH
Catalyst
Solvent
Yield Ref(%) erence
Z
Me4Sn
Cl2Pd(CH3CN)2 N
OTf
O
DMF
70
[22]
Pd2(dba)3-TFP
NMP
85
[25]
LiCl
CO2R′ S
BuO2CNH
Me4Sn
N
OTf
O
CO2CHPh2
Me4Sn
PhBr
PhCH2Pd(PPh3)2Cl
HMPA
89
[15]
Me4Sn
4-MeC6H4Br
PhCH2Pd(PPh3)2Cl
HMPA
84
[15]
4-FC6H4Br
PhCH2Pd(PPh3)2Cl
HMPA
89
[15]
PhCH2Pd(PPh3)2Cl
Me4Sn
4-MeCOC6H4Br MeSnBr3 3-HO2CC6H4I MeSnCl3 4-HO2CC6H4I
HMPA
99
[15]
PdCl2
KOH-H 2O
98
[30]
PdCl2
KOH-H 2O
82
[31]
Me4Sn
4-MeCOC6H4OTf
Pd(PPh3)4
Dioxane
75
[20]
Me4Sn
2,6-(MeO)2C6H3OTf
PdCl2(PPh3)2-LiCl
DMF
92
[24]
Me4Sn
4-ClC6H4N2BF4
Pd(OAc) 2
CH3CN
88
[16]
Me4Sn
4-NO2C6H4N2PF6
Pd(OAc) 2
CH3CN
95
[16]
Me4Sn
HO
Pd(PPh3)4
Dioxane
80
[23]
Cl2Pd(PPh3)2
DMF
75
[29]
Pd(PPh3)4
THF
61
[19]
Pd(PPh3)4
NMP
92
[28]
Me4Sn
O
Br MeOH2C
Me4Sn MeO
OTf O Br
O
Me4Sn (2)
OMe OAc OMe NH2 N
N
Br
Me4Sn HO
O OH
N
N
III.2.11.1 Pd-CATALYZED CROSS-COUPLING INVOLVING ALKYLMETALS
603
TABLE 2. (Continued ) RM
R′X
Catalyst
Solvent
Pd(PPh3)4, LiCl
DMF
Yield (%)
Reference
OMe
Me4Sn
TfO
77
[27]
7
[16]
N
H
Me
Et4Sn
PhN2BF4
Pd(OAc) 2
CH3CN
Et4Sn Me2CHSnCl3
(2) 4-HO2 CC6H4I
Pd(PPh3)4 PdCl2
THF KOH-H2O
44 25
[19] [31]
HO2C(CH2)2 SnCl3
4-HOC6H4I
PdCl 2
[30]
HO2C(CH2)2SnCl3
3-HO2CC6H4I
PdCl2
KOH-H2O 98% E,E)
I B
A
65%
62%
I
A
B
78%
78%
Br
D
50% Scheme 8
III.2.11.2 REACTIONS BETWEEN HOMOALLYL-, HOMOPROPARGYL
627
O O E
mokupalide (62%) A B C D
= = = =
Me 3 A1 C1 2 Zr Cp 2 then I 2. Me 3 SiC C(CH 2 ) 2ZnCl, 5% Pd(PPh 3 ) 4 , then KF . 2H2O. (i) Me 3 Al Cl 2 Zr Cp 2 , (ii) n -BuLi , (iii) (CH 2 O) n. (i) Me3Al Cl2 Zr Cp 2 , (ii) n -BuLi , (iii) , O (iv) p -TsCl, Py, then LiBr in acetone. Br
E = (i) Mg, ZnBr2, (ii)
O, Cl 2 Pd(PPh3 ) 2 and 2 i -Bu 2 AlH.
O
Scheme 8 (Continued )
1. Me3Al Cl2 ZrCp2 2. BuLi 3. O [12],[33]
I 89%
OH
I2, PPh3 imidozole
73%
1. t-BuLi 2. ZnCl2 3. I OZnCl 5% Pd(dba)2 10% TFP
OH (2Z, 6E)-farnesol (86%, >98% Z, E)
1. n-BuLi 2. (CH2O)n
A and B in Scheme 8
OH
1. 2.4 equiv i-BuHgCl 10% Cp2TiCl 2 2 . MeI [34]
86%
OH
(2Z, 6E)-farnesol (81%, >98% Z, E) Scheme 9
628
III Pd-CATALYZED CROSS-COUPLING
C.iii. Efficient and Selective Iterative and Convergent Synthesis of Oligomeric Isoprenoids Containing E- and/or Z-Trisubstituted 1,5-Diene Units The two-step H-to-T protocol discussed above has provided a highly selective and reasonably efficient route to all-E-isoprenoids, and its appropriate modifications have permitted incorporation of the Z-end capping isoprene units. However, efficient and highly stereoselective incorporation of the Z-trisubstituted alkene unit in the main chain of an oligomeric isoprenoid has remained an elusive synthetic goal.[2] Critically needed were stereo- and regiodefined difunctional trisubstituted C5 isoprene synthons, permitting stereo- and regiospecific homologation. As presented in Scheme 3, (E )- and (Z )-1,4diiodo-2-methyl-1-butenes (1 and 2, respectively) promised to satisfy all of the abovementioned requirements. Indeed, the use of 2 has permitted, for the first time, a highly efficient and selective (98% Z ) incorporation a (Z )-trisubstituted C5 isoprene unit in the synthesis of the (2E,6Z )- and (2Z,6Z )-isomers of farnesol, as shown in Scheme 10.[12] The T-to-H mode of synthesis is dictated by the relative reactivities of the two C—I bonds in 1 or 2. Capping the head with 1-halo-2-methyl-1-propene can readily be achieved by Pd-catalyzed homoallyl – alkenyl coupling. A remarkably higher efficiency and stereoselectivity as compared with the previously available method[2] based on Protocol I should be noted. The synthetic schemes shown in Scheme 10 do not involve the iterative use of 1 or 2 for isoprenoid chain homologation. As expected, homologation of isoprenoid chains with 1 and/ or 2 by a one-pot cycle consisting of Pd-catalyzed homoallyl – alkenyl coupling and metallation of homoallyl iodides via lithiation with t-BuLi followed by zincation has been shown to be highly satisfactory,[12] even though the cross-coupling yield observed with 2 can further be improved. The stereoselectivity observed with either 1 or 2 was 98%. The synthesis of (2E,6Z,10E )-geranylgeraniol[12] further indicates that it is now practical to incorporate at will either the E- or Z-trisubstituted C5 isoprene unit with essentially complete control of regio- and stereochemistry in one pot (Scheme 11). Thus far, only linear syntheses of oligoisoprenoids have been discussed. However, the T-to-H protocol using 1 and/or 2 is readily applicable to convergent syntheses of oligomeric isoprenoids. In practice, a proper mix of iterative and convergent steps may be found for a given target to optimize the overall efficiency of the synthesis. In this respect, it should clearly be noted that essentially any combinations of linear and iterative steps are available with roughly comparable facility. A remarkably efficient and highly selective synthesis of coenzyme Q10 shown in Scheme 12[12] incorporates all of the desirable features discussed above. Ni-catalyzed alkenyl– benzyl or alkenyl–allyl coupling[35],[36] can be substituted with the Pd-catalyzed procedure, which yields comparable results, as detailed in Sect. III.2.9. Once the preparation of 4-iodo-1-(trimethylsilyl)1-butyne in two steps, 1 in two steps, 6 in two steps, and 9[37] in four steps from commercially available compounds was possible, the synthesis of coenzyme Q10 involving (i) the construction of all nine stereodefined trisubstituted alkene units, (ii) the formation of nine carbon–carbon bonds linking ten trisubstituted C5-alkene units via Pd-catalyzed homoallyl–alkenyl or homopropargyl–alkenyl coupling, and (iii) coupling of the side chain with the quinone moiety via Ni- or Pd-catalyzed alkenyl–allyl coupling can be achieved in 39% overall yield in seven longest linear steps with essentially full control of regio- and stereochemistry.
629
III.2.11.2 REACTIONS BETWEEN HOMOALLYL-, HOMOPROPARGYL
BrZn
I
SiMe3
I
Cl2Pd(dppf)
2
SiMe3
I 84%, >98% Z
1. t-BuLi 2. ZnBr2 3.
, Pd2(dba)3, TFP I 4. 0.2 M KOH-MeOH
78%, >98% Z 1. Me3Al, Cl2ZrCp2 2. n-BuLi 3. (CH2O)n
OH
(2E, 6Z )-farnesol (71%, >98% E,Z )
1. n-BuLi 2. (CH2O)n
OH 1. i-BuMgCl 10% Cl2TiCp 2 2. MeI
OH (2Z, 6Z)-farnesol (81%, >98% Z,Z) Scheme 10
BrZn
I
I
Cl2Pd(dppf)
2
I
1. t-BuLi 2. ZnBr2 3.
SiMe3
SiMe3 84%, >98% Z
I
SiMe3
1. t-BuLi 2. ZnBr2 3.
I I 1 10% Cl2Pd(dppf ) 20% DIBAH
81%, >98% Z, E
1. Me3Al, Cl2ZrCp2 2. n-BuLi 3. (CH2O)n
I 5% Cl2Pd(dppf) 10% DIBAH 4. NBu4F
67%
OH
(2E, 6Z, 10E )-geranylgeraniol 73%, >98% E, Z, E Scheme 11
630
III Pd-CATALYZED CROSS-COUPLING
1. A 2. I
1
I
Me3Si
1. A 2. 1 3. B
I
3. B
Me3Si
I 96%
1. A, 2. 1 3. B
Me3Si
Me3Si
I
2
3
I
5 (79%)
90% 1. A 2. I
1. C, 2. D 3. I2, THF
6
Me3Si
3. B
4
83% I 4
7 (88%)
1. A, 2. 7, 3. B
Me3Si 3
I
5 Me3Si 8
8 (86%)
O
O
1. C, 2. D MeO
MeO 8
3. 9, E
MeO
Cl
9= MeO
O
coenzyne Q10 (90%)
A = (1) 2.2 t-BuLi, Et2O, −78 °C, 0.5 h; (2) ZnBr2, THF. B = 2% Cl2Pd(dppf), THF, 23 °C C = KOH, MeOH, 40 °C, 2 h. D = Me 3Al, cat. Cl2ZrCp2, (CH2Cl)2, 23 °C, 8 h. E = Cl2Ni(PPh3)2 + 2 n-BuLi, 2PPh3, THF, 23 °C. Scheme 12
O
III.2.11.2 REACTIONS BETWEEN HOMOALLYL-, HOMOPROPARGYL
631
D. OTHER Pd-CATALYZED CROSS-COUPLING REACTIONS WITH HOMOALLYL-, HOMOPROPARGYL-, AND HOMOBENZYLMETALS As in the case of Pd-catalyzed alkylation, the only metal currently used in Pd-catalyzed cross-coupling that can potentially compete with Zn is B, and the accessibility of homoallylboranes via hydroboration along with high chemoselectivity associated with B is the main attractive feature associated with B. The results summarized in Scheme 13 show the feasibility of synthesizing oligomeric isoprenoids via hydroboration of conjugated dienes and Pd-catalyzed homoallyl – alkenyl coupling.[38],[39] Although the yields of 1,5-diene products are moderate (60 – 70%) the stereospecificity appears to be very high. It should also be noted that all cross-coupling reactions shown in Scheme 13 fall into the category of intrinsically favorable Pd-catalyzed conjugate substitution (Sect. III.2.15). So, it is not clear if the same reaction is applicable to those cases where more usual alkenyl halides are used. The feasibility of iterative homologation of oligomeric isoprenoids has not yet been explored. Clearly, further investigations are necessary to clarify these synthetically important aspects.
COOEt Br Cl2Pd(dppf ) K2CO3
COOEt 60%
9-BBN
Br OTHP Cl2Pd(dppf ) K3PO4
B
67%
OTHP
TfO COOEt Pd(PPh3)4, K3PO4
COOEt 65% Scheme 13
E. SUMMARY Pd-catalyzed cross-coupling between homoallyl-, homopropargyl-, and homobenzylzincs with alkenyl and aryl iodides, bromides, and related electrophiles can proceed selectively in high yields. All six possible combinations have been shown to be generally satisfactory. Particularly noteworthy are the Pd-catalyzed homoallyl – alkenyl and homopropargyl – alkenyl
632
III Pd-CATALYZED CROSS-COUPLING
coupling reactions that can be applied to some highly efficient and selective syntheses of oligomeric isoprenoids with essentially full control of regio- and stereochemistry, and many natural products of this class have been synthesized using these reactions. The iterative and convergent protocol using (E )- and/or (Z )-1,4-diiodo-2-methyl1-butenes is efficient as well as regio- and stereoselective, requiring hardly any isomeric separation even in the synthesis of a decameric isoprenoid. It permits both iterative and convergent modes of construction of oligomeric isoprenoids in any desired ratio of the two modes of operation to best suit a given synthetic task. At any point of synthesis, either the E- or Z-trisubstituted C5-alkene unit can be incorporated. This synthetic method promises to find many additional applications in the area of isoprenoid synthesis. Magnesium and boron are two other metals besides Zn that can potentially be useful in some cases. Boron is particularly interesting since homoallylboranes can be generated by hydroboration of conjugated dienes and since homallylboranes have been shown to undergo Pd-catalyzed coupling with alkenyl halides. The scope of the B-based homoallylation and related reactions must, however, be investigated further to better define their merits and demerits.
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25]
J. F. Biellmann and J. B. Ducep, Tetrahedron Lett., 1969, 3707. N. Ya. Grigorieva, O. A. Pinsker, and A. M. Moiseenkov, Mendeleev Commun., 1994, 129. E. J. Corey and H. A. Kirst, Tetrahedron Lett., 1968, 5041. R. E. Ireland, M. I. Dawson, and C. A. Lipinski, Tetrahedron Lett., 1970, 2247. E. Negishi, C. L. Rand, and K. P. Jadhav, J. Org. Chem., 1981, 46, 5041. G. H. Posner, J. S. Ting, and C. M. Lentz, Tetrahedron, 1976, 32, 2281. H. Westmijze, H. Kleijn, and P. Vermeer, Tetrahedron Lett., 1978, 34, 3125. E. Negishi, L. F. Valente, and M. Kobayashi, J. Am. Chem. Soc., 1980, 102, 3298. M. Kobayashi and E. Negishi, J. Org. Chem., 1980, 45, 5223. J. F. Normant and M. Bourgain, Tetrahedron Lett., 1971, 2583. E. Negishi, S. Y. Liou, C. Xu, and S. Huo, Polyhedron, 2000, 19, 591. E. Negishi, S. Y. Liou, C. Xu, and S. Huo, Org. Lett., 2002, 4, 261. E. Negishi, D. R. Swanson, and C. J. Rousset, J. Org. Chem., 1990, 55, 5406. D. E. Van Horn and E. Negishi, J. Am. Chem. Soc., 1978, 100, 2252. C. L. Rand, D. E. Van Horn, M. W. Moore, and E. Negishi, J. Org. Chem., 1981, 46, 4093. E. Negishi, D. E. Van Horn, A. O. King, and N. Okukado, Synthesis, 1979, 501. S. Ma and E. Negishi, J. Org. Chem., 1997, 62, 784. A. Duchêne, M. Abarbri, J. L. Parrain, M. Kitamura, and R. Noyori, Synlett, 1994, 524. E. Negishi, H. Matsushita, M. Kobayashi, and C. L. Rand, Tetrahedron Lett., 1983, 24, 3823. R. L. Danheiser, D. S. Casebier, and F. Firooznia, J. Org. Chem., 1995, 60, 8341. S. Araki, M. Ohmura, and Y. Butsugan, Bull. Chem. Soc. Jpn., 1986, 59, 2019. J. E. McMurry and G. K. Bosch, J. Org. Chem., 1987, 52, 4885. K. Asao, H. Iio, and T. Tokoroyama, Tetrahedron Lett., 1989, 30, 6401. D. R. Williams and W. S. Kissel, J. Am. Chem. Soc., 1998, 120, 11198. L. Argenti, F. Bellina, A. Carpita, N. Dell’Amico, and R. Rossi, Synth. Commun., 1994, 24, 3167.
III.2.11.2 REACTIONS BETWEEN HOMOALLYL-, HOMOPROPARGYL
[26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39]
633
M. Julia, S. Julia, and R. Gue´gan, Bull. Soc. Chim. Fr., 1960, 1072. E. J. Corey, J. A. Katzenellenbogen, and G. H. Posner, J. Am. Chem. Soc., 1967, 89, 4245. S. F. Brady, M. A. Ilton, and W. S. Johnson, J. Am. Chem. Soc., 1968, 90, 2882. L. J. Altman, L. Ash, and S. Marson, Synthesis, 1974, 1129. P. A. Grieco and Y. Masaki, J. Org. Chem., 1974, 39, 2135. B. M. Trost and L. Weber, J. Org. Chem., 1975, 40, 3617. F. W. Sum and L. Weiler, J. Am. Chem. Soc., 1979, 101, 4401. E. Negishi, M. Ay, Y. V. Gulevich, and Y. Noda, Tetrahedron Lett., 1993, 34, 1437. F. Sato, H. Ishikawa, H. Watanabe, T. Miyake, and M. Sato, J. Chem. Soc. Chem. Commun., 1981, 718. E. Negishi, H. Matsushita, and N. Okukado, Tetrahedron Lett., 1981, 22, 2715. B. H. Lipshutz, G. Bulow, R. F. Lowe, and K. L. Stevens, J. Am. Chem. Soc., 1996, 118, 5512. B. H. Lipshutz, S. K. Kim, P. Mollard, and K. L. Stevens, Tetrahedron, 1998, 54, 1241. N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Satoh, and A. Suzuki, J. Am. Chem. Soc., 1989, 111, 314. T. Oh-e, N. Miyaura, and A. Suzuki, J. Org. Chem., 1993, 58, 2201.
R1COX + R2M
Pd
III.2.12 Palladium-Catalyzed CrossCoupling Involving -Hetero-Substituted Organic Electrophiles III.2.12.1 Palladium-Catalyzed Cross-Coupling with Acyl Halides and Related Electrophiles TAKUMICHI SUGIHARA
A. INTRODUCTION Although the Pd-catalyzed cross-coupling reactions of organometallic compounds with alkenyl and aryl halides to produce the substituted alkenes and arenes have been extensively investigated (see previous sections), the reaction with acyl halides giving ketones has attracted little attention. The major reason may be the existence of various known methods. A variety of organometallic compounds, such as organomagnesium,[1] zinc,[1] cadmium,[1] aluminum,[2] copper,[3] iron,[4] boron,[5] rhodium,[6] silicon,[7] mercury,[8] manganese,[9] zirconium,[10] and tin compounds,[11] have frequently been used for reactions with acyl halides. Even when the reactions are carried out under strictly controlled conditions, the side reaction upon the further addition of the organometallic compounds to the produced ketones cannot be suppressed completely. To overcome this problem, mild conditions using organotransition metal complexes, especially palladium-derived ones, as catalysts have been developed. The plausible mechanism of the Pd-catalyzed crosscoupling reaction of organometallic compounds with acyl halides is shown in Scheme 1. First, coordinatively unsaturated active palladium catalyst, PdL2, is produced via dissociation of the ligands, which then reacts with acyl halide to give the acylpalladium intermediate. Since deinsertion of CO of the acylpalladium derivatives may occur simultaneously,[12] the next step, transmetallation (so-called metathesis), is the most crucial for the efficiency of the overall reaction. A variety of organometallic compounds, such as boron, aluminum, copper, zinc, mercury, silicon, tin, lead, zirconium, and bismuth, are used as the partner in this coupling reaction without loss of CO. In this section, the important features of the cross-coupling reactions of a variety of organometallic compounds with acyl halides and related electrophiles are discussed.
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
635
636
III Pd-CATALYZED CROSS-COUPLING
R1 PdL2X
PdL4
− CO
− 2L
O R1
CO
O L
C X
+
PdL2
R1 oxidative addition
C Pd X L R2 M
L
O L R
1
transmetallation
C Pd L R2
isomerization
O L
O R1
C
MX
R2
R1
PdL
C Pd R2
−L
L
O R1 reductive elimination
L C Pd R2
ligand dissociation
Scheme 1
B. COUPLING REACTIONS WITH ORGANOZINC COMPOUNDS As discussed before (Sect. III.2.1), Pd-catalyzed cross-coupling reactions of organozinc compounds with alkenyl and aryl halides can be carried out under mild conditions and are the fastest among all reactions using various organometallics. The reaction with acyl halides is not an exception. Usually, the reaction is completed at lower than room temperature within a couple of hours.[13]–[16] Since organozinc compounds are coordinatively unsaturated and sterically less bulky, the transmetallation step is facilitated,[17] therefore the overall reaction proceeds under mild conditions. Another interesting feature using organozinc compounds is that not only alkynyl and alkenyl groups but also an alkyl group can couple with acyl chlorides with great success (Scheme 2).[15] It is known that alkylpalladium intermediates having -hydrogens tend to undergo dehydropalladation to give the alkenes.[19] This process can be suppressed completely by the use of organozinc compounds to give the desired alkyl ketones in excellent yields even when the alkylzinc compounds have -hydrogens.[15] Not only alkenoyl and aroyl chlorides but also alkyloyl chloride and chloroformates can be used as the partner in this coupling reaction.[15] While monoalkylzinc halides[13]–[15] and dialkylzincs[20] can be used for the cross-coupling reaction with acyl chlorides, the reaction of lithium trialkylzincate does not proceed efficiently (Scheme 3).[21] When organozinc halides are synthesized in situ by the reaction of organic halides with zinc metal or the zinc–copper couple, DME or benzene-DMA can be used as the solvent.[13],[14],[16] In the case of organozinc halides prepared by transmetallation of
637
III.2.12.1 CROSS-COUPLING WITH ACYL HALIDES
Ph Ph
Cl
+
Br
+ O
Ph
PdCl2(PPh3)3 (5 mol %)
Zn (2 equiv)
Ph
DME, r.t., 20 min [13]
O 83%
PdCl2(PPh3)2 + 2 DIBAH [18] EtO2C
ZnBr “Pd(PPh3)2” (2 mol %)
+
EtO2C
DME, 0 °C, 2 h [14]
Cl
Me
Me
O O 89%
O O
MeO n-C8H17ZnCl
Cl
+
THF, 25 °C, < 6 h [15]
O
Me
n-C6H13
Cl
ZnCl +
O 78% Me
n-C6H13
same conditions [15]
O
Me
OMe
n-C8H17
“Pd(PPh3)2” (2.5 mol %)
Me
O
95% (selectivity >99%) ZnCl
n-C5H11
+
Me
Cl O same conditions
n-C5H11 Me
[15]
O 89% (selectivity >98%) Scheme 2
Me Me
Me Zn
Cl
n-C3H7 Me
+
Et2O, 0−23 °C, 1 h [20]
O
Me
1 mol % (PhCH2)PdCl(PPh3)2
n-C3H7
Me O 98% MeO
MeO
Ph
Cl
+ Zn(Me)2Li
O
cat. Pd(PPh3)4
Ph
THF, −78 °C to r.t. [21]
O 52%
Scheme 3
638
III Pd-CATALYZED CROSS-COUPLING
the corresponding lithium or magnesium compounds with zinc halides, use of THF as the solvent is necessary to bring about satisfactory results, whereas the reaction in Et2O or THF-Et2O becomes sluggish.[15] In contrast, Et2O can also be used as the solvent in the coupling reaction of dialkylzincs prepared by the transmetallation method.[20] A variety of palladium–phosphine complexes are used as catalyst in the crosscoupling reactions. Since the coordinatively unsaturated palladium complexes are considered as the active catalyst, Pd(PPh3)2, which is prepared by treatment of PdCl2(PPh3)2 with 2 equiv of DIBAH[18] or n-BuLi,[22] is reliable to carry out the reaction successfully. The use of Pd[P(o-tol)3]4, which easily produces the coordinatively unsaturated complex due to the steric repulsion between the ligands, also brings about good results.[16],[23],[24] Organozinc compounds can be prepared by direct metallation of organic halides with zinc metal. The procedure makes the coupling reaction more convenient. A mixture of alkyl halide, acyl chloride, and zinc metal upon stirring in the presence of palladium catalyst at room temperature gives the desired ketone.[13],[14] While direct metallation can be carried out efficiently when the zinc–copper couple is used in some cases,[16],[25] the presence of copper ion sometimes prevents the coupling reaction with acyl chloride.[26] An interesting feature of the reaction of organozinc compounds is shown in Scheme 4.[24] Reaction of -iodozinc derivative 1 with benzoyl chloride in the presence of Pd[P(o-tol)3]4 catalyst gave the syn-isomer 2, while the anti-isomer 3 was produced by reaction of 1 with benzaldehyde followed by oxidation. The nucleophilic addition to the aldehyde occurs via inversion of the configurations in contrast to the Pd-catalyzed cross-coupling reaction, which proceeds via retention of the configurations. The Pd-catalyzed cross-coupling reaction of organozinc compounds is fast and can be carried out under mild conditions. Simple extracting work-up gives the desired products, since the by-product of the reaction is water-soluble ZnX2. When the functional groups present do not easily react with organozinc compounds, this method is the most convenient.
5 mol % Pd[P(o-tol)3]4 RCOCl dioxane, r.t. [24]
Me Me Zn I
i-Pr2N
O Ph
O Me 2 90%
Me
i-Pr2N O
Me i-Pr2N
Me O
ZnI 1 RCHO TMS-I
Me i-Pr2N
Ph
then PCC [24]
Scheme 4
O
O Me 3 82%
III.2.12.1 CROSS-COUPLING WITH ACYL HALIDES
639
C. COUPLING REACTIONS OF ORGANOTIN COMPOUNDS Since Heck suggested the potential utility of organotin compounds for his reaction,[27] the cross-coupling reaction of organotin compounds with acyl halides has been studied extensively due to their ease of handling.[28],[29] Not only alkyl, alkenyl, aryl, and alkynyl groups but also hydride[30] is coupled with acyl halides to give the corresponding ketones and aldehydes. The ease of transfer of alkyl group (R1) from the tin center to acyl carbon follows the order R2 PhC#C! n-PrC#C! PCH"CH! CH2"CH! Ph PhCH2 CH3OCH2 CH3 n-Bu Et i-Pr (Table 1).[31] The rate of alkyl transfer of Me4Sn is five times faster than that of Me3SnCl, which is presumably produced in the coupling reaction of Me4Sn with acyl chlorides, and Me2SnCl2 and MeSnCl3 are inert for the coupling reaction.[29] Moreover, disproportionation of organotin halides does not happen easily. This is the reason why more than 1 equiv of organotin compounds is required to bring about fruitful results in the coupling reaction. Originally, benzene and HMPA were used as the solvent in the reaction,[28],[29] but later 1,2-dichloroethane and CHCl3 were found to be as good as HMPA.[32],[33] Oxygen has an accelerating effect on the reaction, and thus, the reaction is reported to be carried out under air atmosphere. In some cases, deinsertion of CO of the acylpalladium intermediate may occur, and this results in lowered yields of the desired ketones. To suppress the deinsertion, the reaction is sometimes carried out under an atmospheric pressure of CO.[33] Typical examples of the coupling reactions are shown in Scheme 5. Another way to suppress the possible decarbonylation of the acylpalladium intermediate is promotion of transmetallation by addition of a catalytic amount of ZnCl2[34] or CuI[35]. Since a single transmetallation process of high activation energy could be replaced by multiple transmetallation processes of low kinetic barriers, coordinatively unsaturated metal salts having low steric requirement, such as Zn and Cu salts, can be utilized to promote the transmetallation.[17] Not only acyl chloride but also sulfonyl chloride[36] and isocyanide dichloride[37] can be used in the coupling reaction (Scheme 6).
TABLE 1. Relative Reaction Rates of Benzoyl Chloride with Organotins Catalyzed by (PhCH2)PdCl(PPh3)2 [31] 5 R13SnR2
R2 Ph
Cl
+
(PhCH2)PdCl(PPh3)2 (2.5−3.0 mol %)
5 R13SnPh
O
solvent, 65 °C
O
Ph
Ph
Ph O
R2 1
R
Solvent
PhCC-
Me n-Bu n-Bu
CHCl3 CHCl3 HMPA
46 100 —
n-PrCC21 48 100
PhC "C-
CH2 "CH-
Ph-
PhCH2-
CH3-
n-Bu-
10 10 —
8 17 70
1 1 1
— — 0.5
0.1 — —
— 0.01 0.14
640
III Pd-CATALYZED CROSS-COUPLING
Ph
Pd(PPh3)4 (2 mol %)
Cl
Sn(n-Bu)3 +
benzene, 40 °C, 5 h [28]
O
Ph
O
(PhCH2)PdCl(PPh3)2 (0.5 mol %)
Cl
Me4Sn +
87%
Me
Ph
HMPA, air (1 atm), 60−65 °C, 10 min [29]
O
Ph Ph
Ph
O Ph
PdCl2(PPh3)2 (2 mol %)
Cl
Sn(n-Bu)3 +
Ph
1,2-dichloroethane, 84 °C, 2 h [32]
O
91%
O
94%
OTBDPS PhCH2OOC
Cl
Sn(n-Bu)3 + O
OTBDPS
(PhCH2)PdCl(PPh3)2 (cat.) CHCl3, CO (1 atm), 65 °C, 30 h [33]
PhCH2OOC O 71%
Scheme 5
EtO
Me Sn(n-Bu)3
Pd(PPh3)4 (2 mol %)
+
EtO
Cl
S O
O
THF, 55 °C, 30 min [32]
Me
EtO
S
EtO
Cl n-Bu
Sn(n-Bu)3 +
Cl N
Ph
PdCl2(PPh3)2 (1 mol %)
O
O
n-Bu
benzene, 70 °C, 5 h [33]
85% n-Bu
N
Ph
70%
Scheme 6
For the palladium catalysts, the order of catalytic activity is as follows: PdCl2(PPh3)2 BnPdCl(PPh3)2 Pd(PPh3)4 PhPdCl(PPh3)2.[32] The combination of Pd2(dba)3/CHCl3 and AsPh3 or P(2-furyl)3 has been reported as the best catalyst so far.[38] Tetraalkyltin compounds having the chiral alkoxy group at the -position undergo the Pd-catalyzed cross-coupling reaction of acyl chlorides with complete retention of the configuration (Scheme 7).[39],[40]
III.2.12.1 CROSS-COUPLING WITH ACYL HALIDES
H O
Ph
Cl
Sn(n-Bu)3 +
O H
PdCl2(PPh3)2 (4 mol %) CuCN (8 mol %) toluene, 95 °C, 18 h [39]
O
O
641
OBn
H Ph
O O O
O H
OBn 60−65% Scheme 7
During the reaction, trialkyltin chloride is produced as the by-product. Tributyltin chloride is known to react with the palladium complex to produce the hydropalladium species via -hydrogen elimination. If the reaction takes a long time, 2-buten-1,4-dione moiety is reduced (Scheme 8).[41] The coupling reactions of organotin compounds have been widely used, since these compounds are quite stable in water. The by-products, such as R3SnX, are considered possible nervous system disturbing agents and/or endocrine disrupting chemicals. Researchers should be very careful when carrying out these reactions.
O
O Pd(PPh3)4 (5 mol %)
O Me
1,4-dioxane, reflux 2−3 h
O
Me O
93%
Cl
Sn(n-Bu)3 + O
O
O same conditions
20−30 h [41]
Me O
70%
Scheme 8
D. COUPLING REACTIONS OF ORGANOMERCURY COMPOUNDS Historically, the first report of the Pd-catalyzed cross-coupling reaction with acyl halide used organomercury compounds.[42] Although alkyl- and arylmercury chlorides did not work, the use of dialkyl- and diarylmercury compounds gave the desired ketones in good yields. Acyl bromides are necessary to bring about fruitful results. The use of HMPA as the solvent is also unavoidable (Scheme 9). Arylmercury chlorides can also be coupled with acyl chloride in the presence of iodine and a catalytic amount of Pd(PPh3)4.[43],[44] In this case, not only HMPA but also acetone and THF can be used as the solvent. More recently, the Pd-catalyzed coupling reaction of
642
III Pd-CATALYZED CROSS-COUPLING
3-(chloromercurio)indol and acryloyl chloride has been carried out without additives (Scheme 9).[45] The reactivity of organomercury compounds in the coupling reaction depends on the type of functionality present. Some organomercury compounds are known to be highly toxic. This may be the reason why the reactions using organomercury compounds have not been studied extensively.
Ph EtHgX
Br
Et
Pd(PPh3)4 (1 mol %)
+
HMPA, 60 °C, 2 h [42]
O
O X = Et 75%
(X = Et or Cl)
Cl Br
Ph
2% O
Br
HgCl Cl + N
Pd(PPh3)4 (1 mol %) HMPA, 85 °C, 2 h [45]
O
N
Ts
Ts
Scheme 9
55%
E. COUPLING REACTIONS OF ORGANOBORON, ALUMINUM, COPPER, SILICON, LEAD, BISMUTH, AND ZIRCONIUM COMPOUNDS Other organometallic compounds have also been utilized for the coupling reaction with acyl halides. The Suzuki protocol (see Sect. III.2.2) for organoboron compounds [R3B and RB(OR)2] cannot be applied for the cross-coupling reaction, since acyl halides react readily with NaOH to give the less reactive carboxylic acids. Instead of these organoboranes, organoborates (R4B) were used for the reaction. Actually, organoborates themselves are known to react with acyl chlorides smoothly in THF-hexane mixed solvent system to give the desired ketones in good yields (Scheme 10).[5],[46] Neither alkenylboranes nor alkenylborates undergo clean acylation even in the presence of palladium catalyst.[15] In contrast, when sodium tetraphenylborate was used, the coupling reaction with acyl chlorides did not proceed, but the desired ketones were produced in the presence of palladium catalyst (Scheme 10).[47]
Li+ B n-Bu –
Ph
Cl
+
+
Cl
Ph O
n-Bu
THF-hexane, 25 °C [5]
O
NaBPh4
“without catalyst ”
Pd(PPh3)4 (1 mol %) THF, 25 °C, 20 h [47]
Scheme 10
Ph O 89%
Ph
Ph O
94%
643
III.2.12.1 CROSS-COUPLING WITH ACYL HALIDES
Organoaluminum compounds undergo the coupling reaction with acyl chlorides in the presence of palladium catalyst.[15],[48] Not only alkyl-, alkenyl-, and alkynylalanes but also alkenylalanates are used for the reaction. This reaction can also proceed in the absence of palladium catalyst, but the stereoselectivity is much better when the reaction is catalyzed by palladium (Scheme 11).[15]
Me
n-Hex
AlMe2
Cl
[15]
O
Me
n-Hex
conditions A or B
+
Me Me
Selectivity
Yield
−
Conditions A: 1,2-dichloroethane, −30 °C B: “Pd(PPh3)2”[18] (cat.), THF, r.t. Me AlMe2(n-Bu)Li +
n-Hex
Cl
66−93% 92%
>90%
conditions B
n-Hex
[15]
O
Me
O
Me Me
O
Yield
Selectivity
>90%
96%
n-Bu Ph n-Bu
AlEt2
Ph
Cl Pd(PPh3)4 (5 mol %)
+
THF, 0−25 °C [48]
O
O
74%
Scheme 11
Organozirconium compounds also undergo the Pd-catalyzed cross-coupling reaction with acyl halides.[15] In the presence of ZnCl2, the reaction can be carried out more efficiently.[17] Acylzirconium species, which are produced via hydrozirconation of alkynes or alkenes by zirconocene hydrochloride followed by insertion of CO, couple with acyl chlorides to give -diketones (Scheme 12).[49]
Cp2ZrHCl
n-Hex
n-Hex
CH2Cl2, r.t., 30 min
n-Hex
ZrCP2 O
CO (1 atm) r.t., 2 h
Cl
Ph Cl
ZrCP2
Cl O
PdCl2(PPh3)2 (5 mol %) toluene, r.t., 48 h [49]
Scheme 12
O n-Hex
Ph O
65%
644
III Pd-CATALYZED CROSS-COUPLING
Organocopper compounds are known to react with acyl halides to produce ketones.[3] In the case of alkenyl- and alkynylcopper compounds, however, the conjugated addition of the organocopper compounds to the resultant ketones has been observed. To carry out the reaction successfully, palladium–phosphine complexes are used as catalysts. Alkenylcopper compounds in association with magnesium salts couple with acyl halides in the presence of Pd(PPh3)4 to give the desired ketones in good yields (Scheme 13).[50] In the case of lithium dialkenylcuprate, MgCl2 or ZnCl2 is required to perform the coupling reaction successfully. The coupling reaction of alkynes with acyl halides can be carried out in the presence of PdCl2(PPh3)2 and CuI catalysts (Scheme 13).[51] H
H + (n-Hept)2CuLi THF
CuLi + n-Hept
Me
H
Me
Cl
Pd(PPh3)4 (3 mol %) ZnBr2 (1.0 equiv) THF, r.t. [50]
O
2
Me n-Hept
O 80%
+ (i-Pr)Cu MgBr2 THF
t-Bu
Me
Cu MgBr2
Pd(PPh3)4 (3 mol %)
Me
THF, r.t. [50]
O
i-Pr
Ph
Cl
t-Bu
+
H + Me2N
Cl O
i-Pr
O 84%
Ph PdCl2(PPh3)2 (0.1 mol %) CuI (0.5 mol %), PPh3 (0.5 mol %) Et3N, 90 °C, 6 h [51]
NMe2 O
92%
Scheme 13
Tetraalkylsilanes are stable compounds. Therefore, it is necessary to activate the compounds for the coupling reaction. Since dialkylsilacyclobutanes have high strain energy, palladium complexes can easily insert into the carbon–silicon bond oxidatively, and the resultant complexes couple with acyl chlorides to give 1-sila-2-oxa-3-cyclohexene derivatives (Scheme 14).[52] As mentioned before, the Pd-catalyzed coupling reaction of tetraalkyltins with acyl halides is troublesome: the reaction is slow and requires high temperature. In particular, when tetraalkyltin compounds bearing longer alkyl chains are used, the reaction becomes sluggish. In such cases, tetraalkylleads can be used instead of tetraalkyltins (Scheme 15).[53] It is noteworthy that two alkyl groups on the lead can be used for the coupling reaction, whereas only one alkyl group can couple with acyl chlorides when organotin compounds are used. The reason for the different reactivity is presumably
645
III.2.12.1 CROSS-COUPLING WITH ACYL HALIDES
PdCl2(PhCN)2 (4 mol %)
Ph
Ph
Me2ClSi
Et3N (0.1 equiv), toluene, r.t., 2 h [52]
O 86%
Cl
SiMe2 + O PdCl2(PhCN)2 (4 mol %)
Me2Si
Et3N (2 equiv), toluene, 80 °C, 4 h [52]
O
Ph
97% Scheme 14
due to the ease of disproportionation of trialkylchloroleads to tetraalkylleads and dialkyldichloroleads. Triphenylbismuth can also be utilized for the coupling reaction (Scheme 15).[54] All three phenyl groups on bismuth can be used, since disproportionation of the intermediary dialkylchloro- and alkyldichlorobismuth is fast. Siloxycyclopropanes are considered as homoenolate equivalents and also undergo the coupling reaction with acyl halides to produce 1,4-dicarbonyl compounds (Scheme 16).[55]
Et4Pb +
Ph
Cl
Pd(PPh3)4 (1 mol %) THF, 65 °C, 3 h [53]
O
(0.6 equiv)
Et
Ph O 84%
Me
Me
n-Bu4Pb + Me
Cl
(0.6 equiv)
O
Cl
Ph3Bi + Me O (excess)
Pd(PPh3)4 (1 mol %) THF, 65 °C, 4 h [53]
Pd(OAc) 2 (5 mol %)
Me O
Ph
HMPA, 65 °C, 5 h [54]
n-Bu 72%
Me O 92%
Scheme 15
Cl OSiMe3 Cl
+ Me
OEt O
PdCl2(PPh3)2 (5 mol %)
EtO CHCl3, 90 −100 °C [55]
Scheme 16
Cl
O
Me
O
93%
646
III Pd-CATALYZED CROSS-COUPLING
F. SUMMARY 1. Palladium-catalyzed coupling reactions of organozinc compounds with acyl halides are the fastest and mildest among the known methods using a variety of organometallic compounds. 2. Since organotin compounds are stable to water and oxygen, the method has widely been utilized for the synthesis of various compounds although the reaction requires a long time and high temperature. 3. Organometallic compounds, such as organomercury, boron, aluminum, zirconium, copper, silane, lead, and bismuth, can also be utilized for the coupling reactions, although these methods have not been studied extensively. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26]
D. A. Shirley, Org. React., 1954, 8, 28. H. Reinheckel, K. Haage, and D. Jahnke, Organomet. Chem. Rev. A, 1969, 4, 47–136. G. H. Posner, Org. React., 1975, 22, 253–400. J. P. Collman, Acc. Chem. Res., 1975, 8, 342. E. Negishi, K. W. Chiu, and T. Yoshida, J. Org. Chem., 1975, 40, 1676. L. S. Hegedus, P. M. Kendall, S. M. Lo, and J. R. Sheats, J. Am. Chem. Soc., 1975, 97, 5448. P. F. Hudrlik, J. Organomet. Chem. Libr., 1976, 1, 127–159. R. C. Larock, J. Organomet. Chem. Libr., 1976, 1, 257–303. G. Cahiez, D. Bernard, and J. F. Normant, Synthesis, 1977, 130. D. B. Carr and J. Schwartz, J. Am. Chem. Soc., 1979, 101, 3521. A. N. Kashin, N. A. Bumagin, I. O. Kalinovski, I. P. Beletskaya, and O. A. Reutov, Zh. Org. Khim., 1980, 16, 1569. H.-U. Blaser and A. Spencer, J. Organomet. Chem., 1982, 233, 267. T. Sato, K. Naruse, M. Enokiya, and T. Fujisawa, Chem. Lett., 1981, 1135. T. Sato, T. Itoh, and T. Fujisawa, Chem. Lett., 1982, 1559. E. Negishi, V. Bagheri, S. Chatterjee, F.-T. Luo, J. A. Miller, and A. T. Stoll, Tetrahedron Lett., 1983, 24, 5181. Y. Tamaru, H. Ochiai, T. Nakamura, and Z. Yoshida, Tetrahedron Lett., 1986, 27, 955. E. Negishi, N. Okukado, A. O. King, D. E. Van Horn, and B. I. Spiegel, J. Am. Chem. Soc., 1978, 100, 2254. E. Negishi, A. O. King, and N. Okukado, J. Org. Chem., 1977, 42, 1821. R. F. Heck, Org. React., 1982, 27, 345–390. R. A. Grey, J. Org. Chem., 1984, 49, 2288. Y. Kondo, M. Uchiyama, and T. Sakamoto, J. Synth. Org. Chem. Jpn., 1997, 55, 547. E. Negishi, T. Takahashi, and K. Akiyoshi, J. Chem. Soc. Chem. Commun., 1986, 1338. R. F. W. Jackson, N. Wishart, A. Wood, K. James, and M. J. Wythes, J. Org. Chem., 1992, 57, 3397. T. Houkawa, T. Ueda, S. Sakami, M. Asaoka, and H. Takei, Tetrahedron Lett., 1996, 37, 1045. Y. Tamaru, H. Ochiai, F. Sanda, and Z. Yoshida, Tetrahedron Lett., 1985, 26, 5529. M. M. Faul and L. L. Winneroski, Tetrahedron Lett., 1997, 38, 4749.
III.2.12.1 CROSS-COUPLING WITH ACYL HALIDES
[27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55]
647
R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5518. M. Kosugi, Y. Shimizu, and T. Migita, Chem. Lett., 1977, 1423. D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1978, 100, 3636. P. Four and F. Guibe, J. Org. Chem., 1981, 46, 4439. L. S. Liebeskind, M. S. Yu, and R. W. Fengl, J. Org. Chem., 1993, 58, 3543. M. W. Logue and K. Teng, J. Org. Chem., 1982, 47, 2549. J. W. Labadie D. Tueting, and J. K. Stille, J. Org. Chem., 1983, 48, 4634. J. Godschalx and J. K. Stille, Tetrahedron Lett., 1980, 21, 2599. J. W. Labadie and J. K. Stille, J. Am. Chem. Soc., 1983, 105, 6129. J.-L. Parrain, A. Duchêne, and J.-P. Quintard, Tetrahedron Lett., 1990, 31, 1857. Y. Ito, M. Inouye, and M. Murakami, Tetrahedron Lett., 1988, 29, 5379. V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585. J. Ye, R. K. Bhatt, and J. R. Falck, Tetrahedron Lett., 1993, 34, 8007. J. Ye, R. K. Bhatt, and J. R. Falck, J. Am. Chem. Soc., 1994, 116, 1. M. Pérez, A. M. Castaño, and A. M. Echavarren, J. Org. Chem., 1992, 57, 5047. K. Takagi, T. Okamoto, Y. Sakakibara, A. Ohno, S. Oka, and N. Hayama, Chem. Lett., 1975, 951. N. A. Bumagin, I. G. Bumagina, A. N. Kashin, and I. P. Beletskaya, Zh. Org, Khim., 1982, 18, 1131. I. P. Beletskaya, J. Organomet. Chem., 1983, 250, 551. L. S. Hegedus, M. R. Sestrick, E. T. Michaelson, and P. J. Harrington, J. Org. Chem., 1989, 54, 4141. E. Negishi, A. Abramovitch, and R. E. Merrill, J. Chem. Soc. Chem. Commun., 1975, 138. C. S. Cho, K. Itotani, and S. Uemura, J. Organomet. Chem., 1993, 443, 253. K. Wakamatsu, Y. Okuda, K. Oshima, and H. Nozaki, Bull. Chem. Soc. Jpn., 1985, 58, 2425. Y. Hanzawa, N. Tabuchi, and T. Taguchi, Tetrahedron Lett., 1998, 39, 6249. N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1983, 24, 5081. Y. Tohda, K. Sonogashira, and N. Hagihara, Synthesis, 1977, 777. Y. Tanaka, H. Yamashita, and M. Tanaka, Organometallics, 1996, 15, 1524. J. Yamada and Y. Yamamoto, J. Chem. Soc. Chem. Commun., 1987, 1302. D. H. R. Barton, N. Ozbalik, and M. Ramesh, Tetrahedron, 1988, 44, 5661. S. Aoki, T. Fujimura, E. Nakamura, and I. Kuwajima, Tetrahedron Lett., 1989, 30, 6541.
R1R2C(X1)X2 + RM
Pd
III.2.12.2 Palladium-Catalyzed Cross-Coupling with Other -Hetero-Substituted Organic Electrophiles TAKUMICHI SUGIHARA
A. INTRODUCTION
-Hetero-substituted organic electrophiles include heteroaromatics and -hetero-substituted alkenes having some leaving group at the -position. Since the heteroaromatics are quite stable due to aromaticity, the Pd-catalyzed coupling reaction of organometallic compounds usually proceeds without decomposition of the aromatic ring. It means that the heteroaromatics having the leaving group at the -position just behave as aryl halides. In contrast, -hetero-substituted alkenes having the leaving group at the -position have three possibilities to react with organometallic compounds giving cis-, trans-, or ,-disubstituted alkenes. In this section, the Pd-catalyzed coupling reaction with hetero-substituted organic electrophiles is discussed.
B. COUPLING REACTIONS WITH HETEROAROMATICS POSSESSING -LEAVING GROUP Since heteroaromatic compounds sometimes exhibit interesting physical properties and biological activities, construction of substituted heteroaromatics has drawn some attention. Heteroaromatics can be divided into two major categories. One is the electron-sufficient heteroaromatics, such as pyrrole, indole, furan, and thiophene; those easily react with electrophiles. The other is the -electron-deficient heteroaromatics, such as pyridine, quinoline, and isoquinoline; those have the tendency to accept the nucleophilic attack on the aromatic ring. Reflecting the electronic nature of heteroaromatics, the -electron-deficient ones are usually used as the electrophiles.[1] The -electronsufficient heteroaromatics having simple structures, such as 2-iodofuran and 2-iodothiophene, have also been utilized as the electrophiles. Not only the electronic nature of the heteroaromatics but also coordination of the heteroatom to the palladium complexes influence catalytic activity. This is another reason why the coupling reaction did not proceed efficiently in some cases.
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
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650
III Pd-CATALYZED CROSS-COUPLING
Organozinc (Negishi’s protocol; see Sect. III.2.1),[2 ]–[5] boron (Suzuki’s protocol; see Sect. III.2.2),[6 ]–[8] tin (Stille’s protocol; see Sect. III.2.3),[9],[10] copper (Sonogashira’s protocol; see Sect. III.2.8.1),[11] magnesium,[4],[12] aluminum,[3] silicon compounds,[13] and siloxycyclopropanes[14] are often used for Pd-catalyzed coupling reactions with heteroaromatics having a leaving group at the -position (Schemes 1 and 2). H MgCl Pd(PPh3)4 (5 mol %) THF, 22 °C [4]
Me
H S
35% +
Me
Me
I
Me S
S
S
24%
H ZnCl Pd(PPh3)4 (5 mol %) THF, 22 °C, 1 h [4]
Me
N
Br IZn N +
Me
H S
PdCl2(PPh3)2 (cat.)
COOEt 3
DMA-benzene, r.t., 2 h [5]
Me
87%
Me
N
COOEt N
Me 91% Scheme 1
C. COUPLING WITH 1,1-DIHALOALKENES 1,1-Dihaloalkenes are easily prepared from aldehydes via the Wittig-type reaction[15] or by carbometallation of metallated alkynes.[16],[17] When the other substituent is present at the 2-position, the steric requirement around two halogens becomes different. Since the halogen cis to the substituent is sterically more hindered than that trans, the palladium complex can approach the trans position faster than the cis one. Owing to the difference of the reaction rate, the Pd-catalyzed cross-coupling reaction of organometallic compounds with 1,1-dihaloalkenes can be stopped at the trans monosubstituted stage. As the second halogen can be displaced by the conventional cross-coupling method, the trisubstituted alkenes can be synthesized in a stereoselective manner. The first successful report of the selective monocoupling reaction was performed by organomagnesium and zinc compounds in the presence of PdCl2(dppb) catalyst (Scheme 3).[18],[19] For aryl metals, the trans-selective coupling reaction was achieved by use of either organomagnesium or zinc compounds. In the case of alkyl metals, not organomagnesium but organozinc compounds brought about fruitful results. The untouched chloride moiety at the cis position further coupled with organomagnesium compounds in the presence of PdCl2(PPh3)2 to give the trisubstituted alkenes in good yields. Since organomagnesium
III.2.12.2 CROSS-COUPLING WITH OTHER α-HETERO- SUBSTITUTED ELECTROPHILES
651
n-HexZnCl Pd(PPh3)4 (3 mol %) THF, r.t., 12 h [3]
N n-Hex 100%
n-HexMgBr Pd(PPh3)4 (3 mol %) THF, r.t., 24 h [3]
N 99, -; 6 (Ph, H, H, COCH3), 7 (H, Ph), 23, 82, >99, -; 6 (H, H, Ph, CO2CH3), 7 (H, Ph), 16, 92, >99, -; 6 (H, H, C3 H7, CO2CH3), 7 (H, C3H7), 5, 78, 80/20, -; 6 (H, CH3, (CH3)2C=CHCH2CH2, CO2CH3), 7 (CH3, (CH3)2C=CHCH2CH2), 5, 89, 71/29, -; 6 (H, (CH3)2C=CHCH2CH2, CH3, CO2CH3), 7 (CH3, (CH3)2C=CHCH2CH2), 5, 80, 71/29, -; (8 (OCO2CH3)), 8 (CN)), 15, 92, -, Pd(CO)(PPh3)3 in toluene under reflux; (9 (OCO2CH3)), (9 (CN)), 18, 88, -, -. Y
Z
8
9 Scheme 29
tBu tBu
ClHg PdCl/2
Li2PdCl4 THF 89%
tBu
CuCN Benzene, reflux 91%[37]
CN
Scheme 30
RX, KCN 5 mol % Pd(OAc) 2, 4 mol % PPh3 DMF, 80 °C
R CN
R, X, Reaction time (h), Isolated yield (%)[46] = (E)-Styryl, Br, 12.5, 81; 10 , I, 18, 65; 11, I,12.5, 60; 12, I, 12, 70; (E)-1-Hexenyl, I, 12, 74; Ph, I, 12, 68; p-Anisyl, 12, 72; p-tButylphenyl, I, 12, 73; 1-Naphthyl, Br, 12.5, 52. C5H11
C5H11
C5H11
OSiMe2tBu
OTHP
10
11
O
O 12
Scheme 31
and 32),[46],[47] or alkenyl or aryl halides, tethered alkenes, and KCN (Scheme 33)[48] by the catalysis of Pd0. The three-component coupling of activated olefins, allylic chlorides, and Me3SiCN also proceeds very well (Scheme 34).[49] In the presence of CO, the insertion of CO into C9Pd bonds precedes the capture of the organopalladium intermediates with CN, resulting in the production of acylpalladium intermediates, which finally react with CN to yield acyl cyanides. In this way, aroyl cyanides are obtained by the
III.2.13.1 CROSS-COUPLING INVOLVING METAL CYANIDES
669
OSiMe2tBu
I
C5H11 (CH2)n
(CH2)n KCN
A
Pd(O) DMF
B
t CN OSiMe2 Bu
A B
C5H11 90% de
CH · CH
A-B, n, Yield (%) [47] = CH2CH2, 1, 95; 13, 1, 71; CH2CH2, 2, 63; CH=CH, 1, 25.
O
O 13
Scheme 32 1.2 equiv KCN
14−19
20−25 10 mol % Pd(OAc) 2 20 mol % PPh3 10 mol % 18-Crown-6 Benzene, 80 °C, 12 h or Toluene, 110 °C, 18 h [48]
I Br PhO2S
N
Bn
O
N
N
I
Bn
14
I
O
15
X
16
17−19 CH2CN
CN O PhO2S
N
N CH2CN
Y
Bz
N
CN X
Y
O
Bn
20
21
22
23
24
25
68%
62%
50%
62%
58%
45%
17, 23: X = O, Y= CH 2 18, 24: X = CH2, Y= O 19, 25: X = CO, Y= NBn Scheme 33
Pd0-catalyzed reaction between aryl halides, CO, and KCN (Scheme 35).[50] The tandem four-component assembly is possible for the combination of aryl halides, alkynes, CO, and KCN, which yields -aryl substituted alkenoyl cyanides by the catalysis of Pd0 (Scheme 36).[51]
670
III Pd-CATALYZED CROSS-COUPLING
R3
E1
0.5 equiv E2
R
1 equiv Me3SiCN
2
R1
R2
1.3 mol % Pd2(dba)3·CHCl3 5 mol % dppf THF, reflux
Cl
E1
E2
R3 CN
R1
R1, R2, R3, E1, E2, Isolated yield (%), Diastereomer ratio[49] = H, H, Ph, CN, CN, 89, -; H, H, p-CH3OC6H4, CN, CN, 80, -; H, H, p-CH3C6H4, CN, CN, 84, -; H, H, p-CH3O2CC6H4, CN, CN, 82, -; H, H, n-C5H11, CN, CN, 77, -; H, H, t-C4H9, CN, CN, >99, -; H, H, i-C3H7, CN, CN, 86, -; H, H, Ph, CN, CO2C2H5, 34, 67:33; H, H, n-C5H11, CN, CO2C2H5, 48, 46:36; H, CH3, t-C4H9, CN, >99, -; CH3, H, t-C4H9, CN, CN, 74, -; Ph, H, t-C4H9, CN, CN, 74, -; H, Cl, t-C4H9, CN, CN, 40, -.
Scheme 34
I
COCN
CO, KCN
R
R
0. 7 mol % PhPdI(PPh3)2 THF, 100 °C
R (or Aryl), PCO (atm), Reaction time (h), GLC yield (%)[50] = H, 20, 20, 91; p-CH3O, 20, 15, 92; p-CH3, 8, 18, 69; (2-Thienyl), 8, 24, 45. Scheme 35
O I CH3
H
Ph, CO (20 atm), KCN 20 mol % Pd(OAc) 2 20 mol % PPh3, 10 mol % dppb THF, 70 °C, 94 h 29 %[51]
CN Ph
CH3
Scheme 36
D. SUMMARY 1. Pd-catalyzed nucleophilic displacement of carbon electrophiles with CN provides an efficient synthetic method of aryl or alkenyl cyanides from the corresponding aryl or alkenyl halides or triflates. Compared to the Rosenmund–von Braun reaction, the advantages of the present method are the necessarily mild reaction conditions, compatibility with a variety of functional groups, and simple work-up procedures. 2. In the most Pd-catalyzed reactions, Zn(CN)2 and dppf give the best results as the metal cyanide and commercially available ligand, respectively. 3. The reaction using aryl or alkenyl chlorides as carbon electrophiles is still not easy. The development of an efficient Pd catalyst, which maintains the active form of Pd at such high temperatures that the less reactive chlorides can react with Pd0, is highly desired.
III.2.13.1 CROSS-COUPLING INVOLVING METAL CYANIDES
671
4. For the same conversion, a Ni-based catalyst is also available.[52] The Pd catalyst is commonly used for the cyanation but this tendency does not necessarily stem from the fact that Pd is more reactive in this reaction than Ni but stems from the fact that the Pd-based one is usually simpler to prepare, purify, handle, and store than Ni. One should try the reaction using a Ni catalyst together with one using Pd, if the reactivity of the substrate is low. 5. The utility of CN as a capping agent in a multicomponent-coupling reaction has only been studied using limited combinations. Judging from the synthetic versatility of the nitrile functional group in products, further study is desired to find new combinations of available components.
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28]
K. Takagi, T. Okamoto, Y. Sakakibara, and S. Oka, Chem. Lett. 1973, 471. G. P. Ellis and T. M. Romney-Alexander, Chem. Rev., 1987, 87, 779 – 794. A. Sekiya and N. Ishikawa, Chem. Lett., 1975, 277. K. Takagi, T. Okamoto, Y. Sakakibara, A. Ohno, S. Oka, and N. Hayama, Bull. Chem. Soc. Jpn., 1975, 48, 3298. K. Takagi, T. Okamoto, Y. Sakakibara, A. Ohno, S. Oka, and N. Hayama, Bull. Chem. Soc. Jpn., 1976, 49, 3177. K. Takagi, Bull. Inst. Chem. Res. Kyoto Univ., 1989, 67, 136. N. Chatani and T. Hanafusa, J. Org. Chem., 1986, 51, 4714. M. Kosugi, Y. Kato, K. Kiuchi, and T. Migita, Chem. Lett., 1981, 69. V. Nair, D. F. Purdy, and T. B. Sells, J. Chem. Soc. Chem. Commun., 1989, 878. V. Nair and G. S. Buenger, J. Am. Chem. Soc., 1989, 111, 8502. J. R. Dalton and S. L. Regen, J. Org. Chem., 1979, 44, 4443. W. Oppolzer and D. A. Roberts, Helv. Chim. Acta, 1980, 63, 1703. D. M. Tschaen, R. Desmond, A. O. King, M. C. Fortin, B. Pipik, S. King, and T. R. Verhoeven, Synth. Commun., 1994, 24, 887. D. M. Tschaen, L. Abramson, D. Cai, R. Desmond, U.-H. Dolling, L. Frey, S. Karady, Y.-J. Shi, and T. R. Verhoeven, J. Org. Chem., 1995, 60, 4324. H. G. Selnick, G. R. Smith, and A. J. Tebben, Synth. Commun., 1995, 25, 3255. C. Kehr, R. Neidlein, R. A. Engh, H. Brandstetter, R. Kucznierz, H. Leinert, K. Marzenell, K. Strein, and W. von der Saal, Helv. Chim. Acta, 1997, 80, 892. H. Kubota and K. C. Rice, Tetrahedron Lett., 1998, 39, 2907. U. Drechsler and M. Hanack, Synlett, 1998, 1207. K. Takagi and Y. Sakakibara, Chem. Lett., 1989, 1957. K. Takagi, K. Sasaki, and Y. Sakakibara, Bull. Chem. Soc. Jpn., 1991, 64, 1118. G. A. Kraus and H. Maeda, Tetrahedron Lett., 1994, 35, 9189. P. E. Maligres, M. S. Waters, F. Fleitz, and D. Askin, Tetrahedron Lett., 1999, 40, 8193. F. Jin and P. N. Confalone, Tetrahedron Lett., 2000, 41, 3271. M. Okano, M. Amano, and K. Takagi, Tetrahedron Lett., 1998, 39, 3001. K. Yamamura and S.-I. Murahashi, Tetrahedron Lett., 1977, 4429. M. Procházka and M. Sˇiroky´, Collect. Czech. Chem. Commun., 1983, 48, 1765. G. Antoni and B. Långstöm, Appl. Radiat. Isot., 1992, 43, 903. Y. Andersson and B. Långström, J. Chem. Soc. Perkin Trans. 1, 1994, 1395.
672 [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]
III Pd-CATALYZED CROSS-COUPLING
E. Piers and F. F. Fleming, J. Chem. Soc. Chem. Commun., 1989, 756. E. Piers and F. F. Fleming, Can. J. Chem., 1993, 71, 1867. T. Okano, J. Kiji, and Y. Toyooka, Chem. Lett., 1998, 425. B. A. Anderson, E. C. Bell, F. O. Ginah, N. K. Harn, L. M. Pagh, and J. P. Wepsiec, J. Org. Chem., 1998, 63, 8224. T. Okano, M. Iwahara, and J. Kiji, Synlett, 1998, 243. N. Sato and M. Suzuki, J. Heterocycl. Chem., 1987, 24, 1371. B. A. Anderson, L. M. Becke, R. N. Booher, M. E. Flaugh, N. K. Harn, T. J. Kress, D. L. Varie, and J. P. Wepsiec, J. Org. Chem., 1997, 62, 8634. R. C. Larock, K. Takagi, S. S. Hershberger, and M. A. Mitchell, Tetrahedron Lett., 1981, 22, 5231. R. C. Larock, S. S. Hershberger, K. Takagi, and M. A. Mitchell, J. Org. Chem., 1986, 51, 2450. T. Sakamoto and K. Ohsawa, J. Chem. Soc. Perkin Trans. 1, 1999, 2323. J. B. Davison, P. J. Peerce-Landers, and R. J. Jasinski, J. Electrochem. Soc., 1983, 130, 1862. Y. Akita, M. Shimazaki, and A. Ohta, Synthesis, 1981, 974. K. Tanji and T. Higashino, Heterocycles, 1990, 30, 435. L.-L. Gundersen, Acta Chem. Scand., 1996, 50, 58. E. C. Taylor, P. Zhou, and C. M. Tice, Tetrahedron Lett., 1997, 38, 4343. Y. Tsuji, N. Yamada, and S. Tanaka, J. Org. Chem., 1993, 58, 16. J. E. Marcone and K. G. Moloy, J. Am. Chem. Soc., 1998, 120, 8527. S. Torii, H. Okumoto, H. Ozaki, S. Nakayasu, and T. Kotani, Tetrahedron Lett., 1990, 31, 5319. S. Torii, H. Okumoto, H. Ozaki, S. Nakayasu, T. Tadokoro, and T. Kotani, Tetrahedron Lett., 1992, 33, 3499. R. Grigg, V. Santhakumar, and V. Sridharan, Tetrahedron Lett., 1993, 34, 3163. H. Nakamura, H. Shibata, and Y. Yamamoto, Tetrahedron Lett., 2000, 41, 2911. M. Tanaka, Bull. Chem. Soc. Jpn., 1981, 54, 637. K. Nozaki, N. Sato, and H. Takaya, J. Org. Chem., 1994, 59, 2679. V. V. Grushin and H. Alper, Chem. Rev., 1994, 94, 1047 – 1062.
Y
Y
C C M or Z
M + R-X
III.2.13.2 Other -Hetero-Substituted Organometals in Palladium-Catalyzed Cross-Coupling FEN-TAIR LUO
A. INTRODUCTION The cross-coupling reaction of -hetero-substituted organometals with organic halides and related electrophiles represents one of the most straightforward methods for making carbon–carbon bonds especially in the formation of various heterocyclic derivatives. This section will emphasize on the Pd-catalyzed cross-coupling reactions via some -hetero-substituted organometals except metal cyanides, which are described in Sect. III.2.13.1. These heteroatoms, incorporated in positions that are to the metals, include halogens (F, Cl, Br, I) and other electronegative elements, such as O, S, Se, N, and P, as well as some metals, such as B, Al, Zn, Si, and Sn (Scheme 1). It is important from the synthetic viewpoint to develop procedures for coupling various -hetero-substituted alkenylmetals or ,-disubstituted alkylmetals, the carbonylanion equivalents, with electrophiles.[1] This section is subdivided according to the use of different metals, such as Al, B, Cu, Li, Mg, Hg, Sn, and Zn, in the -hetero-substituted organometals.
B. ORGANOALUMINUM COMPOUNDS Relatively few reactions on the Pd-catalyzed cross-coupling reaction of organoaluminum with electrophiles have been reported in the literature. However, Negishi and Luo have reported the [Pd(PPh3)4]-catalyzed cross coupling reaction of -trialkylsilyl-, -alkoxy-, or -alkylthio-substituted alkenylaluminum and alkenylzinc compounds with vinyl or aryl halides to form hetero-substituted arylated alkenes or conjugated dienes suitable for the Diels – Alder reaction, respectively; the stereospecificity of the reactions is 98% (Scheme 2).[2] Saulnier and co-workers have reported the chemoselective synthesis of allyltrimethylsilanes by the [Pd(PPh3)4]-catalyzed cross-coupling reaction of vinyl triflates with tris[(trimethylsilyl)methyl]aluminum (Scheme 3).[3]
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
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674
III Pd-CATALYZED CROSS-COUPLING
Y
Y C C M
M + R
or
X
cat. PdLn
Y
Y
or
C C R
Z
R Z
(Z may or may not be the same as Y) Scheme 1
R
SiMe3
H
Al(i-Bu)2
+ H2C CHBr
R
Pd(PPh3)4
SiMe3
THF
68−74% Scheme 2
(Me3SiCH2)3Al, Pd(PPh3)4 cat.
Br OSO2CF3
Br
ClCH2CH2Cl/C6H6, r.t., 2.2 h
SiMe3 84%
Scheme 3
C. ORGANOBORON COMPOUNDS Suzuki and co-workers have reported the reaction of diisopropyl -bromoalkenylboronates, readily obtained from hydroboration of 1-bromoalkynes and followed by the addition of organolithium, with base to give 1-organo-1-alkenylboronates. The [Pd(PPh3)4]-catalyzed cross-coupling reaction with organic halides proceeds smoothly in the presence of base to form highly stereo- and regiospecific trisubstituted alkenes (Scheme 4).[4],[5] Likewise, Waas and co-workers have reported the conversion of iodoalkenylboronates, readily prepared by the hydroboration of 1-iodoalkynes, to 1,1bimetallics of boron and zinc or copper, which react with a wide range of electrophiles to afford polyfunctional boronic esters. After hydrogen peroxide oxidation, polyfunctional ketones were produced in good to excellent yields (Scheme 5).[6] Note that iodoalkenylboronates may undergo cross-coupling with organozinc compounds in the Br R1
i-PrOH
C C Br + HBBr2:SMe2 Br
R1
base
B(OPr-i)2R2
B(OPr-i)2 R1
R2
Scheme 4
R2Li
R1
B(OPr-i)2
R3X Pd(PPh3)4 cat. aq. KOH
R3 R1
R2 61−94%
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
675
presence of Pd catalyst to give 1-organo-1-alkenylboronic esters or -organoalkenylboronates.[7] The Suzuki coupling methodology has widely been used in the preparation of pyrrole derivatives. Thus, the immunosupressive agent undecylprodigiosine can be prepared by the [Pd(PPh3)4]-catalyzed cross-coupling reaction of two pyrrole rings (Scheme 6).[8] The preparation of 2-aryl-1-(phenylsulfonyl)pyrroles can also be realized by cross-coupling of 1-(phenylsulfonyl)pyrrole-2-boronic acid and aryl bromides or iodides (Scheme 7).[9] Similarly, Suzuki coupling of 2-thienylboronic acid with either aryl halides or triflate could give the corresponding thienyl derivatives.[10]–[18] Likewise, 2-furanylboronic acid could cross-coupling with either aryl or vinyl halides or triflate via the Suzuki reaction to give the corresponding furanyl derivatives.[11],[19] – [25] Triethyl(1-methylindol-2-yl)borate has been used for the Pd-catalyzed tandem cyclization and cross-coupling reaction with acetylenic or vinylic aryl halides to form ellipticine analogs (Scheme 8).[26],[27]
Me
Me Me
Me Me
O B O
Me
Me
1. Zn, DMA 2. CuCN 2 LiCl
Me Me
O
Me
B O
3. Pd(dba)2 cat. Hex I
I
Hex 77% Scheme 5
OMe OMe B(OH)2 + TfO N Boc
Pd(PPh3)4 cat.
N
N N
K2CO3
N N C11H23-n
C11H23-n
73%
Scheme 6
Pd(PPh3)4 cat.
N
B(OH)2
N
Ar-X
SO2Ph
Ar
SO2Ph X = Br or I
Ar = Ph, 1-Napth, 4-NO2Ph, 4-AcPh, 4-MeOPh
Scheme 7
(39−91%)
676
III Pd-CATALYZED CROSS-COUPLING
COPh N I Pd(OAc) 2 cat. 1. t-BuLi, THF 2. BEt3
N COPh N Me
R
R = Me, SiMe3 53−78%
+
N Me
N Me
R
Li − BEt3 Pd(OAc) 2 cat. Me N O I
N Me N Me
Me
Me O 75%
Scheme 8
The [Pd(PPh3)4]-catalyzed cross-coupling reaction of -silylalkenylborane with 2-bromomethyl-4-siloxycyclopent-2-enone followed by the conversion to an epoxy and keto group could form a key component for the preparation of 6-keto-prostaglandins (Scheme 9).[28] Suzuki coupling of aryl or vinyl bromides with -silylalkenylborane under basic conditions or -silylalkenylborate could provide the corresponding silylated styrenes and 1,3-dienes with highly stereoselectivity (98%).[2],[29] Soderquist and co-workers have reported that allyl, benzyl, and propargyl silanes can be prepared via Suzuki reaction of vinyl, alkynyl, and aryl bromides with the air-stable organoborane, 10-trimethylsilylmethyl-9-oxa-10-borabicyclo[3.3.2]decane, in excellent yields.[30]
O
1. (o-C6H11)2B
O
CO2Me
CO2Me
TMS
Br
cat. Pd(PPh3)4-NaOH
TBSO
TBSO 2. m-CPBA/CH2Cl2 3. BF3 OEt2/MeOH
O 57%
Scheme 9
D. ORGANOCOPPER COMPOUNDS Kalinin and Min have reported the synthesis of aryl- and vinyl-sydnones from the [Pd(PPh3)4]-catalyzed cross-coupling reaction of 4-copper-3-phenylsydnone with aryl and vinyl halides (Scheme 10).[31]
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
677
Ph N O
Pd(PPh3)4 cat.
Ph N O
N
Ph Li
1. BuLi/THF −78 °C 2. CuBr
O−
N O
N
N
CH CHPh O− 86%
BrCH CHPh
Cu O− Ph
Pd(PPh3)4 cat.
I
R
R = H, NO2, OMe
N O
R
N O− 90−92%
Scheme 10
E. ORGANOLITHIUM COMPOUNDS Araki and co-workers have reported the [Pd(PPh3)4]-catalyzed cross-coupling reaction of isoprene bromohydrin with heteroaromatic organolithium reagents in good yields without rearrangement (Scheme 11).[32] Pelter and co-workers have reported that the [Pd(PPh3)4]catalyzed cross-coupling reactions of 2-lithiofuran with allyl or benzyl bromides work well, but fail with aryl bromide.[33]
OH Br
ArLi, Pd(PPh3)4 cat. Z
Me
OH Ar Me
Ar = Z = O, S, NMe
60−92%
Scheme 11
F. ORGANOMAGNESIUM COMPOUNDS Negishi and co-workers have reported the [Pd(PPh3)4]-catalyzed cross-coupling reaction of trimethylsilylmethylmagnesium chloride with alkenyl iodides to form allylsilanes in excellent yields and in a highly stereo- and regioselective manner (Scheme 12).[34],[35] Sugihara and Ogasawara have reported the [PdCl2(PPh3)2]-catalyzed cross-coupling reaction of optically active 2-chlorovinylcarbinols with trimethylsilylmethylmagnesium chloride to form certain optically active allyl alcohols.[36] Alternatively, Hevesi and coworkers have reported the [PdCl2(PPh3)2]-catalyzed cross-coupling reaction of vinyl selenides with trimethylsilylmethylmagnesium chloride to form allylsilanes.[37] Minato and co-workers have reported the [PdCl2(dppb)]- or [PdCl2(dppf)]-catalyzed cross-coupling reaction of 1-methyl-2-pyrrolylmagnesium bromide with aryl and heteroaryl halides to
678
III Pd-CATALYZED CROSS-COUPLING
give the corresponding 2-substituted pyrroles in good to excellent yields.[38],[39] Likewise, 2-thienylmagnesium bromide could be coupled with p-tert-butylphenyl -O-2-glycopyranoside to form C--aryl-2-glycopyranosides in the presence of PdCl2(dppf) catalyst (Scheme 13).[39],[40] The [PdCl2(dppb)]-catalyzed cross-coupling reactions of silylvinylmagnesium bromide with heteroaryl bromides have also been reported.[7] Buono and co-workers have reported the use of PdCl2(MeCN)2 catalyst and chiral AMPP (aminophosphine phosphinite) ligands[41] in the allylation of 1-trimethylsilylvinylmagnesium bromide with 3-cyclohexenyl acetate to give a versatile synthon, 3-(1-trimethylsilylvinyl)cyclohexene, in high yields and with ee up to 33% (Scheme 14).[42] n-C4H9
H + ClMgCH2SiMe3
Me
Pd(PPh3)4 cat. THF
I
H
n-C4H9 Me
CH2SiMe3 85%
Scheme 12
BnO
BnO S
O
MgBr
O
PdCl2(dppf) cat.
BnO
OC6H4-4-But
BnO
81%
S
Scheme 13 CH2
OAc
SiMe3
PdCl2(ProliNOP) cat.
+
SiMe3
OPPh2
MgBr ProliNOP:
S N PPh2
80% (30% ee)
Scheme 14
G. ORGANOMERCURY COMPOUNDS Bumagin and co-workers have reported the ArPdI(PPh3)2-catalyzed cross-coupling of 2furanyl or 2- thienylmercurials with aromatic halides in the presence of iodide ion to give coupling products in high yields. In the case of acyl halides, unsymmetrical diaryl ketones could be obtained in good yields (Scheme 15).[43],[44] H. ORGANOTIN COMPOUNDS
-Hetero-substituted organotin compounds (Scheme 16) have been used extensively in the Pd-catalyzed cross-coupling reaction with various electrophiles, since the tin
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
S
+ 2 × O2N ) Hg 2
I
p-NO2C6H4PdI(PPh3)4 cat. 2 equiv NaI, DMF
679 S
2 × O2N 94%
S
+ 2 × O2N ) Hg 2
COCl
p-NO2C6H4PdI(PPh3)4 cat. 2 equiv NaI, DMF
O 2 × O2N S 100%
Scheme 15
derivatives may tolerate a variety of functional groups both in the organometallic reagent and in heterocyclic halides. Matthews and co-workers have reported the use of (1-fluorovinyl) tributyltin as a synthetic equivalent for the 1-fluoroethene anion in the Pdcatalyzed cross-coupling with aryl iodide, aryl triflate, or acid chloride to form the corresponding alkenyl fluoride derivatives.[45],[46] Shi and co-workers have reported the addition of copper(I) iodide as a cocatalyst in the [Pd(PPh3)4]-catalyzed cross-coupling reaction of (1-fluorovinyl)tributyltin reagent to give better yields.[47] The cross-coupling of hexabutyldistannane with (4-bromophenyl)methylsulfone in the presence of both Pd(OAc)2 and Pd(PPh3)4 catalysts could give methyl[4-(tributylstannyl)phenyl]sulfone.[21] Likewise, hexamethyldistannane can couple with triflated oxazole by the aid of Pd catalyst to give 4-trimethylstannyloxazole.[48] The Pd-catalyzed cross-coupling of 2-thienyl-, 2-pyrrolyl-, 2-furyl-, and 2pyridyltin reagents with various organic halides or triflates, such as aryl, heteroaryl, allyl, and alkenyl halides, have been extensively studied and reported in the literature.[49]–[98] The intact functional groups include aldehyde,[49],[50] ester,[49],[50] alcohol,[49] amide,[50],[51] amino,[52],[53] nitro group,[54] and uracil moiety.[55],[56] Gronowitz and co-workers have reported the synthesis of dithienopyridines and other fused heterocycles through Pd-catalyzed cross-coupling of 2-thienyltin reagent with N-(haloheteroaryl)carbamates (Scheme 17).[57]–[61] Kang and co-workers have reported the Pd-catalyzed cross-coupling of 2-thienyl and 2-furyltin compounds with iodanes[74] or hypervalent iodonium salts[75] (Scheme 18). Liebeskind and Wang have reported the construction of substituted benzo- and dibenzofurans or thiophenes by the Pdcatalyzed cross-coupling of 2-furyl- or 2-thienyltin reagent with 4-chloro-2,3disubstituted-2-cyclobutenones and followed by thermolysis at 100 °C (Scheme 19).[80] Under the same conditions, both 2-(tri-n-butylstannyl)benzofuran and 2-(tri-nbutylstannyl)thiophene react with 4-chloro-2,3-disubstituted-2-cyclobutenones to form dibenzoheteroaryls.[80] Similarly, 2-benzofuranyl-, 2-benzothiophenenyl-, or 2indolytin reagents may couple with aryl, heteroaryl, alkenyl, alkynyl, or alkyl halides in the presence of Pd catalyst to give the corresponding coupled products in good yields and in a stereoselective manner.[80],[81],[84],[99]–[105] Intramolecular cyclization based on the Pd-catalyzed cross-coupling reaction of 2-indolyltin and vinyl or benzyl bromide could give high yields of the corresponding seven- and nine-membered ring (Scheme 20).[103] 2-Selenienyltin compound also has been used in the Pd-catalyzed cross-coupling reaction with iodopyrimidine.[83] Alkenyltin containing -alkylthio or -alkyloxy substituents reacts readily with chloropurines and aryl halides in the
680
III Pd-CATALYZED CROSS-COUPLING
presence of Pd catalyst to produce alkenylated purines and benzenes, respectively.[86]–[88],[92],[106] Liebeskind and Wang have reported the synthesis of substituted 2-pyrones by carbonylative cross-coupling and thermolysis of 4-halocyclobutenones with 2-ethoxyvinyl-, 2-furyl-, and 2-thienyltin reagents (Scheme 21).[89] Optically active ene carbamates were -lithiated by lithium tetramethylpiperidide in the presence of trialkylstannyl chlorides to produce -stannylated compounds.[107] These stannylated compounds underwent facile Pd-catalyzed cross-coupling with acid chlorides to produce -keto ene carbamates in good yields (Scheme 22). The Pdcatalyzed cross-coupling of stannylated 2- and 4-oxazole,[48],[108] 5-isoxazole,[93],[98] 2benzoxazole,[109] 2-, 4-, and 5-thiazole,[82],[85],[93],[110] 2-benzothiazole,[91],[109] 2-, 4-, and 5-imidazole,[85],[90],[93],[111]–[113] 3-pyrazole,[114]–[116] 2-oxazoline,[117],[118] and 6-uridine[119] with various organic electrophiles have been reported in the literature to give the corresponding regio- and stereoselective products. Iyoda and co-workers have reported the Pdcatalyzed cross-coupling of (trialkylstannyl)tetrathiafulvalene with aryl, naphthyl, or 1,6-methano[10]annulene halides to give the corresponding tetrathiafulvalene-substituted aryl, naphthalene, and 1,6-methano[10]annulene derivatives.[120],[121]
α-Hetero-substituted organotin compounds
S
N
N N
N R
N R
N R
N N
OR
O
N
N
N
N S
S
N R
O
SR
N R
N R
O
S
N
N
N
O
O
Se
N R
O
S
N
N
O
S
O
O S
S
S
S
N
N
Scheme 16
O
N
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
681
O O SnMe3
S
I NHCO2Bu-t
Br 1.
1.
NHCO2Bu-t
Br ,Pd cat./DMF, S S 100 −120 °C 2. 2 N HCl 2. 2 N HCl
1.
,Pd cat./DMF, 100 −120 °C
NHCO2Bu-t S Pd cat./DMF, 100 −120 °C 2. 2 N HCl
S
S S N
S
S
S
N
N
43%
63%
27% Scheme 17
+ − SnBu3 + PhI(OH)OTs or Ph 2I BF4
Z
PdCl2 cat. MeCN/H2O
Ph
Z
Z = O, S
87−95% Scheme 18 OAc
Et
O + n-Bu3Sn
Et
TMS
Z
Cl Z = O, S
1. PdCl2(PhCN)2 cat. tris-2-furylphosphine dioxane, 50−100 °C 2. Ac 2O/pyridine
Et TMS Z
Et 58−71%
Scheme 19 Ts N
N Ts
Pd2(dba)3 CHCl3
Br
SEM
N SEM
tris-2-furylphosphine THF 85%
SnBu3
N
Ts N
N SEM Ts N
Pd2(dba)3 CHCl3
SnBu3 Br
tris-2-furylphosphine THF 89%
N SEM
Scheme 20
682
III Pd-CATALYZED CROSS-COUPLING
O Et
O +
Et
Bu3Sn-R
1. PhCH2PdCl(PPh3)2 cat. 45 psi CO, dioxane 2. 50−100 °C
Cl
Et
O
Et
R 60−80%
R = 2-furyl, 2-thienyl, 2-ethoxyvinyl
Scheme 21
R
O
Me3Sn N Ph
O
+ RCOCl
Ph
PdCl(Bu)(PPh3)2 cat. PhH, 90 °C, CO R = Ph, t-Bu, c-hexyl, Et, Me
O N
O O
Ph
Ph
52−69% Scheme 22
I. ORGANOZINC COMPOUNDS Burton, Davis, and Heinze have reported the [Pd(PPh3)4]-catalyzed cross-coupling reaction of aromatic iodides with (E)-1,2-difluoroethylenylzinc chloride in DMF to form ,difluorostyrenes in good yields and in a stereoselective manner.[122],[123] Gillet and coworkers have reported the [Pd(PPh3)4]-catalyzed cross-coupling reaction of fluorovinylzinc reagents with acid chlorides, ethyl chloroacetate, or alkenyl iodides to form fluorovinyl ketones, esters, and heterocycles in good yields (Scheme 23).[124] A general method for the preparation of 2-(2-pyridyl)indoles based on the [Pd(PPh3)4]catalyzed cross-coupling reaction of 1-(benzenesulfonyl)-2-indolyzinc chloride with 2-halopyridines has been reported.[125] This method has been used in the preparation of the indolo[2,3-a]quinolizidine ring system of a large number of indole alkaloids.[126] 2Deoxyuridines with a five-membered heterocyclic substituent at the 5-position were synthesized by [Pd(PPh3)4]-catalyzed coupling reactions of 5-iodo-2-deoxyuridines with activated heteroaromatics (Scheme 24).[55] Alkenylzinc containing -alkoxy or alkylthio substituents react readily with aryl or alkenyl halides in the presence of a Pd catalyst to produce arylated alkenes or conjugated dienes, respectively, with high (98%) stereoselectivities.[2],[127]–[130] 2-Furylzinc chloride could couple with alkenyl triflates in the presence of Pd(PPh3)4 catalyst to form 2-vinylfurans.[131] Hyuga and co-workers have reported a one-pot synthesis of prostaglandin B1 methyl ester by a stepwise Pd-catalyzed cross-coupling reaction of (E)-(2-bromoethenyl)diisopropoxyborane with -methoxyalkenylzinc chloride followed by addition and elimination of 3-bromocyclopentenone derivatives.[132] Luo and co-workers have reported a one-pot conversion of terminal alkynes into gem-disubstituted alkenes via the addition of in situ generated hydrogen iodide and Pd-catalyzed cross-coupling with organozinc reagents including 2-furyl- and 2-thienylzinc chloride.[133],[134] Luo, Wang, and Chov have reported the tandem cyclization and cross-coupling reaction of acetylenic aryl iodides with 2-heteroarylzinc chloride to
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
R
2
683
R1 CF = CF R2 75−80%
I Pd cat.
R1 CF =CF
ZnCl
ClCO2Et Pd cat.
R1 CF =CF COOEt 57−73%
R3 COCl Pd cat.
Pd cat. = Pd(PPh3)4 1 R = F, n-C4H9, n-C7H15, s-C4H9, Ph 2 R = 2-thienyl, 2-furyl-, 2-pyridinyl 3 R = 2-furyl-, Ph, Me, i-C3H7, vinyl
R1 CF =CF COR3 50−86%
Scheme 23
OTMS N O
O I Pd(PPh3)4 cat.
Y
X
N
O ClZn
TMSO
HN
X
Y
N
HO
1. X = N, Y = S 2. X = N, Y = N-Me
OTMS
48−64%
OH Scheme 24
form 1-indanylidene, (Z)-2,3-dihydro-3-(arylmethylene)benzofurans, or (Z)-3-methylene-2,3-dihydroindole derivatives (Scheme 25).[135]–[138] It is noted that both 2-furyl and 2-thienylzinc chloride can undergo cross-coupling reaction with dichloroethenyl cyclopropanecarboxylates in the presence of PdCl2(dppb) catalyst to form pyrethroids (Scheme 26).[139] The Pd-catalyzed cross-coupling reaction of 2-thienylzinc chloride with other aromatic halides to form thiophene compounds have been extensively applied to new materials with second order optical nonlinearities.[140] Kalinin and co-workers have reported the [Pd(PPh3)4]-catalyzed cross-coupling reaction of 4-bromo-2-pyrone with 2thienylzinc chloride to form 4-substituted 2H-pyran-2-one.[141] Bellina and co-workers have reported a highly regioselective [Pd(PPh3)4]-catalyzed cross-coupling reaction of 2thienylzinc chloride with easily available (Z)- and (E)-alkyl 2,3-dibromopropenoates to form stereoisomerically pure (Z)- and (E)-alkyl 2-bromo-3-(2-thienyl)propenoates in good yields.[142] Takahashi and co-workers have reported the synthesis of novel p-terphenoquinone analogs involving a central dihydrothiophenediylidene structure by the [Pd(PPh3)4]-catalyzed cross-coupling reaction of 4-alkoxyaryl halides and thienylzinc chloride.[143] Goldfinger and co-workers have reported the use of [Pd(PPh3)4]-catalyzed cross-coupling reaction of thienylzinc chloride and p-dibromobenzene for the synthesis of rigid and fused polycyclic aromatics useful for a number of advanced materials applied in nonlinear optical, photoluminescent, electroluminescent, and molecular-based sensory
684
III Pd-CATALYZED CROSS-COUPLING
Z RZnCl/THF, r.t. Pd(PPh3)4 cat. or
I
Z
Pd(OAc) 2/PPh3 (1:2) cat. Et3N
H
R Z = CH2, O, NTs R = 2-thienyl, 2-furyl, 2-pyridinyl, phenyl
H
53−74%
Scheme 25
Me
Me
Cl Cl
O
OPh
ZnCl
PdCl2(dppb) cat. 87%
CO2CH2 Me
Me
OPh
O Cl
CO2CH2
Scheme 26
devices.[144] The efficient Pd-catalyzed synthesis of unsymmetrical donor – acceptor biaryls, polyaryls, or heteroaryls from the cross-coupling of substituted aromatic zinc reagent and aryl halides have been reported.[33],[145],[146],Keenan and Kruse have reported the cross-coupling of 2-furylzinc chloride with 2-methoxy-5-{[(trifluoromethyl)sulfonyl]oxy}tropone in the presence of Pd(PPh3)4catalyst to give 5-(2-thienyl)tropone in good yield.[147] Roth and Fuller have reported the mild [Pd(PPh3)4]-catalyzed cross-coupling reaction of aryl fluorosulfonates with 2-furylzinc chloride in a regioselective manner.[148] Brandão and co-workers have reported a general combined metallation by the aid of an amide group and Pd-catalyzed cross-coupling methodology involving 2-furylzinc or 2-thienylzinc chloride to form the regiospecific hetero-ring-fused o-naphthoquinones.[11] Campbell and co-workers have reported a convenient synthesis of 3-substituted anthranilonitriles by the [PdCl2(dppf)]-catalyzed cross-coupling reaction of 2-furylzinc bromide with 3-iodoanthranilonitrile (Scheme 27).[149] Russell and Hegedus have reported the cross-coupling of zinc salts of allenic ethers with aryl and alkenyl halides by using Pd catalyst to give ,-unsaturated ketones, the allenic ether serving as a source of the acryloyl group (Scheme 28).[128] Suzuki and co-workers and Mazal and Vaultier have reported a stepwise cross-coupling reaction of (E )-(2-bromoethenyl)diisopropoxyborane with methoxyalkenylzinc chloride or -trimethylsilylvinylzinc chloride and organic halides by using PdCl2(PPh3)2 as the catalyst to form ,-unsaturated ketones or (E)-olefins in good yields with high (E)-stereoselectivities (Scheme 29).[150] – [152] Tius and co-workers have shown that the chlorozinc derivative of sugar could give much better results in the cross-coupling reaction with iodoanthracene by the aid of an active Pd catalyst, generated in situ by the reduction of PdCl2(PPh3)2with diisobutylaluminum hydride in THF
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
685
CN CN ZnBr
O
NH2 X
NH2
PdCl2(dppf) cat. 98%
O
X = Br, I Scheme 27
HC C CH2OMe
t-BuOK
OMe 1. n-BuLi H2C C C H
2. ZnCl2
OMe H2C C C ZnCl RX Pd cat. R = aryl, alkenyl
O R
OMe
H+
H2C C C R
27−84% Scheme 28
Pd cat.
B(OPr-i)2
base. 2. H 71%
ZnCl
OMe Br
B(OPr-i)2
1. PhI, Pd cat.
Me
Ph
+
O
OMe Pd cat. ZnCl
B(OPr-i)2 SiMe3
PhI, Pd cat. base 81%
Ph SiMe3
SiMe3
Scheme 29
(Scheme 30).[153] Friesen and co-workers have also reported the [PdCl2(PPh3)2]-catalyzed cross-coupling of 2-furylzinc chloride or 2-furyldimethoxyborane with iodo-glucal to form C-furyl glucals in good yields.[154],[155] Anderson and co-workers have demonstrated the use of oxazol-2-ylzinc chloride has great advantage over the use of the corresponding tin reagent in the Pd-catalyzed cross-coupling of iodoindole derivatives in both yield and toxicity aspects.[156] Ennis and Gilchrist have reported that the [Pd(PPh3)4]-catalyzed crosscoupling reaction of (1-bromovinyl)trimethylsilane with 2-thienyl-, 2-furyl-, or 3-furylzinc bromide may give both 1- and 2-substituted vinylsilanes in about 1:1 ratio (Scheme 31).[157] Gilchrist, Kemmitt, and Germain have reported that the [Pd(PPh3)4]-catalyzed cross-coupling reaction of 2-bromocyclopentene-1-carboxaldehyde N,N-dimethylhydrazone with 2-furyl- and 2thienylzinc chlorides provides a route to the corresponding 2-heteroaryl-cyclopentene-1-carboxaldehyde dimethylhydrazones. These compounds could be cyclized under flash vacuum pyrolysis at 600 °C and 103 mmHg to give 6,7-dihydro-5H-2-pyrindines (Scheme 32).[158] The
686
III Pd-CATALYZED CROSS-COUPLING
OMOM
OTBS TBSO
I
DIBAL-H
+
Me
O
PdCl2(PPh3)2 cat.
ZnCl
OTBS
OMOM
TBSO
OMOM
Me
O OMOM
79% Scheme 30
SiMe3
+ ArZnBr
SiMe3
Pd(PPh3)4 cat. 80−89%
Br
Ar (1
SiMe3
+ Ar :
1)
Ar = 2-thienyl, 2-furyl, 3-furyl Scheme 31
Br
Z
RZnCl
10−3 mmHg 53%
Pd(PPh3)4 cat.
N NMe2
R = 2-thienyl, 2-furyl
600 °C
N NMe2 51−52%
Z N Z = O, S
Scheme 32
cross-coupling product from 2-bromocyclopentene-1-carboxaldehyde N,N-dimethylhydrazone with -trimethylsilylvinylzinc chloride may undergo cyclization at or below 60 °C with a loss of dimethylamine.[158] – [160] Normally, -trimethylsilylvinylzinc chloride may couple with aryl, 2- or 3-heteroaryl, and alkenyl halides in the presence of a pertinent Pd catalyst to form regio- and stereoselective products.[39],[161] It is noted that trimethylsilylmethylzinc chloride may couple with (Z)-2-bromo-1-alkenylboranes, prepared from the bromoboration of 1-alkynes with tribromoborane, in the presence of Pd catalyst to give 2,2-disubstituted alkenylboranes, which in turn can be used for further Pd-catalyzed cross-coupling to form the trisubstituted alkenes directly.[162] Treatment of the allylsilane, obtained from the first step in the previous reaction, with acid could give 2-methyl-1-alkenes in good yields.[7],[162] Chatani and co-workers have reported the use of (Me3SiCH2)2Zn, Me3SiI, and phenyl acetylene to form (E)-2-phenyl-1,3bis(trimethylsilyl)-2-phenylprop-1-ene in 66% yield.[163] Kercher and Livinghouse also have reported the [PdCl2(PPh3)2]-catalyzed cross-coupling of (Me3SiCH2)2Zn with 1,1-dibromoalkenes to form 1,1-bis(trimethylsilylmethyl)-alkenes.[164] Tamao and co-workers have reported that the cross-coupling of (diisopropoxymethylsilyl)-methylzinc chloride with aryl bromides followed by oxidation could give benzyl alcohols in fair
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
Br (i-PrO)Me2SiCH2ZnCl + CO2Me
1. PdCl2(dppf) cat.
687
O
2. CH3CO3H
O 90% Scheme 33
to good yields.[165] Here, (diisopropoxymethylsilyl)methylzinc chloride reagent serves as a nucleophilic hydroxymethylating agent of aryl halide via Pd-catalyzed cross-coupling and subsequent oxidative cleavage of the silicon–carbon bond (Scheme 33).
REFERENCES [1] E. Negishi, in Current Trends in Organic Synthesis, H. Nozaki, Ed., Pergamon, New York, 1983, 269–280. [2] E. Negishi and F. T. Luo, J. Org. Chem., 1983, 48, 1562. [3] M. G. Saulnier, J. F. Kadow, M. M. Tun, D. R. Langley, and D. M. Vyas, J. Am. Chem. Soc., 1989, 111, 8320. [4] M. Satoh, N. Miyaura, and A. Suzuki, Chem. Lett., 1986, 1329. [5] N. Miyaura, M. Satoh, and A. Suzuki, Tetrahedron Lett., 1986, 27, 3745. [6] J. R. Waas, A. Sidduri, and P. Knochel, Tetrahedron Lett., 1992, 33, 3717. [7] T. Moriya, N. Miyaura, and A. Suzuki, Chem. Lett., 1993, 1429. [8] R. D’Alessio and A. Rossi, Synlett., 1996, 513. [9] J. G. Grieb and D. M. Ketcha, Synth. Commun., 1995, 25, 2145. [10] C. Coudret and V. Mazenc, Tetrahedron Lett., 1997, 30, 5293. [11] M. A. F. Brandão, A. B. de Oliveira, and V. Snieckus, Tetrahedron Lett., 1993, 34, 2437. [12] K. Jones, M. Keenan, and F. Hibbert, Synlett., 1996, 509. [13] R. Rossi, F. Bellina, and A. Carpita, Synlett., 1996, 356. [14] I. Kaswasaki, M. Yamashita, and S. Ohta, Chem. Commun., 1994, 2085. [15] T. Ishiyama, M. Murata, A. Suzuki, and N. Miyaura, Chem. Commun., 1995, 295. [16] M. J. Burk, J. R. Lee, and J. P. Martinez, J. Am. Chem. Soc., 1994, 116, 10847. [17] H. Finch, D. H. Reece, and J. T. Sharp, J. Chem. Soc. Perkin Trans. I, 1994, 1193. [18] S. Gronowitz and D. Peters, Heterocycles, 1990, 30, 645. [19] F. Bracher and D. Hildebrand, Liebigs Ann. Chem., 1992, 1315. [20] B. J. Newhouse, A. I. Meyers, N. S. Sirisoma, M. P. Braun, and C. R. Johnson, Synlett, 1993, 573. [21] W. Hanefeld and M. Jung, Liebigs Ann. Chem., 1994, 59. [22] W. C. Shieh and J. A. Carlson, J. Org. Chem., 1992, 57, 379. [23] N. Yasuda, L. Xaier, D. L. Rieger, Y. Li, A. E. DeCamp, and U. H. Dolling, Tetrahedron Lett., 1993, 34, 3211. [24] B. Joseph, B. Malapel, and J. Y. Mérour, Synth. Commun., 1996, 26, 3289. [25] B. E. Armer, J. S. Barlow, C. J. Dutton, D. H. J. Greenway, S. D. W. Greenwood, N. Lad, and I. Tommasini, Bioorg. Med. Chem. Lett., 1997, 7, 2585. [26] M. Ishikura, Chem. Commun., 1995, 409. [27] M. Ishikura, M. Terashima, K. Okamura, and T. Date, Chem. Commun., 1991, 1219.
688
III Pd-CATALYZED CROSS-COUPLING
[28] Y. Kawanaka, N. Ono, Y. Yoshida, S. Okamoto, and F. Sato, J. Chem. Soc. Perkin Trans. I, 1996, 715. [29] J. A. Soderquist and G. León-Colón, Tetrahedron Lett., 1991, 32, 43. [30] J. A. Soderquist, B. Santiago, and I. Rivera, Tetrahedron Lett., 1990, 31, 4981. [31] V. N. Kalinin and S. F. Min, J. Organomet. Chem., 1988, 352, C34. [32] S. Araki, M. Ohmura, and Y. Butsugan, Bull. Chem. Soc. Jpn., 1986, 59, 2019. [33] A. Pelter, M. Rowlands, and G. Clements, Synthesis, 1987, 51. [34] E. Negishi, F. T. Luo, and C. L. Rand, Tetrahedron Lett., 1982, 23, 27. [35] P. V. Fish, Synth. Commun., 1996, 26, 433. [36] Y. Sugihara and K. Ogasawara, Synlett., 1994, 665. [37] L. Hevesi, B. Hermans, and C. Allard, Tetrahedron Lett., 1994, 35, 6729. [38] A. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett., 1981, 22, 5319. [39] A. Minato, K. Suzuki, K. Tamao, and M. Kumada, Tetrahedron Lett., 1984, 25, 83. [40] C. Moineau, V. Bolitt, and D. Sinou, Chem. Commun., 1995, 1103. [41] G. Buono, C. Siv, G. Peiffer, C. Triantaphylides, P. Denis, A. Mortreux, and F. Petit, J. Org. Chem., 1985, 50, 1781. [42] F. Fotiadu, P. Cros, B. Faure, and G. Buono, Tetrahedron Lett., 1990, 31, 77. [43] N. A. Bumagin, P. G. More, and I. P. Beletskaya, J. Organomet. Chem., 1989, 364, 231. [44] N. A. Bumagin, P. G. More, and I. P. Beletskaya, J. Organomet. Chem., 1989, 365, 379. [45] D. P. Matthews, P. P. Waid, J. S. Sabol, and J. R. McCarthy, Tetrahedron Lett., 1994, 35, 5177. [46] D. P. Matthews, R. S. Gross, and J. R. McCarthy, Tetrahedron Lett., 1994, 35, 1027. [47] G.-Q. Shi, Z.-Y. Cao, and X.-B. Zhang, J. Org. Chem., 1995, 60, 6608. [48] A. G. Barrett and J. T. Kohrt, Synlett., 1995, 415. [49] G. T. Crisp, Synth. Commun., 1989, 19, 307. [50] B. Jousseaume, H. Kwon, J. B. Verlhac, F. Denat, and J. Dubac, Synlett., 1993, 117. [51] C. Pedregal, J. Ezquerra, and C. Ramirez, J. Chem. Res. (S), 1996, 294. [52] S. V. Calenbergh, C. L. M. J. Verlinde, J. Soenens, A. de Bruyn, M. Callens, N. M. Blaton, O. M. Peeters, J. Rozenski, W. G. J. Hol, and P. Herdewijn, J. Med. Chem., 1995, 38, 3838. [53] V. Ozola, T. Persson, S. Gronowitz, and A.-B. Hörnfeldt, J. Heterocycl. Chem., 1995, 32, 863. [54] C. Kitamura, S. Tanaka, and Y. Yamashita, Chem. Mater., 1996, 8, 570. [55] P. Wigerinck, C. Pannecouque, R. Snoeck, P. Claes, E. De Clercq, and P. Herdewijn, J. Med. Chem., 1991, 34, 2383. [56] M. E. Hassan, Collect. Czech. Chem. Commun., 1991, 56, 1944. [57] Y. Yang, A.-B. Hörnfeldt, and S. Gronowitz, Synthesis, 1989, 130. [58] P. Björk, T. Aakermann, A.-B. Hörnfeldt, and S. Gronowitz, J. Heterocycl. Chem., 1995, 32, 751. [59] Y. Zhang, A.-B. Hörnfeldt, and S. Gronowitz, J. Heterocycl. Chem., 1995, 32, 771. [60] J. Malm, B. Rehn, A.-B. Hörnfeldt, and S. Gronowitz, J. Heterocycl. Chem., 1994, 31, 11. [61] S. Gronowitz, J. Malm, and A.-B. Hörnfeldt, Collect. Czech. Chem. Commun., 1991, 56, 2340. [62] K. Tamao, S. Yamaguchi, and M. Shiro, J. Am. Chem. Soc., 1994, 116, 11715. [63] L. Antolini, F. Goldoni, D. Iarossi, A. Mucci, and L. Schenetti, J. Chem. Soc. Perkin Trans. 1, 1997, 1957. [64] H. H. Johannes, W. Grahn, A. Reisner, and P. G. Jones, Tetrahedron Lett., 1995, 36, 7225. [65] L. L. Miller and Y. Yu, J. Org. Chem., 1995, 60, 6813. [66] J. Sandosham, K. Undheim, and F. Rise, Heterocycles, 1993, 35, 235.
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
689
[67] K. Tamao, S. Yamaguchi, M. Shiozaki, Y. Nakagawa, and Y. Ito, J. Am. Chem. Soc., 1992, 114, 5867. [68] M. P. Maguire, K. R. Sheets, K. McVety, A. P. Spada, and A. Zilberstein, J. Med. Chem., 1994, 37, 2129. [69] G. Barbarella and M. Zambianchi, Tetrahedron, 1994, 50, 11249. [70] R. Rossi, A. Carpita, M. Ciofalo, and V. Lippolis, Tetrahedron, 1991, 47, 8443. [71] R. Grigg, R. Rasul, J. Redpath, and D. Wilson, Tetrahedron Lett., 1996, 37, 4609. [72] R. Rossi, A. Carpita, and T. Messeri, Synth. Commun., 1991, 21, 1875. [73] S.-K. Kang, E.-Y. Namkoong, and T. Yamaguchi, Synth. Commun., 1997, 27, 641. [74] S.-K. Kang, H.-W. Lee, J.-S. Kim, and S.-C. Choi, Tetrahedron Lett., 1996, 37, 3723. [75] S.-K. Kang, H.-W. Lee, S.-B. Jang, T.-H. Kim, and J.-S. Kim, Synth. Commun., 1996, 26, 4311. [76] H. Nakamura, D. Takeuchi, and A. Murai, Synlett., 1995, 1227. [77] S. S. Labadie, Synth. Commun., 1994, 24, 709. [78] S. Usse, G. Guillaumet, and M. C. Viaud, Tetrahedron Lett., 1997, 38, 5501. [79] P. L. Floch, D. Carmichael, L. Ricard, and F. Mathey, J. Am. Chem. Soc., 1993, 115, 10665. [80] L. S. Liebeskind and J. Wang, J. Org. Chem., 1993, 58, 3550. [81] G. P. Roth, V. Farina, L. S. Liebeskind, and E. Peña-Cabrera, Tetrahedron Lett., 1995, 36, 2191. [82] T. R. Bailey, Tetrahedron Lett., 1986, 27, 4407. [83] D. Peters, A.-B. Hörnfeldt, and S. Gronowitz, J. Heterocycl. Chem., 1991, 28, 1613. [84] P. Rocca, F. Marsais, A. Godard, and G. Quéguiner, Tetrahedron, 1993, 49, 3325. [85] A. J. Gutierrez, T. J. Terhorst, M. D. Matteucci, and B. C. Froehler, J. Am. Chem. Soc., 1994, 116, 5540. [86] L.-L. Gundersen, G. Langli, and F. Rise, Tetrahedron Lett., 1995, 36, 1945. [87] L.-L. Gundersen, A. K. Bakkestuen, A. J. Aasen, H. Øverås, and F. Rise, Tetrahedron, 1994, 50, 9743. [88] L.-L. Gundersen, Tetrahedron Lett., 1994, 35, 3155. [89] L. S. Liebeskind and J. Wang, Tetrahedron, 1993, 49, 5461. [90] G. Kennedy and A. D. Perboni, Tetrahedron Lett., 1996, 37, 7611. [91] R. R. Hark, D. B. Hauze, O. Petrovskaia, M. M. Joullie, R. Jaouhari, and P. McComiskey, Tetrahedron Lett., 1994, 35, 7719. [92] G. Langli, L.-L. Gundersen, and F. Rise, Tetrahedron, 1996, 52, 5625. [93] H. Park, J. Y. Lee, Y. S. Lee, J. O. Park, S. B. Koh, and W. H. Ham, J. Antibiotics, 1994, 47, 606. [94] M. H. Sosabowski and P. Powell, J. Chem. Res. (S), 1997, 12. [95] D. Peters, A.-B. Hörnfeldt, and S. Gronowitz, J. Heterocyclic. Chem., 1990, 27, 2165. [96] R. Grigg, J. Redpath, V. Sridharan, and D. Wilson, Tetrahedron Lett., 1994, 35, 7661. [97] J. Malm, P. Björk, S. Gronowitz, and A.-B. Hörnfeldt, Tetrahedron Lett., 1992, 33, 2199. [98] H. M. R. Hoffmann, K. Gerlach, and E. Lattmann, Synthesis, 1996, 164. [99] P. Gmeiner, J. Kraxner, and B. Bollinger, Synthesis, 1996, 1196. [100] G. Palmisano and M. Santagostino, Helv. Chim. Acta 1993, 76, 2356. [101] E. Desarbre, S. Coudret, C. Meheust, and J. Y. Mérour, Tetrahedron, 1997, 53, 3637. [102] R. L. Hudkins, J. L. Diebold, and F. D. Marsh, J. Org. Chem., 1995, 60, 6218. [103] G. Palmisano and M. Santagostino, Synlett., 1993, 771. [104] R. Grigg, J. Redpath, V. Sridharan, and D. Wilson, Tetrahedron Lett., 1994, 35, 4429. [105] S. S. Labadie and E. Teng, J. Org. Chem., 1994, 59, 4250. [106] C. Booth, H. Imanieh, P. Quayle, and Lu Shui-Yu, Tetrahedron Lett., 1992, 33, 413.
690 [107] [108] [109] [110] [111] [112]
[113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144]
III Pd-CATALYZED CROSS-COUPLING
P. A. Lander and L. S. Hegedus, J. Am. Chem. Soc., 1994, 116, 8126. A. Dondoni, G. Fantin, M. Fogagnolo, A. Medici, and P. Pedrini, Synthesis, 1987, 693. M. Kosugi, M. Koshiba, A. Atoh, H. Sano, and T. Migita, Bull. Chem. Soc. Jpn., 1986, 59, 677. A. Dondoni, M. Fogagnolo, A. Medici, and E. Negrini, Synthesis, 1987, 185. H. Yoshioka, Y. Matsuya, T. Choshi, E. Sugino, and S. Hibino, Chem. Pharm. Bull., 1996, 44, 709. N. J. S. Harmat, R. Giorgi, F. Bonaccorsi, G. Cerbai, S. M. Colombani, A. R. Renzetti, R. Cirillo, A. Subissi, G. Alagona, C. Ghio, F. Arcamone, A. Giachetti, F. Paleari, and A. Salimbeni, J. Med. Chem., 1995, 38, 2925. M. D. Cliff and S. G. Pyne, Tetrahedron, 1996, 52, 13703. M. G. Hoffmann, Tetrahedron, 1995, 51, 9511. K. Yagi, T. Ogura, A. Numata, S. Ishii, and K. Arai, Heterocycles, 1997, 45, 1463. T. Sakamoto, F. Shiga, D. Uchiyama, Y. Kondo, and H. Yamanaka, Heterocycles, 1992, 33, 813. A. Dondoni, M. Fogagnolo, G. Fantin, A. Medici, and P. Pedrini, Tetrahedron Lett., 1986, 27, 5269. M. Kosugi, A. Fukiage, M. Takayanagi, H. Sano, T. Migita, and M. Satoh, Chem. Lett., 1988, 1351. G. Palmisano and M. Santagostino, Tetrahedron, 1993, 49, 2533. M. Iyoda, Y. Kuwatani, N. Ueno, and M. Oda, Chem. Commun., 1992, 158. U. Kux and M. Iyoda, Chem. Lett., 1994, 2327. C. R. Davis and D. J. Burton, Tetrahedron Lett., 1996, 37, 7237. P. L. Heinze and D. J. Burton, J. Org. Chem., 1988, 53, 2714. J. P. Gillet, R. Sauvêtre, and J. F. Normant, Synthesis, 1986, 538. M. Amat, S. Hadida, and J. Bosch, Tetrahedron Lett., 1993, 34, 5005. M. Amat, S. Hadida, S. Sathyanarayana, and J. Bosch, Tetrahedron Lett., 1996, 37, 3071. A. Pimm, P. Kocienski, and S. D. A. Street, Synlett., 1992, 886. C. E. Russell and L. S. Hegedus, J. Am. Chem. Soc., 1983, 105, 943. P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1990, 31, 1889. D. Y. Yang, Y. Zhang, and X. Huang, J. Chem. Res. (S), 1997, 298. A. Arcadi, A. Burini, S. Cacci, M. Delmastro, F. Marinelli, and B. Pietroni, Synlett, 1990, 47. S. Hyuga, S. Hara, and A. Suzuki, Bull. Chem. Soc. Jpn., 1992, 65, 2303. F. T. Luo, S. L. Fwu, W. S. Huang, Tetrahedron Lett., 1992, 33, 6839. F. T. Luo and L. C. Hsieh, J. Org. Chem., 1996, 61, 9060. F. T. Luo and R. T. Wang, Heterocycles, 1990, 31, 1543. F. T. Luo and R. T. Wang, Heterocycles, 1990, 31, 2181. F. T. Luo and R. T. Wang, Heterocycles, 1991, 32, 2365. R. T. Wang, F. L. Chou, and F. T. Luo, J. Org. Chem., 1990, 55, 4846. A. Minato, J. Org. Chem., 1991, 56, 4052. G. Mignani, F. Leising, R. Meyrueix, and H. Samson, Tetrahedron Lett., 1990, 31, 4743. V. N. Kalinin, O. S. Shilova, D. S. Okladnoy, and H. Schmidhammer, Mendeleev Commun., 1996, 244. F. Bellina, A. Carpita, M. De Santis, and R. Rossi, Tetrahedron Lett., 1994, 35, 6913. K. Takahashi, T. Suzuki, K. Akiyama, Y. Ikegami, and Y. Fukazawa, J. Am. Chem. Soc., 1991, 113, 4576. M. B. Goldfinger, K. B. Crawford, and T. M. Swager, J. Am. Chem. Soc., 1997, 119, 4578.
III.2.13.2 OTHER -HETERO-SUBSTITUTED ORGANOMETALS IN CROSS-COUPLING
[145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158] [159] [160] [161] [162] [163] [164] [165]
691
C. Amatore, A. Jutand, S. Negri, and J. F. Fauvarque, J. Organomet. Chem., 1990, 390, 389. A. Pelter, M. Rowlands, and I. H. Jenkins, Tetrahedron Lett., 1987, 28, 5213. R. M. Keenan and L. I. Kruse, Synth. Commun., 1989, 19, 793. G. P. Roth and C. E. Fuller, J. Org. Chem., 1991, 56, 3493. J. B. Campbell, Jr., J. W. Firor, and T. W. Davenport, Synth. Commun., 1989, 19, 2265. M. Ogima, S. Hyuga, S. Hara, and A. Suzuki, Chem. Lett., 1989, 1959. C. Mazal and M. Vaultier, Tetrahedron Lett., 1994, 35, 3089. S. Hyuga, N. Yamashina, S. Hara, and A. Suzuki, Chem. Lett., 1988, 809. M. A. Tius, J. G. Galeno, X. Q. Gu, and J. H. Zaidi, J. Am. Chem. Soc., 1991, 113, 5775. R. W. Friesen, R. W. Loo, and C. F. Sturino, Can. J. Chem., 1994, 72, 1262. R. W. Friesen and R. W. Loo, J. Org. Chem., 1991, 56, 4821. B. A. Anderson, L. M. Becke, R. N. Booher, M. E. Flaugh, N. K. Harn, T. J. Kress, D. L. Varie, and J. P. Wepsiec, J. Org. Chem., 1991, 62, 8634. D. S. Ennis and T. L. Gilchrist, Tetrahedron Lett., 1989, 30, 3735. T. L. Gilchrist, P. D. Kemmitt, and A. L. Germain, Tetrahedron, 1995, 51, 9119. T. L. Gilchrist and M. A. M. Healy, Tetrahedron Lett., 1990, 31, 5807. T. L. Gilchrist and M. A. M. Healy, Tetrahedron, 1993, 49, 2543. L. Labaudiniere and J. F. Normant, Tetrahedron Lett., 1992, 33, 6139. Y. Satoh, H. Serizawa, N. Miyaura, S. Hara, and A. Suzuki, Tetrahedron Lett., 1988, 29, 1811. N. Chatani, N. Amishiro, T. Morii, T. Yamashita, and S. Murai, J. Org. Chem., 1995, 60, 1834. T. Kercher and T. Livinghouse, J. Am. Chem. Soc., 1996, 118, 4200. K. Tamao, N. Ishida, and M. Kumada, J. Org. Chem., 1983, 48, 2120.
O RC
C
+
Pd
XAr XC
C
III.2.14 Palladium-Catalyzed CrossCoupling Involving -Hetero-Substituted Compounds III.2.14.1 Palladium-Catalyzed -Substitution Reactions of Enolates and Related Derivatives Other than the Tsuji–Trost Allylation Reaction EI-ICHI NEGISHI
1. INTRODUCTION AND BACKGROUND
-Substitution of carbonyl compounds with a carbon group, as exemplified by enolate alkylation,[1],[2] is a fundamentally important organic transformation. While there are many favorable cases of enolate alkylation, it has also been plagued with some serious limitations and difficulties. Thus, the scope of -substitution of alkali and alkaline earth metal enolates under the usual thermal conditions is essentially limited to introduction of certain types of alkyl groups, such as Me, primary alkyl, allyl, and benzyl. Although its scope was expanded so as to include -arylation through the development of radical processes (SRN1),[3] its application to -alkenylation and -alkynylation remains largely unexplored. Among other methods for -substitution, -alkenylation and -alkynylation of -keto ester with alkenyl- and alkynylleads[4]–[6] are noteworthy. In view of their somewhat circuitous nature and the use of Pb(OAc)4 as a stoichiometric reagent, however, the development of alternate and potentially more favorable procedures would be desirable. Some other indirect methods for -alkenylation of carbonyl compounds[7]–[9] should also be noted. Despite these numerous developments, it is fair to state that none has emerged as a general synthetic method for -substitution of carbonyl compounds with various types of Csp3, Csp2, and Csp groups. Concurrently, several different versions of Ni- and Pdcatalyzed methods for -substitution of carbonyl compounds have been developed over the past few decades. They are, in fact, discussed in several sections spread over Parts III–V, as indicated below. Several representative methods are shown in Scheme 1. Currently, the most extensively developed and general -substitution methodology consists of several mutually related indirect protocols using ,-unsaturated enones as Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
693
694
III Pd-CATALYZED CROSS-COUPLING
Several Pd-catalyzed methods for the synthesis of α-substituted carbonyl compounds Method I (this section, i.e., Sect. III.2.14.1, and Sect. V.2.1 (the Tsuji−Trost reaction)) M O RX +
O
cat. PdLn
C C
R C C
Method II (this section, i.e., Sect. III.2.14.1, and Sect. III.2.14.2) O
O
cat. PdLn
RM + X C C
R C C
Method IIIa (Sect. III.2.14.2) X O RM +
C C C
R O
cat. PdLn
C C C
R
Method IIIb (Sect. III.2.14.2) M O RX +
C C C
HC CH C R O
cat. PdLn
C C C
Method IV (Sect. III.2.14.2, see also Sect. III.2.9) X1 X1 RM + X C C C
O
cat. PdL n
O
R C C C
R C C CH
Method V (Sect. IV.2.1, the Heck reaction) OZ RX + H C C
cat. PdLn
O R C C
Method VI (Sect. V.3.4, Wacker-type C C bond formation) M O
C C H
cat. PdLn
C
C C H
C
O C C C C
PdLn R = C groups. M = Metal or metal groups. X = Heteroatom groups (e.g., halogen, O). Scheme 1
carbonyl compounds represented by Methods I and II in Scheme 2, which are discussed in Sect. III.2.14.2. Although indirect, it is applicable to the introduction of a wide range of carbon groups including alkenyl, aryl, alkynyl, as well as alkyl and benzyl groups in a highly stereo- and regio-controlled manner. -Substituted enones thus obtained can be converted to the corresponding saturated derivatives via conjugate reduction in cases where such a transformation is desirable. Interestingly, attempts to allylate -iodoenones with allylmetals containing Zn under the influence of a Pd catalyst led only to the carbonyl addition products,[10] even though the Pd-catalyzed reaction of -stannylenone with allylic electrophiles proceeds well.[11]
-SUBSTITUTION REACTIONS OF ENOLATES
III.2.14.1
695
Protocols IA and IB 1. RM, cat. PdLn 2. 2N HCl
O
Protocol IA 1. halogenation 2. (CH2OH)2, TsOH
O
n
O X
1. n -BuLi 2. ZnX2 3. RX, cat. PdLn 4. 2N HCl
n
O
conj.
O
R red.
R
n
n
Protocol IB
Protocols IIA and IIB O
I
iodination
O
n
RM, cat. PdLn Protocol IIA
O
Z
n
metallation
O
R conj. red.
n
RI
O
R
n
M cat. PdLn
n
Protocol IIB
Protocols IIIA and IIIB O
Z
1. iodination 2. NaBH4, CeCl3 3. protection
n
OZ1 n
I
1. RM, cat. PdLn 2. deprotection 3. oxidation Protocol IIIA
O
metallation
R conj.
O
red.
OZ1
1. RX, cat. PdLn
n
R
n
M 2. deprotection 3. oxidation
n
Protocol IIIB
n = 1 or 2. M = Zn, Sn, Cu, B, and other metals. R = C group. Z = H, Si, or Sn group. X = I, Br, or Cl. Z 1 = Si or another protecting group. Scheme 2
For -allylation and -propargylation of carbonyl compounds, however, the Tsuji–Trost reaction and related reactions discussed extensively in Part V (Sect. V.2.1) provide a wide range of very satisfactory procedures. Although the Tsuji–Trost reaction has mostly been carried out by using extrastabilized enolates, such as acetoacetates and malonates, subsequent decarboxylation provides more usual -substituted ketones (Scheme 3). With the use of Zn, B, and Sn as enolate countercations, even “ordinary” ketones, aldehydes, and carboxylic acid derivatives, such as esters and amides, can be satisfactorily and selectively -allylated in the presence of Pd catalysts (Scheme 4), as discussed in Sect. V.2.1.4. There are other more indirect and hence less obvious methods for the preparation of -substituted carbonyl compounds via Pd-catalyzed or Pd-promoted C—C bond formation at a carbon center to the carbonyl group. In Method IV in Scheme 1, -hetero-substituted allylic electrophiles serve as masked carbonyl compounds. After Pd-catalyzed cross-coupling with organometals, the hetero-substituted alkenes may be converted to the desired -substituted carbonyl compounds, as discussed in Sect. III.2.14.2 (Subsect. F.i). For a more general discussion of Pd-catalyzed allylation of organometals, Sect. III.2.9 should be consulted.
696
III Pd-CATALYZED CROSS-COUPLING
, base
X
RCOCH2COOR1
O
O decarboxylation
cat. PdLn
R
R 1
COOR X
(R1OOC)2CHR
, base cat. PdLn
decarboxylation
(R1OOC)2C
HOOC
R
R
Scheme 3 OM
O (H)R
C
CR1R2
CR1R2
(H)R
H
M = Zn, B, Sn, etc.
O
X cat. PdLn X = Cl, OAc, etc.
(H)R
R1
R2
Scheme 4
The Heck reaction of hetero-substituted alkenes (Method V in Scheme 1) can also serve as an indirect method for the preparation of -substituted carbonyl compounds, as discussed in Sect. IV.2.1. Some of the earliest examples are shown in Scheme 5. One largely unsolved difficulty is the general lack of regiospecificity. If and when its satisfactory solution is achieved, the method would provide a potentially general and useful route to -substituted carbonyl compounds.
H2C CHOAc
PhHgCl cat. Li2PdCl4 CuCl2, HOAc [12]
OAc
PhCH2CHO + PhCH CHOAc + PhCH CHPh 63% combined (1.1:1) 34% O
ArHgCl cat. Pd(OAc) 2
O
[13]
Ar (60−75%) O Scheme 5
Finally, the C—C bond formation by the reaction of -complexes of Pd derived from alkenes, dienes, and other -compounds with enolates and related carbon nucleophiles à la Wacker reaction (Method VI in Scheme 1) provides yet another alternative, as exemplified by the results shown in Scheme 6.[14] For a more general discussion of the C—C bond formation via Wacker-type reaction of Pd -complexes with carbanions, the reader is referred to Sect. V.3.4. In this section, attention is focused on the Pd-catalyzed -substitution reactions of enolates and related derivatives represented by Method I in Scheme 1, other than Tsuji–Trost allylation and propargylation. Additionally, its charge-affinity inverted version represented by Method II in Scheme 1 is also discussed. In general, it is advisable to consider simultaneously various other alternatives including those shown in Scheme 1, especially Method III. Indeed, Method III discussed in the following section provides the currently most
III.2.14.1
-SUBSTITUTION REACTIONS OF ENOLATES
697
rigorous method for the synthesis of -substituted carbonyl compounds, often permitting strict control of most of the selectivity aspects including regiochemistry, stereochemistry, and the degree of substitution. Nonetheless, the direct -substitution of carbonyl compounds discussed in this section would be the ultimately satisfactory method provided that all crucial requirements, such as yields and selectivity levels, are satisfied.
R
NaC(COOR)2
+ H
R1
Cl2Pd(MeCN)2 2 NEt3
1
C(COOR)2 R2
R2
R1
R2
R
H Me H Me
H H Me Me
Me Me Et Et
Yield (%) 53 58 93 90 Scheme 6
B. Pd- OR Ni-CATALYZED INTERMOLECULAR -SUBSTITUTION OF CARBONYL AND RELATED DERIVATIVES This area of research most probably began when Semmelhack and co-workers reported both inter- and intramolecular versions of Ni-catalyzed arylation of lithium enolates derived from ketones shown in Scheme 7.[15],[16] This work, however, was not developed further perhaps due, at least in part, to the fact that the same organic transformation was achieved much more satisfactorily by resorting to the SRN1 reaction.[3] Li O Br + H2C CPh O O
O cat. Ni(PPh3)4
N
Ni(COD)2
CH2CPh 65% O H
N
O
I LiO
OMe
O
30% OMe
Scheme 7
In 1977 a couple of independent papers by Fauvarque and Jutand,[17] and by Millard and Rathke[18] reported Ni- or Pd-catalyzed -arylation and -alkenylation of esters. These studies have been slowly but steadily followed by a series of investigations on Pd-catalyzed -substitution of ester enolates, nitriles, and other related derivatives in the late 1970s and 1980s, as detailed in Sect. B.i. In the meantime, Kosugi et al.[19] and Kuwajima and Urabe[20] independently reported what appears to be the first Pd-catalyzed -arylation of ketones by using their
698
III Pd-CATALYZED CROSS-COUPLING
trialkylstannyl derivatives. Despite further investigations mainly by Kosugi in the early 1980s,[21]–[24] however, the scope and synthetic utility of the reaction remained rather limited. Thus, for example, the scope of satisfactory -arylation was largely limited to those of methyl ketones, and no reaction of aldehydes was investigated. More recently, however, Pd-catalyzed -arylation of ketones has been reinvestigated mostly by Buchwald,[25]–[27] Hartwig,[28]–[30] and Miura.[31]–[36] It now appears that the reaction is of considerable synthetic value, which is satisfactorily applicable to -substitution of ketones other than methyl ketones as well as to that of phenols,[31] even though the critical issue of regiochemical control in nonobvious cases still remains largely uninvestigated. These more recent studies are discussed in Sect. B.ii. B.i. Early Studies B.i.a. Pd-Catalyzed -Substitution of Ketones. As mentioned above, the first Pdcatalyzed -substitution of ketones was most probably that reported independently in 1982 by Kosugi et al.[19] and by Kuwajima and Urabe[20] (Scheme 8). In both studies, the nucleophilic reagents derived from ketones were tin enolates that could be generated either by treating enol acetates with trialkyltin methoxides[19] or by treating silyl enol ethers with trialkyltin fluorides.[20] It also appears reasonable to assume that, under most of the cross-coupling conditions, tin enolates are in equilibrium with the corresponding -stannyl ketones. The use of Pd(PPh3)4 or Cl2Pd(PPh3)2 was ineffective, but Cl2Pd(Tol3P)2 was a satisfactory catalyst[19] (Scheme 8). PhBr, toluene cat. Pd(PPh3)4 or Cl2Pd(PPh3)2
OAc MeC CH2
Bu3SnOMe Method A
OSiMe3
Bu3SnF
RC CH2
Method B
O MeCCH2Ph 15−22% (GLC)
O MeCCH2SnBu3
[19]
ArBr, benzene cat. Cl2Pd(o-Tol 3P) 2
OSnBu3 RC CH2
O
PhBr, toluene cat.Cl2Pd(o-Tol 3P)2
[20]
MeCCH2Ph 83% (GLC) O
RCCH2Ar
O RCCH2SnBu3 Scheme 8
Some representative results are summarized in Table 1. These results indicate the following. First, as long as the steric requirements of R are not excessive, -arylation can be achieved in moderate-to-excellent yields by using the conditions indicated in Scheme 8. However, the scope is practically limited to -substitution of methyl ketones. The yields of -phenylation observed with 3-pentanone and cyclohexanone were 0% and 15%, respectively,[20] although more favorable results have also been reported in similar cases[21] (Scheme 9). Also disappointing is the yield of -phenylation of pinacolone (29%). Second, various substituents in Ar, such as Me, p-MeO, p-Me2N, and p-Cl, can be accommodated and little electronic effects are noticeable. Curiously, the use of aryl iodides appears to be much less desirable than that of aryl bromides,[20] as indicated by the results shown in Scheme 9.
III.2.14.1
-SUBSTITUTION REACTIONS OF ENOLATES
699
TABLE 1. Pd-Catalyzed -Arylation of Tin Enolates Derived from Methyl Ketones with Aryl Bromides in the Presence of Cl2Pd(o-Tol3P)2 (cf. Scheme 8) R of RCOMe
Ar of ArBr
Me Me Me Me Me Me Me Me n-C7H15 n-C7H15 Me2CH(CH2)2 Me2CH(CH2)2 Me2CH(CH2)2 Me2CH(CH2)2 s-Bu t-Bu Me2CRCH
Ph o-Tol m-Tol p-Tol p-Me2NC6H4 p-Anisyl p-ClC6H4 p-MeCOC6H4 Ph p-Anisyl Ph o-Tol p-Anisyl p-MeCOC6H4 Ph Ph Ph
a b
Method A A A A A A A A B B B B B B B B B
a
Solvent
Temperature (C)
Toluene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene Benzene
100 100 100 100 100 100 100 100 reflux reflux reflux reflux reflux reflux reflux reflux reflux
Yield b of RCOCH2Ar (%) Reference 78 91 88 80 71 51 73 64 61 62 60(84) 59 58(86) —(70) 47 29 —(56)
[19] [19] [19] [19] [19] [19] [19] [19] [20] [20] [20] [20] [20] [20] [20] [20] [20]
See Scheme 8 for A and B. The numbers in parentheses are the yields observed with 1.5 equiv of ArBr.
O
OSnBu3 Et
Me + PhBr
I [20]
OSnBu3
EtCCHPh 0% Me O Ph
I
+ PhBr
[20]
98% E) O Hex-n 85%( >98% Z ) O
OM Hex-n 2 N HCl
Hex-n CuBr
Scheme 19
Hex-n
III.2.14.2 CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS
737
methylcyclohexanone from 6-methyl-2-cyclohexenone in 55% overall yield (Scheme 20).[77] Thus, the feasibility, dependability, and highly selective nature of Protocol IB have been firmly established by the results shown in Schemes 19 and 20. Later studies have further demonstrated that alkenyl- and alkynylstannanes also react analogously (Scheme 21).[79]–[81] Despite its dependability and high selectivity, Protocol I is indirect and cumbersome, and a more direct method—Protocol II— is clearly desirable.
O Me
1. Br2, NEt3 O 2. (CH2OH)2 Me TsOH
1. n-BuLi 2. ZnCl2 Hex-n 3. I O 1% Pd(PPh3)4 Br 4. 2 N HCl Me
1. LiAlH(OMe)3 CuBr Me 2. 2 N HCl
O Hex-n
O Hex-n
Scheme 20 X O
O
X
Bu3Sn cat. PdLn
O
O
O
O
Br I OTf
[79]
O
O
I
Bu3SnC CBu-t cat. Pd(PPh3)4
Pd (%) Pd(PPh3)4 (5) Pd(PPh3)4 (5) Cl2Pd(PPh3)2 (3)
Yield (%) 97%
(54)
The similar reaction of diarylphosphine oxides with aryl halides and triflates has been used more recently to prepare a variety of ligands for asymmetric catalysis. Many of these reactions involve additions of secondary phosphine oxides to di- or monotriflates derived from binaphthol because the triflates are more accessible than 2,2-1,1-dibromobinaphthol. Workers at Syntex described a procedure to use the ditriflate of binaphthol to prepare mixed phosphine oxide, hydroxo ligands, and the monophosphine oxide, binaphthyldiphenylphosphine oxide.[173] Hayashi then developed a route to a number of chiral monodentate phosphine ligands with a 2-(diphenylphosphino)-2-alkoxy-1,1-binaphthyl structure (Eq. 55).[174] Reaction of the ditriflate with diphenylphosphine oxide in the presence of a catalyst generated from Pd(OAc)2 and bis-1,4-(diphenylphosphino)butane gave the substitution product in 95% yield. This product was hydrolyzed, alkylated, and reduced in good yield in all cases except when a methoxymethyl group was installed. In this case reduction followed by alkylation gave the best results. The monosubstitution product was also converted to a 2-alkyl-2-phosphino-1,1-binaphthyl ligand by a Ni-catalyzed Grignard reaction at the remaining triflate. Most recently, Kocovsky has used a similar synthetic approach to convert his 2-amino-2-hydroxy-1,1-binaphthyl (NOBIN) to amino phosphino binaphthyl (MAP) ligands. Conversion of NOBIN to the triflate and phosphination followed by reduction generates the MAP ligands.[175],[176] Finally, Cho and
III.3.2 Pd-CATALYZED AMINATION OF ARYL HALIDES AND RELATED REACTIONS
1089
Shibasaki have prepared mixed diphenylphosphino diphenylarsino ligands by reacting diphenylarsine in the presence of 10% DPPE-ligated Ni(0) with the monophosphine monotriflate that is generated by P—C coupling of a secondary phosphine oxide and reduction with silane.[177] Doucet and Brown used this general method to prepare QUINAP, as shown in Eq. 56.[178]
OTf OTf
Ph 2 POH (2 equiv) Pd(OAc)2 (5 mol %) dppb (5 mol %)
EtMgBr NiCl2(dppe) OT f P(O)Ph2
CH2 CH 3 P(O)P h2
95% 1. aq. NaOH 2. R-X, K 2 CO3
OR HSiCl3 P(O)Ph2 NEt3
OR PPh2 (55)
N OTf
1:1 DMSO Ar2 POH Pd(OAc)2 (4 mol %) Pr i2 EtN dppb (4 mol %) HSiCl 3 NEt 3
N P(O)Ar2
N PAr 2 (56)
1090
III Pd-CATALYZED CROSS-COUPLING
E.ii.b. Synthesis of Phosphorus(III) Coupling Products. In many cases, secondary phosphines, rather than secondary phosphine oxides, can be used as substrates. In one case, phosphine oxides were generated even when starting with secondary phosphines,[179] but this result is atypical. In 1980, Sokolov and co-workers published a stoichiometric P—C bond-forming process to generate one of Kumada’s phosphino amine ligands,[180] and in 1987, Tunney and Stille reported catalytic P—C bondforming cross-coupling reactions to generate phosphine products. As shown in Eq. 57, Stille used stannyl and silylphosphides, with the less toxic silylphosphides reacting at a satisfactory rate.[2] The catalyst used was either (PPh3)2PdCl2 or (CH3CN)2PdCl2. Yields ranged from 55% to 94%, and the reaction tolerated a variety of functional groups on the arene, including esters, ketones, trifluoromethyl groups, and amides. Aldehyde, hydroxyl, amino, and nitro groups were not tolerated. Related chemistry using silylphosphides has been used by Mathey to prepare phosphino-substituted phosphinines from bromophosphinines[181] and by Beletskaya to prepare both 2alkenylphosphines from vinyl halides and unsymmetrical secondary phosphines from silylphosphines.[182],[183] R
R I + Me3 Si(or Sn)PPh 2
Pd(PPh3 )2 Cl 2
PPh2 (57)
It is now common that secondary phosphine and base are used instead of isolated silylphosphine reagents. A paper by Cai and co-workers from Merck Process Research showed that the single substitution products of phosphine oxides with the ditriflate of binaphthol could be converted under catalytic conditions to the disubstitution products with either secondary phosphine or phosphine oxide.[184] Thus, (DPPE)NiCl2 catalyzes the double addition of diphenylphosphine to the ditriflate to generate BINAP. A number of researchers have either used this system or palladium catalysts to generate phosphines. McCarthy and Guiry and Shibasaki and co-workers each used Ni- catalyzed processes to prepare phosphines from aryl halides and secondary phosphines. Guiry prepared QUINAP analogs and Shibasaki prepared BINAs.[185],[186] Others have used palladium catalysts with similar reagents. Beletskaya and co-workers showed that not only silylphosphines but secondary aryl phosphines and base would react with vinyl halides in the presence of palladium catalysts to form - or -alkoxyand - or -aminovinyl phosphines.[187] Stelzer and co-workers used water-soluble secondary phosphines, aryl halides, and base in the presence of palladium acetate or (PPh3)4Pd(0) catalyst to generate water-soluble tertiary phosphines,[188] and Casalnuovo and Calabrese reported the use of water-soluble catalysts to conduct the coupling of dialkylphosphonates with aryl halides in aqueous acetonitrile mixtures.[189] Several methods have been adopted to manage the air sensitivity of either the secondary phosphine reagents or tertiary phosphine products. For example, Gilbertson used Pd-catalyzed chemistry to install a phosphino group into a peptide.[190] Conversion of a tyrosine or related unnatural aromatic residue to a triflate and subsequent coupling gave the peptide phosphine. This product was protected as the phosphine sulfide in situ for chromatography. The sulfide can be converted to the phosphine using Rainey nickel.[191] In an alternative procedure, Oshiki and Imamoto have shown that the secondary phosphine boranes can be used under Pd-catalyzed procedures (5% PPh3-ligated Pd(0),
III.3.2 Pd-CATALYZED AMINATION OF ARYL HALIDES AND RELATED REACTIONS
1091
K2CO3) to prepare tertiary phosphine borane products.[192] Straightforward deprotection of the phosphine borane by addition of amines such as DABCO are known.[193] In this case, resolved secondary phosphine boranes were used and the products showed stereochemistry that depended on the sovent and base used.[192] Lipshutz and co-workers subsequently developed a procedure for using phosphine boranes with aryl triflates and nonaflates to generate phosphine borane products.[194] A final procedure that involves the convenient use of diorganophosphine chlorides and aryl halides is based on nickel catalysts, but will be mentioned briefly. Laneman and co-workers reported a procedure by which aryl or vinyl bromides or triflates react with diaryl chlorophosphines using NiCl2(DPPE) and stoichiometric zinc as reductant to generate triarylphosphines in yields ranging from 45% to 95%. The aryl triflates gave the highest yields.[195] E.ii.c. Mechanism of Palladium-Catalyzed P—C Bond Formation. Little mechanistic information has been generated about the P—C bond-forming catalytic process, but the mechanism certainly involves oxidative addition of aryl halide, and most likely involves formation of a palladium phosphide and reductive elimination of phosphine. Transition metal phosphide chemistry is a large body of literature, but few reductive eliminations of phosphines have been reported. Fryzuk and co-workers reported an alkyliridium phosphido complex that reductively eliminates phosphine,[196] while Glueck and coworkers reported more closely related methylplatinum phosphides that resist such reductive elimination.[197] Brown and co-workers did recently generate arylpalladium phosphidoborane complexes at low temperature by addition of KPh2P(BH3) to DPPPligated arylpalladium halide complexes.[198] In the case of the C6F5 complex, the arylpalladium phosphidoborane complex was stable enough to isolate and obtain X-ray structural data. Most of the arylpalladium phosphidoborane complexes were unstable at room temperature, and their reductive elimination behavior was not investigated in detail. F. FUTURE PROSPECTS A glance at the chart of catalysts and transformations shows the types of aromatic C—N bond formation that are unknown or need improvement. The development of catalysts for formation of aryl phosphines by Pd-catalyzed methods has seen less attention, and the improved catalysts for the amination chemistry may also improve the C—P bond-forming processes in certain cases. Furthermore, general procedures for obtaining fast rates with weakly basic conditions for C—N bond formation are desired in most cases. Improvements in rate and turnover number for most aromatic carbon–heteroatom bond formation using aryl chlorides is needed. The development of new catalysts that accomplish these goals and the recent development of highly active catalysts will continue to create new mechanistic questions about the origin of their activity. They also will provide the potential to apply Pd-catalyzed aromatic carbon–heteroatom bond formation to additional synthetic problems. The analysis of these reactions and their use in complex syntheses are likely to accompany the development of improved catalysts in the future. REFERENCES [1] D. Barañano, G. Mann, and J. F. Hartwig, Curr. Org. Chem., 1997, 1, 287. [2] S. E. Tunney and J. K. Stille, J. Org. Chem., 1987, 52, 748.
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[3] T. Migita, T. Shimiza, Y. Asami, J. Shiobara, Y. Kato, and M. Kosugi, Bull. Chem. Soc. Jpn., 1980, 53, 1385. [4] M. Kosugi, T. Ogata, M. Terada, H. Sano, and T. Migita, Bull. Chem. Soc. Jpn., 1985, 58, 3657. [5] K. Takagi, Chem. Lett., 1987, 2221. [6] T. Yamamoto and Y. Sekine, Inorg. Chim. Acta, 1984, 83, 47. [7] D. L. Boger and J. S. Panek, Tetrahedron Lett., 1984, 25, 3175. [8] D. L. Boger, S. R. Duff, J. S. Panek, and M. Yasuda, J. Org. Chem., 1985, 50, 5782. [9] D. L. Boger, S. R. Duff, J. S. Panek, and M. Yasuda, J. Org. Chem., 1985, 50, 5790. [10] M. Kosugi, M. Kameyama, and T. Migita, Chem. Lett., 1983, 927. [11] M. Kosugi, M. Kameyama, H. Sano, and T. Migita, Nippon Kagaku Kaishi, 1985, 3, 547. [12] J. K. Stille and K. S. Y. Lau, Acc. Chem. Res., 1977, 10, 434–442. [13] C. Amatore, A. Jutand, and A. Suarez, J. Am. Chem. Soc., 1993, 115, 9531. [14] C. Amatore, G. Broeker, A. Jutand, and F. Khalil, J. Am. Chem. Soc., 1997, 119, 5176. [15] A. L. Casado and P. Espinet, Organometallics, 1998, 17, 954. [16] H. Bryndza and W. Tam, Chem. Rev., 1988, 88, 1163–1188. [17] M. D. Fryzuk and C. D. Montgomery, Coord. Chem. Rev., 1989, 95, 1–40. [18] R. G. Pearson, J. Am. Chem. Soc., 1963, 85, 3533. [19] R. G. Pearson, J. Chem. Ed., 1968, 45, 643. [20] R. G. Pearson, J. Chem. Ed., 1968, 45, 581. [21] S. Park, A. L. Rheingold, and D. M. Roundhill, Organometallics, 1991, 10, 615. [22] L. A. Villanueva, K. A. Abboud, and J. M. Boncella, Organometallics, 1994, 13, 3921. [23] M. S. Driver and J. F. Hartwig, J. Am. Chem. Soc., 1997, 119, 8232. [24] M. S. Driver and J. F. Hartwig, J. Am. Chem. Soc., 1995, 117, 4708. [25] J. Louie and J. F. Hartwig, J. Am. Chem. Soc., 1995, 117, 11598. [26] C. A. Tolman, Chem. Rev., 1977, 77, 313. [27] C. P. Casey, G. T. Whiteker, M. G. Melville, L. M. Petrovich, J. A. Gavney Jr., and D. R. Powell, J. Am. Chem. Soc., 1992, 114, 5535. [28] C. P. Casey and G. T. Whiteker, Isr. J. Chem., 1990, 30, 299. [29] P. Dierkes and P. W. N. M. van Leeuwen, J. Chem. Soc. Dalton Trans., 1999, 1519. [30] B. C. Hamann and J. F. Hartwig, J. Am. Chem. Soc., 1998, 120, 3694. [31] For a review see: J. F. Hartwig, Synlett, 1997, 329. [32] J. F. Hartwig, Acc. Chem. Res., 1998, 31, 852–860. [33] J. F. Hartwig, in Modern Amination Methods, A. Ricci, Ed., Wiley-VCH, Weinheim, 2000, 195–257. [34] J. F. Hartwig, Angew. Chem. Int. Ed. Engl., 1998, 37, 2046. [35] J. P. Wolfe, S. Wagaw, J.-F. Marcoux, and S. L. Buchwald, Acc. Chem. Res., 1998, 31, 805–818. [36] C. G. Frost and P. Mendonca, J. Chem. Soc. Perkin Trans. and 1, 1998, 2615. [37] B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999, 576, 125. [38] S. Wagaw and S. L. Buchwald, J. Org. Chem., 1996, 61, 7240. [39] M. Nishiyama, T. Yamamoto, and Y. Koie, Tetrahedron Lett., 1998, 39, 617. [40] J. F. Hartwig, M. Kawatsura, S. I. Hauck, K. H. Shaughnessy, and L. M. Alcazar-Roman, J. Org. Chem., 1999, 64, 5575. [41] J.-F. Marcoux, S. Wagaw, and S. L. Buchwald, J. Org. Chem., 1997, 62, 1568. [42] M. S. Driver and J. F. Hartwig, J. Am. Chem. Soc., 1996, 118, 7217. [43] J. P. Wolfe, S. Wagaw, and S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 7215.
III.3.2 Pd-CATALYZED AMINATION OF ARYL HALIDES AND RELATED REACTIONS
[44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84]
1093
J. Louie and J. F. Hartwig, Tetrahedron Lett., 1995, 36, 3609. A. S. Guram, R. A. Rennels, and S. L. Buchwald, Angew. Chem. Int. Ed. Engl., 1995, 34, 1348. J. P. Wolfe and S. L. Buchwald, J. Org. Chem., 1996, 61, 1133. T. Yamamoto, M. Nishiyama, and Y. Koie, Tetrahedron Lett., 1998, 39, 2367. M. Kawatsura and J. F. Hartwig, J. Am. Chem. Soc., 1999, 121, 1473. A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed. Engl., 1998, 37, 3387. A. F. Littke and G. C. Fu, J. Org. Chem. 1999, 64, 10. D. W. Old, J. P. Wolfe, and S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 9722. X. Bei, T. Uno, J. Norris, H. W. Turner, W. H. Weinberg, and A. S. Guram, Organometallics, 1999, 18, 1840. X. Bei, A. S. Guram, H. W. Turner, and W. H. Weinberg, Tetrahedron Lett., 1999, 40, 1237. K. Kamikawa, S. Sugimoto, and M. Uemura, J. Org. Chem., 1998, 63, 8407. P. Molina, A. Arques, and A. Garcia, Tetrahedron Lett., 1997, 38, 7613. V. V. Grushin and H. Alper, Chem. Rev., 1994, 94, 1047–1062. M. Beller, T. H. Reirmeier, C. Reisinger, and W. A. Herrman, Tetrahedron Lett., 1997, 38, 2073. N. P. Reddy and M. Tanaka, Tetrahedron Lett., 1997, 38, 4807. B. C. Hamann and J. F. Hartwig, J. Am. Chem. Soc., 1998, 120, 7369. J. F. Hartwig, unpublished results. J. Louie, M. S. Driver, B. C. Hamann, and J. F. Hartwig, J. Org. Chem., 1997, 62, 1268. J. P. Wolfe and S. L. Buchwald, J. Org. Chem., 1997, 62, 1264. J. Åhman and S. L. Buchwald, Tetrahedron Lett., 1997, 38, 6363. J. P. Wolfe and S. L. Buchwald, Tetrahedron Lett., 1997, 38, 6359. J. Louie and J. F. Hartwig, J. Am. Chem. Soc., 1997, 119, 11695. S. Thayumanavan, S. Barlow, and S. R. Marder, Chem. Mater., 1997, 9, 3231. E. Bellmann, S. Shaheen, S. Thayumanavan, S. Barlow, R. Grubbs, S. Marder, B. Kippelen, and N. Peyghambarian, Chem. Mater., 1998, 10, 1668. J. Louie and J. F. Hartwig, Macromolecules, 1998, 31, 6737. K. Rossen, P. J. Pye, A. Maliakal, and R. P. Volante, J. Org. Chem., 1997, 62, 6462. I. P. Beletskaya, A. G. Bessermertnykh, and R. Guilard, Tetrahedron Lett., 1997, 38, 2287. Y. P. Hong, C. H. Senanayake, T. J. Xiang, C. P. Vandenbossche, G. J. Tanoury, R. P. Bakale, and S. A. Wald, Tetrahedron Lett., 1998, 39, 3121. A. Togni, C. Breutel, A. Schnyder, F. Spindler, H. Landert, and A. Tijani, J. Am. Chem. Soc., 1994, 116, 4062. H. Blaser and F. Spindler, Chimia, 1997, 51, 297. Y. Kubota, S. Nakada, and Y. Sugi, Synlett, 1998, 183. S. I. Hauck, K. V. Lakshmi, and J. F. Hartwig, Org. Lett., 1999, 1, 2057. N. Spetseris, R. E. Ward, and T. Y. Meyer, Macromolecules, 1998, 31, 3158. T. Kanbara, K. Izumi, Y. Nakadani, T. Narise, and K. Hasegawa, Chem. Lett., 1997, 1185. R. A. Singer, J. P. Sadighi, and S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 213. J. P. Sadighi, R. A. Singer, and S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 4960. J. P. Sadighi, M. C. Harris, and S. L. Buchwald, Tetrahedron Lett., 1998, 39, 5327. S. Vyskocil, M. Smrcina, and P. Kocovsky, Tetrahedron Lett., 1998, 39, 9289. S. Wagaw, B. H. Yang, and S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 6621. J. F. Hartwig, Angew. Chem. Int. Ed. Engl., 1998, 37, 2090. S. Jaime-Figueroa, Y. Liu, J. M. Muchowski, and D. G. Putman, Tetrahedron Lett., 1998, 39, 1313.
1094
III Pd-CATALYZED CROSS-COUPLING
[85] G. Mann, M. S. Driver, and J. F. Hartwig, J. Am. Chem. Soc., 1998, 120, 827. [86] J. P. Wolfe, J. Åhman, J. P. Sadighi, R. A. Singer, and S. L. Buchwald, Tetrahedron Lett., 1997, 38, 6367. [87] C. Bolm and J. P. Hildebrand, Tetrahedron Lett., 1998, 39, 5731. [88] J. P. Wolfe, R. A. Rennels, and S. L. Buchwald, Tetrahedron, 1996, 52, 7525. [89] W. Shakespeare, Tetrahedron Lett. 1999, 40, 2035. [90] S.-K. Kang, H.-W. Lee, W.-K. Choi, R.-K. Hong, and J.-S. Kim, Synth. Commun., 1996, 26, 4219. [91] D. V. Davydov and I. P. Beletskaya, Russ. Chem. Bull., 1995, 44, 1141. [92] I. P. Beletskaya, D. V. Davydov, and M. Morenomanas, Tetrahedron Lett., 1998, 39, 5617. [93] I. P. Beletskaya, D. V. Davydov, and M. Morenomanas, Tetrahedron Lett., 1998, 39, 5621. [94] D. Ma and J. Yao, Tetrahedron: Asymmetry, 1996, 7, 3075. [95] D. W. Ma, Y. D. Zhang, J. C. Yao, S. H. Wu, and F. G. Tao, J. Am. Chem. Soc., 1998, 120, 12459. [96] A. Abouabdellah and R. Dodd, Tetrahedron Lett., 1998, 39, 2119. [97] F. Kerrigan, C. Martin, and G. H. Thomas, Tetrahedron Lett., 1998, 39, 2219. [98] S. Zhao, A. K. Miller, J. Berger, and L. A. Flippin, Tetrahedron Lett., 1996, 37, 4463. [99] S. Morita, K. Kitano, J. Matsubara, T. Ohtani, Y. Kawano, K. Otsubo, and M. Uchida, Tetrahedron, 1998, 54, 4811. [100] S. L. Macneil, M. Gray, L. E. Briggs, J. J. Li, and V. Snieckus, Synlett, 1998, 419. [101] A. J. Peat and S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 1028. [102] Y. P. Hong, G. J. Tanoury, H. S. Wilkinson, R. P. Bakale, S. A. Wald, and C. H. Senanayake, Tetrahedron Lett., 1997, 38, 5663. [103] G. J. Tanoury, C. H. Senanayake, R. Hett, A. M. Kuhn, D. W. Kessler, and S. A. Wald, Tetrahedron Lett., 1998, 39, 6845. [104] N. Chida, T. Suzuki, S. Tanaka, and I. Yamada, Tetrahedron Lett., 1999, 40, 2573. [105] C. A. Willoughby and K. T. Chapman, Tetrahedron Lett., 1996, 37, 7181. [106] Y. D. Ward and V. Farina, Tetrahedron Lett., 1996, 37, 6993. [107] A. G. MacDiarmid and A. J. Epstein, in Science and Applications of Conducting Polymers, W. R. Salaneck, D. T. Clark, and E. J. Samuelsen, Eds., Adam Hilger, New York, 1991, 117 pp. [108] A. G. MacDiarmid and A. J. Epstein, Faraday Discuss. Chem. Soc., 1989, 88, 317. [109] A. G. MacDiarmid, J. C. Chiang, A. F. Richter, and A. J. Epstein, Synth. Met., 1987, 18, 285. [110] A. Ito, K. Ota, K. Tanaka, T. Yamabe, and K. Yoshizawa, Macromolecules, 1995, 28, 5618. [111] K. Yoshizawa, K. Tanaka, and T. Yamabe, Chem. Lett., 1990, 1311. [112] K. Yoshizawa, K. Tanaka, T. Yamabe, and J. Yamauchi, J. Chem. Phys., 1992, 96, 5516. [113] T. Ishida and H. Iwamura, Chem. Lett., 1991, 317. [114] M. Stolka, J. F. Yanus, and D. M. Pai, J. Phys. Chem., 1984, 88, 4707. [115] S. Thayumanavan, S. Barlow, S. R. Marder, P. Lee, J. Anderson, N. R. Armstrong, G. E. Jabbour, Y. Kawabe, M. M. Morrell, S. E. Shaheen, B. Kippelen, and N. Peyghambarian, Abs. Am. Chem. Soc.,1997, 214, 97. [116] M. M. Wienk and R. A. J. Janssen, J. Am. Chem. Soc., 1997, 119, 4492. [117] K. R. Stickley and S. C. Blackstock, J. Am. Chem. Soc., 1994, 116, 11576. [118] M. M. Wienk and R. A. J. Janssen, J. Chem. Soc. Chem. Commun., 1996, 267. [119] K. R. Stickley, T. D. Selby, and S. C. Blackstock, J. Org. Chem., 1997, 62, 448. [120] K. R. Stickley and S. C. Blackstock, Mol. Cryst. Liq. Cryst. Sci. Technol. A, 1995, 271, A81. [121] K. R. Stickley and S. C. Blackstock, Tetrahedron Lett., 1995, 36, 1585. [122] T. Kanbara, A. Honma, and K. Hasegawa, Chem. Lett., 1996, 1135.
III.3.2 Pd-CATALYZED AMINATION OF ARYL HALIDES AND RELATED REACTIONS
[123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152]
[153] [154] [155] [156] [157] [158] [159] [160]
1095
T. Kanbara, K. Izumi, T. Narise, and K. Hasegawa, Polym. J., 1998, 30, 66. F. E. Goodson and J. F. Hartwig, Macromolecules, 1998, 31, 1700. F. E. Goodson, S. I. Hauck, and J. F. Hartwig, J. Am. Chem. Soc., 1999, 121, 7527. F. E. Goodson, T. I. Wallow, and B. M. Novak, Macromolecules, 1998, 31, 2047. F. E. Goodson, T. I. Wallow, and B. M. Novak, J. Am. Chem. Soc., 1997, 119, 12441. T. Kanbara, M. Oshima, T. Imayasu, and K. Hasegawa, Macromolecules, 1998, 31, 8725. T. Kanbara, M. Oshima, and K. Hasegawa, J. Polym. Sci. Polym. Chem., 1998, 36, 2155. B. Witulski, S. Senft, and A. Thum, Synlett, 1998, 504. I. P. Beletskaya, A. G. Bessmertnykh, R. A. Mishechkin, and R. Guilard, Russ. Chem. Bull., 1998, 47, 1416. A. Mendiratta, S. Barlow, M. W. Day, and S. R. Marder, Organometallics, 1999, 18, 454. B. Witulski, Y. Zimmermann, V. Darcos, J. P. Desvergne, D. M. Bassani, and H. BouasLaurent, Tetrahedron Lett., 1998, 39, 4807. J. Ipaktschi and A. Sharifi, Monatsh. Chem., 1998, 129, 915. G. E. Greco, A. I. Popa, and R. R. Schrock, Organometallics, 1998, 17, 5591. I. Cabanal-Duvillard and P. Mangeney, Tetrahedron Lett., 1999, 40, 3877. S. Vyskocil, M. Smrcina, and P. Kocovsky, Collect. Czech. Chem. Commun., 1998, 63, 515. S. Vyskocil, S. Jaracz, M. Smrcina, M. Sticha, V. Hanus, M. Polasek, and P. Kocovsky, J. Org. Chem., 1998, 63, 7727. R. A. Singer and S. L. Buchwald, Tetrahedron Lett., 1999, 40, 1095. J. F. Hartwig, J. Am. Chem. Soc., 1996, 118, 7010. J. F. Hartwig, unpublished results. C. Amatore, E. Carre, A. Jutand, and M. A. MBarki, Organometallics, 1995, 14, 1818. C. Amatore and F. Pfluger, Organometallics, 1990, 9, 2276. J. F. Hartwig and F. Paul, J. Am. Chem. Soc., 1995, 117, 5373. L. M. Alcazar-Roman, J. F. Hartwig, A. L. Rheingold, L. M. Liable-Sands, and I. A. Guzei, J. Am. Chem. Soc., 2000, 122, 4618. L. Alcazar-Roman and J. F. Hartwig, unpublished results. G. Mann, D. Baranano, J. F. Hartwig, A. L. Rheingold, and I. A. Guzei, J. Am. Chem. Soc., 1998, 120, 9205. D. Barañano and, J. F. Hartwig, J. Am. Chem. Soc., 1995, 117, 2937. R. A. Widenhoefer and S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 6504. G. Mann, C. Incarvito, A. L. Rheingold, and J. F. Hartwig, J. Am. Chem. Soc., 1999, 121, 3224. J. Louie, F. Paul, and J. F. Hartwig, Organometallics, 1996, 15, 2794. J. P. Collman, L. S. Hegedus, J. R. Norton, and R. G. Finke, in Principles and Applications of Organotransition Metal chemistry 2nd ed., University Science Books, Mill Valley, CAD 1987, 279–354. G. Mann and J. F. Hartwig, unpublished results. M. D. Fryzuk and W. E. Piers, Organometallics, 1990, 9, 986. J. F. Hartwig, S. Richards, D. Barañano, and F. Paul, J. Am. Chem. Soc., 1996, 118, 3626. H. Heaney, Chem. Rev., 1962, 62, 81–97. R. Rossi and R. H. de Rossi, Aromatic Substitution by the SRN1 Mechanism, Vol. 178, American Chemical Society, Washington, DC, 1983. F. Paul, J. Patt, and J. F. Hartwig, Organometallics, 1995, 14, 3030. R. A. Widenhoefer and S. L. Buchwald, Organometallics, 1996, 15, 3534. R. A. Widenhoefer, H. A. Zhong, and S. L. Buchwald, Organometallics, 1996, 15, 2745.
1096 [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198]
III Pd-CATALYZED CROSS-COUPLING
R. A. Widenhoefer and S. L. Buchwald, Organometallics, 1996, 15, 2755. G. Mann and J. Hartwig, J. Am. Chem. Soc., 1996, 118, 13109. T. Hirao, T. Masunaga, T. Ohshiro, and T. Agawa, Tetrahedron Lett., 1980, 21, 3595. T. Hirao, T. Masunaga, N. Yamada, Y. Ohshiro, and T. Agawa, Bull. Chem. Soc. Jpn., 1982, 55, 909. T. Hirao, T. Masunaga, Y. Ohshiro, and T. Agawa, Synthesis, 1981, 56. Y. Xu, Z. Li, J. Xia, H. Guo, and Y. Huang, Synthesis, 1983, 377. H. Xu, H. Wei, J. Zhang, and G. Huang, Tetrahedron Lett., 1989, 30, 949. J. Zhang, Y. Xu, G. Huang, and H. Guo, Tetrahedron Lett., 1988, 29, 1955. Y. Xu, J. Xia, and H. Guo, Synthesis, 1986, 691. Y. Xu, Z. Li, J. Xia, H. Guo, and Y. Huang, Synthesis, 1984, 781. Y. Xu and J. Zhang, J. Chem. Soc. Chem. Commun., 1986, 1606. D. Milstein and J. K. Stille, J. Am. Chem. Soc., 1979, 101, 4981. L. Kurz, G. Lee, D. Morgans, Jr., M. J. Waldyke, and T. Ward, Tetrahedron Lett., 1990, 31, 6321. Y. Uozumi, A. Tanahashi, S. Lee, and T. Hayashi, J. Org. Chem., 1993, 58, 1945. S. Vyskocil, M. Smrcina, and P. Kocovsky, Tetrahedron Lett., 1998, 39, 9289. S. Vyskocil, M. Smrcina, V. Hanus, M. Polasek, and P. Kocovsky, J. Org. Chem., 1998, 63, 7738. S. Y. Cho and M. Shibasaki, Tetrahedron Lett., 1998, 39, 1773. H. Doucet and J. M. Brown, Tetrahedron: Asymmetry, 1997, 8, 3775. G. Martorell, X. Garcias, M. Janura, and J. M. Saa, J. Org. Chem., 1998, 63, 3463. V. I. Sokolov, L. L. Troitskaya, and O. A. Reutov, J. Organomet. Chem., 1980, 202, C58. P. Lefloch, D. Carmichael, L. Ricard, and F. Mathey, J. Am. Chem. Soc., 1993, 115, 10665. I. P. Beletskaya, Y. A. Veits, V. A. Leksunkin, and V. L. Foss, Bull. Russ. Acad. Sci. Div. Chem. Sci., 1992, 41, 1272. Y. A. Veits, N. B. Karlstedt, and I. P. Beletskaya, Russ. J. Org. Chem., 1994, 30, 70. D. Cai, J. F. Payack, D. R. Bender, D. L. Hughes, T. R. Verhoeven, and P. J. Reider, J. Org. Chem., 1994, 59, 7180. M. McCarthy and P. J. Guiry, Tetrahedron, 1999, 55, 3061. A. Kojima, C. D. J. Boden, and M. Shibasaki, Tetrahedron Lett., 1997, 38, 3459. M. A. Kazankova, E. A. Chirkov, A. N. Kochetkov, I. V. Efimova, and I. P. Beletskaya, Tetrahedron Lett., 1999, 40, 573. O. Herd, A. Hebler, M. Hingst, M. Tepper, and O. Stelzer, J. Organomet. Chem., 1996, 522, 69. A. Casalnuovo and J. C. Calabrese, J. Am. Chem. Soc., 1990, 112, 4324. S. R. Gilbertson and G. W. Starkey, J. Org. Chem., 1996, 61, 2922. S. R. Gilbertson, G. Chen, and M. McLoughlin, J. Am. Chem. Soc., 1994, 116, 4481. T. Oshiki and T. Imamoto, J. Am. Chem. Soc., 1992, 114, 3975. H. Brisset, Y. Gourdel, P. Pellon, and M. Le Core, Tetrahedron Lett., 1993, 34, 4523. B. H. Lipshutz, D. J. Buzard, and C. S. Yun, Tetrahedron Lett., 1999, 40, 201. D. J. Ager, M. B. East, A. Eisenstadt, and S. A. Laneman, Chem. Commun., 1997, 2359. M. D. Fryzuk, K. Joshi, R. K. Chadha, and S. J. Rettig, J. Am. Chem. Soc., 1991, 113, 8724. D. K. Wicht, S. N. Paisner, B. M. Lew, D. S. Glueck, G. P. A. Yap, L. M. Liable-Sands, A. L. Rheingold, C. M. Haar, and S. P. Nolan, Organometallics, 1998, 17, 652. A. C. Gaumont, M. B. Hursthouse, S. J. Coles, and J. M. Brown, Chem. Commun. 1999, 63.
ArX
Pd
ArOR
III.3.3 Palladium-Catalyzed Synthesis of Aryl Ethers and Related Compounds Containing S and Se JOHN F. HARTWIG
A. INTRODUCTION Pd-catalyzed aromatic C—O bond formation is less developed than Pd-catalyzed C––N bond formation. At this point, useful synthetic methods have been developed for the intramolecular formation of oxygen heterocycles,[1] the intermolecular formation of t-butyl aryl ethers,[2] which serve as protected phenols, and the intermolecular formation of diaryl ethers.[2],[3] In general, the formation of aryl alkyl ethers from alcohols that have hydrogens on the carbon to oxygen are not useful substrates for intermolecular formation of aryl ethers, at the time of manuscript preparation, except when reacting them with strongly electron-deficient aryl halides.[3] In these cases, uncatalyzed reactions can be conducted in polar solvents, although different selectivity for reaction with chloride and bromide may prove useful for particular applications. Nevertheless, the extension of the amination chemistry to the formation of aryl ethers has been achieved for some classes of substrates, and further catalyst improvements should increase the generality of these reactions. The electrophile substrates for C—O bond formation have been divided into the following categories: electron-deficient haloarenes, unactivated haloarenes, and vinyl halides. t-Butanol, alcohols with -hydrogens, silanols, and phenols are the classes of nucleophile substrate. Table 1 shows the various ligands for palladium that have been shown to accomplish these different types of transformations as of May 15, 1999, when this section was prepared.
B. SPECIFIC EXAMPLES OF PALLADIUM-CATALYZED C—O BOND FORMATION B.i. Initial Studies with Arylphosphines The initial studies on Pd-catalyzed C—O bond formation were conducted as intramolecular reactions to form oxygen heterocycles (Eq. 1). It is known that copper complexes will catalyze these transformations, and copper acetylide is particularly valuable for these
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 ©2002 John Wiley & Sons, Inc.
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TABLE 1. Effective Catalyst Systems for the Formation of Aryl Ethers from Aryl Halides ROH (R with -H)
t-BuOH ArX, Ar is activated
ArX, Ar is unactivated
FcP(t-Bu) Fc ferrocenyl P(t-Bu)3 BINAP, DPPF FcP(t-Bu) Fc ferrocenyl P(t-Bu)3
Vinyl-X
BINAP
R3SiOH
ArOH
DPPF/Ni(COD)2 BINAP/Pd
FcP(t-Bu) Fc ferrocenyl P(t-Bu)3 DPPF FcP(t-Bu) Fc ferrocenyl P(t-Bu)3
Pd(PPh3)4 (only report)
X
OH
R
R X Br, I; n 1,2,3 n
[Pd(OAc)2 ] (3–5 mol %) L (4 –6 mol %)
O
base, solvent, 80–100 C base K2CO3, NaO-t-Bu solvent toluene or dioxane L BINAP, DPPF
R R n
(1)
cyclizations.[4] Nevertheless, the palladium chemistry offers an alternative procedure and gives good yields for a variety of heterocycles when the alcohol portion of the substrate is a tertiary alcohol and cannot undergo -hydrogen elimination.[1] In cases where -hydrogen elimination can occur, good yields were obtained for aryl halides with a pendant cyclohexanol, but substrates with pendant acyclic secondary alcohols reacted in low yields. The most efficient catalysts that have been published for these reactions are palladium complexes ligated by DPPF and BINAP. Slightly lower catalyst loads were reported for DPPF complexes, and the only examples that could undergo -hydrogen elimination were performed with DPPF as ligand. Intermolecular formation of aryl alkylethers was initially reported independently by Hartwig and Buchwald, while the formation of vinyl ethers was reported by Rossi using tin alkoxides. For all three types of reactions, activated substrates were required. Rossi and co-workers reported the formation of methyl vinyl ethers by reaction of Bu3SnOMe with activated alkenes such as 2,3-dibromopropenoates catalyzed by Pd(PPh3)4 (Eq. 2).[5] Mann and Hartwig reported reactions catalyzed by DPPF-ligated palladium complexes to form t-butyl aryl ethers from NaO-t-Bu and bromo- and chloroarenes that bear electronwithdrawing groups in the p-position (R t-Bu in Eq. 3).[6] Buchwald and co-workers showed that BINAP – palladium complexes could form alkyl aryl ethers with alcohols that can undergo -hydrogen elimination when reacted with activated aryl halides (Eq. 3).[3] Reaction of NaO-t-Bu with an unactivated aryl halide was reported to give ether product in modest yield, and no reaction times were reported.[3] Similar yields after long reaction times were obtained using DPPF as ligand in unpublished work.[7] Br H
Br + MeOSnBu3 COOMe
MeO
Br
Pd(PPh3)4 NMP, 20 C
(2) H
COOR
III.3.3 Pd-CATALYZED SYNTHESIS OF ARYL ETHERS
R R R
X + NaOR
[Pd(dba)2], L toluene 60–80 C
R
1099
(3)
OR
CN, CHO, C(O)Ph alkyl, L DPPF, BINAP
Subsequent work reported some improvements on this chemistry when nickel catalysts were used, particularly for the formation of silyl aryl ethers.[8] However, another approach was the use of phosphines that are weaker donors than standard triarylphosphine ligands. Use of a palladium catalyst containing a DPPF analog bearing p-CF3 groups on each phenyl ring led to improved yields as part of the first examples of Pd-catalyzed formation of diaryl ethers from aryl halides (Eq. 4).[9] Nonetheless, neither of these changes in catalyst composition led to the formation of aryl ethers from unactivated aryl halides in a synthetically valuable fashion.
Y
X + NaOAr
Pd(dba)2 / L toluene
R
OR
L DPPF or CF3 -DPPF X Cl, Br Y CN, C(O)Ph, C(O)CF3
(4)
63–92%
B.ii. Second-Generation Catalysts Containing Sterically Hindered Alkylphosphines The formation of aryl ethers from unactivated aryl halides has been published only recently[2]; subsequent catalysts based on a similar ligand design should provide further improvements. Hartwig’s group assessed the relative importance of steric and electronic properties of the ligand on the rate of C––O bond-forming reductive elimination by preparing (i) ligands with the basic DPPF structure, but containing donating and withdrawing substituents on the phosphorus aryl groups[9] and (ii) sterically hindered alkyl-substituted DPPF analogs such as bis (di-t-butylphosphino)ferrocene (D t BPF).[2] This alkylphosphine ligand showed activity for reactions of unactivated aryl halides (Eq. 5).[2] However, this ligand was shown to undergo facile P—C bond cleavage at the backbone to form two monophosphines, and the active monophosphine was shown to be ferrocenyl di-t-butylphosphine. This ligand forms palladium complexes that catalyze the synthesis of t-butyl aryl ethers from aryl halides under mild conditions and in high yields with unactivated aryl halides (entries 1–5, Table 2). Moreover, catalysts bearing this ligand mediate the formation of diaryl ethers from phenoxides and unactivated aryl halides at temperatures between 80 and 110 °C over the course of 4–12 h (entries 6–10, Table 2). Thus, the problem of -hydrogen elimination from intermediate alkoxides has not been addressed, but C—O bond formation by reductive elimination is now fast enough to allow for certain classes of valuable aryl ether syntheses. Bu t
Bu t
OMe
cat. L/[Pd]
Br + OMe NaO
O
L Dt BPF, 45% L BINAP, DPPF, P(o-tolyl)3 , 0% L P(t-Bu)3 , 27% L PhP(t-Bu)2 , Br−
>I −
>AcO −
> TfO−
S = DMF
Scheme 7
B.iii. Side Products from Aryl Migration in the Oxidative Addition Complex Frequently, a considerable amount of side products, derived from facile aryl–aryl exchange in the oxidative addition complex, is formed in a Heck reaction executed in the presence of phosphine ligands.[77]–[81] This process is particularly significant at higher reaction temperatures and with electron-rich aryl halides. Thus, a reaction of 4-bromoanisole with butyl acrylate with Pd(OAc)2 /PPh3 as the catalyst system and sodium acetate furnish butyl E-cinnamate in addition to the expected coupling product (Scheme 8).[24]
MeO
MeO
2% Pd(OAc) 2 8% PPh3
Br +
CO2Bu
NaOAc, DMAC
66% +
~16%
CO2Bu
CO2Bu
Scheme 8
An equilibrium reaction involving aryl group exchange, as depicted in Scheme 9, is responsible for the product pattern, and donor-substituted derivatives underwent particularly facile aryl–aryl exchange.
Ph2P MeO
Pd
Ph2P X
OMe
Pd X PPh3
PPh3 Scheme 9
Herrmann emphasized that aryl chlorides are unsuitable as arylating agents in Heck reactions primarily because P—C cleavage and loss of Pd(0)-stabilizing phosphines ultimately occur, leading to catalyst deactivation and palladium black formation, rather than resistance of aryl chlorides to oxidative addition.[24] Notably it was demonstrated in 1987 that oxidative addition complexes, substituted with strongly electron-withdrawing groups, O2NPh(PPh3)2I, O2NPh(PPh3)2Br, and
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1139
O2NPh(PPh3)2Cl, in the presence of butyl vinyl ether as an alkene and 2 equiv of triethylamine in toluene at 100 °C, furnish arylated products in modest yields, almost equally divided between products derived from the 4-nitrophenyl group of the palladium reagents and phenylated products formed following rearrangement to the corresponding phenylpalladium species (Scheme 10).[76] Product contamination in reactions in which triarylphosphines are employed is often a severe obstacle, and there is a strong need for more stable ligands that are less prone to undergo decomposition.
X Pd
P
P
NO2 +
Et3N
OBu OBu
OBu +
X = Cl Br I
+
NO2 13% 12% 10%
NO2 28% 25% 10% OBu
NO2 4% 9% 21%
OBu +
X = Cl Br I
28% 21% 5%
OBu
OBu
+
11% 11% 7%
16% 22% 47%
Scheme 10
B.iv. Insertion and Regioselectivity Given the many reports of Heck-type coupling reactions dating from the 1970s and 1980s, it is somewhat surprising that attempts to govern the insertion in either of the two possible directions are rare.[20],[29] The major factors determining the regioselectivity of the aromatic and vinylic migratory insertion into the alkene are electronic and steric parameters, operating in a delicate balance.[14],[82] Therefore, with alkenes carrying a
1140
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
mesomerically electron-donating group, the regioselectivity is dictated by two mutually counteracting effects. The electronic effects correlate with the polarization of the R—Pd bond, and migration of the organic moiety, formally an anion, onto the internal carbon is expected as a consequence of the lower charge density experienced. In contrast, if the insertion is controlled by steric parameters, the organic group, acting as the larger moiety, attaches itself preferentially to the less substituted vinylic carbon. One might speculate, though, that alternatively the formation of terminal (-)substituted acyclic vinyl ethers might be attributable to a strong driving force toward a stable palladium–oxygen coordinated internal -intermediate[83] (a palladaoxacyclopropane) rather than entirely steric effects. Taking the arylation of alkyl vinyl ethers as an example, the regioselectivity is directed strongly by the electronic properties of the aromatic substrate, the counterion in the oxidative addition complex, the presence or absence of phosphine ligands, and the solvent.[76],[84]–[86] Cabri and co-workers discovered that bidentate phosphine ligands promote internal ( -)arylations of heteroatom-substituted alkenes and allylic substrates with very high selectivity.[33]–[35] For this observation Cabri and Candiani proposed a mechanistic rationale in which two different pathways for the coordination–insertion process were taken into account (Schemes 11 and 12).[20] Ozawa, Hayashi, and colleagues, who extensively studied asymmetric arylation of 2,3-dihydrofuran, have made a similar mechanistic proposal.[41]–[45] Y = O, N, (CH 2) Y
+ P Ar Pd P Y P
Ar Pd P
X = OTf, OAc
X
P
ArOTf, ArI, ArBr P
Ar
P Pd (0)
reduction P
P Pd
Y Pd(OAc)2
P
P H Pd P X HBaseX
Ar
Base
Y Scheme 11
α-arylation
X
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
Y = O, N, (CH2)
1141
P
P
Y P + X Pd Ar Ar Pd X P
Y
Y P Ar Pd P
X = I, Br
X
P Ar
ArOTf, ArI, ArBr
Pd (0)
reduction P
P P Pd X + X
Y
P
P
P Pd
Ar
Y
Pd(OAc)2
P
P H Pd P X HBaseX
Base
α- and β-arylation Ar
Ar + Y
Y
Scheme 12
B.v. Insertion Via Charged and Neutral -Complexes A cationic -complex is formed when aryl triflates are employed with dppp,[20] a strongly coordinating difunctional phosphine (Scheme 11). Thus, ionization occurs by dissociation of the weakly coordinating triflate counterion.[58] Alternatively, a neutral -complex is generated after phosphine dissociation of one of the arms of a bidentate ligand (Scheme 12).[34] The neutral intermediate predominates when aryl iodides or bromides are used as arylpalladium precursors. With electron-rich alkenes the cationic -complex favors -substitution, but the neutral intermediate is subject to both - and - substitution due to indecisive electronic control. The electronic requirements become more imporant when the reaction proceeds via the cationic route and an aryl group migration toward the internal electron-deficient carbon predominates. This argument is based on the higher polarization of the olefinic moiety in the charged -complex.[20] For selective internal arylation of vinyl ethers with aryl iodides or bromides for which cationic organopalladium intermediates are required as intermediates, thallium salts are utilized as additives.[34] Although the role of the thallium additives[87]–[90] (or silver additives)[91]–[96] has not been fully elucidated, it is likely that these additives act as halide sequestering agents. Upon addition of thallium acetate, the halide ion in the oxidative addition complex is replaced by the acetate (X OAc).[34] The acetate anion can dissociate more easily[97] and allows
1142
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
coordination of the alkene in a cationic 16-electron -complex, essential for the chargedcontrolled -selectivity. If the counterion (X) in the oxidative addition complex is iodide or bromide (and no thallium or silver salts are present) the dissociation of one of the phosphorus atoms in the bidentate ligand from the metal is probably attributed to the relatively high trans effect exerted by the halides.[98] This reversible displacement facilitates formation of a neutral -complex, in which the -system of the electron-rich alkene is only weakly polarized. Therefore, after insertion and hydridopalladium halide elimination, a larger fraction of -arylated product is formed, since steric factors always favor terminal arylation. Importantly, the Cabri–Hayashi hypothesis also accounts for the mixture of regioisomers produced when less tightly coordinating monodentate ligands such as PPh3 are used together with aryl halides. Overman, Poon, and colleagues have recently suggested a neutral-cationic hybrid reaction pathway.[99],[100] B.vi. Chelation-Controlled Insertion Facile and regioselective chelation-controlled, but stoichiometric, palladations of allylic and homoallylic systems are well known.[21] The directing effect of the heteroatoms in these substrates and the selective formation of the five- or six-membered chelate accounts for the good regiocontrol achieved. There are also examples of catalytic chelationcontrolled insertions but such Heck reactions are more rare. The size and stability of the chelate ring control these reactions and the outcome can be manipulated by the addition of metal salts or ligands and the choice of other reaction parameters. A number of functional groups, such as tertiary amines, diarylphosphines, carbamates, and hydroxyl and sulfinyl groups are effective for chelation to Pd(II). For example, electron-rich alkenes are -arylated or vinylated with high regioselectivity through stabilization of key transition states (Scheme 13).[30]–[32],[101],[102] Formation of a chelated nitrogen palladium -complex presumably directs the migratory insertion through steric control favoring the six-membered ring. Alternatively, insertion may be affected by electronic constraints, by which the electron density on the +
O Pd(OAc) 2 PPh3
O
O
Pd Me
ArOTf + NMe2
NMe2
PPh3 N Me
Ar β-product α/β = 1:99 +
NMe2 Pd(OAc) 2 dppp
Ar
O Ph
NMe2
Ar
O
Pd P
Ph Scheme 13
P
Ph Ph
α-product α/β = 99:1
Ar
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1143
terminal carbon would be reduced by bending the oxygen out of plane (favoring the inductive effect at the expense of the mesomeric effect of the oxygen).[30] In a control experiment an almost equimolar mixture of the linear -product and branched -product was formed after displacing the chelating vinyl ether with butyl vinyl ether.[30],[31] The formation of -complexes in which the palladium atom is coordinated to the dimethylamino group is supported by the early work of McCrindle and co-workers, who isolated a cisPdCl2 -complex very similar to that proposed in Scheme 13.[103] In the presence of a bidentate ligand the branched -product is formed exclusively, reflecting the powerful influence of ligands on the outcome of the reaction.[32] One of the more fascinating applications of the chelating effect is the stereoselective synthesis of 2-aryl-3-sulfinyl-2,5-dihydrofurans (Scheme 14).[104] The high stereocontrol is attributed to the Pd(II) coordination with the dimethylamino group and the subsequent selective presentation of the -adduct during the insertion step (de 70–88%). Consistent with this scenario, Heck arylations of non-amino-containing 4-arylsulfinyl-2,3dihydrofurans resulted predominantly in the opposite diastereomers (de 34–56%). + O S
O
ArI, Pd(OAc) 2 Ag2CO3, dppp
Me2N
O Ar Pd L Me N Me
S
O
O Ar Me2N
S
O
de = 70−88% Scheme 14
In short, arylation of electron-deficient alkenes (good -acceptors, poor -donors) are best conducted with monodentate ligands along the neutral pathway to deliver linear products. No procedures allowing the preparation of branched electron-poor alkenes are yet available. The arylation of electron-rich alkenes (poor -acceptors, good -donors) works well with bidentate ligands according to the cationic pathway and yields branched products with high selectivity. To induce formation of linear products with electron-rich alkenes, strategies based on control by chelating auxiliaries have been most successful to date. It is noteworthy that there is no general and efficient methodology for regioselective arylation of unfunctionalized 1-alkenes. B.vii. -Elimination and Double Bond Migration The development of the intermolecular cyclic version of the Heck reaction began in the late 1970s. It was immediately evident that the problem with reversible hydride eliminations complicated the use of endocyclic alkenes[82],[94],[105]–[107] and long chain acyclic
1144
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
1-alkenes.[16] Mixtures of isomers were obtained. An example of an isomerization process is shown in Scheme 15. X L + Ar
Pd
Y
L Pd Ar
X Y
L
Y = O, N, C, S X
L H
Y
Pd L
L
Ar
H
−HPdX
Y
Ar
L
X
Pd
Ar
−HPdX
Ar
Y
Y
Y
Ar
Scheme 15
The arylpalladium complex inserts in a 1,2-syn mode and a -complex is produced. After -elimination, the allylic compound might be liberated. Alternatively, readdition of the hydridopalladium species in the reverse direction eventually leads to the arylated cyclic system with the double bond in conjugation with the heteroatom. Recently, a bisphosphine C-5--alkylpalladium complex was fully characterized by Brown and coworkers, which suggests that the formation of the conjugated double bond isomer by -elimination of the C-5-palladium -complex also has to be taken into account.[83] The isomer with the double bond conjugated to the aromatic ring is not observed, as expected since formation of that isomer requires either anti-elimination or readdition of the hydridopalladium species at the opposite face of the ring system. A suitably positioned hydrogen, accessible for syn-elimination, is a prerequisite for the -elimination to occur. The elimination of a hydrogen atom in an anti fashion to the palladium is very uncommon and the metal is postulated to be uninterruptedly coordinated to the same side of the cyclic alkene until irreversible elimination of HPdX occurs.[14] In an impressive acyclic case, 10-undecenyl alcohol reacts with iodobenzene to give thermodynamically favored 11-phenylundecanal as the major regioisomer (Scheme 16).[108] The
ArI
Pd(OAc) 2, Bu4NCl
OH
+
LiOAc, LiCl
Ar Ar terminal product
CHO + 91% (88:12) Scheme 16
CHO internal product
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1145
very efficient and repeated elimination of HPdX and subsequent readdition, regardless of the regioselectivity in the original ArPdX insertion, is a clear example of “living” HPdX species. Recent Density Functional Theory (DFT) calculations reveal a substantial agostic interaction between the metal and the -hydrogens in the -complex formed after the migratory insertion.[109]–[111] Most importantly, since the calculations show that hydride complexes are not local minima intermediates, liberation of the product by classic -elimination is not a likely outcome.[110] The calculations instead support a base-promoted deprotonation of the agostic hydrogens.[110] The suggested (revised) directly base-mediated proton transfer from the bonded alkyl group is displayed in Scheme 17. Thus, the existence of the free hydridopalladium species depicted in Schemes 11 and 12 and, consequently, the mechanism for the sequential arylation–double bond migration are under debate.
H
PdL2
+
OTf
−
NR 3′
HNR3′ OTf
Pd(0)L2 Pd(0)L2
R
R Scheme 17
Pd-catalyzed isomerizations are often efficiently suppressed by addition of thallium or silver salts (Sect. B.v). Moreover, additions of both acetate[112],[113] or water[114] are reported to suppress double bond migration in certain systems. Cyclic alkenes give different regioisomers and often product mixtures owing to double bond isomerizations after arylation. For example, in Scheme 18, arylation of cycloheptene gives entirely the homoallylic product.[115] Addition of silver carbonate cleanly suppresses the double bond migration (Scheme 18).[115]
Pd(OAc) 2 n-Bu4NCl, KOAc
PhI + Pd(OAc) 2 PPh3, Ag 2CO3
Ph Ph
99% 99%
Scheme 18
As illustrated in Scheme 19, when allylic alcohols are used as an alkene component in the reaction with aryl halides under standard conditions, elimination of hydrogen occurs from the oxygen-bearing carbon and aldehydes or ketones are obtained rather then allylic alcohols.[82],[116] However, the outcome of the Heck reaction in Scheme 19 can be controlled by silver salt addition. Thus, either the terminally arylated carbonyl compounds or the terminally arylated allylic alcohols can be obtained selectively simply by alteration of the reaction conditions.[116] This silver-mediating effect on double bond migration is attributed to the probable generation of positively charged hydridopalladium complexes that are less prone to undergo readdition. Support for an irreversible elimination of a hydridopalladium species in the presence of silver salts was obtained in an experiment with -iodostyrene and (1-deuteriovinyl)trimethylsilane (Scheme 20).[117]
1146
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Ar
Pd(OAc) 2 NaHCO3, n-Bu4NCl
ArI
O R
OH
+
76−94%
Ar
R Pd(OAc) 2, PPh3
OH
AgOAc
R
60−92%
Scheme 19 D
I
SiMe3 +
Pd(OAc) 2
+
AgNO3
D
SiMe3
SiMe3
Scheme 20
This Heck vinylation provided both regioisomers and revealed that the deuterium atom is contained in the terminally vinylated compound, while it is lost in the internally vinylated derivative. Frequently, elimination of the heteroatom substituent bonded to the alkene is the predominant process. For example, vinylsilanes are prone to undergo palladium-mediated desilylation. Thus, arylation of vinyltrimethylsilane predominantly affords styrene,[118] and employing E-1,2-bis(trimethylsilyl)ethylene as substrate leads to exclusive formation of the (Z)-product as a consequence of syn Me3SiPd elimination (Scheme 21).[119],[120] This desilylation process is efficiently suppressed by addition of silver salts (Scheme 22).[92],[121] Me3Si
I
SiMe3
Pd(OAc) 2
SiMe3
SiMe3 Pd(OAc) 2 PPh3
Z /E = 15:1 Scheme 21
Me3Si
SiMe3
I
Pd(OAc) 2 AgNO3, PPh3
Pd(OAc) 2 AgNO3
Me3Si
SiMe3
SiMe3 Scheme 22
SiMe3
1147
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
In the case of arylation of allyltrimethylsilane with iodobenzene, addition of silver nitrate has a dramatic effect on the reaction (Scheme 23). The silver addition (i) enhances the reaction rate, (ii) changes the direction of -hydrogen elimination, and (iii) suppresses competing desilylation.[91] It is also worth comparing the different regioselectivities obtained with iodobenzene-P(o-Tol)3 (neutral conditions) and phenyl triflate-dppf (cationic conditions, internal/terminal 95:5) in the arylation step.[40] In Scheme 24 two examples are given in which the acetate, as a good leaving group, has been eliminated rather than hydrogen.[122],[123] Ph Ph
PhI Pd(OAc) 2 P(o-Tol) 3
SiMe3
PhOTf
SiMe3
PhI
Ph
SiMe3
Pd(OAc) 2 dppf
Pd(OAc) 2 P(o-Tol) 3 AgNO3
SiMe3 Scheme 23
Me O
I
N
+ N
Pd(PPh3)2(OAc) 2
Me O
O
60% N
O
Me
Me
Fe
N
OAc
I +
Pd(OAc) 2, PPh3
OAc
Fe
Fe
38%
Scheme 24
B.viii. Chelation-Controlled -Elimination The powerful impact exerted by a chelating group on the insertion process has been demonstrated above (Sect. B.vi). Coordinating groups also affect the outcome of the -elimination step. Thus, arylation of the cyclic enamide with 2-iodoaniline furnishes the allylic derivative, while using iodobenzene as arylating agent leads to double bond isomerization until conjugation with the enamide nitrogen on the opposite side of the ring is achieved (Scheme 25).[124] The involvement of nitrogen-coordinated intermediates has also been proposed with Pd-catalyzed arylations of tertiary allylamines.[125] Syn -elimination of H PdX (which leads to enamides) is hindered by the chelating nitrogen group, provided the reaction is performed in a nonpolar solvent (Scheme 26). The short lifetime of the free hydridopalladium species in the presence of base prevents readdition/isomerization. Tamaru and colleagues utilized O-substituted allylalcohols to direct the coupling with aryl iodides, which caused formation of the cinnamyl product with high
1148
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
X
H
NH2
Pd
I
NH2
NH2
N
N
Pd(OAc) 2
MeO
O
MeO
O
I
H
N MeO
X Pd
O
Pd(OAc) 2
N
N MeO
MeO
O
O
Scheme 25 Me
Me
Me N
Hα
PhPdX + Ph
Me
Me
Me
Me N
N
Hα Me
Pd Me
Ph
Hγ Hγ
Scheme 26
selectivity.[126] It is likely that Pd(II) coordinates to the carbamate group in the -adduct and that the hydrogen atom (H ) on the carbamate-bearing carbon is located unfavorably for syn -elimination with Pd(II). Consequently, only the H hydrogens can undergo -elimination (Scheme 27). O ArPdX +
Me
N H
Z O
Me
O Y Pd Hγ X
Hα Hγ
O Me Ar
N H
O Me
Ar
Y = N or O Scheme 27
The selective formation of the arylated or vinylated allylalcohol was rationalized by assuming a cationic four-membered intermediate, in which the hydrogen atom (H ) on the hydroxyl-bearing carbon is located unfavorably for a syn palladium hydride elimination. The cationic intermediates were generated from organic triflates,[127] iodonium salts,[128] or organic iodide/thallium or silver salt combinations[129] (Scheme 28).
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1149
+ R′
OH
R′
RPdX +
R′
OH
OH
Hα
Hγ
Pd R
R Hγ Scheme 28
Heck reactions of allylalcohols, with the involvement of neutral intermediates and more strongly coordinating leaving groups, alternatively provided aldehydes or ketones, as a result of H -elimination or double bond migration by hydridopalladium readdition/elimination to give unstable enols (Sect. B.vii). Hydroxyl coordination may also provide a plausible explanation for the very high selectivity observed in the syn -elimination step with the Pd-catalyzed synthesis of -substituted -butyrolactones by vinylation of 2-butene-1,4-diol (Scheme 29).[130],[131]
H O
OH RPdX + OH
R Hγ
Hα
X Pd
OH
S
Hα OH
R
O OH
R
OH H
Scheme 29
In the absence of phosphine ligands and amines, chelation of the allylic hydroxy group to Pd(II) may yield a five-membered cyclic -complex. This chelate ring makes it difficult to achieve the conformation required for elimination of H and preferentially directs the elimination of the hydridopalladium species to give the enol. Heck arylation of allylic diols, with iodobenzene in the presence of potassium carbonate, resulted in phenyl-substituted diols.[132] A selective -hydride elimination in a chelated ring intermediate may be responsible for this outcome (the authors suggest deprotonated -intermediates) (Scheme 30). Arylation of an allylic substrate lacking the homoallylic hydroxy group under otherwise identical conditions furnished a mixture of products, suggesting that the aforementioned hydroxy group has an impact on the hydride elimination. Interception of the -adduct with an external hydride source, leading to an overall Michael-type addition is a synthetically useful variation of the Heck reaction (see Sect. IV.2.5). But there are also examples of -intermediates that are relatively stable toward elimination due to chelation. One such intermediate as reported by Cheng and Daves Jr. is shown in Scheme 31.[133] This isolated complex underwent -elimination of hydrogen, anti-alkoxide elimination, and replacement by hydrogen in addition to anti-elimination of acetate, depending on the conditions used.
1150
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
RO
RO PhPdI
+
HO
HO
OH
OH
Ph R OH − O Pd
H H Ph Hγ
Hα Hγ
Hγ Hγ
OH Hα
Hγ R − O
Pd
Ph
I
Ph
HO R Hα
Hγ − O Pd
I
Scheme 30 AcO AcO AcO Ph3P Pd Cl O
O
MeN
NMe O
Scheme 31
B.ix. Double Bond Migration Prior to Arylation Palladium is a commonly used catalyst for double bond isomerization.[134]–[136] It is therefore not surprising that double bond isomerization sometimes competes with arylation, in particular, in cases in which alkenes with allylic substituents are subjected to traditional Heck reaction conditions.[137] The arylation of the cyclic allylamine derivative in Scheme 32, which is prone to undergo isomerization, constitutes an illustrative example in which a mixture of compounds is formed.[138] The alkene undergoes two types of Pd-catalyzed reactions: (i) arylation to provide C-3 arylated derivatives and (ii) competing double bond isomerization. Addition of silver carbonate or thallium acetate fully suppresses this isomerization and good yields of 3-substituted compounds could be obtained. Alternatively, aryl triflates were useful as arylating agents, provided that tri(2-furyl)phosphine (TFP)[139] was employed as ligand and lithium Ar
Ar + ArX N CO2Me
Pd(OAc) 2 dppp
N
+
Ar
CO2Me Scheme 32
N
+
CO2Me
N
Ar +
CO2Me
N CO2Me
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1151
chloride[58],[97],[140] was added to accelerate the C-3 arylation. Two examples are presented in Scheme 33.[138] OMe
OH
OMe + N
I
Pd(OAc) 2 Ag2CO3
1. Pd/C, HCO2NH4
P(o-Tol) 3
2. LiAlH4 3. HBr
N
COEt
N
COEt
n-Pr USDA 19 (71%)
(52%)
N
N N + N
Pd(OAc) 2 LiCl
1. Pd/C, HCO2NH4
TFP
2. LiAlH4
OTf
CO2Me
N
N
CO2Me
Me
(52%)
isonicotine (62%)
Scheme 33
B.x. Tetraalkylammonium Salts, Jeffery Conditions The introduction of phase transfer catalysts by Jeffery, in the mid-1980s, contributed significantly to extending the scope of the Heck reaction.[23],[141],[142] Thus, arylations of methyl acrylate, vinyl methyl ketone, and acrolein were found to proceed smoothly at room temperature with a combination of tetra-n-butylammonium chloride and sodium hydrogencarbonate.[141] The reaction rate increased linearly with the concentration of the phase transfer catalyst, up to the use of 1 equiv. In the absence of the phase transfer additive, at room temperature, no conversion took place. Since tetraalkylammonium chlorides appear to be more efficient than bromides, which in turn promote the reactions to a greater extent than hydrogensulfates, it is reasonable to assume that the phase transfer catalysts serve as halide donors. Anion exchange by tetraalkylammonium chloride could transform organopalladium iodides or bromides into organopalladium chlorides, thus leading to higher reactivity in the subsequent -hydride elimination step.[142] On the other hand, addition of alkali metal halides generally does not exert a significant rate-enhancing effect, suggesting that the tetraalkylammonium salts act as true solid–liquid phase transfer catalysts. Jeffery has demonstrated that water could be a determining factor for the efficiency of quaternary ammonium salts in the Heck coupling.[142] Thus, while arylation of methyl acrylate in anhydrous acetonitrile with n-Bu4NCl hydrate delivers a 97% yield of methyl cinnamate, the corresponding reaction with dry tetra-n-butylammonium chloride as additive provides a poor conversion of 10%. Jeffery recently stated that tetraalkylammonium salts may have a multiple and complex role in Heck-type reactions.[23],[142] Among all of the elementary steps in the
1152
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
catalytic cycle that could be affected by tetraalkylammonium salts it is likely that solid–liquid phase transfer could play a very important role in the regeneration of Pd(0) from HPdX, in particular, when inorganic salts serve as bases. Thus, the accelerating effect of the tetraalkylammonium salt can be attributed to the salt assisting in the decomposition of the hydridopalladium species into the zerovalent palladium catalyst. Furthermore, addition of tetra-n-butylammonium chloride improved the selectivity in certain reactions, such as in the arylation of allylic alcohols.[116] Finally, an appropriate selection of tetraalkylammonium salt-based systems can be used to control the product pattern in certain Heck reactions (Scheme 34). In these examples, phase transfer agents have been shown to be an alternative to silver salts in directing the outcome of the reaction.[143],[144]
I O
Pd(OAc) 2
+
O
+
O n-Bu4NOAc n-Bu4NCl, KOAc
97%
3%
8%
92%
Scheme 34
B.xi. New Catalytic Systems At higher reaction temperatures P(o-Tol)3 has often been preferred over PPh3, since the more bulky phosphine was assumed to minimize the undesired quaternization of the phosphorus atom by the aryl halide and also results in more stable 14-electron Pd(P(oTol)3)2 complexes.[14] It was discovered that upon reaction of Pd(OAc)2 with P(o-Tol)3 a dimeric palladacycle in equilibrium with monomers was formed (Scheme 35).[37],[145]–[147] These palladacycles, created by Pd(II)-mediated C—H activation of the ortho-methyl group of the phosphine ligand, are excellent catalysts for both triflates and aryl bromides, although nonactivated aryl chlorides react only reluctantly.[148]–[150] No aryl migration or ligand decomposition leading to precipitation of palladium metal occurs at 150 °C.[37] The isolated pure palladacycle is recommended as a catalyst, since in situ preparation from a mixture of Pd(OAc)2 and P(o-Tol)3 delivers catalytic species that are less stable.[149] Dimeric palladacycles are recovered unchanged and can be recycled with little loss of catalytic activity.[37] Very high turnover numbers were encountered.[37],[151] In 1997 Milstein and co-workers disclosed a new type of cyclometallated catalysts that exhibited exceptionally high activity in the Heck reaction with aryl iodides and bromides X Pd P R R
X
− X−
Pd
+X −
P dimer
R R
Scheme 35
L
+L
X
−L
Pd P R R
X
1153
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
(Scheme 36, A and B).[152] Turnover numbers up to approximately 500,000 were reported for the reaction of iodobenzene with methyl acrylate and an impressive number (about 100,000) was also achieved with bromobenzene and 4-methoxy-bromobenzene. Characteristic features of these tridentate PCP catalysts are thermal stability and air stability. A competitive experiment, including 4-bromoiodobenzene, iodobenzene, 4-methyliodobenzene, and 4-methoxy-iodobenzene with methyl acrylate provided a linear correlation with Hammet -values, which, however, exhibited a low value (1.39).[152] It was concluded that nucleophilic aromatic substitution is not rate determining, but a subsequent step with different electronic requirements, such as alkene insertion, may account for this observation. Chlorobenzene could not be coupled with these catalyst. Very recently, Milstein’s group reported new cyclopalladated, phosphine-free imine complexes as catalysts in the Heck arylation reaction (Scheme 36, C).[153] The new dimeric imine complexes show extremely high activity, leading to more than a million turnovers. Me
Me
Me R2P
Pd
PR2
X
R2P
PR2
Pd
Pd N F3CCO2 R
X B
A
R = isopropyl 2
C Scheme 36
Carbene-containing palladium complexes such as A and B in Scheme 37 have been introduced as suitable catalysts in Heck couplings.[154],[155] These catalysts, characterized by good - and -donor and poor -acceptor capacity are thermally extraordinarily stable and are not, as compared to phosphines, prone to undergo oxidation.[24],[37],[154],[156] The nonchelating N-heterocyclic carbene catalysts A appear to be generally more active than the traditional palladium/phosphine systems but less active than the palladacycles.[24] Mechanistic research by Cavell indicates that the catalytically active species is a 14-electron Pd(0)(carbene)2 complex of type C (Scheme 37).[157] Although these Pd(0)(carbene)2 complexes may be regarded as having Pd(II) character, they endure oxidative additions typical of Pd(0). Thus, there are similarities to related phosphine complexes such as Pd(0)(PR3)2. One clear difference between carbene and phosphine ligands is, however, that carbene ligands are not involved in dissociation equilibria typical for phosphines.[157] Me Me N
N N Me Me
N Me
N
N
Pd I
I A
Me
N N Me
Pd I
I B
Scheme 37
Me
N
Me
N
Me N
Me
N
Me
Pd(0) Me
Me C
1154
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
It has been reported that chelating diphosphine–palladium(II) dihalides, contrary to previously held views,[34],[158] are outstandingly good catalysts for Heck reactions of aryl halides (Scheme 38).[159] The catalysts are active over the temperature range 50–150 °C, and high yields and turnover numbers were observed. It was not advisable to prepare the active catalyst, [(L-L)PdX2], in situ, since a Magnus-type salt, [M(L-L)2](MX4), with very low solubility is proposed to be formed from the diphosphine and the palladium.[159] Thus, the catalyst should be preformed, and the chelating diphosphine ligand and the palladium species should not be added separately to the reaction medium. t-Bu N
t-Bu
(CH2)1–4
N P
Ph
Ph P Ph
P Ph Ph
Pd X
P Ph Pd
Cl
X
Ph P Ph
Ph Cl
P Ph Pd
Cl
Ph Cl
X = Cl, Br, I Scheme 38
Other transition metals than palladium have been reported to activate aryl halides for reactions with alkenes [e.g., Ni(0),[160] Cu(I),[161] Co(I),[162] Rh(I) (Wilkinson’s catalyst)[162] and Ir(I) (Vaska’s complex].[162] B.xii. Shaw Mechanism: Pd(II) to Pd(IV) Interconversions The development of recovered palladacycles and related stable palladium(II) catalysts that showed no signs of being reduced to Pd(0) required that alternative mechanisms, other than the classical mechanism, which relies on the Pd(0)/Pd(II) interconversion, had to be considered.[37] Redox cycling involving Pd(II)/Pd(IV) had to be taken into account. Alkylpalladium(IV) complexes do exist, although they are not very common, and can be formed from reactive aryl halides and Pd(II) complexes encompassing aryl or alkyl groups combined with strongly coordinating N,N-bidentate ligands (Scheme 39).[163],[164]
Me Me
N
N
Pd N
I A
N N
Me
N
I
Pd
H2B
Pd Me
B Scheme 39
N
Me
N N Ph C
1155
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
Shaw has proposed a mechanistic rationale that involves Pd(II) and Pd(IV) complexes (Scheme 40).[47] In the first step, the metallacycle is coordinated to the alkene, which becomes susceptible to nucleophilic attack (e.g., by acetate, carbonate, halide, water, or amines) either at the terminal position as depicted in Scheme 40, or alternatively at the internal carbon. In this process an electron-rich palladium(II) complex, coordinating two alkyl groups, is created. This Pd(II) complex, as compared to monoalkyl (or aryl) complexes, more readily undergoes oxidative addition with an organic halide, and a Pd(IV) complex is subsequently generated. Y−
R X
C
Y− = AcO −, X−, CO32−, OH−, amines, etc. − X C
Pd
Pd
P
P
R
ArX
R
Y − X
C
C
X = I, Br, Cl, OTf, OAc, etc.
Pd 2
X Base
C
P
X P
H
X Pd
P R
X
X
Pd
C
Ar
HY
2
C Pd
P
Pd
= 2
R R R = o-Tol
X
R
Ar Y
X
C
Pd P
X
Pd P
P
X
Ar
R
X R
Ar Scheme 40
Regeneration of an alkeneic -complex is likely to occur smoothly at the high temperatures often employed with the palladacycles. Insertion into the alkene and a -hydride elimination ultimately delivers the coupled product. The palladacycle is recovered after reaction with a base (e.g., acetate).[47] The mechanistic research and discussion concerning the palladacycle systems in Heck reactions is still ongoing. Recent investigations by Beller and Riermeier[150] and
1156
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Herrmann et al.[37] have indicated that the standard palladacycle trans-di( -acetato)-bis[o(di-o-tolylphosphino)benzyl]-dipalladium(II) (A) might be a catalyst precursor to active palladium(0) complexes (Scheme 41). In other words, the palladacycle may act as a thermally stable reservoir for the “real” catalytic species, which is released by heterolytic Pd—C bond cleavage and is activated by subsequent reduction. If this is the actual case a traditional catalytic cycle via Pd(0)/Pd(II) has to be postulated also with palladacycles. In addition, for cross-coupling and amination reactions there is strong evidence for the reduction mechanism of phosphapalladacycle A into a Pd(0) species.[38],[165]
Pd
reduction 2
2
R3P
Pd(0)
P OAc R = o-Tol R R A Scheme 41
B.xiii. Aryl Chlorides as Starting Materials Aryl chlorides are attractive arylpalladium precursors since they are readily available and inexpensive compared to aryl bromides and aryl iodides.[166],[167] In 1973, Julia and co-workers published a successful Heck coupling of styrene with chlorobenzene, catalyzed by palladium on charcoal.[168] Activity in the area since then has been impressive. During the 1990s a series of Heck reactions with chlorobenzenes and electron-poor aryl chlorides were performed with the new catalytic systems developed, and frequently fair conversions were achieved.[166] Activated alkenes such as styrene and alkyl acrylates were most often employed. To increase the reaction rates with aryl chlorides, nickel bromide/sodium iodide additives have been employed successfully.[169] Furthermore, the use of basic ligands, which are anticipated to facilitate oxidative addition, has largely been successful.[54],[170] Littke and Fu very recently devised a protocol that allows conversion of electron-rich aryl chlorides in the Heck reaction (Table 2, entry 13).[171] Thus, Heck reaction of aryl chlorides with styrene or methyl acrylate with Pd2(dba)3 /P(t-Bu)3 as a catalytic system and with Cs2CO3 as a base delivered good yields of isolated products. Contamination as a result of aryl – alkyl exchange between the palladium(II) center and the coordinated phosphine was, as expected with this type of ligand, not encountered. A survey of solvents suggested dioxane to be most suitable. The choice of ligand appeared to be critical for activity, and the bulky, electron-rich P(t-Bu)3 was uniquely effective among the phosphines that were examined.[171] Thus, P(n-Bu)3, PCy3, Cy2PCH2CH2PCy2, dppf, and P(o-Tol)3 all delivered less than 2% yield. Interestingly, Beller and Zapf have reported that electron-poor phosphites are useful ligands for the coupling of electron-deficient aryl chlorides.[172] Reetz and co-workers discovered that palladium salts in the presence of tetraphenylphosphonium salts and dimethylglycine constitute a very active and selective catalyst system for the Heck arylation of styrene.[173] Note that the system is more efficient than the palladacycles for converting nonactivated arylpalladium precursors such as chlorobenzene into products. High yields of coupled products are obtained at 150 °C and only minor amounts of cisstilbene or 1,1-diphenylethene are encountered (Scheme 42).
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
+ Cl
1157
Pd(OAc) 2 Ph4P+Cl− Me2NCH2COOH 150 °C 79% conversion
Scheme 42
B.xiv. Novel Reaction Conditions and Heating Techniques In the mid-1990s, several academic teams started to investigate alternative heating techniques and nonconventional reaction conditions for the Heck reaction. The heating technologies comprised new types of microwave reactors.[174]–[176] The nonclassical reaction conditions included the use of aqueous media at high temperature, solid phase synthesis,[177] and high-pressure methods. With these methods, reaction rate and productivity potentially could be enhanced, and the developments of at least laboratory-scale environmentally benign Heck reactions could be accelerated.[178] B.xiv.a. Microwave-Heated Heck Reactions. If microwave heating is regarded simply as an equivalent to conventional oven heating, then its importance and potential in organic synthesis is limited. However, the input of microwave energy into a chemical reaction mixture is quite different from conventional thermal heating. Microwaves can heat a reaction mixture very rapidly (flash heating), uniformly, and directly, without any problems of heat transfer through the walls of the reaction vessel (since the vessel is microwave transparent, it will be no hotter than its content).[179]–[181] Recently, a wide range of organic reactions have been promoted by microwave irradiation,[182] but in the field of Heck chemistry only a limited number of papers have appeared.[38]–[40],[183]–[185] Two types of microwave heating equipment have been used, a multimode reactor or a monomode reactor.[174],[179],[180] The latter is more expensive but allows the placement of the reaction mixture at a fixed position of much higher continuous electric field strength than can be obtained in a multimode reactor.[186] This is particularly important with Pd-catalyzed reactions since the reaction mixture must be heated to a high temperature in a reproducible and homogeneous fashion. The examples in Table 1 disclose that with an appropriate choice of microwave power and irradiation time, complete conversions and high yields can be obtained in a few minutes.[38] It is surprising to find that the unstable organometallics, participating in product formation, are compatible with the high reaction temperatures achieved during microwave treatment. In general, the same high chemo- and regioselectivity as experienced in classical heating appears to apply to microwave-promoted Heck reactions.[38] 4-Bromostilbene was conveniently synthesized in 4.8 min with high chemoselectivity, in full resemblance with the thermal literature procedure,[187] provided a relatively low microwave power was employed (Table 1). Microwave-promoted Pd-catalyzed dpppcontrolled arylation of butyl vinyl ether with 4-tert-butylphenyl triflate afforded a mixture of the branched arylation product and the corresponding methyl ketone, indicating a highly selective -arylation.[34] Addition of water to the reaction mixture and conduction of the reaction for 2.8 min at 55 W smoothly produced 4-tert-butylacetophenone with an isolated yield of 77%. An equally high selectivity for terminal coupling was encountered by application
1158
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 1. Fast Intermolecular Heck Coupling Reactions Under Microwave Irradiationa Aryl Halide or Aryl Triflate
a b
Alkene
Time and Microwave Power b
Product
Isolated Yield %
The microwave reactions were performed on 1.0 mmol scale in sealed Pyrex tubes under nitrogen. Continuous irradiation (2450 MHz, monomode reactor Micro Well 10, Personal Chemistry AB).
of low-power microwave heating, permitting the isolation of 87% -arylated product and corroborating the use of microwave-assisted chelation-controlled Heck reactions (Table 1).[32] Attempts to shorten the reaction time by increasing the temperature by classical means (warmed up oil baths) were not comparably successful.[38] Since kinetic investigations into specific microwave effects in homogeneous reactions have disclosed that no “magic” molecular activation occurs, the advantage of microwave heating presumably lies in rapid heating and the relative lack of temperature gradients and wall effects.[180] B.xiv.b. High-Temperature Water as Reaction Medium. In order to conduct Heck reactions in pure water, important solubility problems must be overcome. Two different types of modifications can be investigated: either the catalyst/substrates or the reaction environment. First, use of water-soluble phosphine ligands to solubilize the metal catalyst has been investigated extensively, although these ligands are rarely utilized in pure water.[188] Alternatively, Beletskaya and colleagues in their pioneering
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1159
work have carefully matched the properties of the starting materials to the polar aqueous reaction environment.[189] This methodology, unfortunately, demands hydrophilic starting materials. The second route to perform “truly” aqueous Heck reactions is based on increasing the water solubility of the reacting organic compounds. Importantly, water has a dielectric constant, which decreases from 78 at 25 °C to around 20 at 300 °C, this latter value being comparable with that of acetone at ambient temperature.[178] Thus, by taking advantage of the change in polarity, water can behave as a “green” pseudo-organic solvent at elevated temperatures. This approach was investigated by Gron and Tinsley in the arylation of different cycloalkanes at 225 °C at 100 bar (Scheme 43).[190]
I
Pd(OAc) 2, NaOAc H2O, 225 °C
+
54% Scheme 43
The products were surprisingly similar to those found in typical organic solvents, although the isolated yields were lower (17–54% based on conversion of the iodobenzene). A group at Clemson University have also reported aqueous Heck reactions at 260 °C and in supercritical water at 400 °C.[191] Another example of an environmentally benign solvent for Heck chemistry is supercritical carbon dioxide (Scheme 44).[192],[193] Undoubtedly, the future need for cleaner chemical processing is great.
I
OMe
+
Pd(OAc) 2, scCO2 (C6F13CH2CH2)2PPh
OMe O
O 91% Scheme 44
B.xiv.c. Intermolecular Heck Reactions on Polymeric Support. Combinatorial chemistry has initiated a reappraisal and consequent renaissance in synthesis of compounds attached to polymeric supports.[194] Therefore, it comes as no surprise that Pd-catalyzed reactions are among the most widely explored reactions for the generation of combinatorial libraries on solid phase. The first example of the intermolecular Heck reaction on solid phase was reported in 1994.[195] In this article, 4-vinylbenzoic acid was attached to Wang resin and coupled with aryl halides/triflates under catalysis with Pd(OAc)2 (Scheme 45). Similar O O
1. PhI, Pd(OAc) 2 n-Bu4NCl 2. 90% TFA/CH 2Cl2
HO O
Ph 81%
Scheme 45
1160
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
methodologies have thereafter been devised by other research groups and the scope of this chemistry is now approaching the current range of solution Heck chemistry, although naturally the number of examples is still limited.[196]–[198] Bräse and Schroen very recently developed a new cleavage–Heck coupling strategy for combinatorial applications (Scheme 46).[199] Starting from Merrifield resin, an immobilized triazene was prepared in three steps. Acidic release of the diazonium compound and subsequent Pd-catalyzed in situ coupling with different alkenes furnished, after filtration and evaporation, the products in high purity and yield. N N N
N
1. TFA 2. Pd(OAc) 2,
HO
HO
95% yield 92% purity Scheme 46
Although highly successful, solid phase synthesis still has several shortcomings due to the nature of the heterogeneous reaction conditions. These problems in solid phase Heck couplings are now being addressed elegantly by the use of solution chemistry with selectively soluble polymers.[200] Almost quantitative arylation, and excellent stereoselectivity, of the polyethylene glycol-bound (mPEG 5000-bound) 3-substituted acrylic acid was accomplished after purification by the ether precipitation method (Scheme 47).[201] This methodology essentially avoids the difficulties of solid phase synthesis while preserving its positive aspects (easy purification and the possibility of using a large excess of a reagent).
PEG O O
PEG O
MeO 1. p-TolI, Pd(OAc) 2 n-Bu4NCl
O
Me
2. Precipitation
91% OMe
Scheme 47
In another series of Heck experiments, PEG was proposed to act as a solid–liquid phase transfer additive.[202] The enhanced reaction rate was explained by a PEG-mediated solvation of the potassium cation (to transfer the insoluble inorganic base potassium carbonate to the acetonitrile solvent). Much of the reported solid phase organic chemistry has so far described the synthesis of combinatorial libraries. But it should be remembered that the fundamentals of combinatorial chemistry apply also to other applications. Recently, a fluorescence-based assay for high-throughput screening of a Heck reaction was described (Scheme 48).[203] The assay involves coupling of an electron-deficient alkene, containing a tethered fluorophore, with an aryl halide attached to a Wang resin. A
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1161
successful coupling process was identified by the fluorescence of the polymeric support. To evaluate the screening assay, a set of readily available monodentate phosphines was utilized. Comparison of the results from the assay with results from a series of solution phase reactions showed that the fluorescence-based technique accurately selected the most active ligands for the Heck coupling with aryl bromides [P(t-Bu)3] and chlorides [(t-Bu)2PFc]. By employing this method, or analogous strategies, considerable time could be saved in optimizing reaction conditions.[203] O O
O X
Pd(dba)2 ligand
O
+
O
screening
O X = Br or Cl
O
alkene fluorescent tag O
O
filtering washing
O O
O
O
visual observation of resin fluorescence (UV-lamp)
O
Scheme 48
B.xiv.d. High-Pressure Conditions. A wide range of liquid phase organic reactions have been reported to be promoted under high pressure.[204] Pressure can be expected to cause a rate enhancement when the activation volume, that is, the difference of the volume of the transition state and the starting materials, is less than zero. This can easily be understood to be the case in addition reactions. However, a Pd-catalyzed Heck process consists of a number of reaction steps and, consequently, to predict the net effect of pressure in such a reaction is much more difficult.[205] Nevertheless, rate enhancements and increased lifetime of the catalyst have been reported. According to the studies of de Meijere and colleagues (Scheme 49)[206] and Sugihara et al.,[207] high pressure can considerably increase the rate of typical Heck reactions under very mild conditions. Furthermore, de Meijere and Bräse recently discovered that the reaction rates of aryl bromides depend more strongly on the pressure than those of aryl iodides and hence can efficiently be accelerated by increased pressure.[208] Interestingly,
CN +
Ph
Pd(OAc) 2, PPh3
Br
CN Ph 1 bar, 48 h, 20 C, 0% 10 kbar, 48 h, 20 C, 98%
Scheme 49
1162
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Sugihara and co-workers observed suppression of -elimination at high pressure.[207] In yet another investigation, the Pd-catalyzed arylation of 2,3-dihydrofuran, high pressure was found to greatly increase the lifetime of the catalyst.[209] A logical extension of the Heck functionalization of 2,3-dihydrofuran was to carry out a more detailed kinetic study of this pressurized reaction. From this study, the activation volume in the reaction was determined to be negative (12 2 cm3), indicating the benefits of pressure in transition metal-catalyzed reactions.[205]
C. SCOPE OF THE INTERMOLECULAR HECK REACTION C.i. Arylation of Electron-Deficient Alkenes The order of reactivity of the alkenes is monosubstituted disubstituted tri- and tetrasubstituted.[14],[22] Tri- and tetrasubstituted alkenes do not normally undergo intermolecular arylations. The product pattern after arylations of 1,2-disubstituted alkenes is governed by both steric and electronic factors. Arylation of alkenes with one electron-withdrawing group is the most common Heck reaction. The reaction delivers arylated products often in high yields. The (E )-isomers are most often formed but with some alkenes, for example, acrylonitrile, mixtures of the (E )- and (Z )-isomers are obtained. In Table 2 several examples are given. The examples are selected to illustrate the scope of the reaction with focus on the variety of arylpalladium precursors and the catalytic systems that can be employed. Virtually all functional groups are tolerated. pMethylthiobromobenzene, for example, provides a yield of 77%, entry 1,[210] of coupled product (p-Cl, 93%; p-NH2, 73%; p-Me2N, 80%; p-AcNH, 83%, p-NO2, 73%; p-CN, 98%; p-OMe, 54%; p-CHO, 72%; p-OH, 98%; p-CO2Me, 81%; H, 88%)[22] but high yields are also achieved with most ortho-substituted bromobenzenes, such as with 2aminoiodobenzene, which affords the corresponding cinnamic acid in 72% yield, entry 2[211] (o-NO2, 83%; o-OH, 24%; o-CHO, 28%; o-COMe, 89%; o-OAc, 66%; o-CO2Me, 69%).[22] High yields and a highly regioselective -arylation are achieved in reactions of aryl halides with acrylic acid,[187] acrylamides,[210] acrylonitrile,[212] ,-unsaturatd carbonyl compounds,[141] sulfonamides,[213] and vinylphosphonates,[214] and with 1,2-disubstituted alkenes[215] as depicted in entries 3–9. The reactions are preferentially performed in polar nonprotic solvents such as acetonitrile or DMF, and frequently under phase transfer conditions. Thus, acrolein, an example of an easily polymerizable substrate, can be arylated at room temperature in the presence of sodium hydrogencarbonate or potassium carbonate and tetra-n-butylammonium chloride (entry 6). The Heck reaction is compatible with water, and water-soluble catalysts have successfully been employed (entry 10).[188] Alkali metal salts (NaHCO3, K2CO3, and KOAc) are effective bases in the smooth reactions of acrylic acid with o-, m-, or p-iodobenzoic acid or p-iodophenol in which water-soluble salts are formed and very high yields are encountered (entry 11).[189] Activated heteroaryl chlorides are good arylpalladium precursors (entry 12) while nonactivated aryl chlorides have to date been considered to be less useful in the Heck reaction.[216] In entry 13, the recent protocol devised by Littke and Fu for arylation with nonactivated chlorobenzenes is shown.[171] Aryl triflates are suitable arylating agents and, in particular, in the presence of chloride ions.[85] The fact that aryl triflates and other aryl fluoroalkanesulfonates readily take part
1163
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
TABLE 2. Intermolecular Heck Coupling Reactions Entry
Organic Halide or Pseudohalide
Alkene
MeS
OMe
1
Reaction Conditions Pd(OAc)2, P(o-Tol)3 Et3N, 125 °C, 72 h
Product MeS
77% OMe
O
Br
O NH2
OMe
2
NH2
Pd(OAc)2, Et3N 100 °C, 80 h
72% OH
O
I
O Br
OH
3 O
I
Br
Pd(OAc)2, Et3N 100 °C, 1 h
82% OH
MeCN
O NH2
4 O
Br
Pd(OAc)2, P(o-Tol)3 Et3N, 100 °C, 1 h
70% NH2
MeCN
O OHC
Pd(OAc)2, P(o-Tol)3 NaOAc, 130 °C, 24 h
CN
5
OHC
79%
MeCN
Br
H
6 O
I
CN
Pd(OAc)2, n-Bu4NCl NaHCO3, 20 °C, 60 h
90% H
DMF
O
SO2NH2
7
Pd(OAc)2, PPh3 Et3N, 140 °C, 24 h
61%
DMF
Br
Me2N
OEt P OEt
8
Me2N
65% OEt P OEt
MeCN
O
Br
Pd(OAc)2, P(o-Tol)3 Et3N, 100 °C, 6 h
SO2NH2
O MeO
Ph
9 Br
CN
Pd(OAc)2, n-Bu4NBr KOAc, 80 °C, 72 h
MeO 84%
DMF
CN Ph
(Continued )
1164
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 2. (Continued) Organic Halide or Pseudohalide
Entry
Alkene OEt
10 H2N
O
I
OH O
I
Product
Pd(OAc)2, TPPTS Et3N, 37 °C, 10 h,
98% OEt
MeCN/H2O H2N TPPTS = P(m-PhSO3Na)3
11 HOOC
Reaction Conditions
O
Pd(OAc)2, K2CO3 KOAc, 50 °C, 1 h
98% OH
HOOC
H2O
O O
O
N
Me
N
Cl
OEt
12 Me
O
N
Pd(PPh3)4, KOAc 130−140 °C, 15 h
38% OEt
N
Me
DMA
Me
O MeO
OMe
13 O
Cl
Pd2(dba)3, P(t-Bu)3 Cs2CO3, 120 °C, 24 h
MeO 82% OMe
dioxane
O OEt
14 O
Cl
Cl
Pd(PPh3)2Cl2 Et3N, 90 °C, 72 h, 13
OEt
DMF
O
OSO2CF2CF2O(CF2)2H SO2Ph
SO2Ph
Pd(PPh3)2Cl2 i-Pr2NEt, 80 °C
N Ph
15
83%
N
75%
DMF
OTf Ph CO2CHPh2
CO2CHPh2 H
16
Pd(PPh3)2Cl2, Et3N
OtBu 90 °C, 24 h
N
H
DMF
Boc
OTf
O
N
54% OtBu
Boc O
Cl
OBu
17
Cl O
O
PdCl2(PhCN)2, K2CO3 Bzl(Oct)3NCl, 140 °C,
Cl
93% OBu
4 h, m-xylene
O
1165
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
TABLE 2. (Continued) Organic Halide or Pseudohalide
Entry
Alkene
Reaction Conditions
OBu
18 SO2Cl
O
Product
PdCl2(PhCN)2, K2CO3
89%
Bzl(Oct)3NCl, 140 °C
OBu
4 h, m-xylene
O Me
Pd(dba)2, NaOAc r.t., 2 h
OEt
19 N2+BF4−
O
Me
96% OEt
MeCN
O Pd(dba)2, t-BuONO 140 °C, 0.5 h
OEt
20 O
NH2
79% OEt
AcOH
O
21
(PhCO)2O
77%
PdCl2, NaBr 160 °C, 1.5 h
OBu
Ph
O
O Me
Me O
Pd(dppf)Cl2, n-Bu4NI O
O
NMe 2 Et3N, 40 °C,~16 h
N
22
OBu
NMP
O
DMF/H2O
O
PhO
O N O
PhO
60% NMe 2
I O CH2Bu
CH2Bu
47%
Pd(OAc)2, PPh3 Me
O
23
CsCO3, 60 °C, 21 h DMF
I
Br Ph
24
O
Br
Ph
Pd(OAc)2, n-Bu4NBr
56%
K2CO3, 100 °C, 7 h Ph
DMF
Br Ph NHBoc Br CO2Bn
25 I
Pd(OAc)2, n-Bu4NCl NaHCO3, 85 °C, 16 h DMF
Br
NHBoc 52% CO2Bn
(Continued )
1166
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 2. (Continued) Organic Halide or Pseudohalide
Entry I
Alkene
Reaction Conditions Pd(OAc)2 80 °C
Me Ph
26 N2+BF4
Product I
Me
EtOH
_
Ph OEt
I
Me
OEt
Me
O
Ph
OMe
OMe
N
Pd(OAc)2, n-Bu4NCl NaHCO 3
OH
27 Me
N
36% O
DMF
Me
I H2N
NPth
28 O2N
55%
DMF
O
Ph
Pd(OAc)2, NaHCO3 n-Bu4NCl, 100 °C
O
Br
Pd(OAc)2, P(o-Tol)3 Et3N, 100 °C, 18 h
H2N
MeCN
O2N
95% NPth
NPth = N O Pd(PPh3)2(OAc)2 Et3N, 100 °C, 3 h
29
63%
O
I
O
30
OTf
1. Pd(OAc)2, dppp Et3N, 80 °C, 0.5 h, DMF
O
2. HCl
31 OHC
Me
1. Pd(OAc)2, dppp Et3N, 80 °C, 24 h DMF
O OH
OTf
2. HAc
97%
O
76% O OHC
O Me 69%
O
32
Pd(OAc)2, Et3N 60 °C, 18 h
Cl
O
O
O OH
33
Et
O
Br
Pd(OAc)2, PPh3 i-Pr2NEt, 100 °C 16 h
Et
OH
66% O
1167
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
TABLE 2. (Continued) Organic Halide or Pseudohalide
Entry
Alkene
Reaction Conditions
Product
O N
34
N
Br
O
Pd(OAc)2, n-Bu4NCl NaHCO3, 120 °C, 24 h
O N
89% O
N
DMF
Ph Ph
Ph Ph
Me
35
N
OTf Me
O
Pd(OAc)2, dppp Et3N, 100 °C, 7 h DMF
Me
87%
N
O Me
OMe OMe
36 I
68%
Pd(OAc)2, n-Bu4NCl NaHCO3, 80 °C, 24 h
OMe OMe
MeCN
O
O Cl C6H13
37
Cl
O
OEt
C6H13
Pd(OAc)2, n-Bu4NCl NaHCO3, 60 °C
O 67%
DMF
O
I
80%
DMF
I
38
Pd(OAc)2, PPh3 TlOAc 70 °C, ~16 h
O
O
OEt O
O
O 81%
I
Pd(OAc)2, PPh3 Ag2CO3 80 °C, 24 h
39
MeCN
I
OH
40
41 MeO
Pd(OAc)2 n-Bu4NHSO4 Ag2CO3, 70 °C, 24 h
O 54% H
MeCN
OTf
O
1. Pd(OAc) 2, Et3N 65 °C, 3 h, DMSO
O
48%
2. H+
MeO
Me
(Continued )
1168
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 2. (Continued) Entry
Organic Halide or Pseudohalide
Alkene
Reaction Conditions Pd(OAc)2, n-Bu4NOTf K2CO3, 55 °C, ~16 h
O
42 CbzHN
OTf
O
Product 80% O
DMF
CbzHN
Me
SiMe3
O
Me
SiMe3
72%
43
Me
SiMe3
OTf
Pd(OAc)2, NEt3 80 °C, 1.5 h
Me
DMSO
Me
SiMe3 Me O
O Pd(OAc)2, NEt3
Me
OAc
44
Me 42%
80 °C, 1.5 h DMSO
OTf
OAc Me
Me EtO2C P
45 OTf
OEt OEt
Pd(OAc)2, K2CO3 KOAc, 80 °C, 4 h
EtO2C
62%
DMF
O
P
OEt OEt
O 1. C4F9SO2F, n-Bu4NF r.t., 16 h, THF
SO2Ph
46 OSiMe3
Me
47
BF4− I+
Ph
O
2. Pd(OAc)2, K2CO3 KOAc, DMF, 85 °C, 1.5 h
Pd(OAc)2, NaHCO3 r.t., 2 h
39%
SO2Ph
73% Me
DMF
O OMe
48
I
Pd(OAc)2, n-Bu4NCl K2CO3, 20 °C, 6 h
54% OMe
DMF
O
O OMe
49 I
CuBr, K2CO3, NMP 150 °C, 24 h
75% OMe
O O
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1169
in the Heck reaction has extended the scope of the reaction considerably (entries 14–16).[217]–[219] There are a large number of phenols available that can be converted to triflates readily. Although aryl halides and triflates are the most commonly used arylating agents, there are successful examples where both aroyl chlorides[220] and arylsulfonyl chlorides[221] have been employed. Pd-catalyzed decarbonylations and desulfonylations and subsequent Heck couplings are often conducted with trialkylamines such as N-ethylmorpholine as a base, but improved yields are reported in cases in which the tertiary amine is replaced by a mixture of potassium carbonate and benzyltrioctylammonium chloride. In Table 2 two examples are given (entries 17 and 18).[222] Aryl halides are frequently prepared from the corresponding aryldiazonium salts by diazotation procedures. However, diazonium salts can be subjected directly to very mild Heck arylation conditions, which deliver coupled products (entry 19).[223] Preferably, the reaction is executed in nonaqueous solvents such as acetonitrile, acetone, or methylene chloride with sodium acetate as base and with palladiumbis(dibenzylideneacetone) as catalyst. Alternatively, a combination of the amine and t-butyl nitrite, in a mixture of acetic acid and monochloroacetic acid, can provide the desired product directly, which makes the isolation of a diazonium salt unnecessary (entry 20).[224] It is also possible to use aromatic acid anhydrides as oxidative addition precursors (entry 21).[225] Clearly, anhydrides are very interesting starting materials for a number of Heck reactions due to price and absence of halide salt formation. An example of a Heck reaction conducted with an activated alkene on a solid phase is depicted in entry 22 (Table 2).[197] The arylating agent is attached to the resin by an ester linkage and very good yields are achieved in this reaction. Recently, Miura and coworkers reported their interesting observation that arylation of 2-substituted 2-alkenals and 3-substituted 2-cyclohexen- and 2-cyclopenten-1-ones proceeds at their -position and not at the -position as could be expected (entry 23).[226] The Jeffery conditions have allowed for successful use of polyhalogenated arylating agents. Thus, arylation of styrene with 1,2,3-tribromobenzene delivers a 56% yield of tristyrylbenzene (entry 24).[227] A selective twofold coupling of 4-bromoiodobenzene with 2-amidoacrylates is depicted in entry 25.[228] The high reactivity of aryldiazonium salts is reflected in entry 26, where two consecutive selective Heck reactions have been accomplished.[229] C.ii. Arylation of Electron-Rich Alkenes Heck reactions with allylic derivatives as substrates are presented in entries 27[230] and 28.[231] In the absence of Tl(I) or Ag(I) salts and under Jeffery conditions, arylation of allylic alcohols provides a useful highly regioselective direct route to arylethyl ketones.[230] Electron-rich alkenes are more prone to be attacked at the most electron-deficient carbon.[29] Thus, Arai and Daves Jr. have demonstrated that cyclic vinyl ethers are attacked exclusively at the carbon adjacent to the oxygen atom (entry 29).[106] As discussed earlier (Sect. B.vi), methods that result in regiocontrolled arylations of acyclic vinyl ethers have been developed, and a series of representative examples are given in entries 30–33. Heck arylation of methyl vinyl ether with 4-iodoanisole gives a fair yield of 4-acetylanisole but an electron-donating group was required for preparatively useful -arylations to occur.[29] The employment of bidentate ligands constituted a significant improvement with an exclusive internal arylation as a result (entry 30).[33] Arylation of
1170
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
an alkene with a palladium coordinating nitrogen atom in the presence of a bidentate ligand leads to internal arylation but in the absence of this ligand, terminal attack occurs as discussed in Scheme 13.[32] Protected acetals are obtained in cases in which the chelating nitrogen is substituted with a hydroxyl group as depicted in entry 31.[232] Aroyl chlorides are generally good arylpalladium chloride precursors, but under certain conditions the migratory decarbonylation can be suppressed, and procedures that allow a very regioselective formation of semimasked 1,3-dicarbonyl compounds have been developed (entry 32).[233] The first example of a Heck arylation of a free enol is shown in entry 33.[39] Enamides are suitable substrates in the Heck reaction and the regioselectivity depends on both electronic and steric factors. Terminal attack is observed both with vinylphthalimide and the cyclic carbamate in entry 34 (Table 2).[234] As with the vinyl ethers, bidentate ligands can be utilized to afford a highly regioselective internal arylation (entry 35).[35] Enol ethers of arylpyruvates can be prepared smoothly by terminal arylation of methyl -methoxyacrylate under Jeffery conditions, entry 36.[235] Entry 37 provides an example of arylation of a diene, which affords a good yield of the terminally arylated diene.[236] C.iii. Vinylation of Alkenes Vinyl halides and triflates serve as good vinylating agents (entries 38–48). Vinylation occurs in the -position of electron-deficient alkenes, as in the case of the arylation reactions, and the same reaction profiles including double bond migrations are encountered (entries 38–40).[94],[95],[237] However, the vinylation of electron-rich alkenes such as vinyl ethers tends to furnish considerably higher -selectivity than that observed with corresponding arylation reactions under similar conditions (entry 41).[238] In 1996, Crisp and Gebaver reported Heck couplings between protected 2-aminobut-3-en-1-ols and cyclohexenyl triflate.[239] The reactions were carried out utilizing a “ligand-free” palladium catalyst, potassium carbonate, water, and tetra-n-butylammonium triflate (entry 42). The utility of vinyl triflates as starting materials is further substantiated by the reaction of 1-[(trimethylsilyl)ethynyl]-2,2-dimethylethenyl triflate with trimethylvinylsilane in entry 43 (Table 2).[117] Heck-type reactions with enol carboxylates (e.g., vinyl acetate) are generally complex. Most common are reactions in which vinyl acetate is employed as an ethylene equivalent (see Scheme 24). However, an example of a preparatively useful reaction with an intact acetate function is given in entry 44.[240] The reaction of vinyl triflates with vinyl phosphonates affords the corresponding conjugate dienylphosphonates (entry 45).[241] A new access to reactive nonaflates via a one-pot nonaflation–Heck reaction was recently reported (entry 46).[242] This reaction sequence starts from silyl enol ethers and provides functionalized 1,3-dienes in a simple manner. Iodonium salts can be used as RPd precursors (entry 47).[243] It is notable that the palladium(0) insertion preferentially occurs inbetween the iodonium ion and the vinylic, rather than the arylic sp2-hybridized carbon (entry 47). Some years ago, Jeffery used acetylenic halides to achieve (E )-enynoates and (E )-enynones in fair yields at room temperature (entry 48).[244] In recent years there have been a number of reports on the use of nonpalladium catalysts in the Heck-type reaction. An example of a Cu-catalyzed arylation of methyl acrylate is presented in entry 49.[161]
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
1171
D. SUMMARY The strength and growing popularity of the Heck reaction are attributed primarily to the high generality of the reaction, the extreme tolerance of various functional groups, and the simplicity of the experimental procedures—attributes already recognized by Heck in the early 1970s. Today, numerous intermolecular chemoselective, regioselective, and stereoselective (to be discussed elsewhere) reactions can be accomplished successfully. Procedures for oligofold and multiple couplings have been devised. The proposed mechanism outlined by Heck is to a large extent still valid 30 years after the discovery of the reaction, but with regard to the individual organometallic transformation steps, there is much more to be learned. However, interest in the reaction among chemists devoted to detailed mechanistic studies will provide new insights and ensure that new attractive synthetic chemistry will be developed. In the next ten years, fine-tuning of reaction conditions and catalytic systems, aided by a better mechanistic understanding, will extend the scope of the reaction further. It is foreseen by the authors that carefully designed protocols will be available, which enable prediction of the synthetic outcome from any combination of reactants, prior to synthesis. At present there are relatively few industrial processes relying on the Heck reaction as key steps. The fast development in recent years of new catalysts with very high turnover numbers and the ongoing intense research activity aimed at finding new efficient catalytic systems will probably result in a larger number of large-scale industrial processes in the future. Heck reactions performed in water, frequently under high pressure, will be seen and new heating techniques e.g., focused microwave irradiation) will provide dramatic shortening of reaction times. The robust Heck reaction will be established further as a major carbon–carbon bondforming reaction in combinatorial chemistry in solution and on solid support.
ACKNOWLEDGMENT We are heavily indebted to Mr. Gunnar Wikman and Dr. Nicholas Bonham for valuable linguistic revision and very skillful technical assistance.
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5518. R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5526. R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5531. R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5535. R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5538. R. F. Heck, J. Am. Chem. Soc., 1968, 90, 5542. R. F. Heck, J. Am. Chem. Soc., 1969, 91, 6707. I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 1119. Y. Fujiwara, I. Moritani, S. Danno, R. Asano, and S. Teranishi, J. Am. Chem. Soc., 1969, 91, 7166. Y. Fujiwara, R. Asano, I. Moritani, and S. Teranishi, J. Org. Chem., 1976, 41, 1681. T. Mizoroki, K. Mori, and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581.
1172 [12] [13] [14] [15]
[16] [17] [18] [19] [20] [21] [22]
[23] [24] [25] [26] [27]
[28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320. K. Mori, T. Mizoroki, and A. Ozaki, Bull. Chem. Soc. Jpn., 1973, 46, 1505. R. F. Heck, Org. React., 1982, 27, 345–390. B. M. Trost and T. R. Verhoeven, in Comprehensive Organometallic Chemistry, G. Wilkinson, F. G. A. Stone, and E. W. Abel, Eds., Pergamon Press, Oxford, 1982, Vol. 8, 854–883. R. F. Heck, Palladium Reagents in Organic Syntheses, Academic Press, London, 1985, 276–290. R. F. Heck, in Comprehensive Organic Synthesis, B. M. Trost and I. Fleming, Eds., Pergamon Press, Oxford, 1991, Vol. 4, 833–863. J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, and H.-U. Reissig, Organic Synthesis Highlights, VCH, Weinheim, 1991, 174–180. A. de Meijere and F. E. Meyer, Angew. Chem. Int. Ed. Engl., 1994, 33, 2379–2411. W. Cabri and I. Candiani, Acc. Chem. Res., 1995, 28, 2–7. J. Tsuji, Palladium Reagents and Catalysts: Innovations in Organic Chemistry, Wiley, Chichester, 1995, 95–168. B. C. Soderberg, in Comprehensive Organometallic Chemistry II, L. S. Hegedus, Volume Ed., E. W. Abel, F. G. A. Stone, and G. Wilkinson, Eds., Pergamon Press, Oxford, 1995, Vol. 12, 259–287. T. Jeffery, in Advances in Metal-Organic Chemistry, L. S. Liebeskind, Ed., JAI Press, Greenwich, CT, 1996, Vol. 5, 153–260. W. A. Herrmann, in Applied Homogeneous Catalysis with Organometallic Compounds, B. Cornils and W. A. Herrmann, Eds., VCH, Weinheim, 1996, Vol. 2, 712–732. S. Bräse and A. de Meijere, in Metal-Catalysed Cross-Coupling Reactions, P. J. Stang and F. Diederich, Eds., VCH, Weinheim, 1997, 99–166. G. T. Crisp, Chem. Soc. Rev., 1998, 27, 427–436. A. de Meijere and S. Bräse, Transition Metal Catalysed Reactions, IUPAC Monographs Chemistry for the 21st Century, S.-I. Murahashi and S. G. Davies, Eds., Blackwell Science, Oxford, 1999, 99–131. I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009–3066. G. D. Daves, Jr. and A. Hallberg, Chem. Rev., 1989, 89, 1433–1445. C.-M. Andersson, J. Larsson, and A. Hallberg, J. Org. Chem., 1990, 55, 5757. M. Larhed, C.-M. Andersson, and A. Hallberg, Acta Chem. Scand., 1993, 47, 212. M. Larhed, C.-M. Andersson, and A. Hallberg, Tetrahedron, 1994, 50, 285. W. Cabri, I. Candiani, A. Bedeschi, and R. Santi, J. Org. Chem., 1990, 55, 3654. W. Cabri, I. Candiani, A. Bedeschi, S. Penco, and R. Santi, J. Org. Chem., 1992, 57, 1481. W. Cabri, I. Candiani, A. Bedeschi, and R. Santi, J. Org. Chem., 1992, 57, 3558. W. Cabri, I. Candiani, A. Bedeschi, and R. Santi, J. Org. Chem., 1993, 58, 7421. W. A. Herrmann, V. P. W. Bohm, and C. P. Reisinger, J. Organomet. Chem., 1999, 576, 23–41. M. Larhed and A. Hallberg, J. Org. Chem., 1996, 61, 9582. N. Garg, M. Larhed, and A. Hallberg, J. Org. Chem., 1998, 63, 4158. K. Olofsson, M. Larhed, and A. Hallberg, J. Org. Chem., 1998, 63, 5076. F. Ozawa, A. Kubo, and T. Hayashi, J. Am. Chem. Soc., 1991, 113, 1417. F. Ozawa and T. Hayashi, J. Organomet. Chem., 1992, 428, 267. F. Ozawa, Y. Kobatake, and T. Hayashi, Tetrahedron Lett., 1993, 34, 2505.
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
[44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83]
1173
F. Ozawa, A. Kubo, Y. Matsumoto, T. Hayashi, E. Nishioka, K. Yanagi, and K.-I. Moriguchi, Organometallics, 1993, 12, 4188. Y. Sato, M. Sodeoka, and M. Shibasaki, Chem. Lett., 1990, 1953. C. Amatore and A. Jutand, J. Organomet. Chem., 1999, 576, 254–278. B. L. Shaw, New J. Chem., 1998, 22, 77. P. Fitton and E. A. Rick, J. Organomet. Chem., 1971, 28, 287. E. Negishi, C. Copéret, S. Y. Liou, F. Liu, and S. Ma, Chem. Rev., 1996, 96, 365–393. D. L. Thorn and R. Hoffmann, J. Am. Chem. Soc., 1978, 100, 2079. E. G. Samsel and J. R. Norton, J. Am. Chem. Soc., 1984, 106, 5505. E. H. Brooks and F. Glocking, J. Chem. Soc. (A), 1967, 1030. J. M. Brown and K. K. M. Hii, Angew. Chem. Int. Ed. Engl., 1996, 35, 657. M. Portnoy, Y. Ben-David, and D. Milstein, Organometallics, 1993, 12, 4734. E.-I. Negishi, Acc. Chem. Res., 1982, 15, 340–348. J. K. Stille and K. S. Y. Lau, Acc. Chem. Res., 1977, 10, 434–442. C. Amatore and F. Pflüger, Organometallics, 1990, 9, 2276. A. Jutand and A. Mosleh, Organometallics, 1995, 14, 1810. J.-F. Fauvarque, F. Pflüger, and M. Troupel, J. Organomet. Chem., 1981, 208, 419. E. Negishi, T. Takahashi, and K. Akiyoshi, J. Chem. Soc. Chem. Commun., 1986, 1338. C. Amatore, M. Azzabi, and A. Jutand, J. Am. Chem. Soc., 1991, 113, 8375. C. Amatore, E. Carré, A. Jutand, M. A. M’Barki, and G. Meyer, Organometallics, 1995, 14, 5605. F. Y. Zhao, B. M. Bhanage, M. Shirai, and M. Arai, J. Mol. Catal. A, 1999, 142, 383. B. M. Trost and D. J. Murphy, Organometallics, 1985, 4, 1143. R. McCrindle, G. Ferguson, G. Arsenault, and A. J. McAlees, J. Chem. Soc. Chem. Commun., 1983, 571. A. S. Carlström and T. Frejd, Acta Chem. Scand., 1992, 46, 163. F. Ozawa, A. Kubo, and T. Hayashi, Chem. Lett., 1992, 2177. C. Amatore, A. Jutand, and M. A. M’Barki, Organometallics, 1992, 11, 3009. T. Mandai, T. Matsumoto, and J. Tsuji, Tetrahedron Lett., 1993, 34, 2513. C. Amatore, E. Carré, A. Jutand, and M. A. M’Barki, Organometallics, 1995, 14, 1818. C. P. Mehnert, D. W. Weaver, and J. Y. Ying, J. Am. Chem. Soc., 1998, 120, 12289. C.-M. Andersson, K. Karabelas, and A. Hallberg, J. Org. Chem., 1985, 50, 3891. C. Amatore, E. Carre, and A. Jutand, Acta Chem. Scand., 1998, 52, 100. F. Kawataka, I. Shimizu, and A. Yamamoto, Bull. Chem. Soc. Jpn., 1995, 68, 654. J. M. Brown, J. J. Pérez-Torrente, N. W. Alcock, and H. J. Clase, Organometallics, 1995, 14, 207. C.-M. Andersson, A. Hallberg, and G. D. Daves, Jr., J. Org. Chem., 1987, 52, 3529. K.-C. Kong and C.-H. Cheng, J. Am. Chem. Soc., 1991, 113, 6313. W. A. Herrmann, C. Brossmer, K. Öfele, M. Beller, and H. Fischer, J. Mol. Catal., 1995, 133. M. Sakamoto, I. Shimizu, and A. Yamamoto, Chem. Lett., 1995, 1101. D. K. Morita, J. K. Stille, and J. R. Norton, J. Am. Chem. Soc., 1995, 117, 8576. F. E. Goodson, T. I. Wallow, and B. M. Novak, J. Am. Chem. Soc., 1997, 119, 12441. R. F. Heck, J. Am. Chem. Soc., 1971, 93, 6896. K. K. Hii, D. W. Claridge, and J. M. Brown, Angew. Chem. Int. Ed. Engl., 1997, 36, 984.
1174 [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
A. Hallberg, L. Westfelt, and B. Holm, J. Org. Chem., 1981, 46, 5414. C.-M. Andersson and A. Hallberg, J. Org. Chem., 1988, 53, 2112. C.-M. Andersson and A. Hallberg, J. Org. Chem., 1988, 53, 235. R. Grigg, V. Loganathan, S. Sukirthalingam, and V. Sridharan, Tetrahedron Lett., 1990, 31, 6573. R. Grigg, V. Loganathan, V. Santhakumar, V. Sridharan, and A. Teasdale, Tetrahedron Lett., 1991, 32, 687. C. Carfagna, A. Musco, G. Sallese, R. Santi, and T. Fiorani, J. Org. Chem., 1991, 56, 261. L. Ripa and A. Hallberg, J. Org. Chem., 1996, 61, 7147. K. Karabelas, C. Westerlund, and A. Hallberg, J. Org. Chem., 1985, 50, 3896. K. Karabelas and A. Hallberg, J. Org. Chem., 1986, 51, 5286. M. M. Abelman, T. Oh, and L. E. Overman, J. Org. Chem., 1987, 52, 4130. R. C. Larock and W. H. Gong, J. Org. Chem., 1989, 54, 2047. T. Jeffery, Tetrahedron Lett., 1990, 31, 6641. L. Ripa and A. Hallberg, J. Org. Chem., 1997, 62, 595. W. Cabri, I. Candiani, S. DeBernardinis, F. Francalanci, S. Penco, and R. Santi, J. Org. Chem., 1991, 56, 5796. T. G. Appleton, H. C. Clark, and L. E. Manzer, Coord. Chem. Rev., 1973, 10, 335 – 422. L. E. Overman and D. J. Poon, Angew. Chem. Int. Ed. Engl., 1997, 36, 518. A. Ashimori, B. Bachand, M. A. Calter, S. P. Govel, L. E. Overman, and D. J. Poon, J. Am. Chem. Soc., 1998, 120, 6488. D. Badone and U. Guzzi, Tetrahedron Lett., 1993, 34, 3603. K. Nilsson and A. Hallberg, J. Org. Chem., 1992, 57, 4015. R. McCrindle, G. Ferguson, M. A. Khan, A. J. McAlees, and B. L. Ruhl, J. Chem. Soc. Dalton Trans., 1981, 986. N. D. Buezo, I. Alonso, and J. C. Carretero, J. Am. Chem. Soc., 1998, 120, 7129. N. A. Cortese, C. B. Ziegler, Jr., B. J. Hrnjez, and R. F. Heck, J. Org. Chem., 1978, 43, 2952. I. Arai and G. D. Daves, Jr., J. Org. Chem., 1979, 44, 21. R. C. Larock, E. K. Yum, and H. Yang, Tetrahedron, 1994, 50, 305. R. C. Larock, W. Y. Leung, and S. Stolz-Dunn, Tetrahedron Lett., 1989, 30, 6629. P. E. M. Siegbahn, S. Strömberg, and K. Zetterberg, Organometallics, 1996, 15, 5542. R. J. Deeth, A. Smith, K. K. Hii, and J. M. Brown, Tetrahedron Lett., 1998, 39, 3229. M. Ludwig, S. Strömberg, M. Svensson, and B. Åkermark, Organometallics, 1999, 18, 970. R. C. Larock and B. E. Baker, Tetrahedron Lett., 1988, 29, 905. S. Laschat, F. Narjes, and L. E. Overman, Tetrahedron, 1994, 50, 347. H.-C. Zhang and G. D. Daves, Jr., Organometallics, 1993, 12, 1499. R. C. Larock, W. H. Gong, and B. E. Baker, Tetrahedron Lett., 1989, 30, 2603. T. Jeffery, Tetrahedron Lett., 1991, 32, 2121. K. Karabelas and A. Hallberg, J. Org. Chem., 1988, 53, 4909. A. Hallberg and C. Westerlund, Chem. Lett., 1982, 1993. K. Karabelas and A. Hallberg, J. Org. Chem., 1989, 54, 1773. A. M. LaPointe, F. C. Rix, and M. Brookhart, J. Am. Chem. Soc., 1997, 119, 906. K. Karabelas and A. Hallberg, Tetrahedron Lett., 1985, 26, 3131. I. Arai and G. D. Daves, Jr., J. Heterocycl. Chem., 1978, 15, 351.
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
[123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] [156] [157] [158]
1175
A. Kasahara, T. Izumi, and N. Fukuda, Bull. Chem. Soc. Jpn., 1977, 50, 1021. K. Nilsson and A. Hallberg, J. Org. Chem., 1990, 55, 2464. L. Filippini, M. Gusmeroli, and R. Riva, Tetrahedron Lett., 1993, 34, 1643. K. Ono, K. Fugami, S. Tanaka, and Y. Tamaru, Tetrahedron Lett., 1994, 35, 4133. E. Bernocchi, S. Cacchi, P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1992, 33, 3073. S.-K. Kang, H.-W. Lee, S.-B. Jang, T.-H. Kim, and S.-J. Pyun, J. Org. Chem., 1996, 61, 2604. T. Jeffery, Tetrahedron Lett., 1993, 34, 1133. T. Mandai, S. Hasegawa, T. Fujimoto, M. Kawada, J. Nokami, and J. Tsuji, Synlett, 1990, 85. A. Arcadi, E. Bernocchi, S. Cacchi, and F. Marinelli, Tetrahedron, 1991, 47, 1525. S.-K. Kang, K.-Y. Jung, C.-H. Park, E.-Y. Namkoong, and T.-H. Kim, Tetrahedron Lett., 1995, 36, 6287. J. C.-Y. Cheng and G. D. Daves, Jr., J. Org. Chem., 1987, 52, 3083. A. Sen and T.-W. Lai, Inorg. Chem., 1984, 23, 3257. K. T. Wanner and A. Kärtner, Heterocycles, 1987, 26, 917. K. T. Wanner and A. Kärtner, Arch. Pharm. (Weinheim), 1987, 320, 1050. C. Sonesson and A. Hallberg, Tetrahedron Lett., 1995, 36, 4505. C. Sonesson, M. Larhed, C. Nyqvist, and A. Hallberg, J. Org. Chem., 1996, 61, 4756. V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585. A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc., 1987, 109, 5478. T. Jeffery, J. Chem. Soc. Chem. Commun., 1984, 1287. T. Jeffery, Tetrahedron, 1996, 52, 10113. T. Jeffery and M. David, Tetrahedron Lett., 1998, 39, 5751. T. Jeffery, Tetrahedron Lett., 1999, 40, 1673. A. J. Cheney and B. L. Shawl, J. Chem. Soc. Dalton Trans., 1972, 754. E. C. Alyea, S. A. Dias, G. Ferguson, and P. J. Roberts, J. Chem. Soc. Dalton Trans., 1979, 948. T.-A. Mitsudo, W. Fischetti, and R. F. Heck, J. Org. Chem., 1984, 49, 1640. W. A. Herrmann, C. Brossmer, K. Öfele, C. P. Reisinger, T. Priermeier, M. Beller, and H. Fischer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1844. W. A. Herrmann, C. Brossmer, C. P. Reisinger, T. H. Riermeier, K. Öfele, and M. Beller, Chem. Eur. J., 1997, 3, 1357. M. Beller and T. H. Riermeier, Eur. J. Inorg. Chem., 1998, 29. B. L. Shaw, S. D. Perera, and E. A. Staley, J. Chem. Soc. Chem. Commun., 1998, 1361. M. Ohff, A. Ohff, M. E. van der Boom, and D. Milstein, J. Am. Chem. Soc., 1997, 119, 11687. M. Ohff, A. Ohff, and D. Milstein, J. Chem. Soc. Chem. Commun., 1999, 357. W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, and G. R. J. Artus, Angew. Chem. Int. Ed. Engl., 1995, 34, 2371. W. A. Herrmann, C.-P. Reisinger, and M. Spiegler, J. Organomet. Chem., 1998, 557, 93. W. A. Herrmann and C. Köcher, Angew. Chem. Int. Ed. Engl., 1997, 36, 2162 – 2187. D. S. McGuinness, K. J. Cavell, B. W. Skelton, and A. H. White, Organometallics, 1999, 18, 1596. R. F. Heck, Acc. Chem. Res., 1979, 12, 146–151.
1176 [159] [160] [161] [162] [163] [164] [165] [166] [167] [168] [169] [170] [171] [172] [173] [174] [175] [176] [177] [178] [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] [197] [198]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
B. L. Shaw and S. D. Perera, J. Chem. Soc. Chem. Commun., 1998, 1863. S. Iyer, C. Ramesh, and A. Ramani, Tetrahedron Lett., 1997, 38, 8533. S. Iyer, C. Ramesh, A. Sarkar, and P. P. Wadgaonkar, Tetrahedron Lett., 1997, 38, 8113. S. Iyers, J. Organomet. Chem., 1995, 490, C27. A. J. Canty, Acc. Chem. Res., 1992, 25, 83–90. A. J. Canty, J. L. Hoare, J. Patel, M. Pfeffer, B. W. Skelton, and A. H. White, Organometallics, 1999, 18, 2660. J. Louie and J. F. Hartwig, Angew. Chem. Int. Ed. Engl., 1996, 35, 2359. T. H. Riermeier, A. Zapf, and M. Beller, Top. Catal., 1997, 4, 301–309. V. V. Grushin and H. Alper, Chem. Rev., 1994, 94, 1047–1062. M. Julia, M. Duteil, C. Grard, and E. Kuntz, Bull. Soc. Chim. Fr., 1973, 2791. J. J. Bozell and C. E. Vogt, J. Am. Chem. Soc., 1988, 110, 2655. Y. Ben-David, M. Portnoy, M. Gozin, and D. Milstein, Organometallics, 1992, 11, 1995. A. F. Littke and G. C. Fu, J. Org. Chem., 1999, 64, 10. M. Beller and A. Zapf, Synlett, 1998, 792. M. T. Reetz, G. Lohmer, and R. Schwickardi, Angew. Chem. Int. Ed. Engl., 1998, 37, 481. S. A. Stone-Elander, N. Elander, J.-O. Thorell, G. Solås, and J. Svennebrink, J. Labelled Compd. Radiopharm., 1994, 10, 949. T. Cablewski, A. F. Faux, and C. R. Strauss, J. Org. Chem., 1994, 59, 3408. K. D. Raner, C. R. Strauss, R. W. Trainor, and J. S. Thorn, J. Org. Chem., 1995, 60, 2456. R. B. Merrifield, J. Am. Chem. Soc., 1963, 85, 2149. C. R. Strauss, Aust. J. Chem., 1999, 52, 83–96. D. M. P. Mingos and D. R. Baghurst, Chem. Soc. Rev., 1991, 20, 1–47. C. R. Strauss and R. W. Trainor, Aust. J. Chem., 1995, 48, 1665–1692. C. Gabriel, S. Gabriel, E. H. Grant, B. S. J. Halstead, and D. M. P. Mingos, Chem. Soc. Rev., 1998, 27, 213–223. P. Lidström, J. Tierney, B. Wathey, and J. Westman, Tetrahedron, 2001, 57, 9225–9283. A. Wali, S. M. Pillai, and S. Satish, React. Kinet. Catal. Lett., 1997, 60, 189. A. Díaz-Ortiz, P. Prieto, and E. Vázquez, Synlett, 1997, 269. J. Li, A. W.-H. Mau, and C. R. Strauss, J. Chem. Soc. Chem. Commun., 1997, 1275. S. Stone-Elander and N. Elander, in Chemists’ Views of Imaging Centers, A. M. Emran, Ed., Plenum Press, New York, 1995, 445–454. J. E. Plevyak, J. E. Dickerson, and R. F. Heck, J. Org. Chem., 1979, 44, 4078. J. P. Genet and M. Savignac, J. Organomet. Chem., 1999, 576, 305–317. N. A. Bumagin, P. G. More, and I. P. Beletskaya, J. Organomet. Chem., 1989, 371, 397. L. U. Gron and A. S. Tinsley, Tetrahedron Lett., 1999, 40, 227. P. Reardon, S. Metts, C. Crittendon, P. Daugherity, and E. J. Parsons, Organometallics, 1995, 14, 3810. M. A. Carroll and A. B. Holmes, J. Chem. Soc. Chem. Commun., 1998, 1395. B. M. Bhanage, Y. Ikushima, M. Shirai, and M. Arai, Tetrahedron Lett., 1999, 40, 6427. R. E. Dolle and K. H. Nelson, Jr., J. Comb. Chem., 1999, 1, 235–282. K.-L. Yu, M. S. Deshpande, and D. M. Vyas, Tetrahedron Lett., 1994, 35, 8919. M. Hiroshige, J. R. Hauske, and P. Zhou, Tetrahedron Lett., 1995, 36, 4567. B. Ruhland, A. Bombrun, and M. A. Gallop, J. Org. Chem., 1997, 62, 7820. B. A. Lorsbach and M. J. Kurth, Chem. Rev., 1999, 99, 1549–1581.
IV.2.1.1 SCOPE, MECHANISM, AND OTHER ASPECTS OF THE HECK REACTION
[199] [200] [201] [202] [203] [204] [205] [206] [207] [208] [209] [210] [211] [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] [223] [224] [225] [226] [227] [228] [229] [230] [231] [232] [233] [234] [235] [236] [237]
1177
S. Bräse and M. Schroen, Angew. Chem. Int. Ed. Engl., 1999, 38, 1071. D. J. Gravert and K. D. Janda, Chem. Rev., 1997, 97, 489–509. C. G. Blettner, W. A. Konig, W. Stenzel, and T. Schotten, Tetrahedron Lett., 1999, 40, 2101. B. Sauvagnat, F. Lamaty, R. Lazaro, and J. Martinez, C. R. Acad. Sci. C, 1998, 1, 777. K. H. Shaughnessy, P. Kim, and J. F. Hartwig, J. Am. Chem. Soc., 1999, 121, 2123. J. Jurczak and B. Baranowski, High Pressure Chemical Synthesis, Elsevier, Amsterdam, 1989, 1–9. S. Hillers and O. Reiser, J. Chem. Soc. Chem. Commun., 1996, 2197. K. Voigt, U. Schick, F. E. Meyer, and A. de Meijere, Synlett, 1994, 189. T. Sugihara, M. Takebayashi, and C. Kaneko, Tetrahedron Lett., 1995, 36, 5547. A. de Meijere and S. Bräse, J. Organomet. Chem., 1999, 576, 88–110. S. Hillers, S. Sartori, and O. Reiser, J. Am. Chem. Soc., 1996, 118, 2087. B. A. Patel, C. B. Ziegler, N. A. Cortese, J. E. Plevyak, T. C. Zebovitz, M. Terpko, and R. F. Heck, J. Org. Chem., 1977, 42, 3903. C. B. Ziegler and R. F. Heck, J. Org. Chem., 1978, 43, 2941. A. Spencer, J. Organomet. Chem., 1983, 258, 101. S. Hirooka, Y. Tanbo, K. Takemura, H. Nakahashi, T. Matsuoka, and S. Kuroda, Bull. Chem. Soc. Jpn., 1991, 64, 1431. Y. Xu, X. Jin, G. Huang, and Y. Huang, Synthesis, 1983, 556. M. MorenoManas, R. Pleixats, and A. Roglans, Synlett, 1997, 1157. Y. Akita, T. Noguchi, M. Sugimoto, and A. Ohta, J. Heterocycl. Chem., 1986, 23, 1481. Q.-Y. Chen and Z.-Y. Yang, Tetrahedron Lett., 1986, 27, 1171. G. W. Gribble and S. C. Conway, Synth. Commun., 1992, 22, 2129. J. W. Tilley, R. Sarabu, R. Wagner, and K. Mulkerins, J. Org. Chem., 1990, 55, 906. H.-U. Blaser and A. Spencer, J. Organomet. Chem., 1982, 233, 267. M. Miura, H. Hashimoto, K. Itoh, and M. Nomura, Tetrahedron Lett., 1989, 30, 975. M. Miura, H. Hashimoto, K. Itoh, and M. Nomura, J. Chem. Soc. Perkin Trans. 1, 1990, 2207. K. Kikukawa, K. Nagira, F. Wada, and T. Matsuda, Tetrahedron, 1981, 37, 31. K. Kikukawa, K. Maemura, Y. Kiseki, F. Wada, T. Matsuda, and C. S. Giam, J. Org. Chem., 1981, 46, 4885. M. S. Stephan, A. J. J. M. Teunissen, G. K. M. Verzijl, and J. G. deVries, Angew. Chem. Int. Ed. Engl., 1998, 37, 662. Y. Terao, T. Satoh, M. Miura, and M. Nomura, Tetrahedron Lett., 1998, 39, 6203. A. Lansky, O. Reiser, and A. de Meijere, Synlett, 1990, 405. A.-S. Carlström and T. Frejd, J. Org. Chem., 1991, 56, 1289. S. Sengupta and S. K. Sadhukhan, Tetrahedron Lett., 1998, 39, 715. M. Somei and H. Ohnishi, Chem. Pharm. Bull., 1985, 33, 5147. N. J. Malek and A. E. Moormann, J. Org. Chem., 1982, 47, 5395. M. Larhed and A. Hallberg, J. Org. Chem., 1997, 62, 7858. C.-M. Andersson and A. Hallberg, J. Org. Chem., 1988, 53, 4257. C. A. Busacca, R. E. Johnson, and J. Swestock, J. Org. Chem., 1993, 58, 3299. S. Cacchi, P. C. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1987, 28, 3039. T. Jeffery, Tetrahedron Lett., 1992, 33, 1989. M. Sato, N. Yoneda, and C. Kaneko, Chem. Pharm. Bull., 1986, 34, 4577.
1178 [238] [239] [240] [241] [242] [243] [244]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
C.-M. Andersson and A. Hallberg, J. Org. Chem., 1989, 54, 1502. G. T. Crisp and M. G. Gebauer, Tetrahedron, 1996, 52, 12465. P. G. Ciattini, E. Morera, and G. Ortar, Tetrahedron Lett., 1991, 32, 1579. A. Burini, S. Cacchi, P. Pace, and B. R. Pietroni, Synlett, 1995, 677. M. Webel and H. U. Reissig, Synlett, 1997, 1141. R. M. Moriarty, W. R. Epa, and A. K. Awasthi, J. Am. Chem. Soc., 1991, 113, 6315. T. Jeffery, Synthesis, 1987, 70.
IV.2.1.2
Double and Multiple Heck Reactions
STEFAN BRÄSE and ARMIN DE MEIJERE
A. INTRODUCTION The multiple Pd-catalyzed couplings of oligohaloarenes and -alkenes (or perfluoroalkyland fluorosulfonates) with alkenes (Heck reactions) offer the possibility of constructing symmetrically oligosubstituted, highly unsaturated carbon frameworks in a single synthetic operation. The Heck reaction of di- and oligoethenylarenes with di- and oligohaloarenes can be applied to produce conjugated polyvinylenearylene-type polymers that may have important applications in the future. Comparable in scope and limitations to the related multiple Stille and Suzuki couplings, the ready accessibility of starting materials and the ease of removing by-products have made multiple Heck reactions particularly attractive for various synthetic applications. In this section, a double (or multiple) Heck reaction is defined as a coupling of two (or more) alkene molecules with di- or oligohaloarenes or -alkenes as well as a reaction of two (or more) di- or oligohaloarenes or alkenes with one alkene molecule.
B. COUPLING OF OLIGOHALOARENES WITH ALKENES The multiple coupling of oligohaloarenes with alkenes was described early on by Heck and Nolley in one of their first papers.[1] Twofold coupling of 1,4-diiodobenzene with styrene furnished the 1,4-distyrylbenzene in 67% yield; shortly afterwards, the double Heck couplings under palladium catalysis of 4,7-diiodofluorene, p-diiodoterphenyl, and pdiiodobiphenyl with various substituted styrenes were disclosed by Japanese chemists in a patent on the synthesis of dye brighteners.[2] Since then, a large number of ortho-, meta-, and para-dihaloarenes and -heteroarenes have been subjected to double Heck reactions with various alkenes (Tables 1–3, Scheme 1). However, the substitution pattern on the arene is crucial for the success of the Heck reaction. When a second Heck coupling takes place in an ortho position of another alkenyl unit, cyclization of the intermediately formed -(-arylalkyl)palladium complex may occur, as formation of alkylideneindanes and alkylindenes, especially under classical Heck conditions with phosphines in the catalyst cocktail, was observed (Scheme 2, Table 1).
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1179
1180
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 1. Twofold Heck Reactions on 1,2-Dihaloarenes Arene
Alkene
Product
X
R R
X
Conditions
R
Yield (%)
Reference
X=I
R = Ph
R = Ph
Pd(OAc)2, Bu3N, 100 °C, 72 h
37
[1]
X=I
R = CO2Me
R = CO2Me
Pd(OAc)2, PPh3, Et3N, 100 °C, 48 h
69
[7]
X = Br
R = Ph
R = Ph
Pd(OAc)2, Bu4NBr, K2CO3, DMF, 100 °C, 5 d
92
[8]
X = Br
R = Ph
R = Ph
Pd(OAc)2, P(o-Tol)3, Et3N, THF/MeCN, 55 °C, 1 d, 10 kbar Pd(OAc)2, P(o-Tol)3, Et3N, 150 °C (microwave), 22 min
59
[9]
65
[10]
X = Br
R = CO2Me
R = CO2Me
Pd(OAc)2, Bu4NCl, LiCl, K2CO3, DMF, 100 °C, 12 h
86
[11]
X = Br
R = Me (5 bar)
R = Me
Pd(OAc)2, Bu4NBr, LiCl, KHCO3, DMF, 100 °C, 12 h
79
[12]
X = Br
R = H (13.8 bar)
R=H
Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 125 °C
78
[13]
X = Br
R=
Pd(OAc)2, PPh3, Et3N, DMF, 135 °C, 36 h
65
[14]
[15]
P Me
Ph
R=
O
P Me
Ph O
X = Br
R = 4-Py
R = 4-Py
Pd(OAc)2, PPh3, Et3N, 100 °C, 3 d
80
X = Br
R = Fc
R = Fc
Pd(OAc)2, (n-Bu)4NBr, K2CO3, DMF, 70 °C, 3 d
74
Pd(OAc)2, PPh3, Et3N, MeCN, reflux 16 h
77
I
I B O
O
O O
BO
O B
O
a
[16]
[17]
1181
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
TABLE 1. (Continued ) Arene
Alkene
Yield (%)
Reference
Pd(OAc)2,Bu4NBr, K2CO3, LiCl, DMF, 100 °C, 3 d
35
[18]
Pd(OAc)2, P(o-Tol)3, DMF, 100 °C, 2 d
46
[19]
Pd(OAc)2, PPh3, i-Pr2EtN, DMF, 100 °C, 3 d
56 b
[5]
Product
Conditions
Ph Br Ph
Br
Ph
O
OH
I
I
O
a Fc = ferrocenyl. b The diketone was isolated.
R1
X
,,
Pd
R2 ,,
R1
R2
X
R2 X = Br, I;
R2
= aryl, alkyl, etc.
Scheme 1
R2 R1
X
,,
Pd
R2 ,,
R1
R1
R2 and/or
R2
R2
X Scheme 2
This reaction mode plays a dominant role in the sixfold Heck coupling of hexabromobenzene with styrenes yielding complex mixtures of various isomers of the sixfold coupling product. The analogous sixfold Suzuki and Stille coupling reactions with alkenylboronates and alkenylstannanes, respectively, gave the corresponding pure hexakisalkenylbenzene derivatives in high yields.[3] As shown by various experiments with o- and p-dihaloarenes, the second coupling step is generally accelerated by the first introduced alkenyl substituents in the ortho or para position, while a meta-alkenyl substituent does not significantly influence the rate of the second coupling.[4]
1182
R1
I
I
Br
(Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 120 °C, 7 d)
(Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 90 °C, 1 h)
(Pd(OAc)2, PPh3, Et3N, 100 °C, 3 d) (Pd(OAc)2, PPh3, Et3N, DMF, 135 °C, 36 h) (Pd(OAc)2, P(o-Tol)3, Et3N, MeCN)
R2
Ph (Pd/C, Bu3N, 115–120 °C, 3 h)
O (Pd(OAc)2, Bu4NCl, NaHCO3, DMF, 85 °C, 16 h)
OBn
NHBoc
E (Pd(OAc)2, PPh3, Et3N, 100 °C, 19 h)
Alkene (Conditions)
2
1
R1
Br CO2Bn NHBoc
n.r.b 94 56
R1 = HOCHPh, R2 = CO2Et R1 = CH2OH, R = CO2Et R1 = CO2Et, R2 = CN
77
21
52
[24]
[23]
[22]
[14]
[15]
[21]
[20]
[7]
46a
92
R2
Ph
E
Reference
Yield (%)
R = H, R = P(O)MePh
R = H, R = 4-Py
2
1
R2
Ph
BocHN
BnO2C
E
Product
a The bromine substituent does not take part in the coupling under these conditions. b n.r. = not reported.
Br
I
Br
I
I
I
Arene
TABLE 2. Twofold Heck Reactions on 1,3-Dihaloarenes: E = CO2Me
1183
I
I
MeO
Br
MeO
I
Br
OMe
OMe
I
OMe
I
I
MeO
I
C6H4-4-I
I
I
4-I-C6H4
I
Arene
^=
E
MeO
MeO
E
E
MeO
MeO
MeO
RO
NMe2
OMe
E
OR
OMe
O
Ph
t-Bu-4-C6H4
Ph
Ph
C6H4-4-t-Bu
Ph
Alkene
3
OMe
OMe
OMe
Product
E
OR
Ph
OMe
OMe
E
3
C6H4-4-t-Bu
Ph
Pd(OAc)2, P(o-Tol)3, Et3N, 110 °C, 60 h
Pd(OAc)2, P(o -Tol)3, Et3N/MeCN 2:1, 70 °C, 70 h
Pd(OAc)2, PPh3, Et3N, 100 °C, 48 h
Pd(OAc)2, (n-Bu)4NCl, K2CO3, DMF, 800 °C, 16 h
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 100 °C, 17 h
Pd, DMF
Pd(OAc)2, (n-Bu)3N, 100 °C, 72 h
Conditions
TABLE 3. Twofold Heck Reactions on 1,4- and Related para-Substituted Dihaloarenes: E = CO2Me, E = CO2Et
62
89
32
76
11
n.r.a
67
Yield (%)
(Continued )
[28]
[27]
[7]
[26]
[25]
[2]
[1]
Reference
1184
Br
Br
Br
Br
I
Br
Br
I
I
I
R
I
I
Arene
TABLE 3. (Continued )
Ph
Ph
Ph
Ph
R H, CN, NO2, SO2C10H29
O
NHBoc OBn
Alkene
Ph
Ph
Ph
Ph
BocHN BnO2C
R
BocHN
Product
Ph
Ph
Ph
Ph
CO2Bn
PdCl2[P(o-Tol)3]2 (n-Bu)3N, K2CO3, H2O, 100 °C, 6 h
PdCl2(PPh3)2, (n-Bu)3N, K2CO3, H2O, 100 °C, 5 h
Pd(OAc)2, P(o-Tol)3, Et3N, 100–120 °C, 24 h
Pd(OAc)2, (n-Bu)4NBr, LiCl, K2CO3, DMF, 110 °C, 5 d
Pd/C, (n-Bu)3N, 115–120 °C, 3 h
Pd(OAc)2, (n-Bu)4NCl, NaHCO3, DMF, 85 °C, 16 h
Conditions
85
70
74–97
61
81
55
Yield (%)
[31]
[30]
[29]
[18]
[21]
[20]
Reference
1185
I
Br
I
I
Br
I
I
I
OTf
TfO
Br
Br
Br
I
N
Ph
^=
CO2Et
Ph P Ph O
Me O
P
O
OEt
Ph
Ar
P Me
EtO2C
Ar
Ph2(O)P
O
Ph
E′
Ph
Me O P Ph
CO2Et
Ar
P(O)Ph2
E′
Ph
PdCl2(PPh3)2, Et3N, MeCN, 80 °C, 1 h
42b
82
21
Pd(OAc)2, BnEt3NCl, KOAc, 25 °C, 10 d
PdCl2, (n-Bu)3N, DMF, 80 °C, 6h
39
85
72
97
Pd(OAc)2, PPh3, Et3N, MeCN, 125 °C, 24 h
Pd(OAc)2, PPh3, Et3N, DMF, 135 °C, 36 h
PdCl2(PPh3)2, Et3N, DMF, 130 °C, 24 h
PdCl2, P(o-Tol)3, (n-Bu)3N, K2CO3, H2O, 100 °C, 3 h
(Continued )
[36]
[35]
[34]
[33]
[14]
[32]
[30],[31]
1186
Br
Br
Br
Br
OHept
I
I
R=
Et N
Fc
(30 bar)
O
NHBoc OBn
Ph
Alkene
BnO2C
SO2Me
Fc
NHBoc
Ph
RO
Product
b The
= not reported. monosubstitution product (iodine replaced) was isolated in 22% yield. c Total yield of coupling products. The mono-α-substituted styrene was isolated in 12% yield. d Fc = ferrocenyl.
a n.r.
I
I
RO
Arene
TABLE 3. (Continued )
Fc
BocHN
OHept
Ph
CO2Bn
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 1000–120 °C
Pd(OAc)2, (n-Bu)4NBr, K2CO3, DMF, 70 °C, 3 d
Pd(OAc)2, (n-Bu)4NCl, NaHCO3, DMF, 85 °C, 16 h
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 80 °C, 5 h
Conditions
74
24
59
90 c
Yield (%)
[39]
[38]
[20]
[37]
Reference
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
1187
The primary coupling product of 1,2-diiodobenzene with allyl alcohol, a dicarbaldehyde, underwent an intramolecular aldol condensation under the reaction conditions (Scheme 3).[5] OH
O CHO
Pd(OAc) 2, Et3N 80 °C, 44 h
I
H H
I
81%
O Scheme 3
Double and even triple Heck–Diels–Alder cascade reactions involving bicyclopropylidene and 1,4-diiodo- or 1,3,5-triiodobenzene, respectively, have been accomplished. In these sequences, the carbopalladation across the highly strained alkene is followed by a cyclopropylmethyl to homoallyl rearrangement with concomitant -hydride elimination to yield an allylidenecyclopropane, which subsequently undergoes a smooth [4 2] cycloaddition to furnish the spiro[5.2]octene moiety (Scheme 4).[6]
I +
CO2Me
+
Pd(OAc) 2, PPh3, Bu4NCl, K2CO3, MeCN, 80 °C, 2 d
MeO2C
64% CO2Me
I
CO2Me
Pd(OAc) 2, PPh3, Bu4NCl, K2CO3, MeCN, 80 °C, 2 d
X +
+ X
X
CO2Me
X = Br: 34% X = I: 72% MeO2C
CO2Me
Scheme 4
In later studies by Heck and co-workers,[7] extension to threefold and higher multifold couplings with the corresponding oligoiodoarenes failed, and only major fractions of reduced starting materials were observed. This drawback was completely overcome by applying the Jeffery protocol,[40] that is, with a base like potassium carbonate in the presence of a tetrabutylammonium halide.[41],[42] Under these conditions, three alkene units and more can be attached to an arene ring in excellent yields (Tables 4 and 5).
1188
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 4. Threefold Heck Reaction on 1,2,3-, 1,2,4-, and 1,3,5-Trihaloarenes: E = CO2Me, Fc = Ferrocenyl
Arene Alkene
Product E
I
Yield (%)
Reference
Pd(OAc)2, PPh3, Et3N, 100 °C, 12 h
52
[7]
Pd(OAc)2, (n-Bu)4NBr, K2CO3, DMF, 2 h, 60 °C
46 a
[16]
Conditions
I
E I
CO2Me E
Br
Br
R
R
Br R
R = Fc
Fc
4-Py
R = 4-Py
Pd(OAc)2, PPh3, Et3N, 100 °C, 3 d
70 (60)
[43] ([15])
2-Py
R = 2-Py
Pd(OAc)2, K2CO3, (n-Bu)4NBr, DMF, 100 °C, 5 d
92
[44]
R=H
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 125 °C
71
[45]
R = Ph
Pd(OAc)2, (n-Bu)4NCl, K2CO3, LiCl, DMF, 110 °C, 30 h
82
[4]
Pd(OAc)2, PPh3, Et3N, 100 °C, 3 d
>40
[43]
Pd(OAc)2, (n-Bu)4NBr, K2CO3, DMF, 100 °C, 7 d
56 X=H
[8]
Pd(OAc)2, (n-Bu)4NCl, K2CO3, LiCl, DMF, 100 °C, 4d
66 X = NO2
[4]
Pd(OAc)2, (n-Bu)4NCl, K2CO3, LiCl, DMF, 3 d, 90 °C
58
[11]
(8 bar) Ph
R = C6H4-4-OMe
C6H4-4-OMe
Ph
Br Br
Br
Ph Ph
X X = H, NO2
X
Ph
R
Br Br
Br
CO2t-Bu
R
R
R = CO2t-Bu
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
1189
TABLE 4. (Continued )
Arene Alkene
Product
Br
Reference
Pd(OAc)2, (n-Bu)4NBr, K2CO3, LiCl, DMF, 100 °C, 3d
37
[18]
Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 100 °C, 3 d
51
[46]
Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 80 °C, 5 h
[47] 63 E= CO2Me
Ph
Br Br
Ph Ph
Ph
Br
Yield (%)
Conditions
Ph
Br
Ph
Br Ph
Br
Ph
E
Br
E
Br E aFc
E
= ferrocenyl.
TABLE 5. Fourfold Heck Reaction on 1,2,4,5- and Related Tetrahaloarenes Arene Alkene
Product
Conditions
X
X
R
R
X
X
R
R
R
Yield (%)
Reference
X = I, R = CO2Me
Pd(OAc)2, PPh3, Et3N, 100 °C, 48 h
16
[7]
X = Br, R = H
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 125 °C, 8 d
76
[45]
X = Br, R = Ph
Pd(OAc)2, BnEt3NCl, K2CO3, LiCl, DMF, 110 °C, 3 d
62
[8]
(Continued )
1190
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 5. (Continued ) Arene Alkene
Product
Br
Ph Ph
Br Ph
Br
Br
Br
Pd(OAc)2, (n-Bu)4NBr, K2CO3, LiCl, DMF, 100 °C, 3 d
70
[18]
as above
45
[18]
as above, no LiCl, 80 °C, 6 d
17
[38]
Ph
Ph
Ph
Br Ph
Ph
Br
Reference
Ph
Br Br
Br
Yield (%)
Conditions
Br
Fc
Ph
Fc
Br Fca
Fc
Fc
a Fc = ferrocenyl.
Similarly, the reaction of tetrahaloarenes with alkenes gives rise to the formation of tetraalkenylarenes. Arenediazonium salts, which are readily available from a large stock of anilines, have proved to be valuable starting materials for Heck reactions since their reactivities exceed even those of the corresponding triflates and hence allow coupling at lower temperatures. Twofold Heck reactions of bisdiazonium salts with various substitution patterns have been investigated (Table 6).[48] Even a fourfold Heck reaction utilizing the tetradiazonium salt with a tetraphenylmethane framework has been demonstrated with various alkenes to yield the corresponding fourfold coupling products.[49] Allyl alcohols did not couple with the tetradiazonium salt, but the tetrakis( p-iodophenyl)methane did yield the tetraaldehyde upon coupling with allyl alcohol (Scheme 5).[49] The multiple Heck reaction with oligohaloheteroarenes provided a general access to highly symmetrical, often biologically active, molecules. The failure of 2,6-dihalopyridine to undergo a twofold Heck coupling was associated with the presence of a heteroatom.[50] However, 2,5-dihalothiophenes are excellent substrates for a twofold Heck coupling, even with 1,1-dimethylallene, the product of which subsequently undergoes a twofold Diels – Alder reaction (Scheme 6, Table 7).[51],[52]
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
1191
TABLE 6. Twofold Heck Reaction of Arenebisdiazonium Salts[48]: E = CO2Me Arene Alkene
Product
+
+
E
N2
N2
Conditions
2 BF4
Pd(OAc)2, MeOH, 65 °C, 1 h
E
–
Yield (%)
83
CO2Me R1
R1
R1
R
R1
2
N2+
+
N2
Pd(OAc)2, Et OH,80 °C, 1h
R2
2 BF4–
R1 = H, R2 = CO2Me R1 = Me, R2 = CO2Me R1 = Me, R2 = Ph
R2
X
X +
N2
70 73 60
N2+
2 BF4–
E
E
Pd(OAc)2, EtOH, 80 °C, 1h 80 60
X=O X = SO2
CO2Me
+
N2
N2+
2 BF4–
E E
Pd(OAc)2, EtOH, 80 °C, 1h
60
CO2Me
TABLE 7. Twofold Heck Reaction on Dihaloheteroarenes: E = CO2Et Arene I
Alkene O
I
E
E
Br
S
Br
Conditions
Yield (%)
Reference
E
86
[53]
E
83–85
[51]
Product
Pd(OAc)2, PPh3, Et3N, DMF,
E
Pd(OAc)2, PPh3, Et3N, MeCN, 100 °C, 12–20 h
E
O
S
1192
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
R
R
R
R
Pd(OAc) 2, EtOH/H2O
X
R, 80 °C
X
+
X = N2 BF4–
X=I
CHO
OHC
X
X
Pd(OAc) 2,Bu4NCl, NaHCO3, CH2 CHCH2OH, THF/DMF, r.t., 48 h
R = Ph (80%); CO2Et (75%), SO2Ph (20%) OHC
CHO
Scheme 5
I
S
I
+
Pd(OAc) 2, PPh3 Ag2CO3, PhMe, 120 °C, 48 h
•
S
50%
S O
N Me
O
H O
H N Me
O
H O
H N Me
O
Scheme 6
C. MULTIPLE HECK COUPLINGS OF 1,2-DIBROMOCYCLOALKENES AND RELATED COMPOUNDS Double Heck reactions of vicinal cis-1,2-dihaloalkenes provide an easy access to (E,Z,E)1,3,5-hexatrienes, which are valuable building blocks for organic synthesis.[11],[40],[54] The first example of a twofold double, that is, essentially a fourfold, Heck reaction with a bis(dibromo)cycloalkene has been conducted on the strained 1,2,9,10-tetrabromo[2.2] paracyclophane-1,9-diene, which is available in multigram quantities. The Heck reaction proceeded cleanly under phase transfer conditions, as developed by Jeffery,[41],[42] to give the tetraalkenylated products in moderate to good yields (Table 8). The resulting bishexatrienes
1193
X = Br X = Br
R
X=I
a Isolated yield of 1,2-dicoupling product after aromatization. b Isolated yield of the reduced monocoupling product.
X
R R
R
R
R = CHO
R = SiMe3
R = CO2Me R = Ph
R = CO2Me R = Ph R = CO2t-Bu
R
R
Pd(OAc)2, AgNO3 , Et3N, DMSO, 20 °C, 2 d, 5 bar Ar
Pd(OAc)2, PPh3, Et3N, DMF, 100 °C, 40 h Pd(OAc)2, P(o-Tol)3, Et3N, THF/MeCN, 55 °C, 1 d, 10 kbar
Pd(OAc)2, PPh3, Et3N, DMF, 100 °C, 72 h As above, 90 °C, 4 d As above, 90 °C, 20 h
Pd(OAc)2, Bu4NBr, K2CO3, DMF, 40 °C, 2 d
90
81 82
57 (41)b
55 69
38 (0)a
(20) b
As above, 70 °C, 2 d
Ar = C6H4-4-F R
58 (80) a
50 (50) a
Yield (%)
As above, 70 °C, 36 h
Pd(OAc)2, Bu4NBr, K2CO3, DMF, 100 °C, 3 d
Conditions
Ar = Ph Ar = C6H4-4-CO2Me
Ar
Ar
R
X
Br
Br
R
Ar
Ar
Oligobromocycloalkenes
R
Br
Br
Ar
Alkene
Br
Br
Br
Br
Br
Br
Oligobromocycloalkenes
TABLE 8. Multiple Heck Reaction on 1,2-Dibromocycloalkenes and Related Compounds
[56]
[9],[56] [9]
[11],[56] [56] [11]
[54]
[40],[54]
[40] [54]
Reference
1194
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
upon heating underwent a clean twofold 6-electrocyclization to yield, after subsequent dehydrogenation, the bisbenzoannelated [2.2]paracyclophanediene derivatives (Scheme 7). In contrast, the twofold alkenylations of cis-1,2-dibromoethene, 1,2-dibromocyclopentene, and 1,2-dibromocyclohexene proceed in better yields under the classical Heck conditions (Table 8).[11] The (E,Z,E)-1,3,5-hexatrienes resulting from 1,2-dibromocycloalkenes undergo 6-electrocyclizations reasonably cleanly upon heating (130–150 °C) in an inert Br
Br
Pd(OAc) 2, Bu4NBr K2CO3 or NaHCO3 DMF, 40–100 °C, 12 h to 5 d
Br
Br
15–57%
+4
R
R
R
R
R
R
R
R
R
DDQ or S8 0–80%
R = H, SiMe3, CHO, CO2Me, Ph, p-MeO2C-C6H4, p-F-C6H4, p-t-Bu-C6H4, p-Ph-C6H4 Scheme 7
solvent such as di-n-butyl ether or xylene in the absence of oxygen to give the ring-annelated cis-5,6-disubstituted 1,3-cyclohexadienes. In the presence of oxygen these products are easily dehydrogenated to the corresponding ring-annelated benzene derivatives (Scheme 8). Another use of these hexatrienes was demonstrated by the epoxidation of the tetrasubstituted double bond to give dialkenylepoxides, which in turn were selectively ring-opened by Pdcatalyzed reduction. The alcohols resulting from the six- and seven-membered ring epoxides, upon deprotonation at 78 °C, undergo an oxyanion-accelerated Cope rearrangement to give the corresponding trans-cycloalkenones.[55],[56] R ( )n R Pd(OAc) 2, PPh3, Et3N, DMF, 40−100 °C,
Br ( )n
Br
[O2]
( )n
55−81%
n = 1, 2, 3 R = CO2Me, CO2t-Bu, Ph
79−87%
O
R
n=1
24−83%
R
(n-Bu)2O, N2 150 °C, 5 h
R
50−94%
1. MCPBA or DMDO 2. Pd0, HCO2H, 20 °C
OH
KHMDS, 18-c-6 THF, –78 °C
R
R
( )n H n = 1, 2, 3 Scheme 8
R R
R ( )n n = 1, 2, 3 O
KHMDS, 18-c-6 THF, –78 °C 51−94%
R
( )n
R R
n = 2, 3
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
1195
As alternatives to the 1,2-dihalocycloalkenes, 1-halo-2-perfluoroalkanesulfonyloxycycloalkenes may serve as starting materials for twofold Heck reactions. Since they can easily be prepared from the corresponding ketones via the -haloketones and subsequent sulfonylation of the enolates, this sequence provides a straightforward access to various substituted 1,3,5-hexatrienes (Scheme 9, Table 9).[57]
1. LDA, THF, –78 °C, 0.5 h, → 20 °C
O
OSO2RF
Hal 2. (RFSO2)2O or
R Pd(OAc) 2, PPh3, Et3N, LiCl, DMF, 40−100 °C
R
Hal RF = CF3 or n-C4F9 Hal = Br, Cl
(RFSO2)2NPh or RFSO2F
R
Scheme 9 TABLE 9. Twofold Heck Reaction on 1-Halo-2-perfluoroalkanesulfonyloxycycloalkenes[56],[57] 1-Halo-2-perfluoroalkanesulfonyloxycycloalkane Alkene
Product
OTf
E
Br
E
Conditions
Yield (%)
Pd(OAc)2, PPh3, Et3N, LiCl, DMF, 90 °C, 96 h
73
E = CO2t-Bu
E
E
OTf
E
Br
Pd(OAc)2, PPh3, Et3N, LiCl, DMF, 90 °C, 40 h
86
Pd(OAc)2, PPh3, Et3N, DMF, 80 °C, 20 h
64
Pd(OAc)2, PPh3, Et3N, LiCl, DMF, 90 °C, 40 h
71
Pd(OAc)2, PPh3, Et3N, DMF, 75 °C, 8 d
23 (64)a
R = CO2t-Bu
E
E
OTf
E
Br OR
OR
R = SiMe2t-Bu E = CO2t-Bu
E
E
ONf
E
Br
E = CO2Me
E ONf
E
Cl
E
E
E = CO2Me a Yield of the monocoupling product in parentheses.
1196
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
D. INTRA–INTERMOLECULAR TWOFOLD HECK COUPLING OF 1,3-BIS(NONAFLUOROBUTANESULFONYLOXY)CYCLOHEXADIENE The intra–intermolecular Heck reaction of dienediol bisnonaflates containing an -alkenyl substituent with an external alkene such as an acrylate gives rise to the formation of a bicyclic tetraene by an intramolecular coupling followed by an intermolecular Heck reaction (Scheme 10).[58] O t -BuO
Ph NfO
ONf
Pd(OAc) 2, PPh3 Et3N, DMF 80 °C, 12 h
O
Ph
t-BuO
43%
Scheme 10
E. MULTIPLE HECK 1,1- AND 1,2-BISARYLATIONS OF ETHYLENE AND RELATED COMPOUNDS The twofold Heck arylation of ethylene[13],[59] and ethylene equivalents provides an easy access to stilbene derivatives (Scheme 11, Table 10). In the case of ethylene, the pressure has to be carefully controlled, otherwise styrene derivatives, which are the primary products in this process, will be found as major products. In general, slightly pressurized (1 – 5 bar) reaction conditions are suitable for the twofold coupling and lead to stilbenes in up to 91% yield and with turnover numbers up to 18,200. The linear dependency on ethylene pressure in the arylation of ethylene with aroyl chlorides to give stilbenes (low pressure of ethenyl) or styrenes (high pressure) has been shown previously.[60] X
,,
+ H 2 C CH2
Pd
,,
Scheme 11
Besides ethylene, ethenylsilanes and ethenyl acetate, which are easy to handle, can yield stilbenes by 1,2-arylation with elimination of the functionality, in good yields (Scheme 12, Table 11).
X
,,
+
Pd
,,
Y
Y = Si(OEt)3, OAc, etc. Scheme 12
1197
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
TABLE 10. Double Heck 1,2-Arylations of Ethylene
Ethylene (Pressure)
Halorene
Product (Conditions)
20 psi
Yield (%) (Reference) 34 (54)a ([13])
Me
Br Me
Me
(Pd(OAc)2, P(o-Tol)3, MeCN, 125 °C, 20 h)
Br
120 psi
X
X
X = NHAc
48
(Pd(OAc)2, P(o-Tol)3, DMF, 125 °C, 2 h) X = CHO (as above, 8 h, 1 bar ethylene)
([13]) 75 ([61])
X
COCl
R1–3
1 bar
R1–3
8 examples
R1–3
8 examples
(Pd(OAc)2, P(o-Tol)3, BnMe2N or N -ethylmorpholine, p-xylene, 120 °C, 4.5–7.5 h )
Br 1.5 bar
R
45 ([60])
R R
R = H or SO3H
a
R = H or SO3H (Pd(OAc)2, P(o-Tol)3, Et3N, MeCN or NMP, 125 °C)
66−72 ([59])
Yield of the styrene formed is given in parentheses.
In general, the Heck coupling of aryl halides with terminal alkenes yields styrene derivatives. However, under certain conditions such as with an excess of the aryl halide,[64] at elevated temperatures, under high pressure,[65] and with electron-deficient alkenes, a terminal twofold coupling to yield 1,1-diarylalkene derivatives may take place (Scheme 13, Table 12). Under high pressure (10 kbar), the -hydride elimination is retarded and the metastable -alkylpalladium halide may insert into the double bond of a second acrylate
1198
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 11. Double Heck 1,2-Diarylation of Ethylene Equivalents
Ethylene Equivalent
Haloarene
Product (Conditions)
Yield (%) (Reference) O
O
OAc O
O
I
O
O
O
O
(polymer supported Pd, Bu3N, MeCN,
O
50 ([62])
130 °C, 16 h) +
N2 BF4
–
I
Si(OEt)3
I I
(Pd (OAc)2, PPh3, MeOH, 25 °C, 30 min)
,,
X +
Pd
62 ([63])
,,
R R Scheme 13
TABLE 12. Double Heck 1,1-Arylation of Acrylates and Related Compounds Haloarene Alkene
Conditions
Yield (%) (Reference)
CO2Me
Pd(OAc)2, P(o-Tol)3, Et3N, 100 °C, 34 h
78 ([64])
CO2Me
Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 100 °C, 43 h
52 ([66])
Pd(OAc)2(PPh3)2, Et3N, MeCN, 80 °C, 10 h
73 ([67])
PdCl2 on modified montmorillonite, Bu3N, 100 °C, 4 h Pd(OAc)2(PPh3)2,Et3N, DMF, 140 °C, 4 h, 10 kbar
90 ([68])
Product Ph
PhBr
CO2Me excess PhI
Ph Ph
CO2Me
Ph
excess HO
CHO I
CHO
PhI
HO Ph
CN
PhI CO2Et
OH CN Ph
Ph
CO2Et Ph
76 ([65])
1199
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
to eventually—after double shift—yield a diethyl(arylmethylene)glutarate.[65] Alternatively, the acrylate may dimerize first,[69] and the diethyl-2-methyleneglutarate may subsequently undergo a Heck arylation (Scheme 14).
E E
,,
E
Pd
Br
,,
,,
+
E
Pd
,,
E E
PdX
E
E
E
E
E
PdX
Scheme 14
Alkynes may undergo a threefold coupling if suitably substituted. For example, 3phenylallyl propargyl ether yields an E /Z mixture of 3-diarylmethylene-4-benzylidenetetrahydrofuran, when treated with an aryl halide under Jeffery conditions (Scheme 15).[70] This domino reaction starts with an intermolecular coupling, followed by intramolecular coupling of the intermediate -ethenylpalladium complex and finally a second intermolecular Heck coupling.
R Ph
R Pd(OAc) 2, PPh3 (n-Bu) 4NHSO4, DMF, 80 °C, 15–40 h
+ O
Ph
R
X O X
R
%
I Br Br
H OMe NO2
46 53 36
Scheme 15
1200
I
t-Bu
R=
t-Bu
R
Pd(OAc)2, Et3N, P(o-Tol)3, 100 °C, 17 h
Pd(OAc)2, Bu 4NBr, K2CO3, 90 °C, 2 d
CHO
Br
R
Oligo(ethenyl)arene Conditions
Haloarene
R
R
CHO
Product
R
R
TABLE 13. Heck Reaction of Haloarenes and Haloalkenes with Diethenylarenes, Conjugated Dienes, and Trienes
43 ([25])
56 ([71])
Yield (%) (Reference)
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
1201
F. REACTION OF HALOARENES AND HALOALKENES WITH DIETHENYLARENES, CONJUGATED DIENES, AND TRIENES The multiple arylation of oligoenes was investigated in the early 1980’s by Heck and colleagues. While conjugated dienes such as 1,3-butadiene in the presence of secondary amines with haloarenes yield monoarylated allylamines by nucleophilic substitution on the intermediately formed -allylpalladium complexes, 1, -diaryldienes are formed by twofold coupling. Even 1,3,5-hexatriene can serve as a substrate to give 1,6-diarylsubstituted 1,3,5-hexatrienes (Table 13). In general, electron-withdrawing substituted haloarenes give higher yields (up to 89%) than donor-substituted ones. Similarly, bromoalkenes such as -bromostyrenes can be used. In this case, the reaction with 1,3,5-hexatriene gave a decapentaene derivative, though in low yield. However, this coupling provides an easy access to conjugated oligoene hydrocarbon skeletons. As by-products, Diels–Alder adducts from the newly formed oligoene reacting as the dienophile and the starting material were observed. Even the successful twofold coupling of brominated zincatoporphyrins with diethyl octa-2,6-dienoate to give all-carbon tethered bisporphyrins has been reported (Scheme 16).[72] Although the yields were low to moderate, the example demonstrates the feasibility of this coupling methodology for the preparation of highly functionalized molecules.
)2
(EtO2C Br N
N
Pd(OAc) 2, LiCl Bu4NBr, DMF 90 °C, 20–40 h
CO2Et
N
N
N
)2
Zn
Zn N
29%
N
N
Scheme 16
G. FORMATION OF POLYMERS BY THE REACTION OF DIHALOARENES WITH DIETHENYLARENES The Heck reaction has been applied to couple quite a variety of dihaloarenes with different diethenylarenes to give various polyvinylenearylene polymers. In some cases, analogous polymers have been obtained by Heck coupling of -ethenyl- -haloarenes (Table 14)
1202
I
d
O
I
a
C9H19O
I
I
^ ArX a–e = 2
I
N
N
C6H13
M
N
N
e
b
OC9H19
C6H13
I
I
I
I
I
C6H13
C6H13
c
Oligohaloarene, Oligoethenylarenes
O
Br
Fe
Br
C6H13
N
N
C6H13
M
C6H13
Fe
N
N
C6H13
Product
Ar
n
TABLE 14. Heck Reactions of Oligohaloarenes with Oligoethenylarenes to Give Polymers
n
OC9H19
OC9H19
Pd(OAc)2, PPh3, Et3N, DMA, 100 °C, 3−4 h
Pd(OAc)2, P(o-Tol) 3, Bu3N, DMF, 100 °C, 3–4 h
Conditions
[74]
[73]
Reference
n.r.a b DP = 2.1−6.4
M = H2: 3 h: 73 (4.6 × 10 4) 3 h: 73 (5.3 × 10 3) M = Zn: 4 h: 75 (8.3 × 10 3) 4 h: 78 (1.3 × 10 4)
Yield (%) (MW)
1203
a
Br
Br
Br
Br
Br
c
b
c
a
n
n
n
n
b
n
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 90 °C, 1 d
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 90 °C, 1 d
Pd(OAc)2, P(o-Tol)3, Et3N, DMF, 90 °C, 1 d
DP = 12
[75] [76]
[75]
[75] [76]
(Continued )
15 repeat units per chain
~100
1204
I
O
Br
C12H25O
I
O
Hex2N NO2
I
OC12H25
I
OC12H25
^ ArI = 2
N H
C12H25O
I
O
I
N H
O
S
Oligohaloarene, Oligoethenylarenes
TABLE 14. (Continued )
C12H25O
C12H25O
N H
O
OC12H25
OC12H25
Hex2N NO2
O
S
Product
n
n
n
N H
O Ar
n
Pd(OAc)2, P(o -Tol) 3, Bu3N, DMF
PdCl2(PPh3)2 , Et3N, DMF
PdCl2(PPh3)2 , Et3N, DMF, 100 °C, 12 h
Pd-graphite, Bu3N, DMF, 100 °C, 40 h
Conditions
>95 (35,000)
n.r.
62
95 0.95 dL g−1
Yield (%) (MW)
[77]
[79]
[79]
[78]
Reference
1205
RO
I
OHex
N
N
N
R=
Ru
N
N N
HexO
OHex
I
at random
and
with Ar =
Ar
HexO
N
Hex O
b
OHex
N
N N
OHex
Ru N
N
= not reported. Degree of polymerization. c Various ratios of starting materials lead to different degrees of polymerization/properties, but all polymers were obtained in excellent yields.
a n.r.
I
HexO
I
OHex
Pd(OAc)2, P(o-Tol) 3, Bu3N, DMF
c
[37]
1206
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
REFERENCES [1] R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320. [2] U. D. Matsunaga and M. Sumitani, U.S. Patent 3980713 (1976) to Nippon Kayaku K. K., DE 2325302. Chem Abstr., 1974, 80, 84709. [3] P. Prinz, A. Lansky, T. Haumann, R. Boese, M. Noltemeyer, B. Knieriem, and A. de Meijere, Angew. Chem. Int. Ed., 1997, 36, 1289. [4] A. Lansky, Dissertation, Universität Göttingen, 1992. [5] G. Dyker and A. Thöne, J. Prakt. Chem., 1999, 341, 138. [6] A. de Meijere, H. Nüske, M. Es-Sayed, T. Labahn, M. Schroen, and S. Bräse, Angew. Chem. Int. Ed. Engl., 1999, 38, 3669. [7] W. Tao, S. Nesbitt, and R. F. Heck, J. Org. Chem., 1990, 55, 63. [8] A. Lansky, O. Reiser, and A. de Meijere, Synlett, 1990, 405. [9] K. Voigt, U. Schick, F. E. Meyer, and A. de Meijere, Synlett, 1994, 189. [10] A. Diaz-Ortiz, P. Prieto, and E. Vazquez, Synlett, 1997, 269. [11] K. Voigt, A. Lansky, M. Noltemeyer, and A. de Meijere, Liebigs Ann. Chem., 1996, 899. [12] S. Bräse, J. Rümper, K. Voigt, S. Albecq, G. Thurau, R. Villard, B. Waegell, and A. de Meijere, Eur. J. Org. Chem., 1998, 671. [13] J. E. Plevyak and R. F. Heck, J. Org. Chem., 1978, 43, 2454. [14] K. M. Pietrusiewicz, M. Kuznikowski, and M. Koprowski, Tetrahedron: Asymmetry, 1993, 4, 2143. [15] A. J. Amoroso, A. M. W. C. Thompson, J. P. Maher, J. A. McCleverty, and M. D. Ward, Inorg. Chem., 1995, 34, 4828. [16] B. König, H. Zieg, P. Bubenitschek, and P. G. Jones, Chem. Ber., 1994, 127, 1811. [17] S. K. Stewart and A. Whiting, J. Organomet. Chem., 1994, 482, 293. [18] B. König, B. Knieriem, and A. de Meijere, Chem. Ber., 1993, 126, 1643–1650. [19] G. C. Bazan, W. J. Oldham, R. J. Lachicotte, S. Tretiak, V. Chernyak, and S. Mukamel, J. Am. Chem. Soc., 1998, 120, 9188. [20] A. S. Carlstroem and T. Frejd, J. Org. Chem., 1991, 56, 1289. [21] V. K. Chaikovskii, A. N. Novikov, and T. A. Sarycheva, J. Org. Chem. USSR (Engl. Transl.), 1985, 21, 1783; Zh. Org. Khim., 1985, 21, 1947. [22] K. N. Dack, R. P. Dickinson, C. J. Long, and J. Steele, Bioorg. Med. Chem. Lett., 1998, 8, 2016. [23] R. P. Dickinson, K. N. Dack, C. J. Long, and J. Steele, J. Med. Chem., 1997, 40, 3442. [24] R. Klopsch, S. Koch, and A. D. Schlüter, Eur. J. Org. Chem., 1998, 1275. [25] T. Mitsudo, W. Fischetti, and R. F. Heck, J. Org. Chem., 1984, 49, 1640. [26] C.-M. Andersson, J. Larsson, and A. Hallberg, J. Org. Chem., 1990, 55, 5757. [27] H. A. Staab, J. Weiser, M. Futscher, G. Voigt, A. Rückemann, and C. Anders, Chem. Ber., 1992, 125, 2285. [28] H. A. Staab, J. Weiser, and E. Baumann, Chem. Ber., 1992, 125, 2275. [29] H. Detert and E. Sugiono, J. Prakt. Chem. 1999, 341, 358. [30] N. A. Bumagin, L. I. Sukhomlinova, T. P. Tolstaya, and I. P. Beletskaya, Dokl. Akad. Nauk, 1993, 332, 454. [31] N. A. Bumagin, V. V. Bykov, L. Sukhomlinova, T. P. Tolstaya, and I. P. Beletskaya, J. Organomet. Chem., 1995, 486, 259. [32] M. Takeuchi, T. Tuihij, and J. Nishimura, J. Org. Chem., 1993, 58, 7388.
IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS
1207
[33] K. M. Pietrusiewicz and M. Kuznikowski, Phosphorus, Sulfur Silicon Relat. Elem., 1993, 77, 57. [34] P. Lorenz, D. Becher, D. Steinborn, E. Poetsch, and B. Akermark, J. Prakt. Chem., 1995, 337, 375. [35] A. F. Shmidt, T. A. Vladimirova, E. Yu. Shmidt, T. V. Dmitrieva, Izv. Acad. Nauk, Ser. Khim., 1993, 1962, [Russ. Chem. Bull., 1993, 42, 1879 (Engl. Transl.)]. [36] M. Moreno-Manas, M. Perez, and R. Pleixats, Tetrahedron Lett., 1996, 37, 7449. [37] Z. Peng, A. R. Gharavi, and L. Yu, J. Am. Chem. Soc., 1997, 119, 4622. [38] K. Y. Kay, Y. G. Baek, D. W. Han, and S. Y. Yeu, Synthesis, 1997, 35. [39] H. Detert and E. Sugiono, J. Prakt. Chem., 1999, 341, 358. [40] O. Reiser, S. Reichow, and A. de Meijere, Angew. Chem. Int. Ed. Engl., 1987, 26, 1277. [41] T. Jeffery, Tetrahedron Lett., 1985, 26, 2667. [42] T. Jeffery, Tetrahedron, 1996, 52, 10113. [43] A. J. Amoroso, J. P. Maher, J. A. McCleverty, and M. D. Ward, J. Chem. Soc. Chem. Commun., 1994, 1273. [44] K. Albrecht, Dissertation, Universität Göttingen, 1993. [45] J. Rümper, Dissertation, Universität Göttingen, 1993. [46] H. Meier, N. Hanold, and H. Kalbitz, Synthesis, 1997, 276. [47] M. W. Majchrzak, J. N. Zobel, D. J. Obradovich, and G. A. Peterson, Org. Prep. Proc. Int., 1997, 29, 361. [48] S. Sengupta, S. K. Sadhukhan, S. Bhattacharyya, and J. Guha, J. Chem. Soc. Perkin Trans. 1, 1998, 407. [49] S. Sengupta and S. K. Sadhukhan, Tetrahedron Lett., 1998, 39, 1237. [50] B. Basu and T. Frejd, Acta Chem. Scand., 1996, 50, 316. [51] M. Malesevic, G. Karmiski-Zamola, M. Bajic, and D. W. Boykin, Heterocycles, 1995, 41, 2691. [52] R. Grigg, S. Brown, V. Sridharan, and M. D. Uttley, Tetrahedron Lett., 1998, 39, 3247. [53] H. Diaz and J. W. Kelly, Tetrahedron Lett., 1991, 32, 5725. [54] O. Reiser, B. König, K. Meerholz, J. Heinze, T. Wellauer, F. Gerson, R. Frim, M. Rabinovitz, and A. de Meijere, J. Am. Chem. Soc., 1993, 115, 3511. [55] A. de Meijere and S. Bräse, J. Organomet. Chem., 1999, 576, 88 – 110. [56] P. V. Zezschwitz, K. Voigt, M. Noltemeyer, A. de Meijere, Synthesis, 2000, 1327. The 1,2diallenylcyclopentanols, upon deprotonation, did not yield the cyclononenones as reported, but only the 2-substituted 3-alkenylcyclohexanones. R. von Essen, P. V. Zezschwitz, A. de Maijere, unpublished results. [57] K. Voigt, P. von Zezschwitz, K. Rosauer, A. Lansky, A. Adams, O. Reiser, and A. de Meijere, Eur. J. Org. Chem., 1998, 1521. [58] S. Bräse, Synlett, 1999, 1654. [59] J. Rümper, V. V. Sokolov, K. Rauch, and A. de Meijere, Chem. Ber./Recueil, 1997, 130, 1193. [60] A. Spencer, J. Organomet. Chem., 1983, 247, 117. [61] A. Spencer, J. Organomet. Chem., 1983, 258, 101. [62] L. Li, Z. Zhunangyu, and H. Hongwen, Synth. Commun., 1995, 25, 595. [63] S. Sengupta, S. Bhattacharyya, and S. K. Sadhukhan, J. Chem. Soc. Perkin Trans. 1, 1998, 275. [64] R. F. Heck, Acc. Chem. Res., 1979, 12, 146 – 151. [65] T. Sugihara, M. Takebayashi, and C. Kaneko, Tetrahedron Lett., 1995, 36, 5547. [66] N. A. Cortese, C. B. Ziegler, Jr., B. J. Hrnjez, and R. F. Heck, J. Org. Chem., 1978, 43, 2952. [67] S. Cacchi and G. Palmieri, Synthesis, 1984, 575.
1208 [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
B. M. Choudary, R. M. Sarma, and K. K. Rao, Tetrahedron, 1992, 48, 719. S. Bräse, B. Waegell, and A. de Meijere, Synthesis, 1998, 148. J.-F. Nguefack, V. Bolitt, and D. Sinou, Tetrahedron Lett., 1996, 5527. S. K. Deb, T. M. Maddux, and L. Yu, J. Am. Chem. Soc., 1997, 119, 9079. N. Risch, R. Gauler, and R. Keuper, Tetrahedron Lett., 1999, 40, 2925. Z. Bao, Y. Chen, and L. Yu, Macromolecules, 1994, 27, 4629. M. Bochmann, J. Lu, and R. D. Cannon, J. Organomet. Chem., 1996, 518, 97. U. Scherf and K. Müllen, Synthesis, 1992, 23. H. P. Weitzel and K. Müllen, Makromol. Chem., 1990, 191, 2837. M. Pan, Z. Bao, and L. Yu, Macromolecules, 1995, 28, 5151. M. Jikei, Y. Ishida, M.-A. Kakimoto, and Y. Imai, React. Funct. Polym., 1996, 30, 117. H. Okawa, T. Wada, and H. Sasabe, Synth. Met., 1997, 84, 265.
Ind. Appl. of Heck Type Rct.
IV.2.1.3 Palladium-Catalyzed Coupling Reactions for Industrial Fine Chemicals Syntheses MATTHIAS BELLER and ALEXANDER ZAPF
A. INTRODUCTION Pd-catalyzed coupling processes of C—X compounds (X Cl, Br, I, N2, COCl, SO2Cl, CO2C(O)R, OSO2Rf, OMs), such as the Heck and Suzuki reactions, the Stille and Sonogashira couplings, and similar carbonylation reactions are well established methods for carbon – carbon bond formation in organic synthesis on a laboratory scale. Due to their generality and broad tolerance of functional groups these methods have been used extensively in natural product synthesis. As an example, the alkenylation of aryl—X derivatives (the Heck reaction)[1]–[8] has been called “one of the true power tools of contemporary organic synthesis.”[9] For a number of currently used industrial fine chemicals the coupling reactions shown in Scheme 1 offer the opportunity of shorter and more selective routes to substituted arene and alkenes compared to classic stoichiometric organic transformations. Despite the utility of the products available by Pd-catalyzed coupling reactions, until recently relatively few industrial applications have been realized. What are the reasons for this paradox? On the one hand, a number of the reactions shown in Scheme 1 still suffer from low catalyst efficiency. Typically 1–5 mol % of a certain palladium precatalyst is used. Hence, catalyst costs dominate the raw material costs* and only extremely highprice products may be produced by these methods. With the use of relatively large amounts of palladium catalysts it is also difficult to keep the palladium contents in pharmaceutical and agrochemical end products at a tolerably low level. In general, organic chemists ignore the problem of catalyst activity (turnover frequencies), which is important for cost-effective manufacturing. In accordance with Blaser, Pugin, and Spindler,[10] we believe that fine chemical production requires catalyst productivities of ca. 1000 – 10,000 and catalyst activities of 200–500 h1 in order to be competitive with noncatalytic routes. For bulk chemicals the requirements are significantly higher.
*Using current industrial prices for palladium ($20 per g Pd; February 2000), catalyst costs for a hypothetical organic product with a molecular weight of 200 are $106 per kg of product (TON 100) or $11 per kg of product (TON 1000).
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506 © 2002 John Wiley & Sons, Inc.
1209
1210
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION CHO
CO2R R
R
R
R X
CN
R
R
R
R NR2 OR R
R R Scheme 1
Even in the recent past, academic organic synthesis research has paid little attention to the industrial availability and price of starting materials. For example, most university groups developed new catalysts and coupling reactions applying aryl iodides and aryl triflates instead of commercially more interesting aryl chlorides[11]–[13] and anilines.[14]–[20] Hence, only a few of these developments were of significant interest to industry. However, this behavior is changing and currently several university groups worldwide work on the aspects of economical aryl—X activation. This section tries to give an overview of Pd-catalyzed coupling reactions currently applied in industry. In addition, several reactions are covered, which have been used on a kilogram scale in order to be commercialized. Due to the difficulty of getting information on actual industrial processes, we are not always certain about the real scale of these reactions. However, we believe that other Pd-catalyzed coupling reactions are applied in industry, which are not known to the public. We welcome any information on this topic for future reviews.
B. INDUSTRIAL PROCESSES One of the first examples of a Pd-catalyzed coupling reaction realized on an industrial scale is the Matsuda–Heck reaction of an aryl diazonium salt with 1,1,1-trifluoropropene developed by Baumeister and co-workers at Ciba-Geigy and today performed on ton scale by Novartis for the synthesis of a sulfonylurea herbicide (Prosulfuron).[21],[22] By combining three synthetic steps (diazotization, alkenylation, and hydrogenation) in a
IV.2.1.3 INDUSTRIAL FINE CHEMICALS SYNTHESES BY HECK REACTION
1211
one-pot sequence with an overall yield of 93% (i. e., an average yield of 98% per step), this elegant process was made economically feasible (Scheme 2). Due to the high stability of the in situ generated diazonium salt, safety issues are not a cost-intensive problem in this reaction. Despite diazotization, only 2 kg of wastes per kg of product are produced. _
SO3
SO3
1. Pd(dba)2
+
CF3
+
N2
_
2. charcoal 3. H2
CF3
SO2NHCONH CF3
N N
N O
Scheme 2
An example of an industrial Heck reaction of an aryl bromide is the announced synthesis of Naproxen by Albermarle.[23] Toward that end, 2-bromo-6-methoxynaphthalene is reacted with ethylene in the presence of a homogeneous palladium catalyst. Apparently, as a ligand a sterically hindered basic phosphine is used.[24] Known Pd-catalyzed hydrocarboxylation of 2-methoxy-6-vinylnaphthalene and subsequent resolution give access to Naproxen (Scheme 3). In addition, it was shown that Ketoprofen can be produced by a similar reaction sequence. Br +
“Pd”/ L
O
O
CO2H O Scheme 3
The key step—the alkenylation—in the Naproxen process has also been developed with the so-called palladacycle catalyst on a kilogram scale by Hoechst AG and Hoechst-Celanese in 1995. Here, 2-methoxy-6-vinylnaphthalene was obtained in 89% yield at 20 bar ethylene pressure.[25] High catalyst turnover numbers of ca. 10,000 were realized, but due to a shift in the company’s strategy no further development was made. Similar alkenylations of aryl bromides with ethylene have been used by Dow Chemical to make high-purity 2- and 4-vinyltoluenes, which are of interest as comonomers for styrene polymers (Scheme 4).[26]
1212
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Br
Pd(OAc) 2 / P(o-Tol) 3
+
Scheme 4
A practical route to a new class of LTD4 receptor antagonists was developed at Merck.[27] An aryl bromide or triflate was coupled with a vinylquinoline (Scheme 5) in DMF at 100 °C utilizing 3 mol % of palladium(II) acetate as precatalyst. In the case of the bromide, tris(o-tolyl)phosphine is the optimum ligand yielding 91% of the desired product. In contrast, using the corresponding triflate as aryl source, triphenylphosphine performed better than tris(o-tolyl)phosphine. Although yields could be further enhanced by addition of lithium bromide only 66% of coupling product was isolated. O
O Cl
N
Cl
N
+
O Pd(OAc) 2 / L
X
Et3N, DMF, 100 °C
O
O
O
CO2H Cl
N
S
O
Scheme 5
Other examples for which homogeneously catalyzed Heck reactions have been exploited toward an industrial production include the preparation of the fragrance Lilial developed by Givaudan,[28],[29] the synthesis of the nonsteroidal anti-inflammatory drug Nabumeton by Hoechst-Celanese,[30] and the synthesis of the sunscreen agent 2-ethylhexyl p-methoxycinnamate (EHMC) by Hoechst AG * and other companies (Scheme 6). Noteworthy, Nabumeton is obtained in one step via coupling and domino isomerization reaction of 2-bromo-6-methoxynaphthalene with 3-buten-2-ol.[30],[31] However, to the best of our knowledge, none of these reactions is actually used in industry. Interestingly, 2-ethylhexyl p-methoxycinnamate (EHMC), the most common UV-B sunscreen on the market, was produced for some time by a heterogeneously *M. Beller, K. Kühlein, and H. Fischer, unpublished results.
IV.2.1.3 INDUSTRIAL FINE CHEMICALS SYNTHESES BY HECK REACTION
1213
catalyzed Heck reaction by an Israeli chemical company.[32] The IMI process for EHMC involves bromination of anisole and a Heck coupling with 2-ethylhexyl acrylate in N-methylpyrrolidone (NMP) in the presence of Pd/C as a catalyst (Scheme 7). Pilot plant runs were carried out in a 250 L reactor.[33] By using an optimized concentration of starting materials product yields of 80 – 90% were realized after high vacuum distillation. The same technology was used for the synthesis of 2-ethylhexyl p-dimethylaminocinnamate, which has a potential of being a UV-A B filter agent.
O CHO
O
O
O O
Lilial
Nabumeton
EHMC Scheme 6 O
Br O +
O
C8H17
Pd/C, Na2CO3
C8H17
180−190 °C, NMP
O O O Scheme 7
In addition, IMI developed a route to disubstituted benzophenones based on a heterogeneously catalyzed Heck reaction in conjunction with an oxidative cleavage reaction. As an example, the synthesis of 4,4-difluorobenzophenone, which is used as a monomer for polyether ketones, has been performed by a double Heck reaction of 4-fluorobromobenzene with 2-ethylhexyl acrylate. Subsequent oxidative cleavage of the double adduct yields the desired product.[34],[35] The Pd-catalyzed Suzuki reaction[36]–[38] of arylboronic acid derivatives with aryl halides is probably the most powerful method for the construction of an unsymmetrically substituted biaryl derivative (see Sects. III.2.2 and III.2.5). Due to the importance of substituted biaryls as building blocks for pharmaceuticals and new materials, there is currently a great deal of interest in the coupling of economically attractive aryl halides with arylboronic acids.[39]–[52] Industrial realizations of the Suzuki reaction include the production of intermediates for AT II antagonists developed by Hoechst AG and now used by Clariant AG in Frankfurt/Main on a multiton scale (Scheme 8)[53] and of some biaryls at E. Merck KG in Darmstadt (Germany).[54]
1214
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION NC
NC “Pd”/ TPPTS
B(OH)2 + Cl
Scheme 8
2-Cyano-4-methylbiphenyl is produced by coupling of 4-tolylboronic acid and 2-chlorobenzonitrile in the presence of a palladium/sulfonated triphenylphosphine (TPPTS) catalyst in yields higher than 90%. The reaction is conducted at 120 °C in a polyhydric alcohol solvent (e.g., ethyleneglycol), which contains small amounts of sulfoxide or sulfone for catalyst stability reasons. At the end of the reaction two phases form. The catalyst and salts remain in the polar phase, and the product forms the organic phase. This biphasic procedure allows an efficient recycling of the homogeneous catalyst. Researchers from Merck elaborated a convergent synthesis for the AT II antagonist Losartan with the key biaryl coupling step in the final stage of the protocol (Scheme 9).[55] The two reaction partners are coupled very efficiently (99% yield) utilizing 1 mol% of palladium(II) acetate and 4 mol% triphenylphosphine. As the solvent, a 1:4 mixture of THF and diethoxymethane containing a defined amount of water is crucial for the high reaction rates and yields.
N
CPh3
Cl N N N
OH
N
N
Pd(OAc) 2 / 4 PPh
+ B(OH)2
3
K2CO3, H2O/ THF / DEM
Br N N
N
Cl OH
CPh3 N N N
N
N H+
Cl OH
N NH N
N
Scheme 9
The ecological advantages of a Pd-catalyzed process compared to a process that relies on stoichiometric organic reactions is nicely demonstrated by the Sandoz process for the antifungal Terbinafin.[56] Terbinafin is the active agent of the broad-spectrum antimycotic Lamisil®. It was the first pharmaceutical drug with a 1,3-enyne unit as an integral structural element on the market. The new production process for Terbinafin, which has been awarded with the Sandmeyer Prize of the Swiss Chemical Society, is shown in Scheme 10. An important step is the Pd-catalyzed coupling of a substituted alkenyl chloride with
1215
IV.2.1.3 INDUSTRIAL FINE CHEMICALS SYNTHESES BY HECK REACTION
tert-butylacetylene. This coupling reaction proceeds stereoselectively in the presence of less than 0.05 mol % of the precatalyst PdCl2(PPh3)2. As cocatalyst Cu(I)I is added. A cross-coupling reaction of an o-iodoaniline and an alkyne is a key step in Merck’s synthesis of MK-0462, a 5-HT1D receptor agonist and potential antimigraine drug (Scheme 11). As a catalyst, simple palladium(II) acetate, although in relative high concentrations (2 mol %), is used without any ligand. Under these conditions, 80% of the (partially de-O-protected) substituted indole is formed in DMF at 100 °C.[57]
N
Cl
N Pd(PPh3)2Cl2
+
CuI
Scheme 10 N N
O
N
Pd(OAc) 2, Na2CO3
+
I
DMF, 100 °C
SiEt3
NH2 N
SiEt3
N
O SiEt3
N
OH
N
N
N
CO2H .
SiEt3 N H
N H Scheme 11
Another example of a cross-coupling process with an alkyne, which has been developed in industry, is the reaction of an iodo-substituted dideoxynucleoside with trifluoroacetyl-protected propargylamine. By using a homogeneous Pd(0)/Cu(I) catalyst in dimethylformamide, smooth coupling is achieved.[58] This reaction has been used for the synthesis of DNA sequencing agents by DuPont (Scheme 12).[29] O O
O H N
I
HN
CF3
+ O HO
O
N
O
HN Pd /Cu(I)
O HO
Scheme 12
O
N
N H
CF3
1216
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Apart from alkenylations and other cross-coupling procedures, carbonylation reactions of aryl and benzyl halides, which make use of the inexpensive reagent carbon monoxide, have attracted industrial interest. (Pd-catalyzed carbonylations are discussed in Sect. VI.2.1 in general.) Simply by changing the nucleophile used in this reaction, acids, esters, amides, aldehydes, ketones, and other compounds are accessible. The synthesis of Ibuprofen, one of the most important nonsteroidal anti-inflammatory agents, developed by Hoechst-Celanese in the late 1980s, demonstrates the synthetic utility of this method. Toward this target, iso-butylbenzene is acetylated in the para position and the resulting acetophenone is reduced to the corresponding benzylic alcohol. Subsequent carbonylation proceeds in concentrated HCl in the presence of a PdCl2/PPh3 catalyst system (Scheme 13).[59],[60] Due to the lower amount of by-products compared to the original Boots process, this catalytic route is now the main industrial production process ( 3000 t/year) for Ibuprofen. CO2H
OH PdCl2 / PPh 3 HCl, CO
Scheme 13
Among the carbonylation reactions of aryl halides, those of heteroaryl halides were of special interest to industrial research groups. The attachment of carbonyl functionalities onto heterocyclic frameworks by replacing a halide substituent provides an easy access to valuable intermediates for the manufacture of antifibrotics, herbicides, and other pharmaceuticals. Hence, this type of carbonylation reaction has been used for the production of Lazabemide, a monoamine oxidase B inhibitor, from commercially available 2,5-dichloropyridine. The original eight-step laboratory synthesis of Lazabemide was replaced by a one-step protocol (Scheme 14).[61],[62] The product Lazabemide was isolated in 65% yield. Due to the fact that only small amounts of catalyst have to be used (TON 3000) traces of palladium in the product could be removed by appropriate workup. Cl
Cl + N
Cl
H2N
NH2
“Pd” CO
H N
N
NH2 · HCl
O Scheme 14
Another example of a carbonylation of chloropyridines is the synthesis of alkyl 3-chloropicolinates and dialkyl pyridine-2,3-dicarboxylates by Bessard and Roduit at Lonza AG.[63] Starting from 2,3-dichloro-5-(methoxymethyl)pyridine, both the mono- and the dicarbonylated pyridine derivatives can be obtained at low CO pressure (15 atm) with high selectivities and yields (Scheme 15). Utilizing PdCl2(PPh3)2 and dppb at 145 °C, 94% of methyl 3-chloropicolinate has been isolated, whereas palladium(II) acetate and dppf at 160 °C leads to a double alkoxycarbonylation reaction.
1217
IV.2.1.3 INDUSTRIAL FINE CHEMICALS SYNTHESES BY HECK REACTION
Cl
O
EtOH, CO
MeOH, CO
Pd(OAc) 2 / dppf
N
Cl
PdCl2(PPh3)2 / dppb
O O
O
N
Cl
O
O
O
N O
O Scheme 15
C. RECENT DEVELOPMENTS OF INTEREST FOR AN INDUSTRIAL FINE CHEMICALS SYNTHESIS As stated before, the refinement of economically attractive aryl — X compounds is of general interest in fine chemicals synthesis. In the last decade tremendous progress in the development of new catalysts has been achieved. Since the properties of the central metal palladium can significantly be tuned by ligand variation, the introduction of new ligands was the key to success. This is convincingly demonstrated by the catalyst developments for Heck and Suzuki reactions of aryl chlorides. Tables 1 and 2 present an overview of recent achievements. The Suzuki aryl–aryl coupling reaction is thoroughly discussed in Sects. III.2.2 and III.2.5. TABLE 1. Catalyst Development for Pd-Catalyzed Alkenylations of Aryl Chlorides Cl R
+ R
R
Entry Reference 1 2 3 4 5 6 7
a
R [64]
8
Julia/Kuntz (1973) Davison (1984)[66] Spencer (1984)[67] Milstein (1992)[68] Milstein (1993)[69] Herrmann (1995)[70] Herrmann/Beller (1995)[71] Reetz (1998)[72]
9 10 11
Beller (1998)[31] Fu (1999)[73] Hartwig (1999)[74]
R1
4-CF3 H H Ph 4-CO2Me CN H 4-C6H4OMe H Ph 4-NO2 CO2n-Bu 4-CF3 Ph H
Ph
4-CF3 H Me
Ph Ph CO2n-Bu
Catalyst Pd/C Pd(OAc)2/2 PPh3 Pd(OAc)2/4 PPh3 Pd(OAc)2/2 dippb a Pd(OAc)2/2 dippp b Pd(dba)2/carbene Palladacycle c Pd(OAc)2/6 Ph4PCl/ 6 DMG d Pd(OAc)2/10 P(OR)3 Pd2(dba)3/2 P(t-Bu)3 Pd(dba)2/2 t-Bu2PFc e
dippb: 1,4-Bis(di-iso-propylphosphinyl)butane. Base free, with Zn; dippp: 1,3-Bis(di-iso-propylphosphinyl)propane. c trans-Di(-acetato)-bis[o-(di-o-tolylphosphinyl)benzyl]dipalladium(II). d N,N-Dimethylglycine. e Di-tert-butylphosphinylferrocene. b
R1
catalyst
1
Yield (%)
TON
62 49 51 77 88 99 45
40 25 51 77 88 1000 45.000
65
130
84 80 67
840 400 27
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IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 2. Catalyst Development for Pd-Catalyzed Suzuki Reactions of Aryl Chlorides Cl
B(OH)2 +
catalys t
R R Entry 1 2 3 4 5 6
Reference
R [41]
Beller (1995) Fu (1998)[48] Trudell/Nolan (1999)[51] Bei/Guram (1999)[52] Buchwald (1999)[49] Beller (2000)[65]
4-COMe 4-Me 4-Me 2-Me 4-Me 4-CF3
Catalyst a
Palladacycle Pd2(dba)3/1.2 P(t-Bu3) Pd2(dba)3/Lb Pd(dba)2/3 Lc Pd(OAc)2/2 Ld Pd(OAc)2/10 P(OR)3
Yield (%)
TON
82 87 96 95 94 88
820 29 32 48 1880 88
trans-Di(-acetato)-bis[o-(di-o-tolylphosphinyl)benzyl]dipalladium(II). N,N1-Dimesitylimidazolium chloride. c 2-(21-Dicyclohexylphosphinylphenyl)-2-methyl-1,3-dioxolane. d 2-(Dicyclohexylphosphinyl)biphenyl. a b
Milstein and co-workers were the first to introduce catalysts capable of activating various aryl chlorides. By using palladium complexes of highly basic and sterically demanding chelating bisphosphines, for example, dippb [1,4-bis(di-iso-propylphosphinyl)butane], even chlorobenzene has been coupled with alkenes in good to very good yields (70–95% yield; TON 70 – 95). However, these catalysts are extremely sensitive to air. The introduction of the more robust palladacycles [cyclopalladated complexes of the general formula Pd2(-L)2(P-C)2; L bridging ligand, e.g., OAc, Cl, Br; P-C cyclometallated P-donor, e.g., o-CH2C6H4P(o-Tol)2] as highly active catalysts (TON 40,000 for Heck reactions of 4-chloroacetophenone) by Herrmann, Beller, and co-workers initiated the search for more productive palladium catalysts. Apart from palladacycles, a number of catalyst systems are currently known that show productivities up to 100,000 for Heck and Suzuki reactions of all kinds of aryl bromides. It is important to note that coupling reactions of electron-deficient aryl bromides (e.g., 4-bromoacetophenone), which are often used in academic laboratories, are not suitable as test reactions to judge the productivity of a new catalyst, because simple palladium salts without any ligand give turnover numbers up to 100,000 with these substrates. Recently, palladium complexes in combination with sterically congested basic phosphines (e.g., tri-tert-butylphosphine), carbenes, and also phosphites[65] led to productive palladium catalysts for the activation of various aryl chlorides. It is obvious that the development of improved catalysts will continue in the near future. For example, it is believed that new molecularly defined palladium catalysts* will prove to be advantageous to the usually applied in situ generated, undefined catalytically active species. Apart from the already mentioned Pd-catalyzed coupling reactions it can be predicted that other coupling reactions will be of value to industry in the foreseeable future. Among others, coupling reactions of aryl halides with Grignard reagents, aminations, cyanations, *M. Gómez Andreu, A. Zapf, and M. Beller, unpublished results.
IV.2.1.3 INDUSTRIAL FINE CHEMICALS SYNTHESES BY HECK REACTION
1219
and new types of carbonylations will be of interest. While Pd-catalyzed C—N coupling reactions have attracted considerable interest in the last few years (Scheme 16),[75]–[92] cyanations and reactions with Grignard compounds have been underestimated so far. With respect to carbonylations, reductive carbonylations of aryl halides to benzaldehydes,[93]–[97] amidocarbonylations[98]–[100] of in situ produced -haloamides to yield N-acylamino acids, and double carbonylations of C—X bonds are of interest to industry. R1
X R1 +
H N R2
N
R2
[Pd] NaOt-Bu
R
R Scheme 16
D. CONCLUSION AND OUTLOOK Pd-catalyzed coupling reactions offer numerous interesting possibilities for fine chemicals synthesis. The last decade has seen a number of industrial applications of this methodology. Due to significant improvements in the last five years, it is estimated that this situation will continue at a faster pace in the next decade. With the foreseeable growth of advanced fine chemicals synthesis it is certain that new Pd-catalyzed coupling reactions will flourish in industry. Without doubt, the fine chemicals industry in search of improved competitiveness will use these Pd-catalyzed reactions more often because the coupling processes shown in Scheme 1 offer opportunities for an environmentally cleaner production, and, probably more importantly, the possibility to easily reduce the number of steps in a given synthesis of important intermediates for the production of pharmaceuticals and agrochemicals by one or more steps. While ten or fifteen years ago Pd-catalyzed reactions were uncommon reaction steps in the synthesis of more advanced pharmaceutical and agrochemical building blocks, today most synthetic chemists are very familiar with these methods. Hence, Pd-catalyzed coupling reactions are used more and more frequently even in the first laboratory synthesis of potential drugs. This fact will also lead to an increased use of this type of reactions on a larger scale. From a technology standpoint, for most coupling reactions using aryl bromides, catalyst costs are no longer the cost-limiting factor. However, this does not yet hold true for the economically more interesting aryl chlorides. Despite significant breakthroughs, further improvement is necessary and appears possible. It is important to note that in most of the Pd-catalyzed coupling reactions presented here at least 1 equiv of salt (often sodium bromide) is produced. Hence, chemical companies with knowhow in halide compounds, especially bromides (transformation of bromide salts into bromine and bromination of aromatics), have advantages in technology and feedstocks. Most likely they will be the primary industrial users of the described coupling reactions. The development of a new Naproxen process by Albermarle is an example for this strategy. Interestingly, de Vries and co-workers from DSM demonstrated that in special cases Pd-catalyzed coupling reactions may be performed with only small amounts of salt
1220
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
by-products. By using benzoic anhydride as starting material and a clever recycling process no halide salts were produced.[101]
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31]
R. F. Heck and J. P. Nolley, Jr., J. Org. Chem., 1972, 37, 2320. T. Mizoroki, K. Mori, and A. Ozaki, Bull. Chem. Soc. Jpn., 1971, 44, 581. R. F. Heck, Org. React., 1982, 27, 345. J. Tsuji, Palladium Reagents and Catalysts, Wiley, Chichester, 1995. T. Jeffery, Adv. Met. Org. Chem., 1996, 5, 153–260. W. A. Herrmann, in Applied Homogeneous Catalysis with Organometallic Compounds, B. Cornils and W. A. Herrmann, Eds., VCH, Weinheim, 1996, Vol. 2, 712. A. de Meijere and F. E. Meyer, Angew. Chem. Int. Ed. Engl., 1994, 33, 2379. S. Bräse and A. de Meijere, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 99. K. C. Nicolaou and E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996. H. U. Blaser, B. Pugin, and F. Spindler, in Applied Homogeneous Catalysis with Organometallic Compounds, B. Cornils and W. A. Herrmann, Eds., VCH, Weinheim, 1996, Vol. 2, 992. T. H. Riermeier, A. Zapf, and M. Beller, Top. Catal., 1997, 4, 301. R. Stürmer, Angew. Chem. Int. Ed. Engl., 1999, 38, 3307–3308. V. V. Grushin and H. Alper, Chem. Rev., 1994, 94, 1047–1062. K. Kikukawa, K. Nagira, F. Wada, and T. Matsuda, Tetrahedron, 1981, 37, 31. K. Kikukawa, K. Nagira, N. Terao, F. Wada, and T. Matsuda, Bull. Chem. Soc. Jpn., 1979, 52, 2609. S. Sengupta and S. Bhattacharya, J. Chem. Soc. Perkin Trans. 1, 1993, 1943. K. Kikukawa, K. Maemura, Y. Kiseki, F. Wada, T. Matsuda, and C. Giam, J. Org. Chem., 1981, 46, 4885. F. Akiyama, H. Miyazaki, K. Kaneda, S. Teranishi, Y. Fujiwara, M. Abe, and H. Taniguchi, J. Org. Chem., 1980, 45, 2359. M. Beller, H. Fischer, and K. Kühlein, Tetrahedron Lett., 1994, 35, 8773. M. Beller and K. Kühlein, Synlett, 1995, 441. R. R. Bader, P. Baumeister, and H.-U. Blaser, Chimia, 1996, 50, 99. P. Baumeister, G. Seifert, and H. Steiner (Ciba-Geigy AG), EP-A 584 043, 1992; Chem. Abstr. 1994, 120, 322 928n. T.-C. Wu (Albermarle), U.S. Patent 5,315,026, 1994. T.-C. Wu (Albermarle), U.S. Patent 5,536,870, 1996. M. Beller, A. Tafesh, and W. A. Herrmann (Hoechst AG), DE 19 503 119, 1996. R. A. DeVries and A. Mendoza, Organometallics, 1994, 13, 2405. R. D. Larsen, E. G. Corley, A. O. King, J. D. Carroll, P. Davis, T. R. Verhoeven, P. J. Reider, M. Labelle, J. Y. Gauthier, Y. B. Xiang, and R. J. Zamboni, J. Org. Chem., 1996, 61, 3398. A. J. Chalk and S. A. Magennis, J. Org. Chem., 1976, 41, 1206. G. W. Parshall and W. A. Nugent, CHEMTECH, 1988, 376. M. Asslam and V. Elango (Hoechst-Celanese), U.S. Patent 5,225,603, 1993. M. Beller and A. Zapf, Synlett, 1998, 792.
IV.2.1.3 INDUSTRIAL FINE CHEMICALS SYNTHESES BY HECK REACTION
1221
[32] A. Eisenstadt, in 17th Conference on Catalysis of Organic Reactions, New Orleans, 1998. [33] A. Eisenstadt, in Catalysis of Organic Reactions, F. E. Herkes, Ed., Marcel Dekker, New York, 1998, 415. [34] A. Eisenstadt, Isr. Patent 103, 506, 1992. [35] A. Eisenstadt, Isr. Patent 115, 000000000102 855, 1995. [36] N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483. [37] H. Geissler, in Transition Metals for Organic Synthesis, M. Beller and C. Bolm, Eds., Wiley-VCH, Weinheim, 1998, Vol. 1, 158. [38] A. Suzuki, in Metal-Catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang, Eds., Wiley-VCH, Weinheim, 1998, 49. [39] A. F. Indolese, Tetrahedron Lett., 1997, 38, 3513. [40] S. Saito, S. Oh-tani, and N. Miyaura, J. Org. Chem., 1997, 62, 8024. [41] M. Beller, H. Fischer, W. A. Herrmann, K. Öfele, and C. Broßmer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1848. [42] M. B. Mitchell and P. J. Wallbank, Tetrahedron Lett., 1991, 32, 2273. [43] M. T. Reetz, R. Breinbauer, and K. Wanninger, Tetrahedron Lett., 1996, 37, 4499. [44] S. Saito, M. Sakai, and N. Miyaura, Tetrahedron Lett., 1996, 37, 2993. [45] W. Shen, Tetrahedron Lett., 1997, 38, 5575. [46] W. A. Herrmann, C.-P. Reisinger, and M. Spiegler, J. Organomet. Chem., 1998, 557, 93. [47] F. Firooznia, C. Gude, K. Chan, and Y. Satoh, Tetrahedron Lett., 1998, 39, 3985. [48] A. F. Littke and G. C. Fu, Angew. Chem. Int. Ed. Engl., 1998, 38, 3387. [49] J. P. Wolfe and S. L. Buchwald, Angew. Chem. Int. Ed. Engl., 1999, 39, 2413. [50] R. A. Singer and S. L. Buchwald, Tetrahedron Lett., 1999, 40, 1095. [51] C. Zhang, J. Huang, M. L. Trudell, and S. P. Nolan, J. Org. Chem., 1999, 64, 3804. [52] X. Bei, H. W. Turner, W. H. Weinberg, and A. S. Guram, J. Org. Chem., 1999, 64, 6797. [53] S. Haber, in Aqueous-Phase Organometallic Catalysis, B. Cornils and W. A. Herrmann, Eds., VCH-Wiley, Weinheim, 1998, 444. [54] E. Poetsch, Kontakte, 1988, 15. [55] 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, P. J. Reider, Y. S. Lo, L. T. Rossano, A. S. Brookes, D. Meloni, J. R. Moore, and J. F. Arnett, J. Org. Chem., 1994, 59, 6391. [56] U. Beutler, J. Mazacek, G. Penn, B. Schenkel, and D. Wasmuth, Chimia, 1996, 50, 154. [57] C.-Y. Chen, D. R. Lieberman, R. D. Larsen, R. A. Reamer, T. R. Verhoeven, P. J. Reider, I. F. Cottrell, and P. G. Houghton, Tetrahedron Lett., 1994, 35, 6981. [58] M. J. Robins and P. J. Barr, J. Org. Chem., 1983, 48, 1854. [59] M. Beller, in Applied Homogeneous Catalysis with Organometallic Compounds, B. Cornils and W. A. Herrmann, Eds., VCH, Weinheim, 1996, Vol. 1, 148. [60] E. J. Jang, K. H. Lee, J. S. Lee, and Y. G. Kim, J. Mol. Catal. A Chem., 1999, 138, 25. [61] R. Schmid, Chimia, 1996, 50, 110. [62] M. Scalone and P. Vogt (Hoffmann-La Roche), EP 385210, 1990. [63] Y. Bessard and J. P. Roduit, Tetrahedron, 1999, 55, 393. [64] M. Julia, M. Duteil, C. Grard, and E. Kuntz, Bull. Soc. Chim. Fr., 1973, 2791. [65] A. Zapf and M. Beller, Chem. Eur. J., 2000, 6, 1830. [66] J. B. Davison, N. M. Simon, and S. A. Sojka, J. Mol. Catal., 1984, 22, 394. [67] A. Spencer, J. Organomet. Chem., 1984, 270, 115.
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IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
[68] Y. Ben-David, M. Portnoy, M. Gozin, and D. Milstein, Organometallics, 1992, 11, 1995. [69] M. Portnoy, Y. Ben-David, and D. Milstein, Organometallics, 1993, 12, 4734. [70] W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, and G. R. J. Artus, Angew. Chem. Int. Ed. Engl., 1995, 34, 2371. [71] W. A. Herrmann, C. Broßmer, K. Öfele, C.-P. Reisinger, T. Priermeier, M. Beller, and H. Fischer, Angew. Chem. Int. Ed. Engl., 1995, 34, 1844. [72] M. T. Reetz, G. Lohmer, and R. Schwickardi, Angew. Chem. Int. Ed. Engl., 1998, 37, 481. [73] A. F. Littke and G. C. Fu, J. Org. Chem., 1999, 64, 10. [74] K. H. Shaughnessy, P. Kim, and J. F. Hartwig, J. Am. Chem. Soc., 1999, 121, 2123. [75] M. Kosugi, M. Kameyama, and T. Migita, Chem. Lett., 1983, 927. [76] A. S. Guram, R. A. Rennels, and S. L. Buchwald, Angew. Chem. Int. Ed. Engl., 1995, 34, 1348. [77] J. Louie and J. F. Hartwig, Tetrahedron Lett., 1995, 36, 3609. [78] J. P. Wolfe, S. Wagaw, and S. L. Buchwald, J. Am. Chem. Soc., 1996, 118, 7215. [79] M. S. Driver and J. F. Hartwig, J. Am. Chem. Soc., 1996, 118, 7217. [80] J. P. Wolfe and S. L. Buchwald, J. Org. Chem., 1997, 62, 1264. [81] J. Louie, M. S. Driver, B. C. Hamann, and J. F. Hartwig, J. Org. Chem., 1997, 62, 1268. [82] S. Wagaw and S. L. Buchwald, J. Org. Chem., 1996, 61, 7240. [83] J.-F. Marcoux, S. Wagaw, and S. L. Buchwald, J. Org. Chem., 1997, 62, 1568. [84] S. Zhao, A. K. Miller, J. Berger, and L. A. Flippin, Tetrahedron Lett., 1996, 37, 4463. [85] Y. D. Ward and V. Farina, Tetrahedron Lett., 1996, 37, 6993. [86] C. A. Willoughby and K. T. Chapman, Tetrahedron Lett., 1996, 37, 7181. [87] T. Kanbara, A. Honma, and K. Hasegawa, Chem. Lett., 1996, 1135. [88] I. P. Beletskaya, A. G. Bessmertnykh, and R. Guilard, Tetrahedron Lett., 1997, 38, 2287. [89] M. Beller, T. H. Riermeier, C.-P. Reisinger, and W. A. Herrmann, Tetrahedron Lett., 1997, 38, 2073. [90] M. Beller, Angew. Chem. Int. Ed. Engl., 1995, 34, 1316. [91] M. Beller and T. H. Riermeier, in Organic Synthesis Highlights III, J. Mulzer and H. Waldmann, Eds., Wiley-VCH, Weinheim, 1998, 126. [92] J. F. Hartwig, Synlett, 1997, 329. [93] A. Schoenberg and R. F. Heck, J. Am. Chem. Soc., 1974, 96, 7761. [94] T. Okano, N. Harada, and J. Kiji, Bull. Chem. Soc. Jpn., 1994, 67, 2329. [95] I. Pri-Bar and O. Buchmann, J. Org. Chem., 1984, 49, 4009. [96] Y. Ben-David, M. Portnoy, and D. Milstein, J. Chem. Soc. Chem. Commun., 1989, 1816. [97] V. Dufaud, J. Thivolle-Cazat, and J. M. Basset, J. Chem. Soc. Chem. Commun., 1990, 426. [98] M. Beller, M. Eckert, F. Vollmüller, S. Bogdanovic, and H. Geissler, Angew. Chem. Int. Ed. Engl., 1997, 36, 1494. [99] M. Beller, M. Eckert, W. A. Moradi, and H. Neumann, Angew. Chem. Int. Ed. Engl., 1999, 38, 1454. [100] M. Beller, M. Eckert, H. Geissler, B. Napierski, H.-P. Rebenstock, and W. Holla, Chem. Eur. J., 1998, 4, 935. [101] M. S. Stephan, A. J. J. M. Teunissen, G. K. M. Verzijl, and J. G. de Vries, Angew. Chem. Int. Ed. Engl., 1998, 37, 662.
Br Pd(0)
IV.2.2 Intramolecular Heck Reaction IV.2.2.1
Synthesis of Carbocycles
STEFAN BRÄSE and ARMIN DE MEIJERE
A. INTRODUCTION The possibility of constructing carbocycles by intramolecular Heck reaction makes it particularly versatile for organic synthesis.[1],[2] The starting materials, alkene-tethered haloalkenes and haloarenes, are in general readily available from simple precursors, and thus this strategy has been used for the preparation of various types of carbocyclic systems. In this section, the cyclization of haloalkadienes to give carbomonocyclic structures is described. While the carboannelation of heterocycles is included here, the domino and cascade reactions involving two or more intramolecular Heck coupling steps are covered in Sect. IV.3.
B. CYCLIZATION OF 2-HALO-1,(n1)-ALKADIENES AND RELATED COMPOUNDS B.i. General Remarks By Pd-catalyzed intramolecular coupling of 2-halo-1,(n1)-alkadienes and related compounds, all ring sizes from three- to nine-membered are attainable, either by exo – trig for three- to nine- or endo – trig cyclizations for six- to nine-membered rings (Table 1).[1] Applications toward the construction of larger rings (sizes 13 – 24) have been demonstrated for substrates on solid support in combinatorial syntheses (see also Sect.X.3),[3] by employing slow addition of the substrate and/or high dilution techniques.[4] B.ii. Synthesis of Cyclopropanes The synthesis of cyclopropanes by simple cyclization of 2-halo-1,4-pentadienes has not been achieved, presumably because the product 1,2-dimethylenecyclopropane would not be stable under the reaction conditions necessary for ring closure. However, the formation of bicyclo[n.1.0]alkanes from certain 2-halo-1,3-pentadienes (Sect. IV.2.2.1.C.iii.a) or by a cascade reaction (Sect. IV.3.1) has been achieved. Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1223
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IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 1. Examples of Ring Sizes Achieved by Intramolecular Heck Reactions Ring Size 3 4 5 6 7 8 9 10 – 15 16 – 19 19
Reference for endo-trig(dig)
Reference for exo-trig(dig)
[14],[36]–[38],[80] [38],[54]–[57],[80] [42],[54,[55],[59],[63] [54],[55] [4],[66] (13) [68] (16), [69] (16, 18) [66] (21), [69] (20, 22), [3] (20 – 24), [4] (26)
[5]–[7]a [8],[10] [4],[12]–[35] [13],[16],[23],[27],[38],[39]–[53] [16],[58]–[62] [60],[61],[64],[65] [66]b [66] (11,12)b, [67] (12 – 15)c [66] (18)b, [67] (16, 17)c
a
The formation of three-membered rings is reversible: Compare Ref. [38c]. With allene coupling partners instead of alkenes. c Heck – Stille cascade. b
B.iii Synthesis of Cyclobutanes: Cyclization of 2-Halo-1,4-hexadienes and Related Compounds The cyclization of simple 2-halo-1,5-hexadienes to yield 1,2-dimethylenecyclobutanes has not been achieved so far.[34] Presumably, a rapid Cope rearrangement of the starting 1,5-hexadiene may inhibit such a process or ring-opening polymerization of the initially formed 1,2-dimethylenecyclobutane derivative may prevent its isolation. However, when the functionalized double bond is incorporated in a six-membered ring, cyclization with a tethered alkenyl group to give an 8-methylenebicyclo[4.2.0]oct-1-ene derivative does occurs. Starting from dimedone, novel cyclohexa-1,4-diene-1,5-diyl bis(nonafluorobutanesulfonates) have been prepared and cyclized under palladium catalysis to cleanly give bicyclo[4.2.0]octadienes and bicyclo[4.2.0]octenones, respectively, by unprecedented 4-exo-trig processes (Scheme 1). In the presence of a chiral Ph NfO
ONf
Pd(OAc) 2, PPh3 Et3N, DMF
Ph H
80 °C, 12 h
56% R O
ONf
Pd(OAc) 2, PPh3 Et3N, DMF
R O
80 °C, 12 h
52–65% R = Bn, allyl Ph NfO
ONf
CO2t-Bu Pd(OAc) 2, PPh3 Et3N, DMF
Ph t -Bu O2C
80 °C, 12 h
43%
Nf = C4F9SO2
Scheme 1
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1225
catalyst the BINAP ligand furnished the products with modest asymmetric induction (up 53% ee).[10] B.iv. Synthesis of Cyclopentanes: Cyclization of 2-Halo-1,6-heptadienes and Related Compounds Intramolecular Heck reactions have frequently been used for the synthesis of cyclopentanoid structures. In nearly all cases reported so far, the ring closure occurs as a 5-exo process (for an exception, see Table 4, entry 6), for which 2-halo-1,6-heptadienes and related compounds are the appropriate starting materials. In some cases, however, these substrates cyclize by a 6-endo mode to give cyclohexane derivatives (see Sect. IV.2.2.1.B.v). Simple open-chain 2-bromoheptadienes have frequently been used as substrates to generate 1,2-dimethylenecyclopentanes (Tables 2 and 3), which in turn have served as valuable starting materials in Diels – Alder cycloadditions. It has turned out to be even more favorable to carry out the intramolecular Heck reaction and subsequent Diels–Alder reaction as a domino-type sequence in a single operation (see Table 6). In the presence of secondary amines, aminoalkylcyclopentanes are produced (Sect. IV.3.2). Cycloalkenyl groups as acceptors in the carbopalladation step have frequently been employed to form bicyclic systems (Table 3, entries 2, 5, 6; Table 4, entries 2, 3, 5, 12). These developments have contributed toward applications in the total synthesis of natural products as, for example, aphidicolin (Table 3, entry 5; see also Table 9, entry 9). [17],[18] In some cases, the formation of 6-endo products (Scheme 2) and/or double bond isomers can be prevented by using 2,6-dihaloheptadienes rather than the monohalodiene substrates (see Table 2, entry 8).[31]
X
“Pd”
+
5-exo
6-endo
Scheme 2
Especially under classical Heck conditions, that is, in the presence of PPh3, the coupling of an o-halostyrene formed in the first two coupling steps of an o-dihalobenzene derivative may yield alkylideneindane and alkylindene derivatives by 5-exo-trig cyclization of the intermediate o-alkenyl(phenylethyl)palladium (Scheme 3) This side reaction played a dominant role in the attempted sixfold Heck coupling of hexabromobenzene with styrenes and led to mixtures of various isomers of the expected hexakisstyrylbenzene derivatives.[75] Sixfold Suzuki and Stille coupling reactions of hexabromobenzene, however, worked perfectly well, to give hexakisalkenylbenzene derivatives in high yields. Five-membered ring closure has also been observed upon Pd-catalyzed coupling of o-halostyrene derivatives with alkenes.[19] Apparently, an intramolecular carbopalladation with 5-exo-trig ring closure can favorably compete with -hydride elimination in the intermediate -(o-ethenylphenyl)ethylpalladium halide. This reaction mode for the alostyrene is observed especially under Jeffery conditions when the alkene is ethylene, propene, or an
1226
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 2. Synthesis of Cyclopentanes: Cyclization of Open-Chain 2-Halo-1,6-heptadienes and Related Compounds Entry
1
Starting Material
E E
Product
E
Br
2
E
E E
E
E
Br
E Ph
Ph
92
[34]
90
[35]
Pd(OAc)2, PPh3, MeCN, 80 C, 6 h
45
[70]
Pd(OAc)2, PPh3, K2CO3, MeCN, 30 C, 96 h
88
[33]
45
[33]
Pd(OAc)2, PPh3, K2CO3, MeCN, 80 C, 12 h
74
[33]
Pd(OAc)2, PPh3, K2CO3, MeCN, 80 C, 2.3 h
55 (19)a
[32],[33]
Pd(PPh3)4, Et3N, MeCN/THF
68
[26]
Pd(OAc)2, PPh3, K2CO3, MeCN, 30 C, 35 h
E
Br
E E
E = CO2Me
4
Pd(OAc)2, PPh3, K2CO3, MeCN, 80 C, 3.5 h Pd(OAc)2, PPh3, MeCN, 80 C, 75 min
E = CO2Me
3
Yield (%)
Reference
E
E = CO2Et
E
Catalyst, Solvent, Temperature
E
E
Br
E = CO2Me
5
R R
R Br
R
R = MeCO R
6
I
R = OSiMe2(t-Bu)
R
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1227
TABLE 2. (Continued) Entry
I
Refrence
Pd(PPh3)4, Et3N, MeCN, 100 C, 16 h
63
[26]
Pd(PPh3)4, Ph2P-C6H4 polystyrene, K2CO3, MeCN, 135 C (sealed tube), 46 h
68
[31]
E
E C4H9
Yield (%)
Catalyst, Solvent, Temperature
Product
Starting Material
C4H9
7
E E E = CO2Me
8
H2N
Br
H2N
E
Br
E E = CO2Et
OMe
OMe
N
N
9 N
N
MeO a b
Pd(PPh3)4, K2CO3, MeCN, 80 C, 48 h
Br
51 (1:1.1)b [30]
MeO
Yield of the corresponding cyclohexene derivative formed by a 6-endo process (in parentheses). Mixture of double bond positional isomers (ratio in parentheses).
R1
X
R2
R2
R1
R
2
“Pd”
R1 +
R2
R2
X Scheme 3
alkenyl ether (R2 H, Me or OR) (Scheme 4).[19] Under the same conditions, however, odibromobenzene gives very high yields of o-dialkenylbenzene derivatives (see Sect. IV.2.1.2). When the -hydride elimination in the intermediate is retarded or even impossible, as in the carbopalladation products of alkynes or norbornene, the respective cyclopentannelation products are formed in higher yields (Scheme 5).[19],[20] Benzyl halides and other benzyl esters can be coupled under Heck conditions, and the pioneering work of Heck and co-workers on such intermolecular couplings has been extended by Negishi and co-workers to intramolecular cases to give indane derivatives (Table 5).[16] Similarly, acid chlorides have been found to undergo an oxidative addition to palladium(0) species and the intermediates to cyclize, if a vicinal allyl group is present, to give -methyleneindanone derivatives. As a stoichiometric reaction, this cyclization has been demonstrated as early as 1985 by Tour and Negishi (Scheme 6).[21] The intramolecular Heck reaction followed by a Diels–Alder cycloaddition[33] leading to bicyclo[4.3.0]nonene derivatives has been developed into a one-pot cascade reaction.[22],[23] Various 2-bromo-1,6-heptadienes including systems with heteroatoms in the tether between the double bonds were cyclized under palladium catalysis producing vicinal exodimethylenecycloalkanes, which reacted with dienophiles (either present
1228
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 3. Sythesis of Cyclopentanes: Cyclization of Monocyclic 2-Halo-1,6-heptadienes and Related Compounds Entry
Catalyst, Solvent, Temperature
Product
Starting Material CO2Me
CO2Me
Pd(PPh3)4, MeCN/THF, 100 °C, 6 h
73
Pd(PPh3)4, MeCN/THF, 100 °C, 20 h
68
Pd(OAc)2, PPh3, K2CO3, Et4NCl, 80 °C, 1 h
55 a
Pd(OAc)2, PPh3, Et3N, MeCN, 70 °C
88
OR Pd(PPh ) , LiCl, 3 4 Li2CO3, THF, reflux, 3 h
91
1 I
Yield (%)
Bu Bu
2 O
I
Bu
O Bu
Br
3 E
E
E
E
E = CO2Et
OTf 4
O
O
OR OTf
5 H
H
R = SiMe2t-Bu E
E
OTf
Pd(PPh3)4, LiCl, Li2CO3, THF, reflux, 3 h
6 H
E = CO2 Et
HO
O E
O
E 8
H HO
Br
7
E
E I
E = CO2Me a
Mixture of regioisomers, depending on type and amount of added base. Mixture of isomers.
b
98 (5:1)b
Pd(OAc)2, P(o-Tol)3, K2CO3, MeCN, reflux, 2 h
90
PdCl2, sulfonated triphenylphosphine, (i-Pr)2NEt, MeCN/H2O 6:1, 70 °C, 12 h
68
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1229
TABLE 4. Synthesis of Indanes: Cyclization of 1-Halo-2-butenylarenes and Related Compounds Entry
Catalyst, Solvent, Temperature
Product
Starting Material I
1
I
2 H
I
3 CN
CN
E
E
I 4
Yield
Reference
(%)
Pd(PPh3)2Cl2, Et3N, MeCN/PhH (1:1), 100 °C, 12 h
89 (60:40)a
[21]
Pd(PPh3)4, MeCN/THF, 60 °C, 24 h
80
[27]
Pd(OAc)2, PPh3, Ag2CO3, MeCN, 62 80 °C, 72 h Pd(OAc)2, n-Bu4NCl, 77 KOAc, DMF, (5.25:1)a 25 °C, 25 h
[27] [27]
Pd(PPh3)4, MeCN/PhH, 60 °C, 24 h
71
[26]
Pd(PPh3)4, Et3N, MeCN, 100 °C, 16 h
50
[26]
E = CO2Me I 5
E E E = CO2Me
E
E
I 6 E O
E E = CO2Me I
O
7 O
Pd(PPh3)4, Et3N, MeCN, 100 °C, 16 h
65
[26]
Pd(PPh3)4, MeCN/THF, 100 °C,16 h
50 (30)b
[25]
68
[26]
Pd(OAc)2, PPh3 MeCN, 80 °C, 24 h
86
[24]
Pd(OAc)2, TlOAc or AgOAc, anisole, 120–148 °C
80c
[29]
O
Br
Pd(OAc)2(PPh3)2
8
DMF, 80 °C, 36 h Br
9
Bu OH Bu
OH I
10 E
E
E = CO2Me
(Continued)
1230
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 4. (Continued) Entry
Starting Material
Product
Catalyst, Solvent, Temperature
E
Yield (%)
Reference
E
OTf
11
Pd(PPh3)4, LiCl, Et3N, THF, 90 °C, 3 h
80a (1.5:1)
[28]
Pd(PPh3)4, LiCl, Et3N, THF, 90 °C, 3 h
72a (6:1)
[28]
Pd(OAc)2, Ag2CO3, dppp, MeCN, 80 °C, 2h
96
[71],[72]
Pd(OAc)2, Ag2CO3, dppp, MeCN, 80 °C, 2h
96
[71],[72]
67
[73]
Pd(OAc)2, K2CO3, MeCN, 100 °C, 168 h
54
[74]
Pd(OAc)2, (+)BINAP, Et3N, cyclohexene, MeCN, 60 °C, 3h
54
[74]
Pd(OAc)2, TlOAc, Et3N, MeCN, 80 °C, 17 h
79
[74]
E = CO2Et
OTf
12
Br
13 OBn
OBn
Br
14
BnO
BnO
OMe
OMe I
Pd(OAc)2, PPh3, Ag2CO3, MeCN, reflux, 24 h
15
I N
16 t-BuN
Nt-Bu
N
I
17
N t-BuN
Nt-Bu
N
I
18
N t-BuN
a
Nt-Bu
N
Mixture of double bond isomers (ratio in parentheses). Yield of the corresponding cyclohexane derivative, formed by 6-endo process. c Mixture of double bond positional isomers. b
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1231
TABLE 5. Synthesis of Indanes: Cyclization of 1-Halomethyl-2-propenylarenes and Related Compound[16] Entry
Product
Starting Material
OSO2Me
1
OCO2Me
2
I
3
Cl
5
Yield (%)
Pd(PPh3)2, Et3N, MeCN, reflux, 1 h
60 a
Pd(PPh3)2, Et3N, MeCN, reflux, 5 d
26 (23)b
64
Pd(PPh3)2, Et3N, MeCN, reflux, 0.5 h
Br
4
Catalyst, Solvent, Temperature
(18)b
Pd(PPh3)2, Et3N, MeCN, reflux, 0.5 h
82a
Pd(PPh3)2, Et3N, MeCN, reflux, 1 h
82a
Cl Pd(PPh3)2, Et3N, MeCN, reflux, 24 h
6
60 (70:30)c
a
The isomeric 2-methylindene was produced in 1% yield. Yield of the isomeric compound, 2-methylindene, in parentheses. c Ratio of double bond positional isomers in parentheses. b
R2
R1 X
Pd(OAc) 2, K2CO3 LiCl, Bu4NCl, DMF 60–100 °C
R1 R2 +
X = Br, I 34–74%
R2
R1 = H, Me R2 = H, Me, Ph, OEt
O
Pd(OAc) 2, K2CO3, LiCl Bu4NCl, NMP 80 °C, 48 h
Br
R1
41%
H
H O Scheme 4
1232
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Pd(OAc) 2, KOAc anisol 120 °C, 18 h
Ph
E
+ Ph
E Ph
80%
I E = CO2Me
Ph
E E
Pd(OAc) 2, PPh3, TlOAc, MeCN reflux
+
H
62%
Br
H
E = CO2Me Scheme 5 O
Pd(PPh3)4, NEt3, MeCN/PhH 55 °C, 1 h
Cl
O
50%
Scheme 6
during the cyclization or added afterwards in a one-pot process) to give bicyclo[4.3.0]nonene derivatives and heterocyclic analogs in good to excellent yields (Schemes 7 and 8, Tables 6 and 7). While methyl 2-chloro-2-cyclopropylideneacetate and methyl 2-cyclopropylideneacetate as the dienophiles gave the corresponding fivemembered ring annelated spiro[2.5]octene derivatives in very good yields in both the onestep and the two-step procedure (Table 6, entries 13 and 14), the highly strained methyl dimethylcyclopropenecarboxylate and 1,2-dicyanocyclobut-1-ene gave the expected tricyclic products in only moderate yields (Table 6, entries 16 and 17). The yield of the latter reaction could be increased by performing the second step under high pressure R1
R6 R5 X
R4
R5 R6
R2 R3 “Pd”
X
Br
R4 R3 +X R2 1 R
isomer I
R5 R6
R1 R2 R3 4 R
isomer II
Scheme 7 R1
R4
R2 R3 “Pd”
R 5O
Br
R 5O
Scheme 8
R1 R2 R3 4 R
H H H H H H H H H H H H H H H H H H H H H H Me H
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
H H H H H H H H H H H H H H H H H H H H H H H Me
R6
Entry R5
C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2
X
CO2Me CO2Me
H CN H
CN COMe CO2Me CO2R*b COX*c CN CO2Me CO2Et CO2Et CO2Me CN CO2Et
R1
−CH2-CH2− −CH2-CH2−
H H
H H H H H Cl H H H H CN CO2Et
R2
−CH2-CH2-CO− − CH2-CH2− −C(CH2)2− EtO2C-C≡C-CO2Et EtO2C-N=N-CO2Et 1,4-benzoquinone 1,4-benzoquinone 1,4-naphthoquinone H H
H H H H H H CO2Me CO2Et CO2Et H CN CO2Et CO2Me CO2Me
R3
H H
H H H H H H H H H CO2Me CN CO2Et H Cl H CN CO2Me
R4 A A A A A A A B A A A A A A A A A A A A A A A C
Methoda 83 81 93 –d –d 74 85 88 94 93 – 78 83 83 – – – – – 43 71 78 60 (II) 48g (II)
One Step (Isomer)
(Continued)
70 70 60 55 52 – – – – – 79 48 79 61 30e 71f 48 94 78 – – – – –
Two Step (Isomer)
TABLE 6. Synthesis of Hydroindanes: One-Pot Cyclization of 2-Bromo-1,6-heptadienes and Subsequent One-Pot Diels-Alder Reaction (see Scheme 7)[22],23]
1233
25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
H H H H H H H H H H H H H H H H H H H
−CH2-CH2− −CH2-CH2− −CH2-CH2-CH2− −(CH2)4−
Entry R5
TABLE 6. (Continued)
1234
H H H H H H H H H H H H H H H H H H H
R6
C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 C(CO2Et)2 NCHO NCHO NCHO NCHO NCOMe NCOMe NCOMe NCOMe NCOMe NBoc NBn NTs NTs NTs NTs NNs NNs NCHO NCHO
X CO2t-Bu CO2X*c CO2Me CO2Me CO2t-Bu CO2t-Bu CN CN CO2Me CO2t-Bu CO2t-Bu CN CN CO2Me CO2Me CO2Me CO2t-Bu CN CN CO2Me CO2t-Bu CO2Me CO2Me
R1 H H H H H H H Cl H H H H Cl H H H H H Cl H H H Cl
R2 H H H H H H H H H H H H H H H H H H H H H
R3
−(CH2-CH2)− −(CH2-CH2)−
H H H H H CO2t-Bu H H H H CO2t-Bu H H H H H H H H H H
R4 A A C C A A A A A A A A A A A A A A A A A A A
Methoda
68 (I) –d 18 + 32h (I + II) 43i (II) 54 56 63 44 54 62 55 60 46 45 46 48 51 43 41 48 73 41 55
One Step (Isomer)
– 57 (I) – – – – – – – – – – – – – – – – – – – – –
Two Step (Isomer)
H H H Me H Me
H H H H H H
NCOMe NBoc NTs NBn O O
CO2Me CO2Me CO2Me CO2Me CO2Me CO2Me
Cl Cl Cl H H H
b
A: Pd(OAc)2, Ag2CO3, PPh3. B: Pd(OAc)2, Ag2CO3, dmphen. C: Pd(OAc)2, K2CO3, PPh3. R* = (R)-myrtenyl. c X* = camphorsultam. d Not carried out. e In the presence of AlCl3. f At 10 kbar, 28% yield at ambient pressure. g Together with 24% of isomerized 1,3-diene. h Together with 15% of isomerized starting material. i Together with 45% of the isomerized intermediate diene. j As a 1:5.8 mixture of diastereomers and 16:84 mixture of regioisomers I and II. k As a 1:4.2 mixture of diastereomers and 14:86 mixture of regioisomers I and II.
a
48 49 50 51 52 53
1235
H H H
−(CH2-CH2)− −(CH2-CH2)− −(CH2-CH2)− H H H
A A A A A A
68 43 44 41j (I + II) 42 55k (I + II)
– – – – – –
1236
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 7. Synthesis of Hydroindanes: Cyclization of 2-Bromo-1,6-heptadienes and Subsequent One-Pot Diels–Alder Reaction[23] Entry
R2
R2
R3
R4
R5
One Step
Two Step
1 2 3 4 5 6 7 8
CO2Me CO2Me CO2H CO2t-Bu CO2Me CO2Me CO2Me CO2Me
H H H H H H Me H
H H H H H H H H
H H H H CO2Me H H H
H COMe TBDMS TBDMS TBDMS THP THP TBDMS
87 87 77 73 80 77 86 56
— — — — — — 87 67
(10 kbar). Reaction of the bromodiene with chiral, nonracemic dienophiles such as (R)myrtenyl acrylate and N-acryloyl camphorsultam according to the two-step procedure gave the correspondingly substituted bicycles with a diastereomeric excess of 82% and >95%, respectively (Table 6, entries 4 and 5). When 0.5 equiv of p-benzoquinone was used with the 2-bromohepta-1,6-diene, a linearly annelated pentacycle was isolated in 71% yield along with a trace of the tricyclic monoadduct (Table 6, entries 20 and 21) while 1,4-naphthoquinone as a dienophile led to a tetracyclic system (Table 6, entry 22). When (E)/(Z)-2-bromo-1,6-octadienes, which correspond to the parent 2-bromohepta1,6-diene with a methyl group on the alkene moiety, were treated in the usual manner [Pd(OAc)2, PPh3, Ag2CO3 plus a suitable dienophile], the expected bicycles were isolated only in moderate yields (24 – 35%) because a competing -hydride elimination from the methyl group in the intermediate alkylpalladium halide after 5-exo-trig carbopalladation yields a 1,4-diene rather than the desired 1,3-diene (Scheme 9). In addition, 1,6heptadienes with a methylenecyclopropane terminator or starter were cyclized under Pd catalysis in the presence of methyl vinyl ketone and methyl acrylate (Scheme 9) and other dienophiles to give spirocyclopropane-annelated bicyclo[4.3.0]nonenes as single regioisomers in good yields (Table 6, entries 25 and 26; Scheme 7). These are the first intramolecular Pd-catalyzed coupling reactions with methylenecyclopropane moieties, which occur without opening of the three-membered ring. When Trost’s protocol for the cycloisomerization of 1,6-enynes was applied to the enyne with a methylenecyclopropane terminator, neither the exocyclic diene nor its cycloadduct—in the presence of methyl acrylate—was observed. The higher homologues of the 1,6-diene with a bromomethylenecyclobutane and a bromomethylenecyclopentane, respectively, instead of a bromomethylenecyclopropane starter, did not cyclize when treated with the Pd(OAc)2/Ag2CO3 system in the presence of a variety of ligands (PPh3, dppe, dppf, 2,9dimethyl-1,10-phenanthroline) or without added ligands. Surprisingly, when Ag2CO3 was replaced by K2CO3, both compounds as well as the (Z )-substituted and the 1,1-dimethylhepta-1,6-dienes, which did not react under the previously favored conditions, cyclized smoothly in a 5-exo-trig mode (Table 6, entries 24, 27 and 28). One equivalent of silver salt in relation to the added amount of palladium catalyst was sufficient to block the Heck reaction. The rationale of these unprecedented experimental results and the role of silver salts in this process are not clear at present. While the methylenecyclopropane derivative as well as the methylenecyclopentane derivative each yielded only one regioisomer, respectively, in the Diels – Alder reaction with methyl acrylate, the corresponding methylenecyclobutane compound gave two isomers in a ratio of about 1:1.7.
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1237
R3
E E
O Pd(OAc) 2, Ag 2CO3, PPh3, MeCN, 90 °C, 45 min
Br
COR3
E E
R2
R1 R2
R1 R1
R2
Me Me – (CH2)2 – – (CH2)2 –
R3
Yield (%)
OMe OMe Me
24 86 86
Scheme 9
B.v. Synthesis of Cyclohexanes: Cyclization of 2-Halo-1,7-octadienes and Related Compounds The syntheses of cyclohexane derivatives by 6-exo-cyclizations of 2-halo-1,7-octadienes and 1-halo-1,6-heptadienes are well documented, yet the formation of seven-membered rings during these cyclizations has also been observed (Scheme 10). This type of ring closure to cyclohexane derivatives has been applied in various total syntheses of natural products and been further elaborated applying chiral ligands in the catalysts to enable an enantioselective control (Tables 8 and 9).
X
“Pd”
+
6-exo
7-endo
Scheme 10
An interesting example concerning the competition between six- and seven-membered ring formation has been provided by Ma and Negishi (Scheme 11).[66] At least when an allenyl group competes with an ethenyl group, seven-membered ring formation occurs with approximately the same rate as six-membered ring closure. The first reported cascade consisting of an intermolecular Suzuki cross-coupling and a subsequent intramolecular asymmetric Heck reaction involving a 6-exo-trig cyclization[46] has been developed as a key step in an elegant access to halenaquinone, the oxidation product of halenaquinol, a marine natural product with interesting antibiotic, cardiotonic, and protein kinase inhibitory activities (Scheme 12). The two-step process consisting of a Suzuki coupling and a subsequent Heck cyclization has been demonstrated to be similarly efficient.[53] While the cyclization of 2-halo-1,6-heptadienes under standard Heck conditions leads to the formation of five-membered rings, predominant six-membered ring formation by a formal 6-endo-trig process was observed in an aqueous solvent mixture comprising a catalyst system with a water-soluble sulfonated triphenylphosphine ligand. However, the methylenecyclohexene derivative was obtained in 30% yield only
1238
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
E Br
Pd(PPh)2Cl2, K2CO3, Bu4NCl, DMF, 120 °C, 23 h
• E E
E
E E
E E +
47% (2:1) E = CO2Et
E E E E
Scheme 11
9-BBN
OTBDPS OTBDPS
OMe OTf
Pd(OAc) 2, (S)-BINAP, K2CO3, THF, 60 °C
OTf
78% 87% ee
OMe
OMe
OMe Scheme 12
(Table 10, entry 2). The 6-endo-trig cyclization has been discussed as a result of a sequence of a 5-exo-trig, 3-exo-trig, and retro-3-exo-trig (cyclopropylmethyl to homoallyl rearrangement) cyclizations (Scheme 13 and Table 10). This rearrangement cascade has unquestionably been poven for some examples.[38] Since the process is reversible, it is difficult to state whether the cyclopropyl intermediate has been formed in every single case, see e.g.[24] A six-membered ring formation has also been observed in the cyclization of 2bromo-1,7-heptadienes with (1-methylmethylene)cyclopropyl end groups (Scheme 14). Most probably, the six-membered ring intermediate C is not formed by a 6-endo-trig carbopalladation of the first formed alkenylpalladium bromide, but by a sequence of 5-exo-trig, 3-exo-trig carbopalladation to give B via A, and subsequent cyclopropylmethyl- to homoallylpalladium bromide rearrangement. Intermediate C would then undergo the same rearrangement once more, and the resulting D finally would undergo -hydride elimination to furnish a cross-conjugated triene, a so-called dendralene. The same products are also obtained by a Pd-catalyzed cycloisomerization of a terminal acetylene with a (1-methylmethylene)cyclopropyl group at the other end. The same eneynes, when treated with iodobenzene under Heck conditions, yield phenyl-substituted dendralenes in addition to the cross-coupling product of iodobenzene and the eneyne (Scheme 14).[80] The cyclization of o-butenylbenzyl halides proceeds by a 6-exo-trig carbopalladation to yield 2-methylenetetraline (Scheme 15).[16]
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
TABLE 8. Synthesis of Cyclohexanes: Cyclization of 2-Halo-1,7-octadienes, 1-Halo-1,6heptadienes, and Related Compounds by a 6-exo Process
Entry
Starting Material
Catalyst, Solvent, Temperature
Product
Yield (%)
Reference
OH OH
1
67 Pd(OAc2), PPh3, MeCN, 80 °C, 23 h (2:1)a
Br
Br
2
Pd(OAc2), PPh3, K2CO3, MeCN, 80 °C, 4 h
E E
E
E = CO2Et
E C6H13
C6H13
3 I
4
Bu
Bu
I
E E I E′
[27] [27]
70 (7:3)a
[27]
91
[26]
Pd(OAc2), PPh3 Et3N, MeCN, 70 °C, 80 12 h
[9]
PdCl2, sulfonated triphenylphosphine, (i-Pr)2NEt, MeCN/H2O 6 : 1, 70 °C, 12 h
[37]
E
E
5
86 [32] (4:1)a (cf. [34])
Pd(PPh3)4, Et3N, 70 MeCN/THF, reflux, (9:1)a 2h 97 Pd(PPh3)4, NaOAc, MeCN/THF, reflux, (GLC)b 2h Pd(PPh3)4, Et3N, MeCN/THF, reflux, 1 h
[32],[33]
Bu
Pd(PPh3)4, Et3N, MeCN, reflux, 1.5 h
Bu
E = CO2Et E′ = CO2Me
E′
OTf
6 O
O E
7
E
E
I
E
H
80c
E = CO2Me
H
OTf
8
PivO PivO
Pd(OAc)2, (R)76 BINAP, t-BuOH, (86% K2CO3, ee) ClCH2CH2Cl, 60 °C, 42 h
[52]
OH
(Continued)
1239
1240
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 8. (Continued)
Entry
Starting Material
Product
PMBO
Yield (%)
Pd2(dba)3, dppb, KOAc, DMA, 75 °C
65–70
[47]
Pd(OAc)2, PPh3, Et3N, MeCN, 70 °C, 30 h
95 (3:1)a
[51]
90 (7:1)a
[50]
77
[49]
Reference
PMBO
O
9
Catalyst, Solvent, Temperature
TfO O O O
TfO
O
O
10
OBn
Br
OBn
H
NCbz
11
NCbz Pd(OAc)2, P(o-Tol)3, H
E
E
N H
N H E = CO2Me
O
O
Br
E
E
N(Me)Boc
12
PdCl2, dppp, Ag3PO4, CaCO3, DMF, 100 °C, 5 h
N(Me)Boc
N Ts
Et3N, MeCN, 110 °C, 26 h
E = CO2Me
N Ts
a
Mixture of double bond positional isomers. Purity according to gas chromatography. c Equimolar mixture of cis- and trans-fused products. b
–HPdX “Pd”
PdX 3-exo
5-exo
X “Pd” 6-endo
–HPdX
PdX Scheme 13
PdX
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1241
TABLE 9. Synthesis of Tetralines: Cyclization of 1-Halo-2-pentenylarenes and Related Compounds
Entry
Starting Material
Yield (%)
Reference
Pd(PPh3)4, Et3N, MeCN, 50–100 °C
82
[26]
Pd(OAc)2, PPh3, Et3N, MeCN, 80 °C, 48 h
62
[24]
Pd(OTfa)2(PPh3)2, PMP, toluene, 120 °C, 42 h
60
[76]
Pd(OAc)2, (R)BINAP, K2CO3, toluene, 80 °C, 72 h
71a (95% ee)b
[77]
Pd(OAc)2 (R)-BINAP, K2CO3, THF, 50 °C, 50h
85 (87%) ee
[84]
Catalyst, Solvent, Temperature
Product E
E
E
E
1 I E = CO2Et E′ = CO2Me
E′
E′
O
E E
2
E Br
E
E = CO2Me OH OMe
DBS-N
OBn
3
OBn
I DBS-N
4
OMe
OTf
OR TfO
5 R = SiMe2t-Bu RO MeO
OR OMe OMe
6 TfO OMe
Pd(OAc)2, (S)BINAP, K2CO3, THF, 60 °C, 22 h
78 [46],[79], (87% ee) [85]
R = SiPh2t-Bu
RO
(Continued)
1242
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 9. (Continued) Entry Starting Material
Product
Catalyst, Solvent, Temperature
Yield (%)
Reference
Pd(dppb), KOAc, DMA, 120 °C, 30 h
65
[47]
Pd(OAc)2, PPh3, Ag2CO3, t-BuOMe, reflux, 15 h
67
[48]
PdCl2, dppp, Ag3PO4, CaCO3, DMF, 100 °C, 5 h
77
[49]
BnO TfO
7 OR OR
R = SiMe2t-Bu
OBn
O
I
O
O O
8
OH
HO
Br
E
E
N(Me)Boc
9 N Ts
N(Me)Boc N
E = CO2Me
Ts a b
Mixture of double bond positional isomers. Determined by HPLC analysis of an oxidation product.
TABLE 10. Synthesis of Cyclohexanes: Cyclization of 2-Halo-1,6-heptadienes by a Formal 6-endo-trig Process
Entry
Starting Material
Yield (%)
Reference
PdCl2, Et2NH, Et3N, DMF, 80 °C, 8 h
69
[38]
PdCl2, sulfonated triphenylphosphine, (i-Pr)2NEt, Ag2CO3, MeCN/H2O 6:1, 90 °C, 24 h
30
[37]
Catalyst, Solvent, Temperature
Product
1 OH
I HO
2
E E
E Br
E E = CO2Me
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
E E
Br
Pd(OAc) 2 PPh3, Et3N DMF, 100 °C
PdBr
E E
72%
1243
E = CO2Me
A PdBr PdBr
E E
E
E E
PbBr
E C
B
D Pd2(dba)3•CHCl3 P(o-Tol) 3, HOAc PhH, 20 °C, 12 h
E
78%
E
E E
PhI, Pd(OAc) 2, PPh3, Et3N, DMF, 100 °C, 12 h
Ph
Ph + E
E
E
E 45%
42%
Scheme 14 Cl
Pd(PPh3)4, Et3N MeCN, reflux, 2 h 65%
Scheme 15
B.vi. Synthesis of Cycloheptanes: Cyclization of 2-Halo-1,8-nonadienes and Related Compounds Several 7-exo-trig cyclizations of 2-halo-1,8-nonadiene systems have been reported over the last decade; however, a substantial fraction of 8-endo-trig cyclization product has been observed in these cases (Scheme 16, Table 11). This type of 7-exo-trig cyclization between an iodofurane moiety and a tethered cyclohexenone system served as a key step in the total syntheses of the squalene synthase inhibitors CP-225,917 and CP-263,114 (Scheme 17). Crucial at this point was the fact that the syn--hydride elimination was essential to install the correct double bond pattern.[62] The formation of cycloheptanes via a 7-endo-trig process might be envisaged as a sequence of a 6-exo-trig, 3-exo-trig, and retro-3-exo-trig process related to the formal 6-endo cyclization. This sequence ought to be the major pathway for disubstituted alkenes as acceptor alkene moieties whereas electron deficient alkenes like ,-unsaturated ketones are added in the 7-endo mode (Table 12).
1244
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 11. Synthesis of Cycloheptanes: Cyclization of Halo-1,7-octadienes and Related Compounds. ECO2Me, ECO2Et Starting Material
Catalyst, Solvent, Temperature
Product
I
HO
Reference
Pd(PPh3)2(OAc)2, Et3N, THF, 70 °C
52
[61]
Pd(OAc)2, Et3N, PPh3 DMF, 100 °C, 12 h
53
[80]
Pd(PPh3)Cl2, Et3N, DMF, 100 °C, 7 h
49
[86]
Pd(PPh3)4, Et3N, MeCN, reflux, 10 h
80
[57]
Pd(PPh3)Cl2, Et3N, DMF, 100 °C, 7 h
67
[86]
OH O
O
Br
E
Yield (%)
E E E E
E
Br 3
E′ N H
E′ N H
I E E E E
E E Br
3
N Ts
N Ts
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1245
TABLE 12. Synthesis of Cycloheptanes: Cyclization of Halo-1,6-octadienes
Starting Material
Catalyst, Solvent, Temperature
Product
Yield (%)
Reference
PdCl2, Et2NH, Et3N, DMF, 80 C, 8 h
68
[38]
Pd(OAc)2, K2CO3, n-Bu4NCl, DMF, 23 C, 12 h
53
[57]
OH
I HO I
O
O
Br
“Pd”
+ 7-exo
8-endo
Scheme 16 TBS
I
O
O Pd(OAc) 2(PPh 3)2 HO Et3N, dioxane, 100 °C, 24 h
O TBS RO
H
PMBO
O
77%
PMBO
6
TBS = SiMe 2t-Bu PMB = p-MeOC 6H 4CH 2 O O
O O O OH
HO 2C OH
R CP-225,917 Scheme 17
O
6
1246
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 13. Synthesis of Cycloheptanes: Cyclization of 1-Halo-2-(penta-4,5-dienyl)benzene Derivative: E CO2Et Entry
Starting Material
Catalyst, Solvent, Temperature
Yield (%)
Reference
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 4 h
65
[66]
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 4 h
65
[66]
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 110–120 8C, 4 h
40
[66]
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 110–120 8C, 4 h
20
[66]
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 22 h
58
[66]
58
[66]
E
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 4 h
66
[66]
E
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 3 h
Product
Br
1 E
E
•
E
E R
R Br
2 E E
E
•
E
R = CH2C(CO2Et)2CH2Allyl or CH2C(CO2Et)2(CH2)C≡CMe
E
E
E
E Br
3 E E
E
•
E
OH
O Br
4 E E
E
•
E
Br
5 E
•
E
E E
I
6
E
•
E
Bu
E
I Bu
7 E E
•
E
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1247
Seven-membered rings are also formed by a Pd-catalyzed 7-exo-trig cyclization of benzyl halides with an ortho-tethered 4-pentenyl group as reported by Negishi and coworkers (Scheme 18).[16]
Pd(PPh3) 4 , Et 3 N MeCN, reflux, 6 h
Cl
64%
E
E
E = CO2Et
E
E Scheme 18
B.vii. Synthesis of Cyclooctanes: Cyclization of 2-Halo-1,8-decadienes and Related Compounds In their studies toward the total synthesis of Taxol®, Danishefsky and co-workers have focused their attention on the formation of eight-membered rings by an intramolecular Heck reaction proceeding by an 8-exo-trig cyclization of a 2-halo-1,8-decadiene system (Scheme 19, Table 14).
X
“Pd”
+
8-exo
9-endo
Scheme 19
B.viii. Synthesis of Cyclononanes and Larger Ring Systems: Cyclization of 2-Halo-1,n-decadienes and Related Compounds The possibility of forming cyclononanes and larger rings by Pd-catalyzed intramolecular cross-coupling reactions has been investigated to a far lesser extent than that of the smaller rings. Very good yields have been reported for the cyclization of 2-bromo-1,8,9trienes in which allenyl groups serve as terminators and/or with the aid of high dilution techniques (Scheme 20, Table 15).
Br
“Pd”
9
• 9-endo Scheme 20
1248
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATIONS
TABLE 14. Synthesis of Cyclooctanes: Cyclization of 2-Halo-1,8-nonadienes and Related Compounds Entry
Starting Material
Product
I
Catalyst, Solvent, Temperature
Yield (%)
Pd(OAc)2, K2CO3, 80 C, 46 h
80
[61]
Pd(PPh3)4, K2CO3, MeCN, 90 C, 72 h
70
[65]
Pd(PPh3)4, K2CO3, MeCN, MS, 90 C
49
[60]
Reference
O
HO 1
O
O
O
O
OSiEt3
I
OSiEt3
2 O
O
O
O
O OTf OR
OR
3 O
O
O
O
Bn R = SiMe2t-Bu
O
O O
O
Bn
TABLE 15. Synthesis of Cyclononanes and Larger Rings: Cyclization of 2-Halo-1,9,10decatrienes and Related Compound: E CO2Et
Starting Material
Br
Product
9
1
Reference
9
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
55
[66]
9
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
62
[66]
10
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
47 (E/ Z = 73:27)
[66]
11
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
40
[66]
5
Br E
•
2
9
3
E
E E
•
I 3
10
•
6
I
4
11 7
Catalyst, Solvent, Temperature
Yield (%)
•
Entry
Ring Size
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1249
TABLE 15. (Continued)
Entry Starting Material
Product
12
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
50
[66]
12
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
27
[66]
•
5
12 E
E 4
E
E E
E
E E
I
•
Bu
Reference
E E
Br
Bu
6
12 E
E 4
E
E E
E
O
Catalyst, Solvent, Temperature
Yield (%)
Ring Size
O
HO
13
7
Pd(OAc)2, EtNiPr2, LiCl, (8 mmol L21) 61/17 DMF, 80 8C, 2d
[4]
20
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
86
[66]
20
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
47 a
[66]
21
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
66
[66]
13/26
Br
O O
O
26
O
O
E E
•
Br
8
20 E E
E E
I
•
Bu
12
E
E
9
E E Bu 12
9 E
E 12
E
E
9
E
Br
E E
10
21 E
E 12
E E
8
(Continued)
1250
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 15. (Continued)
Entry Starting Material Bu
Ring Size
Product
I
E
E
21 E
E 12
E
E
E
E
O
Yield Ref(%) erence
21
Pd(PPh3)2Cl2, (n-Bu)4NCl, K2CO3, DMF, 120 8C, 12 h
15
[66]
16
Pd(MeCN)2Cl2, Et3N, MeCN, 25 8C, 11 h
55
[68]
Bu
11
Catalyst, Solvent, Temperature
8
O
I 16
12 O
O
O
O
a
Yield determined by NMR spectroscopy with an internal standard.
C. SYNTHESIS OF BICYCLIC SYSTEMS C.i. Cyclization of 8-Substituted 6-Halo-1,6-octadienes and Related Compounds with an Additional Leaving Group Starting from 6,8-disubstituted 1,6-octadienes having two leaving groups in a 1,3relationship, Pd-catalyzed cyclization leads to the formation of bicyclic vinylcyclopropanes (Scheme 21).[78] The insertion of palladium into the vinylic carbon–halogen bond is regarded as the first step. The thus formed intermediate might rearrange to a palladium–carbene complex, which in turn cyclopropanates the other double bond. Alternatively, the alkenylpalladium halide carbopalladates the other double bond and a 3-exo-trig cyclization with subsequent elimination of a palladium(II) salt follows up to form the bicyclic system. Besides bromoallyl esters, propargyl carbonates with an alkenyl tether can also serve as starting materials; however, the presence of sodium formate and Et4NBr is required to suppress the formation of dehydrodimers (Table 16). Propargyl carbonates have also been used in a domino carbocyclization–methylation sequence by means of zincates as nucleophiles (Sect. IV.3.2). Similar approaches to ethenylcyclopropanes from open-chain halodienes or haloenynes have been published by the groups of Oppolzer and Grigg. However, these cascades proceed with a different termination (zincates).[80]–[82]
E E
“Pd”
Br
X Scheme 21
E E
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
1251
TABLE 16. Synthesis of Bicyclo[3.1.0]hexanes: Cyclization of 6-Halo-1,6-octadienes and 1,6Octenynes[78] Entry
1
Starting Material
E E
Catalyst, Solvent, Temperature
Product
E
Br
E
X
Yield (%)
Pd(OAc)2, PPh3, Et3N, MeCN, 85 C, 5–6 h
22–34a
Pd(OAc)2, PPh3, Et3N, NaO2CH, Et4NBr, MeCN, 85 C, 2 h
68
Pd(OAc)2, PPh3, Et3N, MeCN, 85 C, 1.5 h
36
E = CO2Me
X = OAc, OCOCF 3, OCO2Et
2
E
E
E
E
OCO2Me
E = CO2Me
E
3
E
E
E E = CO2Me
OCO2Me
E E
a
The influences of different bases and ligands lead to byproducts and different product compositions.
D. OTHER METHODS Intramolecular Heck reactions leading to carbocycles involving domino, tandem, or cascade reactions terminated with tethered alkenes and other nucleophiles will be covered in Sect. IV.3.1 and V.3.2, respectively. E. SUMMARY 1. Various ring sizes (4 to 21 carbon atoms) have been achieved by intramolecular Heck reactions. 2. All formations of four- and five- as well as most of the 6-membered rings proceed via an n-exo-trig carbopalladation, while the formation of larger rings has mostly been achieved by n-endo-trig processes. REFERENCES [1] S. Bräse and A. de Meijere, in Metal-Catalyzed Cross Coupling Reactions, (F. Diederich and P. J. Stang, Eds.), Wiley-VCH, Weinheim, 1998, 99–166.
1252 [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
A. de Meijere and S. Bräse, J. Organomet. Chem., 1999, 576, 88–110. M. Hiroshige, J. R. Hauske, and P. Zhou, J. Am. Chem. Soc., 1995, 117, 11590. G. Dyker and P. Grundt, Eur. J. Org. Chem., 1999, 323. F. E. Meyer, J. Brandenburg, P. J. Parsons, and A. de Meijere, J. Chem. Soc. Chem. Commun., 1992, 390. F. E. Meyer, P. J. Parsons, and A. de Meijere, J. Org. Chem., 1991, 56, 6487. F. E. Meyer, H. Henniges, and A. d. Meijere, Tetrahedron Lett., 1992, 33, 8039. R. Grigg, V. Sridharan, and S. Sukirthalingam, Tetrahedron Lett., 1991, 32, 3855. N. E. Carpenter, D. J. Kucera, and L. E. Overman, J. Org. Chem., 1989, 54, 5846. S. Bräse, Synlett, 1999, 1654. H. Iida, Y. Yuasa, and C. Kibayashi, J. Org. Chem., 1980, 45, 2938. R. Grigg, P. Fretwell, C. Meerholtz, and V. Sridharan, Tetrahedron, 1994, 50, 359. R. Yoneda, Y. Sakamoto, Y. Oketo, K. Minami, S. Harusawa, and T. Kurihara, Tetrahedron Lett., 1994, 35, 3749. R. Grigg, V. Sridharan, P. Stevenson, S. Sukirthalingam, and T. Worakun, Tetrahedron, 1990, 46, 4003. T. J. Katz, A. M. Gilbert, M. E. Huttenloch, G. Min-Min, and H. H. Brintzinger, Tetrahedron Lett., 1993, 34, 3551. G.-z. Wu, F. Lamaty, and E. Negishi, J. Org. Chem., 1989, 54, 2507. M. Toyota, Y. Nishikawa, and K. Fukumoto, Tetrahedron Lett., 1994, 50, 6495. M. Toyota, Y. Nishikawa, and K. Fukumoto, Tetrahedron, 1994, 50, 11153. S. Bräse, J. Rümper, K. Voigt, S. Albecq, G. Thurau, R. Villard, B. Waegell, and A. de Meijere, Eur. J. Org. Chem., 1998, 671. R. Grigg, P. Kennewell, A. Teasdale, and V. Sridharan, Tetrahedron Lett., 1993, 34, 153. J. M. Tour and E. Negishi, J. Am. Chem. Soc., 1985, 107, 8289. F. E. Meyer, K. H. Ang, A. G. Steinig, and A. de Meijere, Synlett, 1994, 191. K. H. Ang, S. Bräse, A. G. Steinig, F. E. Meyer, A. Llebaria, K. Voigt, and A. de Meijere, Tetrahedron, 1996, 52, 11503. J. M. Gaudin, Tetrahedron Lett., 1991, 32, 6113. Y. Zhang, B. OConnor, and E. Negishi, J. Org. Chem., 1988, 53, 5588. B. OConnor, Y. Zhang, and E. Negishi, Tetrahedron Lett., 1988, 29, 3903. E. Negishi, Y. Zhang, and B. OConnor, Tetrahedron Lett., 1988, 29, 2915. S. Liang and L. A. Paquette, Acta Chem. Scand., 1992, 597. R. Grigg, V. Loganathan, V. Santhakumar, V. Sridharan, and A. Teasdale, Tetrahedron Lett., 1991, 32, 687. B. Moeller and K. Undheim, Tetrahedron, 1998, 54, 5789. M. Moren-Manas, R. Pleixats, and A. Roglans, Liebigs Ann. Chem., 1995, 1807. R. Grigg, R. Stevenson, and T. Worakun, J. Chem. Soc. Chem. Commun., 1984, 1073. R. Grigg, P. Stevenson, and T. Worakun, Tetrahedron, 1988, 44, 2033. R. Grigg, P. Stevenson, and T. Worakun, Tetrahedron, 1988, 44, 2049. R. Grigg, R. Stevenson, and T. Worakun, J. Chem. Soc. Chem. Commun., 1985, 971. J. W. Dankwardt and L. A. Flippin, J. Org. Chem., 1995, 60, 2312. S. Lemaire-Audoire, M. Savignac, C. Dupuis, and J.-P. Genet, Tetrahedron Lett., 1996, 37, 2003. Z. Owcarczyk, F. Lamaty, E. J. Vawter, and E. Negishi, J. Am. Chem. Soc., 1992, 114, 10091.
IV.2.2.1 SYNTHESIS OF CARBOCYCLES
[39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64]
[65] [66] [67] [68] [69] [70] [71] [72] [73]
1253
D. Wensbo, U. Annby, and S. Gronowitz, Tetrahedron, 1995, 51, 10323. A. K. Mohanakrishnan and P. C. Srinivasan, Tetrahedron Lett., 1996, 37, 2659. S. Kirschbaum and H. Waldmann, Tetrahedron Lett., 1997, 38, 2829. C. Liljebris, B. Resul, and U. Hacksell, Tetrahedron, 1995, 51, 9139. R. Grigg, V. Santhakumar, V. Sridharan, M. Thorntonpett, and A. W. Bridge, Tetrahedron, 1993, 49, 5177. C. M. Huwe and S. Blechert, Tetrahedron Lett., 1994, 35, 9537. L. F. Tietze and O. Burkhardt, Synthesis, 1994, 1331. A. Kojima, T. Takemoto, M. Sodeoka, and M. Shibasaki, J. Org. Chem., 1996, 61, 4876. W. Deng, M. S. Jensen, L. E. Overman, P. V. Rucker, and J.-P. Vionnet, J. Org. Chem., 1996, 61, 6760. M. M. Abelman, N. Kado, L. E. Overman, and A. K. Sarkar, Synlett, 1997, 1469. Y. Yokoyama, K. Kondo, M. Mitsuhashi, and Y. Murakami, Tetrahedron Lett., 1996, 37, 9309. H. Muratake, I. Abe, and M. Natsume, Tetrahedron Lett., 1994, 35, 2573. S. Laschat, F. Narjes, and L. E. Overman, Tetrahedron, 1994, 50, 347. K. Kondo, M. Sodeoka, M. Mori, and M. Shibasaki, Synthesis, 1993, 920. K. Ohrai, K. Kondo, M. Sodeoka, and M. Shibasaki, J. Am. Chem. Soc., 1994, 116, 11737. S. E. Gibson and R. J. Middleton, J. Chem. Soc. Chem. Commun., 1995, 1743. S. E. Gibson, N. Guillo, R. J. Middleton, A. Thuilliez, and M. J. Tozer, J. Chem. Soc. Perkin Trans. 1, 1997, 447. R. Grigg, V. Santhakumar, V. Sridharan, P. Stevenson, A. Teasdale, M. Thornton-Pett, and T. Worakun, Tetrahedron, 1991, 47, 9703. E. Negishi, S. Ma, T. Sugihara, and Y. Noda, J. Org. Chem., 1997, 62, 1922. L. F. Tietze and R. Schimpf, Synthesis, 1993, 876. D. C. Horwell, P. D. Nichols, G. S. Ratcliffe, and E. Roberts, J. Org. Chem., 1994, 59, 4418. J. J. Masters, J. T. Link, L. B. Snyder, W. B. Young, and S. J. Danishefsky, Angew. Chem. Int. Ed. Engl., 1995, 34, 1723. J. J. Masters, D. K. Jung, W. G. Bornmann, S. J. Danishefsky, and S. de Gala, Tetrahedron Lett., 1993, 34, 7253. O. Y. Kwon, D. S. Su, D. F. Meng, W. Deng, D. C. D’Amico, and S. J. Danishefsky, Angew. Chem. Int. Ed. Engl., 1998, 37, 1877. J. H. Rigby, R. C. Hughes, and M. J. Heeg, J. Am. Chem. Soc., 1995, 117, 7834. S. J. Danishefsky, J. J. Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K. Jung, R. C. A. Isaacs, W. G. Bornmann, C. A. Alaimo, C. A. Coburn, and M. J. DiGrandi, J. Am. Chem. Soc., 1996, 118, 2843. W. B. Young, J. J. Masters, and S. Danishefsky, J. Am. Chem. Soc., 1995, 117, 5228. S. Ma and E. Negishi, J. Am. Chem. Soc., 1995, 117, 6345. A. Casaschi, R. Grigg, J. M. Sansano, D. Wilson, and J. Redpath, Tetrahedron Lett., 1996, 37, 4413. F. E. Ziegler, U. R. Chakraborty, and R. B. Weisenfeld, Tetrahedron, 1981, 37, 4035. M. J. Stocks, R. P. Harrison, and S. J. Teague, Tetrahedron Lett., 1995, 36, 6555. P. Müller and Z. Miao, Helv. Chim. Acta, 1994, 77, 1826. P. Wiedenau, B. Monse, and S. Blechert, Tetrahedron, 1995, 51, 1167. D. L. Boger and P. Turnbull, J. Org. Chem., 1998, 63, 8004. A. Ali, G. B. Gill, G. Pattenden, G. A. Roan, and T.-S. Kam, J. Chem. Soc. Perkin Trans. 1, 1996, 1081.
1254
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
[74] L. Ripa and A. Hallberg, J. Org. Chem., 1996, 61, 7147. [75] P. Prinz, A. Lansky, T. Haumann, R. Boese, M. Noltemeyer, B. Knieriem, and A. de Meijere, Angew. Chem. Int. Ed. Engl., 1997, 36, 1289. [76] C. Y. Hong, N. Kado, and L. E. Overman, J. Am. Chem. Soc., 1993, 115, 11028. [77] K. Kondo, M. Sodeoka, and M. Shibasaki, Tetrahedron: Asymmetry, 1995, 6, 2453. [78] A. G. Steinig and A. de Meijere, Eur. J. Org. Chem., 1999, 1333. [78] A. G. Steinig and A. de Meijere, Eur. J. Org. Chem., 1999, 1333. [79] A. Kojima, T. Takamoto, M. Sodeoka, and M. Shibasaki, Synthesis, 1998, 581. [80] S. Bra¨se and A. de Meijere, Angew. Chem. Int. Ed. Engl., 1995, 34, 2545. [81] W. Oppolzer, A. Pimm, B. Stammen, and W. E. Hume, Helv. Chim. Acta, 1997, 80, 623. [82] R. Grigg, R. Rasul, J. Redpath, and D. Wilson, Tetrahedron Lett., 1996, 37, 4609. [83] R. Grigg, V. Sridharan, and L. H. Xu, J. Chem. Soc., Chem., Commun., 1995, 1903. [84] T. Takemoto, M. Sodeoka, H. Sasai, and M. Shibasaki, J. Am. Chem. Soc., 1993, 115, 8477. [85] A. Kojima, C. D. J. Boden, and M. Shibasaki, Tetrahedron Lett., 1997, 38, 3459. [86] Y. Yokoyama, H. Matsushima, M. Takashima, T. Suzuki, Y. Murakami, Heterocycles, 1997, 46, 133.
X Het Het
IV.2.2.2
Synthesis of Heterocycles
GERALD DYKER
A. INTRODUCTION This section gives a concise overview on the construction of heterocycles by Heck-type reactions: all reactions covered here mechanistically start with an oxidative addition of a C–halide or another appropriate C–heteroatom bond to a Pd(0) species and go on either with a carbopalladation step (intramolecular in Sect. B and intermolecular in Sect. C) or a cyclopalladation step (Sect. D). The examples presented in the subsections are organized according to types of starting materials, since certain substructures turned out to be typical.
B. HETEROCYCLES BY INTRAMOLECULAR CARBOPALLADATION A starting material that is suitable for the direct construction of a heterocycle by an intramolecular Heck-type reaction has to fulfil some simple but fundamental requirements: there has to be the halide function or a triflate for the oxidative addition onto the Pd catalyst, a side chain with an unsaturated functionality such as an alkene or an alkyne in an appropriate distance, and of course the heteroatom in this side chain. Figure 1 presents a substructure typical for very many starting materials, which were transformed to heterocycles by intramolecular Heck-type reactions (X halide, Het heteroatom). This type of substructure with an allylic side chain is easily accessible by derivatization of 2-bromo- and 2-iodo anilines, phenols, and thiophenols and leads to interesting heterocycles such as indoles and benzofurans, which are related to many natural products and other biological active compounds. The Heck reaction with the simple representatives of this substructure shown in Scheme 1 generally involves a double bond migration to give aromatized products in moderate to good yields.[1]–[4] The highest yield was achieved for 3-methylindole, because in this case the reaction was driven to completion by the addition of several portions of Pd catalyst. The presence of silver salts inhibits the migration of the double bond: as a result, products with an exocyclic methylene group can be isolated (Scheme 1).[5] The construction of the indole nucleus is also possible with more highly substituted starting materials. Esters, nitriles, and various nitrogen functionalities do not disturb the reaction (Scheme 2), which was proved to be useful for natural product synthesis.[6]–[8]
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1255
1256
1V Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
X Het
Figure 1 I
[I]
Het
Het
Het = NH: 87% Het = O: 47% Het = S: 70% OAc
OAc PhO2S N
I
[II]
N
PhO2S
N OMe SO2 Ph
N OMe SO2 Ph
90% [I] = cat. Pd(OAc)2, Et3N or Na2CO3, DMF or MeCN, 80–140 °C, 15–72 h. [II] = 2 mol % Pd(OAc)2, 1.5 equiv Ag2CO3, DMF, 20 °C, 2 h. Scheme 1 CO2 Me Br
CO2 Me [I]
N Ac
N Ac
43%
CN I MeO H N
[II]
N OBn H
SO2 Br
CN
MeO H N
N R H
N OBn H 89% R
H
[III]
N COCF3 [I] = cat. Pd(OAc)2, PPh3, 2 equiv TMEDA, 125 °C, 5 h. [II] = 5 mol% Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, reflux, 3 h. [III] = cat. Pd(OAc)2, Et3N, DMF, ∆ . Scheme 2
N
SO2
N H 81%
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
1257
However, some cases are known in which electronic effects of substituents strongly influence the outcome of the intramolecular Heck reaction. The example presented in Scheme 3 is especially illustrative: the bisamide underwent a monocyclization to give a highly substituted indole, whereas the corresponding dimethoxy-substituted starting material did not react at all.[9] Ac
Ac
OR
N
Br
OR
N
[I]
N OR Ac OR Ac R = Ac: 64% R = Me: 0% [I] = cat. Pd(OAc)2, P(o-Tol)3, Et3N, MeCN, 50−110 °C. Br
Br
N
Scheme 3
In all these examples the ring closing carbopalladation step has to be classified as a 5-exo-trig reaction. Of course, there is no rule without exception: the cyclization of the indole derivative in Scheme 4 obviously proceeds as a 6-endo-trig reaction, thereby avoiding the formation of a rather strained ring system with two annelated five-membered rings.[10] In order to achieve the rather high yield in this reaction a large amount of catalyst (43 mol %) had to be applied. OMe
OMe Br
[I]
N
MeO Ph
N
MeO
Ph
Ph
Ph R = Me 94% [I] = 43 mol % Pd (OAc)2, 73 mol % P (o-Tol)3, Et3N, MeCN, 100 °C, 15 h.
Scheme 4
,-Unsaturated amides as starting materials (Schemes 5, 6, and 7) are structurally closely related to the allylic amines discussed before and also match the substructure shown in Figure 1. The additional carbonyl group prevents aromatization and does not influence the regioselectivity of the carbopalladation step. The stereoselectivity observed for the product in Scheme 5 is the result of the stereochemical requirements of the -H-elimination step.[11] Ph Br
Ph [I]
O N N H H 58% [I] = 1 mol % Pd(OAc)2, 4 mol % P(o-Tol)3, Et3N, MeCN, 100 °C, 18 h. O
Scheme 5
1258
1V Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
MeO
OTIPS N I
10% Pd 2dba3.CHCl3 (R)-BINAP
CHO
MeO
O N Me
O
Me
84% (95% ee)
Scheme 6
O
O
O
O
5% Pd2 dba3 . CHCl 3 (R)-BINAP
O I
N Me
O
N Me with Ag3PO4 : without Ag3PO4 :
S-enantiomer: 81% (71% ee) R-enantiomer: 77% (66% ee)
Scheme 7
Related substrates were repeatedly cyclized in an enantioselective fashion.[12],[13] For these examples the formation of a quaternary carbon as the chiral center is crucial. Very often BINAP has been applied as the chiral ligand: the synthesis of the chiral aldehyde in Scheme 6 represents an important step in the synthesis of physostigmine.[14] In certain cases the stereoselectivity of the cyclization reaction is rigorously influenced by the addition of silver salts[15]: using the same enantiomer of BINAP both enantiomers of a spiroannelated indole could be selectively obtained depending on the presence or absence of silver salts (Scheme 7). Numerous examples of Heck-type reactions are known, where the common -Helimination usually following the carbopalladation step is inhibited because of structural or stereochemical reasons. Either the intermolecular reaction with an additional reagent or another cyclization reaction then terminates the Pd-catalyzed process. Such reactions are discussed below, again starting from substrates related to the substructure shown in Figure 1. The product in Scheme 8, reminiscent of a prostaglandin, is the result of an intramolecular carbopalladation followed by an intermolecular Heck reaction, which becomes possible because the decisive intermediary alkylpalladium complex is lacking an appropriate hydrogen in synperiplanar position for the -H-elimination.[16] Similarly, the intermediary alkylpalladium complexes, which have to be assumed for the reactions in Scheme 9, have a sufficient lifetime to interact with an additional reagent: in these cases reduction by sodium formate takes place. The resulting furobenzofurans are model compounds for the synthesis of aflatoxines.[17],[18] For the reactions presented in Scheme 10 the catalytic cycle is terminated by a second ring-closing step, again becoming possible because of the inhibition of the -H-elimination.[19]–[21] These examples illustrate the versatility of this type of domino processes. In view of the numerous possibilities for structural variation of the substrate and of additional reagents a broad variety of highly functionalized polycylic systems are easily accessible.[22],[23]
1259
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
O
I
OH
[I]
OH O
O CO2 Et
[I] = 5 mol % Pd(OAc)2, 10 equiv 1-octen-3-one, i-Pr2Et, n-Bu4NCl, DMF, 50 °C.
CO2Et 42%
Scheme 8 O I
[I]
O
O O
O 86% OBn
O
OBn I
O
[II]
O
O O
O
PhO 2SO
O PhO 2SO 71% I [I] = cat. Pd(MeCN)2Cl2, Et3N, HCOOH, DMF, 50 °C, 3 d. [II] = cat. Pd(MeCN)2Cl2, n-Bu4NCl, Et3 N, HCOONa, DMF. Scheme 9
N
N
PhO2S N
O
O I
I
[I]
N SO2 Ph 68%
N SO2 Ph Ph
PhO 2S
EtO2C
N SO2 Ph EtO2C CO2 Et O
CO2 Et
N I N SO2 Ph
N SO2 Ph
42%
[II]
[III]
N SO2 Ph 50%
[I] = 11 mol % Pd(OAc)2, 25 mol % PPh3 , Et4NCl, K2CO3, MeCN, reflux, 17 h. [II] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , Ph4BNa, Et4NCl, K2CO3, MeCN. [III] = 10 mol % Pd(OAc)2, 25 mol % PPh3 , 1 atm CO, TlOAc, MeCN. Scheme 10
1260
1V Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
The assembly of polyfunctional compounds is further illustrated by a recent example of a one-pot reaction (Scheme 11).[24] In the first reaction step a rhodium-catalyzed [2 2 2] cyclization of a bisalkyne with a monoalkyne takes place, building up a functionalized benzene nucleus. Subsequent addition of a palladium catalyst initiates the Heck-type heterocyclization, which is finally followed by the capturing of the intermediary alkyl–Pd complex with a boron-substituted pyridine. Closely related to the allyl-substituted starting materials discussed above are of course propargylic derivatives (Scheme 12).[25],[26] Since the carbopalladation of alkynes leads to alkenylpalladium species, which normally do not undergo -H-elimination, additional reagents such as formic acid or a alkenyltin compound can take part in the process. The ethenyl-substituted substructures in Figure 2 are typical for a variety of substrates, which also lead to five-membered heterocycles. Compared to the structure in Figure 1, only the position of the heteroatom has changed in the case of the first structure. Generally, this does not significantly influence the reactivity or induce a change in mechanism. The cyclization proceeds in the sense of a 5-exo-trig reaction in analogy to the processes discussed above for allylic substrates. Frequently, spirocyclic products are obtained as shown in Scheme 13.[26]–[28] Another prominent example is the final step in a total synthesis of camptothecin presented in Scheme 14.[29] 1. Rh catalyst
N CO2 Me CO2 Me
I
O N
2. Pd catalyst
O
N CO2 Me
BEt2 N
CO2 Me 49%
Scheme 11
N N [I]
I
N N O O +
I
56%
SnBu3 [II]
N
N 60%
O
O
[I] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , Ag2CO3, HCOONa, MeCN, 60 °C, 15h. [II] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , MeCN, 5−25 °C, 2−6 h.
Scheme 12
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
1261
X
X Het
Het
Figure 2
I
[I]
N
N Ph Ph O 60%
O +
N I
SnBu3 [II]
N Bn Bn O 63%
O NC + NaCH(CN)2 [III]
N I
NC N Bn
Bn O 60%
O
[I] = 10 mol % Pd(OAc)2, 20 mol % PPh3, K2CO3, Et4NCl, MeCN, 80 °C, 2.5 h. [II] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , MeCN, 80 °C, 1 h. [III] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , MeCN, 80 °C.
Scheme 13 O HO HO N
O
Br
O N
[I]
N N
O
O
O [I] = cat. Pd(OAc)2, AcOK, n-Bu4NBr, DMF, 90 °C, 3 h.
59 %
Scheme 14
The mechanism of the cyclization reactions in Scheme 15 is yet unclear[30]–[32]: either an unusual 5-endo-trig carbopalladation takes place as key step or a cyclopalladation[33] followed by reductive elimination. More typical examples of the latter type of process are discussed in Sect. D. Whatever the mechanism, the yields achieved are good to excellent in every case. Moreover, this type of starting material is easy to build up, even in situ from aniline derivatives and suitable carbonyl compounds (Scheme 16).[34]
1262
1V Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Br
CO2Et
CO2Et
[I]
N
N H
H 80% CO2Et
Br
CO2Et
N H
CO2Et
[II]
CO2Et N H 88%
O
O
MeO
Br
MeO
N
CO2Et
CO2Et
MeO
[III]
N
MeO O
O
97% [I] = 5 mol % Pd(OAc)2, 15 mol % P( o-Tol) , Et3 N, MeCN, 100 °C, 20 h. [II] = 5 mol % Pd(OAc)2, Et3N, DMF, 120 °C, 3 h. [III] = 6.8 mol % Pd(OAc)2, Et3N, MeCN, r.t., 2 h.
Scheme 15
Me Me
I + NH2
O
[I]
H
Me Me N H
H
79%
[I] = 5 mol % Pd(OAc)2, DABCO, DMF, 105 °C, 3 h.
Scheme 16
Compared to Figure 1, the substructures of Figure 3 have side chains elongated by one carbon atom. Heck-type cyclization of substrates that match these substructures should lead to six-membered heterocycles because the intramolecular carbopalladation in the sense of a 6-exo-trig reaction should clearly be favored against the 7-endo-trig pathway. The cyclization of the benzyl bromide in Scheme 17 results in a tetrahydroquinoline derivative: variations of the final product are possible by the interaction with additional reagents such as sodium formate and sodium tetraphenylborate.[35]
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
1263
X X
X Het
Het
Het Figure 3
[I]
N Ac 54% N Br
Ph
Ac [II]
N Ac 69% [I] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , HCOONa, MeCN, 80 °C, 4−6 h. [II] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , NaBPh4, anisole, 90 °C, 9 h.
Scheme 17
The homoallyl-substituted substrates of Scheme 18 give benzopyrans and benzoquinolines, respectively.[36] The initially exocyclic double bond of the product tends to migrate into the ring, presumably by readdition of the intermediary hydridopalladium halide and subsequent -H-elimination. In addition, for the N-heterocycle aromatization by dehydrogenation is observed. Similarly the 2-iodobenzylamine with the N-allyl substituent leads to the aromatized isoquinoline.[2] The fourth example of Scheme 18 illustrates that a silyl substituent influences the regioselectivity of the -H-elimination and that an acyl group at the nitrogen has some share in preventing aromatization.[37],[38] Various functional groups are tolerated and especially electron-withdrawing groups on the aryl halide appear to have a beneficial effect on the yields achieved (Scheme 19).[39],[40] Also, multiple annulated ring systems and spirocycles, which are related to drugs and natural products, are efficiently accessible by this methodology (Schemes 20a and 20b).[41]–[43] Similarly, oligocycles are obtained from appropriate allyl benzyl ethers as outlined with representative examples in Scheme 21.[44] Stereochemical aspects of Pd-catalyzed cyclizations in connection with the synthesis of pancratistatin and related natural products have been studied intensively (second reation in Scheme 21).[45],[46] In the presence of an appropriate additional double bond, -allylpalladium complexes are formed stereoselectively as intermediates, which subsequently undergo nucleophilic substitution, for instance, by a malonate (Scheme 22).[47]
1264
1V Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Br [I]
+
O
O 47%
O 28%
I [II]
N H
N 55% [II]
I N
N H
39%
SiMe3 [III]
I N
N
COCF3
COCF 3
81% [I] = 1−2 mol % Pd (OAc)2, 2−4 mol % P(o-Tol)2, Et3N, DMF, 100 °C, 2 d. [II] = 2 mol % Pd (OAc)2, Na2CO3 or NaOAc, n-Bu4NCl, DMF, 80 °C, 1 d. [III] = 5 mol % Pd (OAc)2, 10 mol % PPh3 , KOAc, Pr4NBr, DMF, 55 °C, 3 h.
Scheme 18 NO2
NO2 Br
[I]
N
N
Ac
Ac
95% (mixture of double bond isomers) MeO
MeO
Cl
O
[II]
Cl O CO OC CO
MeO
MeO
Cr
OC
Cr
Cl
CO CO
55% (mixture with decomplexed product) [I] = cat. Pd(OAc)2, P(o-Tol)3, Et3N, 100 °C, 5 min. [II] = cat. Pd(OAc)2, PPh3, Et3N, DMF, 80 °C, 1 d.
Scheme 19
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
I
O
O
[I]
O
O 58%
Br [II]
N Ac
N H
N Ac N H 77% (mixture of double bond isomers) Scheme 20a
Br
MeO O
O
MeO N H
O
[III]
O
O
O
N H
77% (mixture of double bond isomers) [I] = 50 mol % Pd(OAc)2, PPh3, Et3N, MeCN, 70 °C, 12 h. [II] = 5 mol % Pd(OAc)2, 10 mol % PPh3 , Et3N, MeCN, 80 °C, 3 d. [III] = 10 mol % Pd2(dba)3, 20 mol % P( o-Tol)3, i-Pr2NEt, BSA / DMF 1:30, 70 °C, 1 h.
Scheme 20b PhO2S
PhO 2S
I
[I]
O O
O
O O
O 97%
O
O OBn
OBn
I O O
OBn
[II]
O
O
OBn O
O 70%
[I] = 5 mol % Pd (PPh3)4, Et3N, AgNO3, MeCN, reflux, 3.5 h. [II] = cat. Pd(OAc)2, PPh3, Et3N, AgNO3, MeCN, reflux.
Scheme 21
1265
1266
1V Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
CO2 Et
EtO2C I
CO2 Et
+
[I]
CO2 Et
O
[I] = 10 mol % Pd (dba)2, Na2CO3, Et4 NCl, DMSO, 100 °C, 4 h.
O 72%
Scheme 22
In the first example of Scheme 23a the position of the double bond in the tetrahydropyridine moiety enables the formation of a bridged ring system with the nitrogen in a bridgehead position.[48] In principle, there is no limit for the structural complexity of heterocyclic products built up by intramolecular Heck-type reactions, as illustrated by the synthesis of chiral highly functionalized bridged systems in Scheme 23b.[49],[50]
I
[I]
N
N O 88%
O Br
CO2 Et
CO2 Et [II]
O
O O 73% [I] = 10 mol % Pd(OAc)2, Et4 NCl, MeCN, 30−80 °C. [II] = cat. Pd(PPh3)4, Et3N, MeCN, 140 °C, 73 h; sealed tube.
O
Scheme 23a
OMe
OMe OMe O
I MeO2C
N
OMe
[III]
O
MeO 2C
O
N
O
O O
91% [III] = 20 mol % Pd(PPh3)4, Et3N, MeCN, 80 °C, 10 h, sealed tube.
Scheme 23b
Two examples for the formation of spirocyclic structures are presented in Scheme 24. The first one is a key step in the enantioselective total synthesis of the alkaloid ()tazettine.[51] The second is the result of a domino process with two subsequent carbopalladation steps[52]; numerous examples of this type of domino process are found in the literature and are discussed in other sections of this compendium. Substrates that match the substructures shown in Figure 4 are anticipated to lead to sevenmembered heterocycles since the 7-exo-trig cyclization should generally be favored.
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
X
X
X
1267
Het
Het
Het
Figure 4 CO2 Me
O
I
O
[I]
O
O
O
O
O
O
HN
CO2 Me
N O
O
H
73%
O
O
I
[II]
O
O 60%
[I] = 10 mol % Pd (OAc)2, 40 mol % PPh3 , Ag2CO3, THF, 56 °C. [II] = 15 mol % Pd (OAc)2, Et3N, n-Bu4 NCl, DMF, 75 °C.
Scheme 24
This is indeed the case for the first two olefinic examples in Scheme 25a.[53],[54] In analogy, related alkynes cyclize exclusively in the sense of a 7-exo-dig reaction (Scheme 25b).[25],[55] Surprisingly, the very similar allene in Scheme 26 reacts in an endo fashion resulting in an eight-membered heterocycle.[56]
MeO
I
[I]
NCOCF 3
MeO NCOCF3
MeO
MeO 92% OMe OMe
OMe Br
[II]
O
O O 75%
O
O O 6%
[I] = 1 mol % Pd(OAc)2, PPh3, KOAc, n-Pr4NBr, DMF, 80 °C, 12 h. [II] = 50 mol % PdCl2 (PPh3)2 in several portions, NaOAc, MeCN, 90 °C, 2 d.
Scheme 25a
1268
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
[III]
I O 62%
O CO2 Me
N
CO2 CH3 OH
[IV]
Br
N OH
O 60% [III] = 10 mol % Pd(OAc)2, PPh3, piperidine, HCOOH, Et4NCl, MeCN, 80 °C, 16 h. [IV] = cat. Pd(OAc)2, P(o-Tol)3, piperidine, HCOOH, MeCN. O
Scheme 25b
[I]
I O
O 52%
[I] = 5 mol % PdCl2(PPh3)2, K2CO3, EtOH, DMF, 100 °C, 2 h.
Scheme 26
In the spirocyclic starting material of Scheme 27 one can identify the third substructure of Figure 4. The Pd-catalyzed 7-exo-trig cyclization was the key step in the synthesis of cephalotoxine.[57] The examples in Scheme 28 further demonstrate the feasibility of the construction of medium-sized heterocycles. In these cases the endo-type cyclization is favored both by steric and by electronic factors.[58],[59]
O O
H
Br
[I]
O N
N
O 81%
[I] = 4 mol % Pd(OAc)2 / P(o-Tol)3 cyclometallated complex, n-Bu4NOAc, MeCN/DMF/H2O, 110–120 °C.
Scheme 27
The starting materials discussed above were limited to aryl halides (with the exception in Scheme 17). Nevertheless, a broad variety of alkenyl halides are also suitable for the construction of heterocycles by Heck-type cyclizations. Some typical substructures, which can be identified as part of suitable substrates, are depicted in Figures 5 and 6.
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
X
X
X
Het
Het
Het
1269
Figure 5
X
X Het
Het
Figure 6
CO2 Et I
EtO2C
N
N
OMe
OMe
[I]
OMe
OMe N CO2 Me Me
N
CO2 Me Me 89% CO2 Me N
Br
Boc
[II]
N
CO2 Me
Boc [I] = 6 mol % Pd(OAc)2, KOAc, n-Bu4NCl, DMF, 80 °C, 6 h. [II] = 5 mol % Pd(OAc)2, NaOAc, Ph4PCl, DMF, 120 °C, 30 min.
69%
Scheme 28
For the reaction in Scheme 29 one can assume that the resulting double annelation starting from the dihydronaphthalene derivative should not differ from the one that would be achieved with the corresponding aromatic naphthalene.[60]
[I]
Br NSO2 Ph
NSO2 Ph
50% [I] = 10 mol % Pd(OAc)2, 20 mol % PPh3 , AcOK, anisole, 140−150 °C, 18 h.
Scheme 29
1270
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
However, in the case of the alkenyl bromides in Scheme 30 the vinyl group is crucial for the resulting domino processes.[36],[61] In the first example, the initial carbopalladation leads to an allylpalladium complex, which is prone to react with the nucleophilic piperidine. The second example is explained by an unusual threefold carbopalladation, which becomes possible, because after each of the first two carbopalladation steps the -Helimination, normally terminating the process, is inhibited of structural reasons. N
Br [I]
O
O 60%
[II]
Br
O 62% [I] =1−2 mol % Pd(OAc)2, 2−4 mol % P(o-Tol)3, piperidine, MeCN, 100 °C. [II] = 3−5 mol % Pd(PPh3)4, Ag2CO3, MeCN, reflux, 3 d. O
Scheme 30
The starting material in Scheme 31 matches the third substructure of Figure 5. This reaction is an impressive attempt to accomplish strychnos alkaloid synthesis by Hecktype reactions.[62] Also interesting for alkaloid syntheses are substrates with substructures as those in Figure 6: Schemes 32a and 32b demonstrate the synthesis of the indolizidine nucleus even in an enantioselective fashion.[63],[64]
N
N
I [I]
N CO2 Me [I] = 5 mol % Pd(OAc)2, K2CO3, n-Bu4 NCl, DMF, 60 °C.
N CO2 Me 84%
Scheme 31 L*-Pd cat. [I]
I N
H N
O
OH PPh2 PPh2 (R)-(S)-BPPFOH
L*:
Fe
O 94% (86% ee) [I] = Pd2 (dba)3 (4 mol % Pd), 9.6 mol % (R)-(S )-BPPFOH, Ag-exchanged zeolite, CaCO3 , DMSO/ DMF, 0 °C.
Scheme 32a
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
Br
Br
1271
Br
[II]
N
N
O
O 61%
[II] = 2 mol % Pd(OAc)2, 4 mol % PPh3 , HCOONH4 or NH4 OAc, MeCN, reflux. Scheme 32b
In principle, the macrocyclization in Scheme 33 is catalytic in palladium. However, applying 1 equiv of the catalyst was one of the factors minimizing the competing intermolecular reaction and ensuring a rather high yield of the 16-membered lactone.[65] O O I
[I]
O
O Me
O
Me
O 55%
[I] = 1 equiv PdCl2(MeCN)2, HCOOH, Et3N, MeCN, 25 °C. Scheme 33
Although chloro- and bromomethyl substituents at a heteroatom represent sensitive functional groups, which tend to decompose under various conditions, the reactions in Scheme 34 demonstrate that substrates of this kind are nevertheless suitable for Hecktype cyclizations[66],[67]: for the first example an intermediary alkenylpalladium species is assumed, which is trapped with an allylstannane, a reaction that has some precedent (e.g., Schemes 12 and 13). From a mechanistic point of view the net trans-addition to the alkyne is remarkable. On the other hand, the trapping of an alkylpalladium species with iodide anions as in the second reaction is also highly unusual.
Br
[I]
+
O
SnBu3
O
62% I
BnO2C
Cl
[II]
BnO2C
N
N
O
O
[I] = 4 mol % Pd(PPh3)4. [II] = 15 mol % Pd(PPh3)4, i-Pr2NEt, n-Bu4NI, dioxane.
Scheme 34
34%
1272
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
In all of the examples discussed so far, the heterocycle is directly formed in the carbopalladation step. In the following special examples the carbopalladation step provides a Pd functionality, which subsequently undergoes a heterocyclization.[68],[69] The first example of Scheme 35 is best explained by the formation of an alkenylpalladium species by intramolecular carbopalladation of the alkyne followed by a cyclopalladation with the neighboring hydroxyl group, finally allowing reductive elimination to form the C—O bond. As a mechanistic alternative the complexation of the alkyne by the electrophilic arylpalladium iodide activates for the nucleophilic attack by the heterofunction (Wacker-type cyclization). In the second example the carbopalladation gives rise to an allylpalladium complex, which reacts intramolecularly with the nucleophilic phenolate. In any case, highly complex polycyclic compounds important for natural product synthesis are built up in a few steps. O O
OMe
OMe I
[I]
Si(i-Pr3)
Si(i-Pr)3
O
OH OMe
MeO 2C
OMe
O
O 72% MeO2C
N H
N H I
[II]
OH
O
OMe
OMe
56% [I] = 28 mol % Pd2(dba)3, K2CO3, DMF, ambient temperature. [II] = 20 mol % Pd(OCOCF3)2(PPh3)2, 1,2,2,6,6-pentamethylpiperidine, toluene, 120 °C, 10 h.
Scheme 35
C. HETEROCYCLE FORMATION INITIATED BY INTERMOLECULAR CARBOPALLADATION Two types of reactions are summarized in this section: (i) the intermolecular carbopalladation leads to a Pd functionality such as alkyl-, alkenyl-, or allylpalladium complexes, which is intramolecularly trapped by a heteroatom (again Wacker-type processes are mechanistic alternatives); (ii) the palladium catalyst is not directly involved in the heterocyclization step, but the carbopalladation builds up a suitable functionality or changes bond angles so that the heterocyclization can take place. The first type is the intermolecular variant of the reactions in Scheme 35 and has recently been thoroughly reviewed.[70] Alkenes, allenes, dienes, and alkynes are suitable unsaturated coupling components for the carbopalladation. In Scheme 36 two examples of electron-rich alkenes are presented.[70] In Scheme 37 carbon monoxide takes part as a third component in the coupling process resulting in a lactone formation.[71]
1273
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
The reactions in Scheme 38 with allenes as coupling components proceed regioselectively with C—C bond formation at the central carbon and carbon–heteroatom bond formation at the more highly substituted terminal carbon atom.[72],[73] Reactions of this type have recently been performed enantioselectively.[74] Remarkably, for the macrocyclization in Scheme 39 the carbon–heteroatom bond formation takes place at the unsubstituted terminal carbon atom.[75]
O I
O
0
cat. Pd
+
O N
O
NHMs
O
O
O
I
MS 74% O
0
cat. Pd
+
OMe
OMe
OH
O 53%
Scheme 36
I
[I]
+ O 90%
OH
O
[I] = 15 mol % Pd(PPh3)4, K2 CO3, 1 atm CO, anisole, 80 °C, 4 h. Scheme 37
Br I
OMe
[I]
+
OH O
OMe
OH
O
56% O [II]
O O 53%
+
O I + OH
[III]
C8 H17
C8 H17
O 71%
[I] = 5 mol % Pd(OAc)2, 5 mol % PPh3, Na2 CO3, n-Bu4NCl, DMF, 40 °C, 20 h. [II] = 5 mol % Pd(OAc)2, 5 mol % PPh3 , Na2 CO3, n-Bu4NCl, DMF, 25 °C, 3 d. [III] = 5 mol % Pd(OAc)2, 5 mol % PPh3, K2CO3, n-Bu4NCl, DMF, 100 °C, 1 d.
Scheme 38
1274
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Ph I
N
[I]
+
Ts
Ph
NHTs
83% [I] = 5 mol % Pd2(dba)3, 5 mol % PPh3, Na2CO3, n-Bu4NCl, DMA, 100 °C, 3 d. Scheme 39
The carbopalladation of 1,3-dienes as well as of vinylcyclopropanes (Scheme 40)[76],[77] leads to allylpalladium complexes, which are of course suitable for a subsequent heterocyclization (in comparison see second reaction in Scheme 35). Cyclic dienes and 1,4-dienes react in the same way as proved by the synthesis of a tetrahydrocarbazole and a tetrahydroquinoline in Scheme 41.[78],[79] Representative for the numerous examples of analogous coupling reactions with alkynes as coupling components[80]–[83] are the syntheses of multiple functionalized nitrogen hetarenes shown in Scheme 42.[84]–[86] In order to avoid Sonogashira-type coupling reactions, the alkynes applied in this type of reaction have to be disubstituted; the I [I] OH
n-C4H9
O 75%
n-C4H9 [I]
n-C4H9
I
O OH 56% O
O I
[I]
+ OH
83%
I +
O tremetone (main isomer)
[I]
O
OH
70% [I] = 5 mol % Pd(OAc)2, PPh3, NaOAc or KOAc, n-Bu4 NCl, DMF, 80−100 °C, 1−3 d.
Scheme 40
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
1275
trimethylsilyl group at the alkyne in the first reaction of Scheme 42 therefore has to be understood as a protecting group. Similarly, an elegant synthesis of tryptophane was achieved starting from 2-iodoaniline and a silylalkynyl-functionalized amino acid.[87] In the second reaction of Scheme 42 a tert-butyl-substituted imine illustrates the broad variability of the coupling components. In this case the tert-butyl group is eliminated as isobutene during the heterocyclization.[86]
OAc I
OAc
[I]
+ N Ts 75%
NHTs
I
[II]
+
N H 70%
NH2 [I] = 5 mol % Pd(OAc)2, NaHCO3, n-Bu4NCl, DMF, 60 °C, 2 d. [II] = 5 mol % Pd(OAc)2, K2CO3, n-Bu4NCl, DMF, 100 °C, 1.5 d. Scheme 41
OH I
N
[I]
+ NH2
N
OH N
SiMe3 N H
N
SiMe3
51% OH OH Ph
I
[II]
+ N
Ph
Ph N
t-Bu
95%
Ph
[I] = 5 mol % Pd(OAc)2, PPh3, Et3N, n-Bu4 NCl, DMF, 90−100 °C, 19 h. [II] = 5 mol % Pd(OAc)2, PPh3, Na2CO3, n-Bu4NCl, DMF, 100 °C, 2 h.
Scheme 42
In the examples discussed so far, the halide and the heterofunction were part of the same coupling component. In contrast, for the reactions in Scheme 43 the heterofunction is located as a neighboring group of the alkene moiety where the carbopalladation takes place.[88]–[92] The reductive carbopalladation of the alkynyl-substituted steroid in Scheme 44 changes the hybridization of two carbon atoms from sp to sp2 and therefore bond angles from 180° to 120°, bringing the hydroxyl and the ester group into close proximity with each other as a prerequisite for the lactonization.[93]
1276
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
I
[I]
+
NH Bn
N Bn 76%
N Ts
H
+
[II]
I
N Ts 67% O
O
I
[III]
+
O
Ph
O
68% [I] = 2−5 mol % Pd(PPh3)4 , K2CO3, DMF, 70 °C, 1−3 h. [II] = 5 mol % Pd(OAc)2 , Na2CO3, n-Bu4NCl, DMF, 100 °C, 6 h. [III] = 5 mol % Pd(OAc)2, Na2CO3, n-Bu4NCl, DMF, 80 °C, 2 h. Scheme 43
OH
CO2 Me
+
R
MeO
I [I]
O
R
O
R = 3-fluoro: 84% 2-methoxy: 67% 4-methoxy: 93%
MeO
[I] = 5 mol % Pd(OAc)2(P(o-Tol)3)2, n-Bu3N, HCOOH, DMF, 60 °C, 6−9 h.
Scheme 44
Ph
1277
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
The construction of the benzopyran in Scheme 45 is easily understood as a domino process consisting of a Heck reaction followed by a cyclocondensation with the allylic tertiary alcohol.[94] Similarly, Heck reactions with allylic and homoallylic alcohols in Scheme 46 lead to intermediary carbonyl compounds, which subsequently undergo heterocyclization either by formation of a hemiacetal (first example) or by cyclocondensation (second example).[95],[96] In both cases the palladium catalyst is not involved in the heterocyclization step.
OMe
OMe I
OH
+ OHC
[I]
OH
OHC
O 95%
[I] = 2 mol % Pd(OAc)2, Na2CO3, DMF, 120 °C, 3 h. Scheme 45
MeO
OH
MeO
[I]
+
O
I OH
I OH
+
89%
OH
[II]
N
NH2 O
O 43%
[I] = 10 mol % Pd(OAc)2, K2CO3, BnEt3NBr, DMF, 90 °C, 10 h. [II] = 5 mol % Pd(OAc)2, K2CO3, i-Pr2NEt, LiCl, DMF, 120 °C, 2 d. Scheme 46
D. HETEROCYCLES BY CYCLOPALLADATION AS KEY STEP Intramolecular Pd-catalyzed aryl–aryl coupling reactions under dehydrohalogenation are assumed to proceed via palladacycles as illustrated by the example in Scheme 47.[33],[97] Several mechanistic pathways may explain the cyclopalladation step including the C,H-activation; however, a reaction of an electrophilic arylpalladium bromide with the electron-rich phenolate in the sense of an electrophilic aromatic substitution is certainly a plausible explanation. C—C bond formation finally takes place by reductive elimination.
1278
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
This type of aryl–aryl coupling reaction is equally possible on hetarenes such as indoles and imidazoles (Scheme 48a)[98],[99] and has been applied as a key step in natural product synthesis (Scheme 48b).[100] The substituted dibenzopyran in Scheme 49 is obviously formed from 3 equiv of starting material by a Pd-catalyzed coupling process involving C,H-activation at a sp3-hybridized OH
OH [I]
Br
O
O
87% − P d0
+ Pd0 − HBr
Pd
OH
O [I] = 20 mol % Pd(PPh3)4, KOt-Bu, DMA, 95 °C, 2 d.
Scheme 47
N
N
N
N [I]
O
N
O
N
Br 83% [I] = 10 mol % Pd(OAc)2, NaHCO3, n-Bu4NCl, DMA, 150 °C, 1 d. Scheme 48a MeO
OMe
MeO
OMe Br
[II]
O
O
O
O
N
N Bn
Bn 75% [II] = cat. PdCl2(PPh3)2, AcONa, DMA, 130 °C.
Scheme 48b
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
1279
center. Five-membered oxapalladacycles are key intermediates in this process.[101] They can add aryl halides either directly to give PdIV intermediates or by ligand exchange with arylpalladium halides. A number of structural variations of the starting material was studied (Scheme 50), opening up an easy access to various oxygen-containing heterocycles.[102] Especially, when neighboring groups are involved, which either block crucial positions or can react with PdII functions, the domino process takes a short-cut and stops after the coupling of 2 equiv of the starting material (Scheme 50). Based on this type of domino process with intermediary oxapalladacycles also crosscoupling reactions with vinyl bromides are possible as exemplified in Scheme 51.[103]
O I [I]
3
O
O
O + Pd 0
64%
−HI
O [I] = 4 mol % Pd(OAc)2, K2CO3, n-Bu4NBr, DMF, 100 °C, 3 d. Scheme 49
OCH3 I [I]
2
O H3CO
OCH3 OCH3
H3CO I
87% OCH3
[I]
2
OCH3 O 71%
[I] = 4 mol % Pd(OAc)2, K2CO3, n-Bu4NBr, DMF, 100 °C, 3 d.
Scheme 50
1280
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
I [I]
+
OMe OMe
+
Br
O
O
OMe OMe 27% 55% [I] = 10 mol % Pd(OAc)2, K2CO3, n-Bu4NBr, DMF, 100 °C, 3 d. excess
Scheme 51
E. CONCLUSION The synthesis of heterocycles making use of Heck-type reactions is obviously a growing field of current research, which takes advantage both of the broad applicability of palladium catalysis and of the outstanding importance of heterocycles. Palladium catalysis is even more useful for heterocyclic chemistry when taking into account that the Pd-catalyzed derivatization of heterocycles is not included in this overview.
REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
R. Odle, B. Blevins, M. Ratcliff, and L. S. Hegedus, J. Org. Chem., 1980, 45, 2709. R. C. Larock and S. Babu, Tetrahedron Lett., 1987, 28, 5291. R. C. Larock and D. E. Stinn, Tetrahedron Lett., 1988, 29, 4687. N. Arnau, M. Moreno-Manas, and R. Pleixats, Tetrahedron, 1993, 49, 11019. L. F. Tietze and W. Buhr, Angew. Chem. Int. Ed. Engl., 1995, 34, 1366. M. Mori, K. Chiba, and Y. Ban, Tetrahedron Lett., 1977, 1037. K. M. Aubart and C. H. Heathcock, J. Org. Chem., 1999, 64, 16. J. E. Macor, D. H. Blank, R. J. Post, and K. Ryan, Tetrahedron Lett., 1992, 33, 8011. L. S. Hegedus, T. A. Mulhern, and A. Mori, J. Org. Chem., 1985, 50, 4282. I. St. C. Black, P. A. Keller, and N. Kumar, Tetrahedron, 1992, 48, 7601. M. O. Terpko and R. F. Heck, J. Am. Chem. Soc., 1979, 101, 5281. M. Shibasaki and E. M. Vogl, J. Organomet. Chem., 1999, 576, 1. S. E. Gibson and R. J. Middleton, Contemp. Org. Synth., 1996, 3, 447. T. Matsuura, L. E. Overman, and D. J. Poon, J. Am. Chem. Soc., 1998, 120, 6500. A. Ashimori and L. E. Overman, J. Org. Chem., 1992, 57, 4571. R. C. Larock and N. H. Lee, J. Org. Chem., 1991, 56, 6253. S. Wolff and H. M. R. Hoffmann, Synthesis, 1988, 760. B. Schmidt and H. M. R. Hoffmann, Tetrahedron, 1991, 47, 9357. R. Grigg, P. Fretwell, C. Meerholtz, and V. Sridharan, Tetrahedron, 1994, 50, 359. R. Grigg, M. J. Dorrity, J. F. Malone, V. Sridharan, and S. Sukirthalingam, Tetrahedron Lett., 1990, 31, 1343. R. Grigg and V. Sridharan, Tetrahedron Lett., 1993, 34, 7471. R. Grigg and V. Sridharan, J. Organomet. Chem., 1999, 576, 65. R. Grigg, J. P. Major, F. M. Martin, and M. Whittaker, Tetrahedron Lett., 1999, 40, 7709. R. Grigg, V. Sridharan, and J. Zhang, Tetrahedron Lett., 1999, 40, 8277.
IV.2.2.2 SYNTHESIS OF HETEROCYCLES
[25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63]
1281
R. Grigg, V. Loganathan, V. Sridharan, P. Stevenson, S. Sukirthalingam, and T. Worakun, Tetrahedron, 1996, 52, 11479. B. Burns, R. Grigg, P. Ratananukul, V. Sridharan, P. Stevenson, S. Sukirthalingam, and T. Worakun, Tetrahedron Lett., 1988, 29, 5565. R. Grigg, V. Sridharan, P. Stevenson, and S. Sukirthalingam, Tetrahedron, 1989, 45, 3557. R. Grigg, V. Sridharan, S. Sukirthalingam, and T. Worakun, Tetrahedron Lett., 1989, 30, 1139. D. L. Comins, M. F. Baevsky, and H. Hong, J. Am. Chem. Soc., 1992, 114, 10971. A. Kasahara, T. Izumi, S. Murakami, H. Yanai, and M. Takatori, Bull. Chem. Soc. Jpn., 1986, 59, 927. T. Sakamoto, T. Nagano, Y. Kondo, and H. Yamanaka, Synthesis, 1990, 215. J. R. Luly and H. Rapoport, J. Org. Chem., 1984, 49, 1671. G. Dyker, Chem. Ber./Recueil, 1997, 130, 1567. C. Chen, D. R. Lieberman, R. D. Larsen, T. R. Verhoeven, and P. J. Reider, J. Org. Chem., 1997, 62, 2676. R. Grigg, S. Sukirthalingam, and V. Sridharan, Tetrahedron Lett., 1991, 32, 2545. L. Shi, C. K. Narula, K. J. Mak, L. Kao, Y. Xu, and R. F. Heck, J. Org. Chem., 1983, 48, 3894. L. F. Tietze and R. Schimpf, Angew. Chem. Int. Ed. Engl., 1994, 33, 1089. L. F. Tietze and R. Schimpf, Chem. Ber., 1994, 127, 2235. B. C. Söderberg, S. R. Rector, and S. N. O’Neil, Tetrahedron Lett., 1999, 40, 3657. S. Bräse, Tetrahedron Lett., 1999, 40, 6757. S. A. Ahmad-Junan, P. C. Amos, and D. A. Whiting, J. Chem. Soc. Perkin Trans., 1, 1992, 539. J. Cossy, C. Poitevin, D. Gomez Pardo, J.-L. Peglion, and A. Dessinges, J. Org. Chem., 1998, 63, 4554. T. Okita and M. Isobe, Tetrahedron, 1994, 50, 11143. Z. Jin and P. L. Fuchs, Tetrahedron Lett., 1993, 34, 5205. L. M. Grubb, A. L. Dowdy, H. S. Blanchette, G. K. Friestad, and B. P. Branchaud, Tetrahedron Lett., 1999, 40, 2691. N. Chida, M. Ohtsuka, and S. Ogawa, J. Org. Chem., 1993, 58, 4441. R. C. Larock and X. Han, J. Org. Chem., 1999, 64, 1875. R. Grigg, V. Sridharan, P. Stevenson, and T. Worakun, J. Chem. Soc. Chem. Commun., 1986, 1697. B. Wünsch, H. Diekmann, and G. Höfner, Tetrahedron: Asymmetry, 1995, 6, 1527. K. F. McClure, S. J. Danishefsky, and G. K. Schulte, J. Org. Chem., 1994, 59, 356. M. M. Abelman, L. E. Overman, and V. D. Tran, J. Am. Chem. Soc., 1990, 112, 6959. S. D. Knight and L. E. Overman, Heterocycles, 1994, 39, 497. L. F. Tietze and R. Schimpf, Synthesis, 1993, 876. M.-P. Denieul and T. Skrydstrup, Tetrahedron Lett., 1999, 40, 4901. H. Finch, N. A. Pegg, and B. Evans, Tetrahedron Lett., 1993, 34, 8353. S. Ma and E. Negishi, J. Am. Chem. Soc., 1995, 117, 6345. L. F. Tietze and H. Schirok, J. Am. Chem. Soc., 1999, 121, 10264. R. J. Sundberg and R. J. Cherney, J. Org. Chem., 1990, 55, 6028. S. E. Gibson, J. O. Jones, R. McCague, M. J. Tozer, and N. J. Whitcombe, Synlett, 1999, 954. R. Grigg, V. Sridharan, and S. Sukirthanlingam, Tetrahedron Lett., 1991, 32, 3855. F. E. Meyer, P. J. Parsons, and A. de Meijere, J. Org. Chem., 1991, 56, 6487. V. H. Rawal and C. Michoud, J. Org. Chem., 1993, 58, 5583. Y. Sato, S. Nukui, M. Sodeoka, and M. Shibasaki, Tetrahedron, 1994, 50, 371.
1282 [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
H. McAlonan, D. Montgomery, and P. J. Stevenson, Tetrahedron Lett., 1996, 37, 7151. F. E. Ziegler, U. R. Chakraborty, and R. B. Weisenfeld, Tetrahedron, 1981, 37, 4035. R. K. Bhatt, S. D. Shin, J. R. Falck, and C. Mioskowski, Tetrahedron Lett., 1992, 33, 4885. M. Mori, N. Kanda, and Y. Ban, J. Chem. Soc. Chem. Commun., 1986, 1375. A. Kojima, T. Takemoto, M. Sodeoka, and M. Shibasaki, J. Org. Chem., 1996, 61, 4876. C. Y. Hong and L. E. Overman, Tetrahedron Lett., 1994, 35, 3453. R. C. Larock, J. Organomet. Chem., 1999, 576, 111. Z. W. An, M. Catellani, and G. P. Chiusoli, J. Organomet. Chem., 1989, 371, C51. R. C. Larock, Y. He, W. W. Leong, X. Han, M. D. Refvik, and J. M. Zenner, J. Org. Chem., 1998, 63, 2154. R. C. Larock, N. G. Berrios-Pena, and C. A. Fried, J. Org. Chem., 1991, 56, 2615. J. M. Zenner and R. C. Larock, J. Org. Chem., 1999, 64, 7314. R. C. Larock, C. Tu, and P. Pace, J. Org. Chem., 1998, 63, 6859. R. C. Larock, N. G. Berrios-Pena, and K. Narayanan, J. Org. Chem., 1990, 55, 3447. R. C. Larock and E. K. Yum, Tetrahedron, 1996, 52, 2743. R. C. Larock and L. Guo, Synlett, 1995, 465. R. C. Larock, N. G. Berrios-Pena, C. A. Fried, E. K. Yum, C. Tu, and W. Leong, J. Org. Chem., 1993, 58, 4509. R. C. Larock, M. J. Doty, and X. Han, Tetrahedron Lett., 1998, 39, 5143. R. C. Larock, E. K. Yum, M. J. Doty, and K. K. C. Sham, J. Org. Chem., 1995, 60, 3270. R. C. Larock, X. Han, and M. J. Doty, Tetrahedron Lett., 1998, 39, 5713. N. Beydoun and M. Pfeffer, Synthesis, 1990, 729. D. Wensbo, A. Eriksson, T. Jeschke, U. Annby, and S. Gronowitz, Tetrahedron Lett., 1993, 34, 2823. F. Ujjainwalla and D. Warner, Tetrahedron Lett., 1998, 39, 5355. K. R. Roesch and R. C. Larock, J. Org. Chem., 1998, 63, 5306. T. Jeschke, D. Wensbo, U. Annby, S. Gronowitz, and L. S. Cohen, Tetrahedron Lett., 1993, 34, 6471. I. W. Davies, D. I. C. Scopes, and T. Gallagher, Synlett, 1993, 85. R. C. Larock, P. Pace, H. Yang, C. E. Russel, S. Cacchi, and G. Fabrizi, Tetrahedron, 1998, 54, 9961. S. Cacchi, G. Fabrizi, R. C. Larock, P. Pace, and V. Reddy, Synlett, 1998, 888. S.-K. Kang, T.-G. Baik, and A. N. Kulak, Synlett, 1999, 324. S.-K. Kang, T.-G. Baik, and Y. Hur, Tetrahedron, 1999, 55, 6863. A. Arcadi, B. Bernocchi, A. Burini, S. Cacchi, F. Marinelli, and B. Pietroni, Tetrahedron, 1988, 44, 481. X. Garcias, P. Ballester, and J. M. Saa, Tetrahedron Lett., 1991, 32, 7739. T. Mandai, S. Hasegawa, T. Fujimoto, M. Kawada, and J. Tsuji, Synlett, 1990, 85. G. Dyker and H. Markwitz, Synthesis, 1998, 1750. D. D. Hennings, S. Iwasa, and V. H. Rawal, J. Org. Chem., 1997, 62, 2. T. Kuroda and F. Suzuki, Tetrahedron Lett., 1991, 32, 6915. A. P. Kozikowski and D. Ma, Tetrahedron Lett., 1991, 32, 3317. G. Bringmann, J. R. Jansen, H. Reuscher, M. Rübenacker, K. Peters, and H. G. von Schnering, Tetrahedron Lett., 1990, 31, 643. G. Dyker, Angew. Chem. Int. Ed. Engl., 1992, 31, 1023. G. Dyker, Chem. Ber., 1994, 127, 739. G. Dyker, J. Org. Chem., 1993, 58, 6426.
R1X
+
R2CH
C CH
PdL*n
R1 * CH C R2
C
IV.2.3 Asymmetric Heck Reactions MASAKATSU SHIBASAKI and FUTOSHI MIYAZAKI
A. INTRODUCTION The Pd-mediated coupling of aryl or vinyl iodides, bromides, or triflates with alkenes in the presence of a base, in other words, the Pd-catalyzed arylation or vinylation of alkenes, is generally referred to as the Heck reaction. It has been known to synthetic chemists since the late 1960s.[1]–[3] It is a great advantage that this reaction is not limited to activated alkenes. The substrate can be a simple olefin (with ethylene being the most reactive one), or it can contain a variety of functional groups, such as ester, ether, carboxyl, hydroxyl including phenolic ones, or cyano groups. Despite displaying many of the benefits usually associated with Pd-mediated reactions[4] (e.g., ease of scale-up and tolerance of water and/or other functional groups), interest in the reaction has been sporadic, largely due to problems of regiocontrol in the case of unsymmetrical alkene substrates and to an incomplete understanding of the reaction mechanism. In recent years, however, the attention paid to the reaction has increased dramatically,[5] and perhaps one of the most significant developments to date has been the advent of an enantioselective variant.[6],[7] Given the many reports of chiral phosphine ligands dating from the early 1970s,[8] it is perhaps somewhat surprising that the phosphine-mediated Heck reaction was not subjected to dissymmetrization attempts until the late 1980s. However, it can be pointed out that the reaction has not usually been used to generate stereogenic centers,[9] and that for many years chelating diphosphines in general were thought to be unsuitable catalysts.[10] First reports of successful examples of the asymmetric Heck reaction (AHR) were received in 1989, and the reaction has since been successfully developed to the point where both tertiary and quaternary centers can be generated with ee values 80%. The bulk of the reported examples involves intramolecular reactions (i.e., ring closures),[11] which have the advantage of allowing relatively easy control of alkene regiochemistry and geometry in the product and of tolerating less reactive alkene substrates. In contrast, successful intermolecular reactions have until very recently been limited to quite reactive substrates, mainly O- and N-heterocycles, and to the formation of tertiary centers on ring carbon atoms, which again simplifies the question of alkene regiochemistry (but see Sect. F). What follows is a survey of the relevant literature up to late 2000, including a discussion of the mechanistic aspects relevant for stereoselection in the AHR. The classification of the sections proceeds according to the various types of underlying carbon skeletons or natural product fragments of the resulting compounds. Diastereoselective variations,[5]
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1283
1284
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
which have frequently been utilized for the construction of natual products, are generally not included.
B. REACTION CONDITIONS The AHR is carried out under similar or identical reaction conditions generally associated with versions of the Heck reaction leading to racemic products using standard laboratory glassware. The solvents that have been used include benzene, dichloroethane, diglyme, dimethylacetamide, DMSO, THF, or even mixtures containing water. The reaction usually requires elevated temperatures (reflux, about 60–100 °C) to proceed at a reasonable rate. Generally, degassed solvents and an inert atmosphere (nitrogen or argon) are necessary to avoid decomposition of the Pd intermediates or oxidation of the phosphine ligand and the formation of other side products. Numerous bases have been applied, ranging from K2CO3 to proton sponge. The catalyst is conveniently generated in situ. Examples for palladium catalyst precursors are Pd(OAc)2 or Pd2(dba)3 CHCl3 (dba dibenzylideneacetone) among others, with usually at least about 3–10 mol % catalyst required for reasonable yields and reaction rates. The catalyst stability and the turnover numbers are relatively low compared to other catalytic processes and recovery of the catalyst is usually not practical. However, as AHRs can be employed for the construction of valuable natural products a somewhat higher catalyst cost is acceptable.
C. MECHANISTIC ASPECTS The current state of mechanistic theory regarding the Heck reaction in general has been provided in recent review articles.[5],[12] In the following, the discussion will be a selective one, focusing primarily on the factors that influence the regio- and enantiocontrol.[13],[14] C.i. Factors Governing Regioselectivity The mechanism of the Heck reaction (Scheme 1a) with bidentate phosphine ligands is generally thought to follow the four-step catalytic cycle shown in Scheme 1b, with the individual steps being: (i) oxidative addition of 1 to the Pd0 species 4, bearing a bidentate phosphine ligand, to give the PdII species 5; (ii) coordination and then syn-insertion of the alkene substrate 2 into the Pd—R1 bond of 5 to give 6; (iii) - or -hydride elimination from 6 to give either 3a or 3b; and finally; (iv) regeneration of 4 by reductive elimination of HX from 7. The three major factors governing regioselectivity are: 1. The regioselectivity of the insertion into the Pd—R1 bond heavily depends on the nature of the steric and electronic environment provided by R2, R3, and R4 for unsymmetrically substituted alkenes. This lack of selectivity, which has tended to limit the scope of the reaction somewhat, can be overcome by selecting appropriate chiral ligands and reaction conditions. 2. The problem of competing - or -hydride elimination from 6 further complicates the regioselectivity issue, to the extent that the majority of reported Heck reactions simply avoid the problem by using simple acrylate substrates (R2 CO2R,
IV.2.3 ASYMMETRIC HECK REACTIONS
R2 (a) β
*
R2 4 3b R reductive elimination
*
base HX P D
P
1
A
*
*
P
P
P
X
R1
P PdII
PdII
5
X
*
3a or 3b
7
oxidative addition
Pd0 4
base
H
R3
β′-hydride elimination product
3a R R1
R3
R4 2
1
R3 4
β′
R1 X + R2
(b)
R1
α
β-hydride elimination product
1285
C
β- or β′-hydride elimination
R1 P β
R2
P PdII
α
X
B
2 association and insertion 2 into Pd—R1
R3 R4 β′ 6
Scheme 1
monosubstituted alkene), which through their highly unsymmetrical steric and electronic environment also avoid any problems with regioselectivity in step B. While this constitues a mild and quite powerful method for the synthesis of arylacrylates, by eliminating the possibility of -hydride elimination, an opportunity to form a tertiary chiral center is lost. C can be controlled, a further problem lies in its 3. Even if the regioselectivity of step reversibility, which can result in reinsertion of the alkene 3b into the Pd—H bond in 7 either to regenerate 6 or to form a regioisomer of it with the Pd atom attached to the same carbon atom as R3 and R4. If either of these substituents contains a suitably positioned hydrogen atom, then the possibility exists of a formal shift of the double bond in the alkene from the ,- into a ,-position, a problem that is especially prone to occur for endocyclic alkene products (see Sect. D.ii). Fortunately, methods have been developed to suppress this, involving the addition of thallium[15] or silver[16],[17] salts to the reaction mixture: the latter are usually preferred owing to their lower toxicity and fortuitous double role as enhancers of enantioselectivity (vide infra). A preference for 3b rather than 3a formation is essential for the AHR to occur, and thus C an examination of the factors controlling the competing elimination processes in step
1286
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
and the consequent prerequisites for ensuring the predominance of the desired pathway is clearly apropos. As both the insertion into 5 and the elimination from 6 are syn-processes, rotation around the alkene -bond is required before -hydride elimination can occur. This might be expected to make -hydride elimination the kinetically more favorable pathway. More significantly, for endocyclic alkenes, the necessary -bond rotation is not feasible for steric reasons, making -hydride elimination the only possible course. It is primarily for this reason that all the AHRs forming tertiary centers, which have been reported (with the exception of the allylsilane reactions by Tietze and colleagues—see Sect. D.i.e), C involve endocyclic alkene substrates. Other methods to direct the selectivity of step n involve choosing suitable R groups to influence the relative thermodynamic stabilities of the possible products, the most common tactic being to make R3/R4 OH or OR, resulting in the formation of an enol (which subsequently tautomerizes to the aldehyde or ketone) or enol ether. A similar strategy commonly employed in AHRs is to choose R3/R4 alkenyl, resulting in the formation of a conjugated diene product. Either approach may be used in addition to the choice of a cyclic substrate as a way of providing an extra driving force to the reaction, and this indeed occurs in many of the published AHR examples. C.ii. Factors Governing Enantioselectivity B , assoThe key step in the catalytic cycle with regard to enantioselectivity is clearly ciation of the alkene 2 and insertion of it into the Pd—R1 bond. As with the Heck reaction itself, the mechanism for this process remains a matter for conjecture, with the overall rationale currently in favor having been proposed in 1991 by Ozawa, Kubo, and Hayashi,[18] and independently by Cabri et al.[19] (although the cationic pathway via 8 and 9 had been proposed as early as 1990 [20] ). Its development and subsequent evolution have recently been reviewed by Cabri and Candiani.[12] Two possible routes are proposed (Scheme 2a), the former (“cationic”) pathway beginning with the dissociation of X from 5 to generate the tricoordinate 14e cationic complex 8 with the accompanying counterion X . Complexation of 2 into the vacant site then gives the 16e species 9, and insertion of 2 into the Pd—R1 bond followed by reformation of the Pd—X bond gives 6 as desired, with the chiral bidentate ligand having
*
c pa atio th nic , w ay ,
*
,,
P + P PdII 1 R X−
P + P PdII 1 R
8
9
R4 R3
R2
6 X−
3b high ee
5 P
*
,,
(a)
R4
P PdII R1
X
P
*
,, l ra y ut a ne athw p
R3
P
R2
PdII R1
10
X 11
Scheme 2a
6
3b low ee
IV.2.3 ASYMMETRIC HECK REACTIONS
(b)
1287
*
P
P
Ar
P
Pd
XAr
P
+
Ar Pd
*
X
P
P
Ar
X
P
Pd
*
P
Pd
*
P
P
Ar
Pd
*
X
X− Scheme 2b
remained fully chelated throughout and so having maximized the asymmetric induction. The alternative (“neutral”) pathway starts with dissociation of one arm of the bidentate ligand resulting in the neutral species 10; association and complexation into the vacant site of 2 gives the neutral species 11, which by alkene insertion into Pd—R1 and recomplexation of the previously displaced phosphine moiety also gives 6. The nature of X in 1 (and thus the strength of the Pd—X bond in 5) is clearly an important factor; unless the reaction conditions are modified, aryl and alkenyl triflates are generally assumed to follow the cationic pathway (the Pd—OTf bond being weak [21] ) with either route being available to reactions using aryl/alkenyl halides. In practice, it has proved possible to influence which pathway will be followed in a given Heck process, either by adding silver salts to the reaction of an aryl/alkenyl halide (the halophilic Ag salt sequestering the halide from 5 and replacing it with its own anionic component [6] ), or by adding excesses of halide anions to reactions using triflates (resulting in nucleophilic displacement of the triflate anion from 5 [22] ). The nature of the alkene substrate is also important, with electronrich alkenes favoring the “cationic” pathway (and so being the most suitable for the AHR) while the “neutral” pathway makes for faster reaction with electron-poor substrates.[19] The partial dissociation of the chiral ligand during the “neutral” process would seem to make it less well suited to asymmetric induction, however, and the evidence of most of the AHRs reported so far seems to indicate that conditions which favor the “cationic” route also give the best enantiomeric excesses (ees). However, a significant exception to this rule has been found (see also Sect. E.i). Overman, Poon, and co-workers observed that for a special aryl triflate [(Z )-butenanilide triflate] the addition of halide salts to the reaction mixture resulted in a dramatic increase in ee of the intramolecular Heck reaction product.[23],[24] If, on the other hand, the corresponding aryl iodide was used as starting material, high ees could be obtained without further additives. Overman concluded that in the case of this substrate the “neutral” pathway must be the more enantioselective one. Furthermore, it was shown that, when the bidentate diphosphine ligand (R)-BINAP was substituted by potentially monodentate analog of (R)-BINAP, only low enantioselectivities were obtained for this example. This can be taken as evidence that both phosphines of the diphosphine ligand remain coordinated to the Pd center during the enantioselective step. It was also shown that enantioselectivity in this neutral pathway was unchanged in going from dry DMA to DMA containing 5% water.[24] To account for these findings mechanistically, a “refined” neutral pathway for the AHR involving a pentacoordinate intermediate without partial dissociation of the diphosphine was suggested (Scheme 2b).
1288
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
It is clear that considerations on the geometry of the palladium center during the catalytic cycle are fundamental for further developments of more detailed descriptions of the stereoinduction. Explicit three-dimensional rationalizations on how the chirality is transferred from the ligand to the substrate are not available for the AHR at present or are just beginning to emerge (see Sect. D.i.d).
D. FORMATION OF TERTIARY CARBON CENTERS D.i. Intramolecular D.i.a. Decalins. The first example of an asymmetric Heck reaction was reported in 1989 and involved the conversion of the prochiral alkenyl iodides 12a–c into the chiral decalin systems 13a–c, as shown in Scheme 3.[25] The reaction conditions (dipolar aprotic solvent and presence of silver salts), while similar to those of a previously reported nonenantioselective method,[16] differ crucially in respect of the choice of the chiral ligand and of solvent—very low or negligible ees were obtained using THF, MeCN, or DMSO, with the preferred solvent being N-methyl-2-pyrrolidinone (NMP). Similarly, the widely used chiral phosphine ligands 1-t-butoxycarbonyl-4-diphenylphosphino-2(diphenylphosphinomethyl)azolidine (BPPM) and N,N-dimethyl-1-[1,2-bis (diphenylphosphino)ferrocenyl]ethylamine (BPPFA) failed to give significant asymmetric inductions, with (R)-BINAP proving to be the ligand of choice, a pattern that has been repeated in most (though not all—see Sect. D.i.c) of the reported examples of the AHR. By using a prochiral substrate, two stereocenters can be set in one step, a tactic that is used repeatedly in the tertiary center-generating AHRs reported by the Shibasaki group.
R
R
(a) 74% (46% ee) (b) 70% (44% ee) (c) 66% (36% ee)
Pd(OAc) 2 (3 mol %)
I 12 R
(R)-BINAP (9 mol %), NMP Ag2CO3 (2.0 equiv), 60 °C
H 13 R
Pd(OAc) 2 (5 mol %)
OTf
(R)-BINAP (10 mol %), PhMe K2CO3 (2.0 equiv), 60 °C
14
H
(a) 54% (91% ee) (b) 35% (92% ee) (c) 44% (89% ee) (d) 60% (91% ee)
13
(a) R = CO2Me, (b) R = CH2OTBS, (c) R = CH 2OAc, (d) R = CH 2OPiv Scheme 3
The modest ees reported (33– 46%) for the conversion from 12 to 13 were greatly improved as a result of a study of the effects on the reaction of varying the anionic component of both the Pd source and more particularly the silver salt.[20] It was found that the use of a Pd0 catalyst complex preformed in situ from Cl2Pd(R)-BINAP,[26] (R)-BINAP, and cyclohexene gave greatly improved ees relative to the 1:3 Pd(OAc)2/(R)-BINAP prereduced catalyst used in the original work; in contrast, the use of AgOAc as the Ag source reduced the ee to almost zero, clearly indicating the undesirability of the nucleophilic
IV.2.3 ASYMMETRIC HECK REACTIONS
1289
acetate counterion, which perhaps forms a Pd—OAc bond to replace the easily dissociated Pd—I bond, and so inhibits the cationic pathway. The best Ag source in terms of ee was found to be Ag3PO4 (most likely due to the very low nucleophilicity of the Ag2PO4 anion), with the sparingly soluble CaCO3 being added as the basic component. Under these conditions, 13b was obtained with 80% ee and in 67% yield. The very recent introduction of the new ligand 2,2-bis(diphenylarsino)-1,1-binaphthyl (BINAs),[27] the diarsine equivalent of BINAP, helped to considerably increase the yield for the conversion of 12b to 13b (Scheme 3). After optimization, the product 13b could be prepared in 90% chemical yield and with 82% ee.[27] The use of the alkenyl triflates 14a–d in place of iodides 12a–c gave still better results[28] as well as allowing the omission of expensive silver salts and the use of hydrocarbon solvents (PhMe or PhH), in which the deleterious effects of Pd(OAc)2 on ee seen in NMP are not repeated. Thus, products 13a–d were obtained in 35–60% yields and with uniformly excellent (89–92%) ees under the conditions indicated. The scope of the reaction was extended somewhat by the use of the trisubstituted alkenyl iodide 15, which gave the decalin systems 16a and 16b in yields of 63% (83% ee) and 67% (87% ee), respectively (Scheme 4).[28] The deleterious effect of the acetate counterion on ee and favorable influence of the Ag3PO4/CaCO3 additive combination seen for the AHR conversion of 12 to 13 are reproduced here. Interestingly, 16a was accompanied by a minor amount (35%) of the desilylated alcohol 16c, which displayed a higher ee (92%)—control experiments indicated that desilylation was occurring via transmetallation to Pd after completion of the ring closure. No such free hydroxyl formation was seen in the case of the acetate 15b.
OTBS
OTBS (a) 63% (83% ee), plus (c) 35% (92% ee)
Cl2Pd[(R)-BINAP] (10 mol %)
I
15a,b
Ag3PO4 (2 equiv), NMP, 60 °C CaCO3 (2.2 equiv)
H RO
16a−c
(b) 67% (87% ee)
OR (a) R = TBS, (b) R = Ac, (c) R = H Scheme 4
A more significant extension in scope was the synthesis of a range of bicyclic enones and dienones, including a key intermediate 20 in Danishefsky’s synthesis [29] of vernolepin 21. The AHR involved was initially the conversion of the bisallylicalcohol 17 to the chiral decalin system 19, via the intermediate 18 (Scheme 5).[30] The best solvent for this was found to be 1,2-dichloroethane (DCE), with the addition of t-BuOH having a beneficial effect on the reaction rate and the chemical yield without reducing the ee.[31] Compound 19 was converted to 20 via a nine-step process; an alternative approach was also found, which started from the more readily available 13a.[32] Application of the DCE/tertiary alcohol solvent system for the conversion of 14a to 13a gave an improved yield relative to that previously reported; a study of the various tertiary alcohols found pinacol to be the most efficacious, giving 13a in 78% yield with 95% ee. The authors successfully synthesized ( )-21, thereby making an assignment of its absolute configuration possible.
1290
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
OPiv
OPiv (a)
HO
OPiv (b)
HO H
TfO 17
H Pd + P P *
O 18
H 19
(a) Pd2dba3. CHCl3 (9 mol % Pd), (R)-BINAP (11.3 mol %), K 2CO3 (2 equiv), t-BuOH (11 equiv), ClCH2CH2Cl, 60 °C, 3 d. (b) β-hydride elimination, then tautomerization, 76%, 86% ee. O O O
O
OH
O
H
H
O O
20
21 Scheme 5
D.i.b. Hydrindans. The general method described in Sect. D.i.a for decalin synthesis has also been applied to the synthesis of 6,5-ring systems through the formation of hydrindans (Scheme 6).[33] Both the iodides 22a–e and the triflate 24 could be converted to the corresponding cishydrindans by similar methods to those used for decalins; once again Ag3PO4 was found to be the most effective silver salt in the conversion of the former. Small increases ( 5%) R
R (a)
I
H
22a: R = CO 2Me 22b: R = CH 2OTBS 22c: R = CH 2OAc 22d: R = CH 2OTBDPS 22e: R = CH 2OPv
23a: 73%, 83% ee 23b: 78%, 82% ee 23c: 73%, 84% ee 23d: 53%, 73% ee 23e: 74%, 80% ee
OTBS (b)
23b
OTf 24 (a) PdCl2[(R)-BINAP] (10 mol %), Ag3PO4 (2.0 equiv), CaCO3 (2.2 equiv), NMP, 60 °C. (b) Pd(OAc) 2 (5 mol %), (R)-BINAP (10 mol %), K 2CO3 (2.0 equiv), benzene, 60 °C, 64 h, 63% (73% ee). Scheme 6
IV.2.3 ASYMMETRIC HECK REACTIONS
1291
in ee could be obtained for 22a–c by prereducing the palladium catalyst in situ. The triflate 24 gave 23b with slightly lower ee than seen for the corresponding conversion of 22b, with potassium carbonate being the most effective base. The hydrindan 23b was later converted by the same group into 26 (Scheme 7),[34] which is a key intermediate in the synthesis of ( )-oppositol and ( )-prepinnaterpene.[35] The conversion involved oxidation of the diene moiety with singlet oxygen and is notable for the clean epimerization of the ring junction to give the trans-configuration (from 25 to 26), which demonstrates that both cis- and trans-junctions can be obtained in the AHR products.
Br
Br
23b H
BnO
H
BnO
O
25
OH
26
Scheme 7
D.i.c. Indolizidines. The 6,5-combination bicycle synthesis outlined above has been extended to indolizidines, formed by AHR of a suitable prochiral alkenyl iodide such as 28, which can easily be prepared by allylation of the lactam 27. In contrast to purely carbocyclic systems, however, the most effective ligand proves to be (R)--[(S)-1,2bis(diphenylphosphino)ferrocenyl]ethyl alcohol (BPPFOH) 31,[36] which gives results clearly superior to those obtained with BINAP (Scheme 8).[37],[38]
H I
(a)
NH
(b)
N
N
O 27
O
O 28
H +
N O
(c)
30
29
(a) NaH, DMF, then (Z)-CHI=CH CH 2I, 68%. (b) Pd2dba3.CHCl3 (4 mol % Pd), (R)-(S)-BPPFOH (9.6 mol %), Ag-exchanged zeolite (corresponds to ca. 6 equiv Ag), CaCO3, DMSO-DMF, 0 °C, 94% (86% ee). (c) Pd/C, MeOH, 23 °C, quantitative.
OH PPh2
Fe
PPh2 31
H
H
OH
N
OH
N C6H13
32 Scheme 8
33
1292
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
The use of an Ag-exchanged zeolite also appears to give somewhat better results than the more usual Ag3PO4 silver source. The desired indolizidine 30 is obtained as a mixture (94% yield, 86% ee) with the isomer 29; however, treatment of the mixture with catalytic Pd/C in MeOH at room temperature gives clean isomerization to 30 in essentially quantitative yield. Compound 30 has been converted to the natural products lentiginosine 32, 1,2-diepilentiginosine, and gephyrotoxyn 209D 33.[39] D.i.d. Diquinanes. The successful execution of AHRs for the formation of 6,6- and 6,5ring systems from prochiral substrates clearly suggested an extension of the method to the formation of 5,5-systems, which form the backbone of a large number of natural products. The use of prochiral cyclopentadienyl systems, however, involves the generation of a -allylpalladium species, which must then be trapped with a suitable nucleophile.[40] The greater reactivity of the 1,3-diene substrate toward the silver salts used in the reactions and the propensity for undesirable side reactions such as Diels–Alder cycloadditions must also be borne in mind. The former problem, in fact, figures prominently in the first example of an AHR-based diquinane synthesis to be published (Scheme 9).[41],[42]
Me Me
I
Me
H
(a)
Me
Pd
+
H
Me
Me 35
34 EtO2C OTf
Me 36
OAc
Ln*
H
OAc
(b)
O
H 7 steps
H Me
Me
37
38
Me (a) [Pd(allyl)Cl]2, (R,R)-CHIRAPHOS, Bu4NOAc, PhMe, 60 °C, 6 d, 61% (20% ee). (b) Pd(OAc) 2, (S)-BINAP, Bu 4NOAc, DMSO, 25 °C, 2.5 h, 89% (80% ee).
OTf
Me 39
Scheme 9
Although cyclization of the iodide 34 could be carried out to give the bicyclo[3.3.0]octane 35 in reasonable yield, the observed ees were low [ca. 20%; a slightly higher ee was obtained with (S)-BINAP, but at the cost of greatly reduced yield]. The authors attribute this failure in large part to a clearly observed instability of 34 in the presence of silver salts, necessitating their omission from the reaction medium and so forfeiting the beneficial effects noted in earlier work.[20] The presence of tetrabutylammonium acetate, a source of nucleophilic acetate, appears to be essential, as the reaction does not proceed in its
IV.2.3 ASYMMETRIC HECK REACTIONS
1293
absence; this was in fact the first example of an AHR followed by anion capture. The problem of low ee was circumvented by employing the triflate 36 (chosen instead of the more obvious analog 39 on the grounds of ease of synthesis), which gave the diquinane 37 with 80% ee and in 89% yield. The authors converted this to the triquinane 38, an intermediate in a previously described synthesis of 9(12)-capnellene-3, 8, 10-triol,[43] and later developed the first catalytic asymmetric synthesis of 9(12)-capnellene 41 itself by trapping the -allylpalladium intermediate with a suitable -dicarbonyl carbanion (Scheme 10).[44]
* minor
P
Pd+ Me
enantiomer of 40
OTf (a)
EtO2C CO2Et Me
H
36
OTBDPS *
major
Br Na Na O O R
P
Me 40
Pd+ P
steps
Me
R′ Me
42
Me H H H
(a) [Pd(allyl)Cl]2 (2.5 mol %), (S)-BINAP (6.3 mol %), NaBr (2.0 equiv), (CO2Et)2C(Na)(CH2)2OTBDPS (2.0 equiv), DMSO, 25 °C, 77%, 87% ee.
Me 41
Scheme 10
In this case BINAP was found to be the most efficient ligand, and the addition of sodium bromide, too, significantly improved the ees in all cases studied. The latter effect is attributed to a suppression (due to formation of a stabilizing complex of type 42 with the sodium enolate) of small fractions of anion exchange, which may be taking place between free malonate anions and the triflate anion in the cationic intermediate of type 9. D.i.e. Allylsilanes. All of the examples discussed so far have relied on the use of an endocyclic alkene substrate to resolve the - versus -hydride elimination regiocontrol problem discussed in Sect. B.i. A more general approach to the problem has been described by Tietze and co-workers and involves the use of allylsilanes as the alkene component (Scheme 11).[45],[46]
1294
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
NCOCF3
NCOCF3
(a)
I Me3Si
H
43
44
MeO
MeO
MeO
(b)
I Me3Si 45
steps
H 46
H 47
(a) Pd2dba3.CHCl3 (2.5 mol %), (S)-BINAP (7.0 mol %), Ag 3PO4 (1 equiv), DMF, 75 °C, 48 h, 63% (72% ee). (b) Pd2dba3 . CHCl3 (2.5 mol %), (R)-BINAP (7.0 mol %), Ag 3PO4 (1.1 equiv), DMF, 80 °C, 48 h, 91% (92% ee).
Scheme 11
By careful choise of reaction conditions either a vinyl- or trimethylsilylvinyl-substituted carbocycle can be produced in the nonenantioselective reaction. Under conditions suitable for the AHR, however, the former product predominates (e.g., transformation of 43 to 44). Yields and ees appear to be good, and the method has been applied successfully to the synthesis of the norsesquiterpene 7-demethyl-2-methoxycalamene 47, via the key cyclization from 45 to 46.[47],[48] D.ii. Intermolecular D.ii.a. Dihydrofurans and Cyclic Enol Ethers. The first example of an intermolecular AHR was reported by Hayashi and co-workers and involved the asymmetric arylation of 2,3-dihydrofurans using aryl triflates.[18] Although little or no ee was obtained when aryl iodide/silver salt combinations were used, the use of triflates along with the familiar Pd(OAc)2/BINAP catalyst system resulted in the formation of the 2-aryl-2,3-dihydrofuran product 54, together with minor amounts of the 2,5-dihydrofuran isomer 55. The rationale proposed by the authors for this outcome is shown in Scheme 12; it is hypohthesized that addition of the catalytic complex to either face of the substrate can take place, ultimately producing the complexes (R)-51 and (S )-51, but that in the case of the latter unfavorable steric factors cause an immediate dissociation of the Pd species, producing the minnor product 55. In contrast, (R)-51 is able to undergo a reinsertion of the alkene into the Pd—H bond followed by a second -hydride elimination to produce the product 54. The overall effect is a kinetic resolution of (R)- and (S)-51, effectively enhancing the facial selectivity shown in the initial transformation from 48 to 49 by selectively removing the 51 enantiomer produced by complexation to the undesired face of 48. As might be expected from the above argument, reaction conditions that give proportionally larger amounts of 55 also appear to give the best ees for major product 54; thus, when proton sponge is used as the base the product 54 is obtained with 96% ee, at the cost of a 71:29 ratio of 54/55, whereas in contrast, using Na2CO3 gives a lower ee (75%) but
1295
IV.2.3 ASYMMETRIC HECK REACTIONS *
+
P
Pd
*
P+ Pd P
*
P
P
Ph
H Ph
–OTf
O
O
(R)-49
P
+
Pd
H –OTf
–OTf
O
Ph (R)-51
(R)-50 *
P
P
+
P
Ph
H
–
OTf
P
+
Pd
H
Pd
O 48
*
*
P+ Pd P O
O –
OTf
Ph (R)-52
–
O 54
Ph
O 55
Ph
OTf
Ph (R)-53
*
+
P
Pd
P
–
OTf
(S)-49
+
P
fast
Pd
H
Ph O
*
P+ Pd P
*
P
H Ph O
–OTf
(S)-50
O
Ph (S)-51
–OTf
Scheme 12
much better regioselectivity (97:3).[49],[50] The authors note that the presence of the nucleophilic acetate anion in the reaction medium assists the dissociation of (S)-51 [and presumably (R)-51 as well], making possible the formation of 55.[51] Even more impressive results have been obtained using alkenyl triflates—for example, the AHR between 48 and triflate 56 gives the expected major product 57 with 94% ee, without formation of the undesired regioisomer (Scheme 13).[52]
CO2Et + OTf
O 48
CO2Et Pd[(R)-BINAP] 2 (3 mol %) proton sponge, toluene, 60 °C 84%, 94% ee
56
O 57
Scheme 13
An interesting corollary to this work has been reported by Hillers and Reiser, who found that at high pressure the ee of the major product in the conversion from 48 to 54/55 is dramatically increased, suggesting that such conditions enhance the kinetic resolution process.[53] Shibasaki and co-workers have shown that the reaction can be carried out using alkenyliodonium salts instead of alkenyl triflates (transformation from 58 to 59, Scheme 14), although yields are lower due to the highly reactive nature of the salts, which leads to competition from an uncatalyzed and/or nonphosphine-mediated process.[54] Interestingly, only the 2-alkenyl-2,5-dihydrofuran product is obtained,
1296
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
BF4−
(a)
+
+
I
O 48
Ph
22% (78% ee)
O
58
59
(a) Pd(OAc) 2 (40 mol %), (R)-BINAP (60 mol %), proton sponge, CH 2Cl2, 25 °C, 20 h. Scheme 14
suggesting that dissociation from the Pd complex formed after the first -hydride elimination is more rapid than when using triflates. Finally, the asymmetric arylation of 60 has also been reported, although the yields and ees are more modest (Scheme 15).[55] Hydrolysis of the product 61 conveniently gives the 1,3-diol 62, an intermediate in Sharpless’s synthesis of fluoxetine.[56]
O
PhX +
9a) or (b)
O 60
steps
O
OH
*
Ph
*
O
Ph
OH
61
62
(a) for X = I: Pd(OAc) 2, (R)-BINAP, Ag2CO3, DMF, 60 °C, 48 h, 62%, 43% ee. (b) for X = OTf: Pd(OAc) 2, (R)-BINAP, i-Pr2NEt, DMF, 60 °C, 48 h, 37%, ~35% ee. Scheme 15
D.ii.b. Dihydropyrroles. The methods described for arylation of dihydrofurans (see above) have also been applied to 2,3-dihydropyrroles such as 63,[57] with similar patterns of regio- and enantioselectivity being observed. Thus, little or no ee was obtained when using aryl iodides, but aryl triflates gave mixtures of 2-aryl-2,3-dihydropyrroles 64 and 2aryl-2,5-dihydropyrroles 65, with the former predominating and the kinetic resolution process again being in effect, as evidenced by another inverse relationship between the ee of 64 and the 64/65 ratio (Scheme 16). The reaction was also extended successfully to alkenyl triflates, which gave even better ees than obtained for the dihydrofurans.[52]
*
+ Ar-OTf N CO2Me
Ar N CO2Me
63
64
+
*
Ar N CO2Me 65
Scheme 16
An example of a reaction with 2,5-dihydropyrroles has also been recently disclosed.[58] Arylation of 66 using 1-naphthyl triflate and an (R)-BINAP/Pd(OAc)2/i-Pr2NEt system in DMF gave the 3-arylation product 67 (Scheme 17) with moderate yield and ee. It was found that the addition of excess acetate served to suppress formation of the undesired 2arylation product (which was formed after initial isomerization of the double bond in 66),
IV.2.3 ASYMMETRIC HECK REACTIONS
Pd(OAc) 2, (R)-BINAP TlOAc, i-Pr2NEt DMF, 60 °C, 16 h
N + CO2Me
OTf
1297
N CO2Me
34% (58% ee)
66
67 Scheme 17
and this was conveniently achieved by adding TlOAc, with the thallium cation acting as a cocatalyst. Unfortunately, attempts to carry out this reaction with other aryl triflates or with aryl iodides were unsuccessful. D.ii.c. Dihydrodioxepines. Arylation of the 4,7-dihydro-1,3-dioxepin system 68 (easily derived from cis-2-butene-1,4-diol), once again using the triflate, was reported by Shibasaki and co-workers in 1994.[59] The reaction is significant in that the resulting enol ethers are easily converted (by hydrolysis and then oxidation of the intermediate lactol) to chiral -aryl--butyrolactones 70, which are themselves useful synthetic intermediates (Scheme 18).[60] Also noteworthy is the important role played by added molecular sieves, which enhance both chemical yield and ee. This was the first time that such an effect had been noted for the AHR. Ar Ar Pd(OAc) 2 (3 mol%)
ArOTf + O
O
1
R2
R
(S)-BINAP, base, benzene, powdered MS, 65 °C
68
O
O
1
R2
R
69
O
O 70
Scheme 18
A combination of MS 3 Å and potassium carbonate base was found to be the most effective, with the best auxiliary system (R1 R2 H) giving 69 with a satisfactory 72% ee and in 84% yield. Gratifyingly, these figures showed only minor perturbations when the Ar ring substituents were varied. Significantly improved ees have recently been reported for this process using a new ligand system (see Sect. F).[61] D.ii.d. Hydroarylations of Bicyclo[2.2.1]heptane Derivatives. Asymmetric hydroarylation/hydroalkenylation, although not strictly a Heck reaction as the -hydride elimination step is replaced by reductive elimination, nevertheless shares a common mechanistic pathway with regard to the enantioselective step and so will be discussed briefly. In 1991 Brunner and Kramler first reported hydrophenylations of norbornene and norbornadiene using aryl iodide, although the ees obtained were low (40%). The preferred ligand was ( )-Norphos; BINAP does not appear to have been tested.[62] The system has since been revisited by Achiwa and co-workers as a means of testing novel phosphine ligands of the general structure 73.[63],[64] Using these, the conversion of 71 to 72 could be carried out in
1298
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
81% yield and with 74% ee (Scheme 19a). Moreover, Namyslo and Kaufmann have demonstrated that the highest enantioselectivity (86.4%) is obtained when phenyl nonaflate is used as a substrate.[65] Hayashi and co-workers have carried out AHRs using alkenyl iodides and triflates both on norbornene and on heteroanalogs such as 74: excellent ees and satisfactory yields were obtained.[66] Hydrophenylation of a similar system has been reported by Moinet and Fiaud.[67] Quite recently, Diaz and co-workers have reported an intramolecular asymmetric hydroarylation of alkene 77, which gives satisfactory ees and moderate yields and also showed that silver zeolites[38],[39] are very effective silver salts to obtain high enantioselectivity in this system[68] (Scheme 19b).
(a)
*
Ph
SO2Me
HN
PAr 2
R 72
71
73
O MeO2C MeO2C
O (b)
Ph
+ Br
MeO2C MeO2C
75
74
Ph
*
76
(a) Ph-OTf, Pd(OAc) 2, 73 (R = CHMe2, Ar = Ph), i-Pr2NEt, HCO2H, DMSO, 65 °C, 20 h, 81%, 74% ee. (b) Pd{(R)-BINAP} 2 (1 mol %), HCO2H, Et3N, Cl(CH2)2Cl, 40 °C, 63%, >96% ee. Scheme 19a
O I
O CO2Me
(a)
77
CO2Me
78
(a) Pd(OAc) 2 (10 mol %), (R)-BINAP (20 mol %), CaCO 3 (2.2 equiv), Ag-zeolites corresponding to ca. 6 equiv of Ag, MeCN, 8 h, 60 °C, 42% yield, 81% ee. Scheme 19b
E. FORMATION OF QUATERNARY CARBON CENTERS E.i. Spirocyclizations and Alkaloid Synthesis The enantioselective formation of quaternary carbon centers remains a significant challenge to the synthetic chemist.[69] To use the AHR in this role has the obvious attraction of removC (see Scheme 1b), as no -hydrogen is ing the problem of competing pathways in step
IV.2.3 ASYMMETRIC HECK REACTIONS
1299
present to compete with the desired -hydride elimination step—the need to use endocyclic alkene substrates is thus removed. The first successful case was reported by Overman and co-workers in 1989,[70] a pioneering strategy, which opened the way for the development of AHRs leading to quarternary centers. Furthermore, it was outlined that polycyclizations are well within the scope of the Heck reaction. According to Scheme 20 it can be expected that contrary to the case of polycyclizations of carbocations and free radicals, cyclizations resulting from sequential intramolecular insertions of palladium metal alkyls will be most effective when the transition metal propagates at the least substituted termini of the participating alkene units.
M
M
Scheme 20
As with the work creating tertiary centers reported by Shibasaki and co-workers, which was described in Sect. D, the ees of the cyclizations obtained at the outset were modest, with the spirocyclic system 80 being obtained in good yield and moderate ee when (S,S)-DIOP was substituted for triphenylphosphine (Scheme 21).
OTf (a)
O
O
79
80
(a) 10 mol % Pd(OAc) 2, 10 mol % (S,S)-DIOP, Et3N, benzene, 25 °C, 1 h, 90%, 45% ee. Scheme 21
Although this work clearly demonstrated the viability of such a process, the full potential of the approach did not become fully apparent until the publication of a remarkable study concerning the synthesis of spiroxindoles (Scheme 22).[71] Carrying out the AH cyclization of iodoanilide 81 in a dipolar aprotic solvent (in this case dimethylacetamide, DMA) in the presence of Ag3PO4 gave (S)-82 in 81% yield and with 71% ee, results very similar to those achieved by other workers, for tertiary centers under such conditions. However, by carrying out the reaction in the absence of Ag salts and using 1,2,2,6,6-pentamethylpiperidine (PMP) as the base, the opposite (R)-82 enantiomer was obtained using the same enantiomer of BINAP. Similar studies of the cyclization of alkene 81 revealed that when (E)-83 was used, the effect is reproduced, although the ees of the enantiomer obtained when using PMP were low (30–40%). In
1300
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
O 5 mol % Pd2dba3 10 mol % (R)-BINAP 1.2 equiv Ag 3PO4 DMA, 80 °C, 26 h
O
O O (S)-82 81%, 71% ee
NMe
O
NMe
I O
O 10 mol % Pd2dba3 20 mol % (R)-BINAP
81
5 equiv PMP, DMA 80 °C, 140 h
NMe
O O (R)-82 77%, 66% ee
Scheme 22
contrast, when (Z )-83 was used in conjunction with (R)-BINAP, both sets of conditions gave the expected (R)-enantiomer of 84 with good yields and excellent (90%) ees.[72] These results appear to suggest that the observed “geometry effect” (identical to that observed by Shibasaki and co-workers for carbocycle formation, vide infra) is rather more powerful than the “base/additive effect” in determining the sense of chiral induction. The use (S)-BINAP under otherwise identical conditions, of course, gives (S)-84, which can be converted to the natural products physostigmine 85 and physovenine 86 (Scheme 23a).[73],[74] Me MeO
I N Me
OTBDMS
O
(a), (b)
MeO
CHO O N Me
Me
(S)-84
83
(c), (d)
MeNHCO2
(e), (f), (g)
Me O N H Me (−)-86
MeNHCO2
Me N N H Me (−)-85
Me
(a) 10 mol % Pd2dba3 . CHCl3, 23 mol % (S)-BINAP, PMP, DMA, 100 °C. (b) 3 N HCl, 23 °C; 84%, 95% ee. (c) MeNH2, Et3N, MgSO4, then LiAlH4, THF, 88%. (d) As in the literature. (e) LiAlH4, THF, 23 °C, 94%. (f) BBr3, CH2Cl2, 23 °C. (g) NaH, Et2O; MeNCO. Scheme 23a
IV.2.3 ASYMMETRIC HECK REACTIONS
1301
These surprising results proved to be a powerful spur to mechanistic investigation of the AHR, as they effectively rebutted the prevailing view that the “cationic” pathway is the only mechanism capable of producing high ees, by demonstrating that the alternative “neutral” pathway is also apt to do so with certain substrates. In fact, Overman and coworkers reported that PMP-promoted AH cyclizations along a “neutral” pathway via a pentacoordinate intermediate were very effective when iodoanilide with an endocyclic alkenyl moiety (87a–89a, 91a–92a, and 94a–95a) were used as substrates, but not so effective when 96a, 97a, and 98a–101a were used as substrates[75] (Scheme 23b). Thus, the “base/additive effect” has yet to be reported for substrates other than acrylamides, a substrate specificity that must be taken into account before broader conclusions can be drawn regarding the AHR mechanism, especially the means by which the enantioselectivity reversal occurs. O
O NR1
I O
NR1 O
O
O
87a−90a
87a−90b
O
O 4
R4
R
I O
O O 96a−97a
O 96a−97b
O
O NMe
I Me
NMe Me
Me 91a
Me
O R2
91b
O NMe
I
R3 98a−101a
NMe
R2
R3 98a−101b
O
O X
NMe
n
NMe
n
92a−95a Scheme 23b (Continued )
92a−95b
1302
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Asymmetric Heck reaction of 87−101
Substrate 87: R1 = Me 88: R1 = Bn 89: R1 = SEM 90: R1 = BOC 91 92: n = 1, X = I 93: n = 1, X = Br 94: n = 2, X = I 95: n = 0, X = I 96: R4 = NCO2Me 97: R4 = O 98: R2 = Me, R3 = Me 99: R2 =Me, R3 = TBDMSO 100: R2 = t-Bu, R3 = TIPSO 101: R2 = Ph, R3 = TIPSO
, Overman s PMP-Promoted Conditions
, Shibasaki s Ag Salt-Promoted Conditions
71% y., 66% ee 66% y., 66% ee 68% y., 75% ee no example 89% y., 71% ee 45% y., 89−95% ee 51% y., 32% ee 50% y., 88% ee 96% y., 56% ee 51% y., 8% ee 66% y., 0−7% ee 91% y., 25% ee 85% y., 38% ee 90% y., 27% ee 74% y., 35% ee
81% y., 71% ee 91% y., 41-51%ee 76% y., 65% ee 65% y., 42% ee 99% y., 72% ee 74% y., 79−81% ee no example 62% y., 0% ee 81% y., 7% ee 90% y., 64% ee 91% y., 49−55% ee 88% y., 59% ee 80% y., 45% ee 41% y., 72% ee 93% y., 73% ee
Scheme 23b
E.ii. Tetrahydropyridines Interesting attempts to asymmetrize an intramolecular Heck reaction with 1,2,3,4-tetrahydropyridines also giving access to spirocyclic systems have not been successful at the beginning.[76] However, by using N-formyl-1,2,3,4-tetrahydropyridines Ripa and Hallberg succeeded in preparing various spirocyclic derivatives of tetrahydropyridines in moderate yields (Scheme 24).[77] The asymmetric cyclization of 102 using (R)-BINAP as a chiral ligand resulted in the formation of three isomers 103, 104, and 105, with a rather long reaction time being required. Good ees have been obtained for the products 104 and 105 (89% and 90%). (R)-BINAP (20 mol %) Pd(OAc) 2 (10 mol %)
TfO
Et3N, toluene, 60 °C, 168 h
N O
H
102
+
N O
H 103 11% yield 8% ee
+
N O
H 104 25% yield 89% ee Scheme 24
N O
H 105 8% yield 90% ee
IV.2.3 ASYMMETRIC HECK REACTIONS
1303
The migration of the double bond could not be controlled effectively by varying the reaction conditions. Interestingly, the introduction of the chiral (phosphinoaryl)oxazoline (first reported by Pfaltz; see Sect. F) as a ligand helped to suppress the formation of the double bond isomer 105. At the same time the regioselectivity could considerably be changed in favor of the formation of 103 to yield a 6:1 mixture of (R)-103 (87% ee) and (R)-104 (99% ee) after 48 h at 110 °C, using (i-Pr)2 NEt as a base.[77] A rationalization for the observed excellent enantioselectivities in the case of (R)-BINAP is shown in Scheme 25. It was suggested that one of the diastereomeric -complexes [(S)-106], formed after oxidative addition of the triflate, could be sterically more crowded. A similar rationalization, based on steric arguments, was used to explain the subsequent migration of the double bond and the considerably differing ees of the double bond isomers.
*
*
+
P
P
Pd N
+
P
P
Pd
CHO
N (S)-106 p-complex disfavored
CHO
(R)-106 p-complex favored Scheme 25
If the corresponding iodide was used instead of the triflate 102, only low to moderate ees have been observed. Furthermore, it seems that the role of the N-formyl moiety could be important for chiral induction and this could provide further information about the mechanism. E.iii. Eptazocine and Halenaquinol The synthesis of benzylic quaternary centers by an AHR has also been reported by Shibasaki and co-workers in connection with syntheses of ( )-eptazocine[78] and of halenaquinone and halenaquinol 112.[79],[80] As in Sect. E.i, the key steps in both syntheses involve the formation of a quaternary carbon center by asymmetric Heck arylation of a trisubstituted alkene, with BINAP being the preferred ligand. The “geometry effect” seen by Overman and co-workers for spiroxindoles (vide supra) is clearly present, with the Zalkene giving much better enantioselectivity and, in the case of model studies of the step 107–108 in the eptazocine synthesis, the opposite enantiomer to that obtained when using the E-alkene. The conversion from 107 to 108 (Scheme 26) was achieved with excellent yield and ee; desilylation gave the corresponding aldehyde,[81] which was converted to ( )-eptazocine via a five-step sequence. The synthesis of halenaquinol 112 (and its oxidation product halenaquinone) initially featured the conversion from 109 to 110 as a key step (Scheme 27), which gave the desired product in 78% yield and with 87% ee under very similar conditions used for
1304
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
OTBDPS MeO
(a)
MeO
OTf
Me
OTBDPS
Me 107
108
(a) Pd(OAc) 2 (7 mol %), (R)-BINAP (17 mol %), K2CO3 (3 equiv), THF, 60 °C, 72 h, 90%, 90% ee, E/Z = 21:3. Me N MeO Me eptazocine Scheme 26 OMe
OMe OTf
OTBDPS
Me
(a)
3
OMe 109
110
OMe
TBSO
(c)
(b)
OMe
HO OTf
O Me
B OTf OMe 111
O
3
TBDPSO 113
HO
O 112
(a) Pd(OAc) 2 (10 mol %), (S)-BINAP (20 mol %), K 2CO3, THF, 60 °C, 78%(87% ee). (b) 113 (1.1 equiv), Pd(OAc) 2 (20 mol %), (S)-BINAP (40 mol %), K 2CO3, THF, 20% (85% ee). (c) 12 steps, 12% overall. Scheme 27
conversion of 107 to 108. However, in line with the current trend toward sequential or “one-pot” transformations[82],[83] (vide infra), the authors were able to combine the AHR step with a Suzuki-type coupling of the trialkylborane 113 (itself prepared in situ by hydroboration) with the C2-symmetric ditriflate 111 and so obtain 110 rather more directly. While the chemical yield of this sequence is still low (20%) and the catalyst loading rather high (20 mol %), the ee is excellent (85%), suggesting that further development of the method should be feasible.
1305
IV.2.3 ASYMMETRIC HECK REACTIONS
E.iv. Sesquiterpenes One further example of quaternary center formation by an AHR has been reported, this being the conversion of the aryl triflate 114 to a 3:1 mixture of the tricycle 115 and its isomer 116, both of which can be converted to the enone 117, a key intermediate in the synthesis of kaurene 118 and abietic acid 119 (Scheme 28).[84],[85] Compound 115 can also be quantitatively isomerized to 116. The essentially complete selectivity toward 6exo cyclization is noteworthy. The authors rationalize this on the basis of unfavorable steric interactions in the alternative intermediates.
TfO
Pd(OAc) 2 (9 mol %) (R)-BINAP (18 mol %)
Me
Me
Me
Me +
K2CO3 (2 equiv), toluene, 50 °C 4 d, 62% (95% ee)
Me
Me 114
115
116 Me
OMe Me
Me
Me H
O
H Me Me
Me 117
118
Me HOOC
Me
H
H 119
Scheme 28
F. FUTURE DEVELOPMENT F.i. Ligands The great majority of AHRs reported so far have utilized the BINAP ligand system, which usually has proved to be the most effective one, when the performance of different ligands has been assessed. The significant number of exceptions to this rule, however, suggest that experimentation with alternatives may prove worthwhile. The most dramatic development in that direction has definitely been the introduction by Pfaltz of the oxazoline-based ligands 120,[86] which give distinctly improved ees with several previously reported AHRs.[61] For example, the Hayashi-type AHR of dihydrofuran 48 with cyclohexenyl triflate catalyzed by Pd(dba)2 and 120 (R t-Butyl) with i-Pr2NEt as the base gives the 2-alkenyl-2,5-dihydrofuran product 59 in 92% yield and with 99% ee, a major improvement on the ees obtained with BINAP. Similar to the alkenylation of 48 using the iodonium salt 58, no trace of the isomeric 2-alkenyl-2,3-dihydrofuran product is formed, indicating that rapid dissociation of the catalyst from the initial product of -hydride elimination occurs. Remarkably, the resistance of the first-formed product alkene to isomerization by this catalyst is so pronounced as to allow the arylation and/or alkenylation of cyclopentene, giving regiodefined products such as 121 with high yields, excellent ees,
1306
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
and only small amounts (5%) of the unwanted regioisomers such as 122 (Scheme 29). This catalyst system is also interesting in terms of reaction rates and decreased catalyst loading, indicating higher catalyst turnover compared to BINAP (see Sect. F.ii). An example for an alkenylation reaction utilizing 120 [R C(Me)3] is given in Scheme 30. Again, excellent selectivity toward the less isomerized product 125 as well as high ees have been observed.[61] The conversions outlined in Schemes 29 and 30 are also noteworthy in so far as they constitute examples of intermolecular AHRs of very simple starting materials with no other functionality or heteroatom present than is required for the Heck reaction to proceed. Simple hydrocarbon skeletons are the resulting products.
O N PPh2 120
R
(a)
+ Ph
Ph
121
122
(a) PhOTf, Pd(dba) 2 (3 mol %), 120 [R = C(Me)3, 6 mol %] i-Pr2NEt, THF, 70 °C, 5 d, 80%, 86% ee, 121/122 = 99:1. Scheme 29
(a)
+
+ OTf
123
124
(a) Pd(dba)2 (3 mol %), 120 [R = C(Me)3, 6 mol %], i-Pr2NEt, C6H6, 40 °C, 4 −5 d.
125
126
69% yield 89% ee
1% yield
Scheme 30
Two further examples for arylation reactions catalyzed by phosphinooxazoline–palladium complexes are shown in Scheme 31 with the formation of 129 and 131 as nitrogencontaining substrates: arylation of the 2,3-dihydropyrrole 63 with phenyl triflate catalyzed by the palladium complex 120 (R CMe3) gave the single isomer 65 in 88% yield and with 85% ee.[87] Interestingly, phosphinooxazolines 120 with smaller R groups than t-butyl have been found to produce less reactive catalysts. This finding was very unusual as with t-butyl being a very bulky group the steric hindrance near the metal center could actually be expected to slow down a metal-catalyzed process.
IV.2.3 ASYMMETRIC HECK REACTIONS
O
(a)
+
O
O
O
OTf 128
127
1307
129 (b)
+ O
O OTf 128
130
131
(a) Pd(dba)2 (3 mol %), 120 (R = CMe3, 6 mol %), i-Pr2NEt, THF, 70 °C, 7 d, 70% y., 92% ee. (b) Pd(dba)2 (5 mol %), 120 (R = CMe3, 10 mol %), i-Pr2NEt, C6H6, 80 ˚C, 5 d, 78% y., 84% ee. Scheme 31
The use of a chiral bisoxazoline ligand 132 for the enantioselective Pd-catalyzed annelation of allenes has been reported by Larock and Zenner (an example is given in Scheme 32a).[88],[89] The use of a chiral phosphinooxazoline ligand 135 for the enantioselective Pd-catalyzed annelation of diene 136 has also been reported (an example is given in Scheme 32b).[90] Even though in these cases the alkene insertion step is followed by an intramolecular nucleophilic attack of the amine functionality (which could be described as an “intramolecular anion capture process”) and the reactions are not strictly AHRs, the high yields and ees obtained for various substrates are remarkable. Looking at the results obtained with BINAP, with the new diarsine ligand mentioned in Sect. D.i.a and with bisoxazoline 132, it seems evident that various donor atoms (N, P, As) can be contained in ligands which provide the best solution to a given AHR problem. Accordingly, recently 2-diphenylarsino-2-diphenylphosphino-1,1-binaphthyl
O
O N Ph
N
132
Ph Ts
NHTs +
(a)
N n-C8H17
n-C8H17CH=C=CH2
I 133
134
(a) Pd(OAc) 2 (5 mol %), 132 (10 mol %), Ag 3PO4 (1.2 equiv of silver ion equiv), DMF, 90 °C, 24 h. Scheme 32a
94% yield 82% ee
1308
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
O N PPh2
Ph
135 I Me
NHCH2Ph
Me
(b)
Me
N
+ 136
137
Me
138
(b) Pd(OAc) 2 (5 mol %), 135 (10 mol %), Ag 3PO4 (1.0 equiv of silver ion equiv), DMF, 100 °C, 48 h, 61% y., 67% ee. Scheme 32b
(BINAPAs, 139) has been synthesized and successfully applied to the AHR of a system similar to 109 (Scheme 33) with superior efficiency compared to BINAP.[91] Whereas the yield for the conversion of 140 to 141 has been 74% using BINAP, it could be improved to 91% by using BINAPAs under otherwise identical conditions. The ee remained virtually unchanged.
AsPh2 PPh2
BINAPAs 139
OTf
OTBDPS
Pd2dba3 (10 mol %) (R)-BINAPAs (30 mol %)
3
OTBDPS
K2CO3 (5 mol equiv) 40 °C, 46 h, 91% 88% ee
141
140 Scheme 33
Another new direction was recently pointed out by Shibasaki and co-workers by successfully carrying out an AHR that allowed a kinetic resolution of the racemic starting material (Scheme 34).[92] With that method, a possible intermediate (143-) for the total synthesis of wortmannin could be isolated with 96% ee after subjecting the
IV.2.3 ASYMMETRIC HECK REACTIONS
1309
O MOMO
O (a)
OTf
H
TBDPSO (rac)-142 (a) Pd(OAc) 2 (20 mol %), (R)-Tol-BINAP (40 mol %), K2CO3 (2.5 mol equiv), toluene, 100 °C, 1.5 h O
MOMO TBDPSO
O
MOMO
O
O
TBDPSO H
H
143-α
143-β
yield 20% (143-α and 143-β) 143-α : 143-β = 1:5 ee (143-β) 96% Scheme 34
racemic triflate ()-142 to Heck conditions (the absolute configuration was determined using Mosher’s method). Such reaction sequences could eventually prove to be extremely valuable and convenient for the enantioselective synthesis of natural products in general. Quite recently, a highly regioselective and enantioselective AHR was reported by Tietze and co-workers by developing a new chiral ligand BITIANP.[93] With the use of BITIANP only 54 was obtained, whereas with BINAP the regioselectivity is rather low; with a substituted MeO-BIPHEP ligand a 22:1 ratio of 54 and 55 was obtained[94]; and with chiral phosphinooxazolines only 55 was obtained (Scheme 35). Remarkable diastereoselectives have also been observed for AHR with the chiral auxiliaries RAMP or SAMP (Scheme 36a)[95] and with the chiral sulfoxides (Scheme 36b).[96],[97] F.ii. Methodological Directions Efforts to increase the catalyst turnover number are indeed another major area where further improvements can be expected.[98] Such improvements have recently been achieved using preformed palladacycles as catalysts[99] or by using a macrocyclic tetraphole as ligand.[100] Dendritic diphosphine–palladium complexes as catalysts for Heck reactions have also been reported to possess superior stability compared to the monomeric parent compounds.[101] In addition, the same research group could considerably activate the rate of the Heck reaction of chlorobenzene and styrene by addition of tetraphenylphosphonium salts and N,N-dimethylglycine.[102] Transferring such innovations to the AHR remains an important goal.
1310
IV PD-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Me S
S PPh2 PPh2
Me
PPh2
Me
PPh2 S
S
Me 145
144 OTf conditions
+
+ O
O 48
128
Ph
Ph
O
54
55
Intermolecular asymmetric Heck reaction of 48 and 128 Run Pd2(dba)3 CHCl3 (mol %) 1 2 3 4 5 6 7
3 3 5 3 5 5 5
Ligand (mol %) BITIANP 144 (12) BITIANP 144 (12) BITIANP 144 (10) BINAP (12) TMBTP 145 (10) TMBTP 145 (10) TMBTP 145 (10)
Base (equiv)
Solvent Temperature Time Ratioa (°C) 54/55
DMF PS (3)c i-Pr2NEt (3) DMF i-Pr2NEt (3) THF DMF PS (3)c i-Pr2NEt (3) DMF i-Pr2NEt (3) THF Benzene PS (3)c
90 90 70 90 90 70 70
18 h 100:99 >96
71 59 67 76
H H H Me H H Cl CF3 H H
Me Decyl Prop-l-enyl Me Me Cl H Me CO2Et H
H H H H Me H H H H H
91 83
>99 >99
72 62 — — — — — — — —
a b
crude mixture. after recrystallization.
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
1565
Again, only monosubstituted amides can be employed as substrates, while one additional substituent—no matter if electron donating or withdrawing— causes failure of the cyclopropanation. Consequently, the cyclic amide 22 combining the advantages of olefinic strain and ,-unsaturated carbonyl compound could be cyclopropanated in excellent yield and good diastereoselectivity (9:1) (Scheme 4).[12],[13] O
O CH2N2
NBoc
NBoc
cat. Pd(OAc) 2 100%
OSiMe2t-Bu 22
OSiMe2t-Bu 23 Scheme 4
The alkene 24 can be cyclopropanated with diazomethane in high yield, offering an attractive way to functionalize ,-unsaturated aldehydes diastereoselectively by first forming the N,O-acetales with chiral amino alcohols (Scheme 5).[14]
H
N
H CH2N2
Ph
O
Ph
N
R
cat. Pd(OAc) 2 100%
O
Ph
> 90% de 24
25 Scheme 5
Attempts to carry out carbene transfer reactions with chiral palladium catalysts were unsuccessful so far. Denmark et al. conducted a detailed study[15] in which cyclopropanations of ,-unsaturated carbonyl compounds with diazomethane catalyzed by bis(oxazoline)palladium(II) complexes were investigated. Virtual no asymmetric induction was obtained in these reactions which led to the conclusion —especially in light of the excellent asymmetric environment bis(oxazolines) metal complexes offer in general — that partial or complete ligand dissociation must have been occurred during the course of the reaction.
C. CYCLOPROPANATION OF ALKENYLBORONIC ESTERS Alkenylboronic esters proved to be good substrates for the palladium catalyzed cyclopropanation by diazomethane (Table 3).[16],[17] Since the substrates can be obtained by hydroboration of alkynes and the resulting cyclopropylboronic ester can be further modified, this strategy offers an especially versatile entry to functionalized cyclopropanes. Besides oxidation to cyclopropanols, functionalization in Suzuki coupling reactions are possible as discussed in Sect. III.2.2.
1566
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 3. Cyclopropanation of vinyl boranes with dizomethane R2 R
O B O
1
R2
Pd(OAc) 2 (5 mol %) 0 °C, CH2N2/Et2O
R
R3
O B O
1
R3
R1
R2
R3
Yield (%)
H n-Bu H Cl(CH2)3 H CH3OCO PhSCH2 Me3Si CH3 CH3 PhS
H H n-Bu H H H H H CH3 H H
H H H H CH3 H H H H CH3 H
92 88 67 90 72 63 62 83 0a 0b 0c
a
Starting material was recovered unchanged. 40/60 mixture of starting material and product. c only unidentified products were obtained which obtained neither the starting material nor the product. b
Moreover, alkenylboronic esters can be modified by chiral auxiliaries,[18]–[20] and especially the TADDOL auxiliary has been demonstrated to be an effective chiral inductor for the cyclopropanation reactions discussed here (Table 4).[19],[20] In order to keep the catalyst concentration low its pretreatment by ultrasonication to guarantee a fine distribution was found to be advantageous. TABLE 4. Cyclopropanation of vinyl boranes modified with the TADDOL auxiliary with diazomethane Ph Ph
R
O B O
OMe OMe
Ph Ph Pd(OAc) 2 (5 mol %) 0 °C, CH2N2/Et2O
R
O B O
Ph Ph
OMe OMe Ph Ph
R
de (%)
Yield (%)
n-Bu t-Bu n-Pentyl TPSO(CH2)3 Ph TBSOCH2 HOCH2
78 74 86 90 72 40 60
98 95 99 89 93 90 98
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
1567
D. CYCLOPROPANATION OF NON FUNCTIONALIZED ALKENES Non functionalized alkenes undergo cyclopropanation with diazomethane/Pd(II) if they are strained[21]–[23] or terminal substituted.[24] Consequently, carbene transfer to alkenyl substituted cyclohexenes occurs highly regioselective,[24] contrasting the reactivity of such derivatives towards cyclopropanation using diiodomethane/zinc or metal carbenoids (Table 5). TABLE 5. Cyclopropanation of unfunctionalized alkenes with diazomethane R2
R2
CH2N2 /Pd(OAc)2
R1
R1
Alkene
Product
n-Oct
n-Oct
CO2Et
CO2Et
Yield (%)
Reference
89
[24]
90
[22]
77
[24]
82
[24]
63
[24]
91a
[23]
93a
[23]
67
[21] (Continued )
1568
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 5. (Continued ) Alkene
a
Product
Yield (%)
Reference
63
[21]
89
[21]
mixture of diastereomers.
Accordingly, the regioselective cyclopropanation of FK506 can be understood despite of the two other C—C double bonds present and, most notably, the carbonyl function at C-9 which reacts with diazomethane in the absence of palladium(II) acetate to the corresponding oxirane (Scheme 6).[25] HO
HO
MeO
Me
MeO
Me
O OH
O N
O
O
Me
O O
CH2N2
[Ref 25]
O
OMe OMe
N
Pd(OAc) 2 87%
Me
9
HO Me
O
O
Me
O Me
9
O
O
OMe
HO Me
FK506
OH
OMe
Scheme 6
A very large number of norbornene derivatives has been cyclopropanated in good yields giving the exo distereomer in all cases (Scheme 7).[5],[6],[21],[23],[26]–[29] Besides strained cyclopentenes, cyclobutenes such as dewar benezene derivatives (see Table 5) also undergo cyclopropanation with respectable yields. In contrast, cyclopropenes react with diazomethane in a complex manner to form mixtures of monomeric
R2 R1
R2
R3 CH2N2 Pd(OAc) 2 62–100%
R3
R1 H H
Scheme 7
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
1569
products as a result of ring opening and insertion accompanied by considerable amounts of oligomeric products.[5] Interesting results are obtained for the cyclopropanation of conjugated dienes and polyenes (Table 6). Not surprisingly, aryl substituted alkenes react selectively at the olefinic double bond, but also in non aromatic polyenes differentiation of the double TABLE 6. Cyclopropanation of polyenes with diazomethane Alkene
Yield (%) Comment
Product
Ph
Reference
90
[30]
98
[5]
Ph S
S
along with 29% of biscyclopropyl product
70
along with 12% of [26] regioisomer and 9% of biscyclopropyl product
90
[6]
65
along with 15% of biscyclopropyl product
91
2
(CH2)3CO2Et
[26]
[6]
49
along with 6% of terminal regioisomer and 8% of α ,ω biscyclopropyl product
75
along with 15% of monocyclopropyl product
[26]
53
along with 13% of biscyclopropyl product
[26]
90
(CH2)3CO2Et 2
[26]
67
[6]
[5]
1570
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 7. Cyclopropanation of allenes with diazomethane R
CH2N2
•
+
Pd(OAc) 2
R
R 27
26
R
28
Yield of 27 (%)
Bu CH2CH2OH CH2CH2OAc CH2CH2OTs CH2CH2Br Ph
Yield of 28 (%)
67 2 34 78 63 49
25 60 56 — 27 —
bonds has been successful. For a number of 1,3-butadienes it was demonstrated that monocyclopropanation preferentially takes place at the sterically less hindered double bond. A terminal conjugated double bond is more reactive than a non conjugated one. Although in many cases regioisomers or biscyclopropanated products are obtained, some impressive cases of regioselective cyclopropanations of dienes or even trienes have been reported (Table 6). However, 1,3,5-cyclohexatriene and 1,3,5,7-cycloocattetraene failed to give cyclopropanation at all.[5] Allenes are also successfully cyclopropanated if a large excess of diazomethane is employed, which preferentially takes place at the less substituted double bond. Nevertheless, the bisadducts are formed in many cases as well (Table 7).[31] However, in these reactions complex mixtures of unusual side products resulting from an oligomethylenation have been also isolated. The products can be explained by invoking intermediates like 29, which undergo methylene insertion into the metal carbon bond (Scheme 8).[32] Ph CH2N2
• R
CH2
Pd(OAc) 2
Pd CH2 29
26 Scheme 8
E. CYCLOPROPANATION OF ALLYLOXY AND RELATED COMPOUNDS Allyloxy[33],[34] and allylamino[12],[33]–[35] are also good substrates for the title reaction. While mostly terminal alkenes have been used, internal alkenes are activated sufficiently in such cases to undergo cyclopropanation (Table 8).
1571
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
TABLE 8. Cyclopropanation of allylic substrates with diazomethane R1
R1
[I], [II] or [III]
X
X
[I] = CH2N2 (2 equiv), PdCl2(PhCN)2 (0.2–0.5 mol %), CH2Cl2/Et2O (1:1), 0–10 °C, 30 min; then r.t. [II] = CH2N2 (excess), Pd(OAc) 2 (10 mol %), Et2O, r.t. [III] = CH2N2 (excess), Pd(OAc) 2 (1 mol %), Et2O, –10 to –25 °C R1
X
Yield (%)
Method
Reference
H CH2CHCH2 H H H H OEt CH2OMs H H H CO2Et
OH OH OMe OPh O-(3-BrC6H4) OAc OEt OCH2P(O)(Oi-Pr)2 NH2 NMe2 NHPh NHBoc
72 31 74 88/97 85 80 81 96 65 68 62 80
I I I I/III I I I I I I I II
[33] [37] [33] [33]/[24] [33] [33] [33] [34] [33] [33] [33] [35] [12]
46
II
15
III
82 76
III III
O O
NHBoc
H
Si(OEt)3 R
N R O
[38] [38]
R
Si
O O
R=H R = Me
Especially, vinylglycins (Scheme 9, see also Table 8) can be used as substrates, opening a synthetic route to conformationally restricted, non-proteinogenic amino acids, which display interesting biological properties.[35],[36] Also, homoallyl amines are converted to the corresponding cyclopropanes by palladium(II)/diazomethane as was demonstrated with the synthesis of the -cyclopropylalaninol derivative 31 (Scheme 10). [39] NHBoc
NHBoc AcO
CH2N2
CO2Me
Pd(OAc) 2 68%
AcO
CO2Me
mixture of 2 diastereomers Scheme 9
1572
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
NBn2
NBn2
CH2N2
OCby
OCby
cat. Pd(OAc) 2 98%
30
31
OCby =
O
O
N O
Scheme 10
In contrast, vinylamines seem to be less useful substrates, i.e. cyclopropanation of -arylvinylamines with diazomethane occurs only in low yields.[40] 1-oxy-1,3-butadienes 32 are cyclopropanated regioselectively and stereospecifically at the terminal alkene double bond, giving rise to vinylcyclopropanes 33 (Scheme 11).[33] Again, use of palladium(II) acetate as the catalyst proved to be superior in comparison with copper(I) chloride, which only resulted in product mixtures.
[I]
OR
OR 32
83–86%
[Ref 33]
33
R = Me, Et, Ac, SiMe 3
[I] = CH2N2 (1.5 equiv) / PdCl2(PhCN)2(0.4 mol %) / CH 2Cl2 / Et2O, 0–10 °C, 30 min; then r.t. Scheme 11
F. CYCLOPROPANATION WITH DIAZOACETATES Diazoacetates are also known to decompose under the influence of palladium catalysts, however, only with ,-unsaturated alkenes and strained cycloalkenes good yields of cyclopropanes are obtained (Table 9). This was investigated in detail by intermolecular competition experiments between olefins having different coordinating power.[41] With styrene and ethyl diazoacetate as model reaction it was also established that palladium(II) acetate is the most efficient catalyst for such reactions (catalyst (Yield): Pd(OAc)2 (98%), PdCl2 (70%), PdCl2 2PhCN (65%), Pd(PPh3)4 (57%), Pd on C (0%)).[42] Doyle et al. reported similar results using PdCl2 2PhCN as a catalyst (Table 10) in a comparative study with rhodium(II) and copper(I) catalysts.[41] Last but not least, formation of the oxazole 35 has been observed in the reaction of methacrylonitirile (34) and diazoacetate catalyzed by palladium(II) acetate (Scheme 12).[45]
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
1573
TABLE 9. Cyclopropanation of alkenes with diazoacetates EtO2C
R2 N2CHCO2R/Pd(OAc)2
R3
R1
R2 R1
R4
R1
R2
R3
R4
Ph Ph Ph 4-Me-Ph 4-MeO-Ph 4-Cl-Ph 2-No2-Ph 4-No2-Ph 4-NMe2-Ph Ph Ph 4-pyridyl 1-imidazoyl n-Bu Me Me Et Me Me n-Pr Me
H H Me H H H H H H Ph H H H H H H H H H H Me
H H H H H H H H H H Ph H H H H Me H H n-Pent H Me
H H H H H H H H H H H H H H Me H Et n-Pent H n-Pr Me
R
R3 R4
Yield (%)
Reference
Et Et Et Me Me Me Me Me Me Me Me Me Me Me Me Me Et Me Me Me Et
76 a 98b 42b 81b 79b 86b 73b,c 77b,c 0b 0b 0b 0b 0b 30b 24b 21b 15b 5b 2b 12b 5b
[43] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42] [42]
Et
37, 11b,d
[42],[44]
Et
35, 13b,d
[42],[44]
Et
37b
[42],[44]
Et
60b
[42]
Me
15 b
[42]
Et n-Bu
b
21 19 b
Et
18–21b
[42],[44]
Et
40b
[42]
(Continued )
1574
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 9. (Continued ) R1
OAc OEt
R2
R3
H H
R4
H H
H H
R
Yield (%)
Reference
Et
20b
[42]
Et
10b
[42],[44]
Et
87b
[42]
Et
95b
[42]
Et
20b
[42]
Et Et
5b 42b
[42] [42]
20b
[42]
Et
88e
[13]
Et
14e , f
[13]
Et Et Et Et Et
85a 30a traceb 76a 64a
[43] [43] [43] [43] [43]
O
NHBoc OTBS
Boc
N O
CO2Me CO2Me CO2Me CO2Me CO2Me
H Me H H H
H H H H H
H H CO2Me H H
a 0.03 mol Alkene, 0.04 mol diazoacetate, 0.4 mmol Pd(OAc)2, benzene, yield based on alkene employed. b 0.03 mol Alkene, 0.002 mol diazoacetate, 0.01 mmol Pd(OAc)2, yield based on diazoacetate employed. c Product was obtained not pure. d Yield for cyclopropanation of disubstituted double bond. e 15 mmol Alkene, 150 mmol diazoacetate, 1.5 mmol Pd(OAc)2, ether, yield based on alkene employed. f
80% of the starting material was recovered.
1575
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
TABLE 10. Cycopropanation of alkenes with ethyl diazoacetate R2
R3
R1
R4
PdCl2 • 2PhCN N2CH2CO2Et
R2
CO2Et R3
R1
R4
R1
R2
R3
Yield (%)
Ph OEt On-Bu t-Bu C(Cl)=CH2 C(Ph)=CH2 C(Me)=CH2 C(t-Bu)=CH2 CH=CHOMe (trans) CH=CHCl (trans) Me t-Bu Me Cl OMe t-Bu
H H H H H H H H H H OMe OMe CH=CH2 CH=CH2 CH=CH2 CH=CH2
H H H H H H H H H H H H H H H H
52 43 34 34 8 5/10 a 16/24 a 4/6 a 16/22 a 8 66 28 8/24 a 2/4 a 12/12 a 2/6 a 31 41
O
20 OMe a
39
Mixture of diastereomers.
CN
N
Pd(OAc) 2
O
N2CH2CO2Et 30%
34
35
OEt
Scheme 12
G. CONCLUSION Palladium(II) compounds are clearly the catalysts of choice for cyclopropanation of alkenes with diazomethane. A broad range of alkenes is amenable for this process, nevertheless, ,-unsaturated carbonyl compounds and strained alkenes generally give the best results. While no enantioselective process by means of chiral palladium catalysts have
1576
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
been developed so far, various auxiliary based strategies have been used to synthesize cyclopropane derivatives with good enantioselectivitiy. Although it also has been demonstrated that cyclopropanations with diazoacetates can be catalyzed by palladium(II), rhodium(II) and copper(I) catalysts seem to be superior in such cases.
REFERENCES [1] W. Kirmse, M. Kapps, Chem. Ber., 1968, 101, 994. [2] M. Kapps, W. Kirmse, Angew. Chem., 1969, 81, 86. [3] Y. V. Tomilov, V. A. Dokichev, U. M. Dzhemilev, O. M. Nefedov, Russ. Chem. Rev., 1993, 62, 799–837. [4] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds. From Cyclopropanes to Ylides, John Wiley & Sons, Inc, New York 1998, 233pp. [5] F. Z. Dörwald, Metal Carbenes in Organic Synthesis, VCH-Wiley, Weinheim 1999, 114pp. [6] U. M. Dzhemilev, V. A. Dokichev, S. Z. Sultanov, R. I. Khusnutdinov, Y. V. Tomilov, O. M. Nefedov, G. A. Tolstikov, Izv. Akad. Nauk., Ser. Khim., 1989, 1861. [7] U. Mende, B. Radüchel, W. Skuballa, H. Vorbrüggen, Tetrahedron Lett., 1975, 629–632. [8] R. A. Periana, R. G. Berman, J. Am. Chem. Soc., 1986, 108, 7346. [9] B. Raduechel, U. Mende, G. Cleve, G.-A. Hoyer, H. Vorbrüeggen, Tetrahedron Lett., 1975, 633–636. [10] J. Vallgaarda, U. Hacksell, Tetrahedron Lett., 1991, 32, 5625–5628. [11] J. Vallgaarda, U. Appelberg, I. Csöregh, U. Hacksell, J. Chem. Soc. Perkin Trans. 1, 1994, 461–470. [12] K. Shimamoto, Y. Ohfune, Tetrahedron Lett., 1989, 30, 3803–3804. [13] K. Shimamoto, Y. Ohfune, J. Org. Chem., 1991, 56, 4167–4176. [14] H. Abdallah, R. Gree, R. Carrie, Tetrahedron Lett., 1982, 23, 503–506. [15] S. E. Denmark, R. A. Stavenger, A.-M. Faucher, J. P. Edwards, J. Org. Chem., 1997, 62, 3375–3389. [16] P. Fontani, B. Carboni, M. Vaultier, R. Carrié, Tetrahedron Lett., 1989, 30, 4814. [17] P. Fontani, B. Carboni, M. Vaultier, G. Maas, Synthesis, 1991, 605. [18] J. E. A. Luithle, J. Pietruszka, Liebigs Ann./Recueil, 1997, 2297–2302. [19] J. E. A. Luithle, J. Pietruszka, A. Witt, Chem. Commun., 1998, 2651–2652. [20] J. E. A. Luithle, J. Pietruszka, J. Org. Chem., 1999, 64, 8287–8297. [21] J. Kottwitz, H. Vorbrüggen, Synthesis, 1975, 636–637. [22] M. P. Doyle, L. C. Wang, K.-L. Loh, Tetrahedron Lett., 1984, 25, 4087–4090. [23] N. S. Zefirov, S. I. Kozhushkov, T. S. Kuznetsova, O. V. Kokoreva, K. A. Lukin, B. I. Ugrak, S. S. Tratch, J. Am. Chem. Soc., 1990, 112, 7702–7707. [24] M. Suda, Synthesis, 1981, 714. [25] A. J. F. Edmunds, K. Baumann, M. Grassberger, G. Schulz, Tetrahedron Lett., 1991, 32, 7039–7042. [26] Y. V. Tomilov, V. G. Bordakov, I. E. Dolgii, O. M. Nefedov, Izv. Akad. Naul, Ser. Khim., 1984, 33, 582. [27] M. Engelhard, W. Lüttke, Angew. Chem., 1972, 84, 346. [28] O. Pilet, A. Chollet, P. Vogel, Helv. Chim. Acta, 1979, 62, 2341.
IV.9 CYCLOPROPANATION AND OTHER REACTIONS OF Pd-CARBENE COMPLEXES
1577
[29] I. V. Kazimirchik, K. A. Lukin, G. F. Bebikh, N. S. Zefirov, Zh. Org. Khim., 1983, 15, 105. [30] R. Paulissen, A. J. Hubert, P. Teysie, Tetrahedron Lett., 1972, 13, 1465–1468. [31] N. S. Zefirov, S. I. Kozhushkov, T. S. Kuznetsova, K. A. Lukin, I. V. Kazimirchik, Zh. Org. Khim., 1988, 24, 673–678. [32] K. A. Lukin, T. C. Kuznetzova, S. I. Kozhushkov, V. A. Piven, N. S. Zefirov, Zh. Org. Khim., 1988, 24, 1644–1648. [33] Y. V. Tomilov, A. B. Kostitsyn, E. V. Shulishov, O. M. Nefedov, Synthesis, 1990, 246–248. [34] K.-L. Yu, J. J. Bronson, H. Yang, A. Patick, M. Alam, V. Brankovan, R. Datema, J. Med. Chem., 1993, 36, 2726–2738. [35] K. O. Hallinan, D. H. G. Crout, W. Errington, J. Chem. Soc., Perkin Trans. 1, 1994, 3537–3543. [36] N. Kurokawa, Y. Ohfune, Tetrahedron Lett., 1985, 26, 83–84. [37] Y. V. Tomilov, A. B. Kostitsyn, V. A. Dokichev, U. M. Dzhemilev, O. M. Nefedov, Izv. Akad. Nauk. SSSR, Ser. Khim., 1989, 2752. [38] G. S. Zaitseva, S. S. Karlov, A. V. Churakov, E. V. Avtomonov, J. Lorberth, D. Hertel, J. Organometal. Chem., 1996, 523, 221–225. [39] K. Rehse, S. Behncke, U. Siemann, W. Kehr, Arch. Pharm., 1980, 313, 221. [40] M. P. Doyle, R. L. Dorow, W. E. Buhro, J. H. Griffin, W. H. Tamblyn, M. L. Trudell, Organometallics, 1984, 3, 44–52. [41] T. Hense, D. Hoppe, Synthesis, 1997, 1394–98. [42] A. J. Anciaux, A. J. Hubert, A. F. Noels, N. Petiniot, P. Teyssié, J. Org. Chem., 1980, 45, 695–702. [43] M. W. Majchrzak, A. Kotelko, J. B. Lambert, Synthesis, 1983, 469–470. [44] A. J. Anciaux, A. Demonceau, A. F. Noels, R. Warin, A. J. Hubert, P. Teyssié, Tetrahedron, 1983, 39, 2169. [45] R. Paulissen, P. Moniotte, A. J. Hubert, P. Teyssié, Tetrahedron Lett., 1974, 37, 3311–3314.
PdLn
PdLn
IV.10
Carbopalladation via Palladacyclopropanes and Palladacyclopropenes
IV.10.1 Palladium-Catalyzed Oligomerization and Polymerization of Dienes and Related Compounds JAMES M. TAKACS
A. INTRODUCTION Simple 1,3-dienes such as 1,3-butadiene, isoprene, and related compounds undergo efficient metal-catalyzed oligomerization. Under palladium catalysis, diene dimerization is the most common oligomerization reaction observed. Four modes of dimerization have been reported (Scheme 1): (i) [2 2] cycloaddition to afford 1,2-divinylcyclobutane (1); (ii) [4 2] cycloaddition to afford 4-vinylcyclohexene (2); (iii) [4 4] cycloaddition to afford 1,4-cyclooctadiene (3); and (iv) linear dimerization to afford 1,3,7-octatriene (4). A number of catalyst systems have been uncovered that produce some 1,2-divinylcyclobutane as a significant component of a product mixture, but, at present, there are no generally applicable, preparative useful catalyst systems that afford 1,2-divinylcyclobutanes with high mode selectivity. Selective diene dimerization via the [4 2] cycloaddition mode[1] or [4 4] cycloaddition mode[2] is best obtained using nickel catalysis, and, in particular, the latter mode has proved very useful for the synthesis of a wide range of functionalized cyclooctadienes.[3],[4] Selective linear dimerization can be accomplished via a variety of metals, including nickel,[5] platinum,[6] rhodium,[7]–[9] cobalt,[8],[9] and iridium[8],[9]; albeit, some of these metal catalyst systems are described only in isolated reports. Generally, palladium is the catalyst of choice for this mode of diene oligomerization. A.i. Palladium-Catalyzed Linear Dimerization: Reaction Modes Four related Pd-catalyzed linear dimerization modes have been observed for the intermolecular reaction of 1,3-dienes (Scheme 2). While potentially of industrial importance for bulk Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1579
1580
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
1
2
4 3 Scheme 1 Y HY catalyst
catalyst
4
5
SiR3
R3SiX
R2C Y
catalyst
catalyst
R
X 6
Y R 7
Scheme 2
chemical production, the relatively least developed of these is the linear dimerization to 1,3,7-octatriene (4) or its substituted derivatives. The coupling of two diene molecules with incorporation of a third component (trapping reagent) is much more common. Three types of trapping reagents have been employed. (i) Protic trapping reagents (e.g., H—Y an alcohol, a phenol, a carboxylic acid, a 1°- or 2°-amine, a sulfinic acid, an active methylene or methine compound, a nitroalkane, or an enamine) afford predominantly 1-substituted 2,7-octadienes 5. (ii) Silanes, stannanes (e.g., R3Si—X or R3Sn—X; X H), or disilanes (e.g., R3Si—X, X SiR3) afford predominantly 2,6-octadiene derivatives 6. (iii) Finally, certain R2C"Y reagents (e.g., aldehydes, ketones, imines, carbon dioxide, or isocyanates) yield 7, the products of a net cycloaddition reaction. Several other miscellaneous trapping reactions are also known. A.ii. Palladium-Catalyzed Linear Dimerization: Mechanism Most of the work on the mechanism of Pd-catalyzed linear diene dimerization has been done on the variant involving dimerization with trapping by a protic trapping reagent H—Y, and a particularly interesting series of papers has been published by Jolly and co-workers.[10]–[14] In these and related papers, structural and spectroscopic data are presented that support the catalytic cycle shown in Scheme 3.[15]–[17] While the Jolly catalytic cycle is not without some controversy,[18] it provides a good working model to rationalize the observed coupling chemistry.
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1581
Y HaY
5
palladium catalyst
Ha LnPd(0)
LnPd(0) complexation
decomplexation
Y Pd Ln
Pd
Ln
Ha 9
8 nucleophilic addition of Y –
oxidative coupling
Ha+
Pd
Ln
Pd Ln
SE2′
Ha
10
11 Scheme 3
The active catalyst is presumably a palladium(0) species,[19]–[22] and the dienes must in some way complex about the metal (e.g., 8).[23] The first directly observed intermediate, the palladacycle 10, is the result of oxidative coupling of the dienes; that is, the dienes undergo oxidative addition onto the palladium concomitant with coupling. In the case of palladium, as well as nickel[24] and platinum,[9] metallacycles of type 10 have been characterized both crystallographically and spectroscopically.[13],[25],[26] An isolated palladacycle 10 was stoichiometrically protonated by H—Y (i.e., methanol) at low temperature (80 °C). The observed site of protonation was at the 1-allyl moiety in an SE2 fashion to afford an intermediate, the NMR spectrum of which is consistent with the chelated -allylpalladium intermediate 11. Upon warming (35 °C), addition of the nucleophile Y afforded the presumed chelate 9, a species shown to be a competent catalyst for further consumption of butadiene.[16],[17] It has been suggested on the basis of calorimetric analysis that, at least under certain conditions, release of product from chelate 9 may be rate determining.[19],[27] The model in Scheme 3 nicely accounts for the selective formation of the 2,7-octadienyl isomer as well as the site of selective deuteration upon reaction with isotopically labeled 2H—Y trapping reagents; for example, reaction with CH3OD or H3CO2D affords 5 wherein the proton labeled Ha is replaced by deuterium. Recent advances in each of the four Pd-catalyzed linear diene dimerization modes (Scheme 2: dimerization without trapping; dimerization with incorporation of protic H—Y trapping reagents; dimerization with incorporation of silanes or disilanes; and
1582
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
dimerization with incorporation of R2C"Y reagents) are discussed below (Sects. B–E). In some cases both the intermolecular reaction of 1,3-dienes as well as recent examples of the corresponding intramolecular cyclization reaction of bisdiene substrates are discussed. For additional details, especially of the older literature in this area, the reader is referred to a number of previous review articles.[25],[28]–[34]
B. DIMERIZATION WITHOUT TRAPPING B.i. Intermolecular Linear Dimerization of Hydrocarbon Dienes The Pd-catalyzed linear dimerization of butadiene or isoprene in the absence of trapping reagent affords the linear dimer 1,3,7-octatriene (4) or its methylated derivative.[29],[35]–[37] Hagihara and co-workers[38] originally reported that, in the absence of trapping reagent, treatment of butadiene with the bis(triphenylphosphine)(maleic anhydride)palladium(0) complex (0.01 mol %, acetone, 115 °C) affords 1,3,7-octatriene in 85% yield. Nickel[39]–[43] and cobalt[44] catalyst systems have also been described. Mechanistically, this reaction can be understood on the basis of the Jolly mechanism. As before, oxidative coupling affords the palladacycle 12, and protonation (adding Ha in an SE2 fashion) leads to the chelated -allyl intermediate 13. In the absence of a good nucleophile, 13 loses proton Hb to afford a palladium(0) complex of the observed triene product (Scheme 4). It should be noted that the initially formed triene may subsequently undergo Pd-catalyzed double bond isomerization and thus in some cases product mixtures will be observed.
0.01 mol % [(Ph3P)2Pd(C4H2O3)] Me2CO, 115 °C
4 (85%) Hb Pd Ln
+ Ha+
Pd 12
Ln
– Hb+
Pd Ln
E2
SE2′
Ha 13
14
Scheme 4
B.ii. Intramolecular Diene Coupling of Alkyl-Substituted Dienes: Bisdiene to Enediene Cycloisomerization The intramolecular version of Hagihara’s dimerization of 1,3-butadiene to 1,3,7octatriene, that is, a bisdiene to enediene cycloisomerization, is also feasible. In the absence of any trapping reagent, bisdiene 15 (Scheme 5) undergoes Pd-catalyzed
1583
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
H E
0.05 equiv [Pd(OAc)2/2 Ph3P]
E
E
Et3N, THF, 65 °C
E
15 E = CO2Et
16 (65%) Scheme 5
cycloisomerization to give 16 in 65% yield (0.05 equiv [Pd(OAc)2 / 2 Ph3P], Et3N, THF, 65 °C).[45],[46] This reaction, however, is not particularly facile under the conditions examined. The enediene 16 is formed as a 1:1 mixture of diastereomers, and although in some cases one of the diastereomers was formed preferentially, the cycloisomerization of the homologous bisdiene leading to a six-membered ring compound proceeded in lower yield. At first glance bisdiene substrates in which the two 1,3-diene subunits are substituted differently (e.g., Scheme 6, 17) appear to be improper candidates for Pd-catalyzed cycloisomerization, as they would probably lead to a mixture of isomers (e.g., 18). This is known for the linear dimerization of simple substituted 1,3-dienes (e.g., isoprene or piperylene). The attempted selective cross-coupling of different 1,3-dienes usually affords a complex mixture of isomeric products (vide infra). Nonetheless, the Pd-catalyzed cyclization of bisdiene 17 does not form any of the isomeric 18 structures, but instead affords the single enediene 19 in near quantitative yield (95%). H
E
0.5 equiv [Pd(OAc)2/2 Ph3P] THF, 65 °C
E 17 E = CO2Et
H
E
R1
E
R2
(R1
H 18 2 = Me, R = H) and/or (R1 = H, R2 = Me)
E E 19 (95%) Scheme 6
This conversion of an acyclic bisdiene to a cyclized enediene constitutes a new Pd-mediated reaction mode, which can be rationalized as outlined in Scheme 7. Complexation of bisdiene 17 following oxidative cyclization (i.e., oxidative addition with intramolecular coupling of the diene moieties) affords palladacycle 20. Protonation in an
1584
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
E E E
Pd−L n
E Pd Ln 20
+ Ha+
21
17
SN2′
19 Hb
H
Hc
E
E
Pd
E Ha
Pd−L n
E Ln 22
– Hc+ E2
H 23
E = CO2Et Scheme 7
SE2 fashion (labeled Ha in structure 22) leads to the chelated -allylpalladium intermediate 22, which can potentially lose either of two protons (labeled Hb and Hc in structure 22) to afford either 18 or 19, respectively. From recent work in the literature, notably that of Krafft and co-workers,[47],[48] it is recognized that chelated -allylpalladium intermediates can show unusual regioselectivity in addition reactions. Perhaps related factors govern the regioselective loss of Hc to afford intermediate 23 and, ultimately, the enediene product 19; there is evidence suggesting that loss of proton Hc occurs via an E2 rather than -hydride elimination pathway.[46],[49] The Pd-catalyzed bisdiene to enediene cycloisomerization appears to be reasonably general. A variety of palladium catalyst precursors can be employed ([Pd(OAc)2 /2 Ph3P] and [(MeCN)2Pd(BF4)2 /2 Ph3P] appear to be quite generally applicable), and as illustrated by the reactions summarized in Scheme 8, five- and six-membered carbocyclic and heterocyclic ring systems are generally formed in high yields and with high diastereoselectivities. For both ring sizes, the cyclization establishes the trans configuration between the unsaturated side chains on the newly formed ring. Control over the double bond configurations can be high, although in some cases, mixtures arise from the failure to control the configuration of the double bond most remote from the newly formed C—C bond (e.g., 25a-b). In such cases, an additional diene substituent can help control the geometry (e.g., 25d-e). In general, electron-donating substituents on the diene slow down the rate of cycloisomerization. Labeling studies show that the hydrogen lost (i.e., Hc in Scheme 7) is not transferred intramolecularly (i.e., Ha Hc), and a large isotope effect associated with the loss of Hc suggests that deprotonation rather than -hydride elimination is mechanistically important.
1585
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
R2 E
R1
E R3
R1
E
0.05 equiv [PdX2/3 Ph3P]
R3
E
R2
Et3N, THF 65 °C
E = CO2Et 24a: (R1 = Et; R2 = R3 = H) b:(R1 = i-Pr; R2 = R3 = H) c: (R1, R2 = (CH2)4 ; R3 = H) d:(R1 = CH2Ph; R2 = H; R3 = Me) e: (R1 = Me; R2 = H; R3 = Me) R
X
25a: (93%, 4:1 E,E:E,Z ) b:(80%, 5:1 E,E:E,Z ) c: (93%) d:(>95%, >20:1 E,E:E,Z ) e: (93%, 15:1 E,E:E,Z )
0.05 equiv [PdX2/2−3 Ph3P]
R
X
Et3N, THF, 65 °C
27a: (84%) b: (86%) c: (88%, 4:1)
26a: (X = NSO, R = Et) b: (X = C(COEt) R = Et) c: (X = CH2, R = CH2C(OCH2)2CH3 Scheme 8
B.iii. Intermolecular Diene Dimerization: Influence of Ester Substituents While the intermolecular reactions of butadiene and related methyl or simple alkylsubstituted dienes have been investigated extensively, relatively few examples of the Pdcatalyzed linear dimerization of higher dienes have been reported. Brun and co-workers[50] in an isolated paper reported that, under palladium catalysis, reaction of methyl 2,4-pentadienoate (Scheme 9, 28) affords the linear dimer 29 in high yield (95%). Two aspects of this reaction are of particular interest. (i) The dimerization yields essentially only the tail-to-tail dimer 29, not the head-to-tail or head-to-head isomers (30 or 31, respectively). This is in contrast to the behavior of alkyl-substituted dienes under similar conditions (vide infra). (ii) Although no details are given, the authors imply that 29 is CO2Me CO2Me
0.01 equiv [Pd(OAc)2/1.7 Ph3P]
CO2Me
i-PrOH / 60 °C 95%
29 CO2Me
28 CO2Me
CO2Me or
NOT:
CO2Me 30
CO2Me 31
Scheme 9
1586
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
formed as a mixture of ,- and , -unsaturated isomers, an aspect of regiochemistry that will be important in the intramolecular case. B.iv. Intramolecular Diene Coupling: Influence of Ester Substituents Pd-catalyzed cyclization of bisdiene 32a (X H) affords enediene 33. Related bisdienes bearing an ester substituent undergo facile cycloisomerization via a complementary reaction pathway. For example, bisdiene 32b (X CO2Et) undergoes Pd-catalyzed cycloisomerization (0.05 equiv [Pd(OAc)2/3 Ph3P], 5 equiv Et3N, THF, 65 °C, 12 h) to afford product 34 in high yield ( 90%) and good diastereomeric purity ( 90%).[51] As in the case of 33, the three substituents on the cyclohexane core in product 34 have predominantly the trans,trans relationship, and the diene side chain is formed with the (E) configuration. The , -unsaturated ester moiety in 34 is formed selectively with a (Z ) double bond (Scheme 10) and a deconjugated ester moiety, somewhat reminiscent of the kinetic protonation of an extended enolate and of the Brun reaction of methyl 2,4-pentadienoate discussed above.
32a
Bn
33
0.05 [Pd(OAc)2 / 3 Ph3P]
X
Et3N, THF, 65 °C
Bn 32a (X = H) 32b (X = CO2Et)
32b
H Bn
H CO2Et
Bn
34 (>90%)
Bn 0.05 [Pd(OAc)2 / 3 Ph3P]
CO2Me
Et3N, THF, 65 °C
H MeO2C
35
H
36 (95%)
Scheme 10
Bisdiene 35 bears a complementary substitution pattern to that of 32b; that is, the benzyl substituent resides adjacent to the methyl-bearing 1,3-diene moiety. Bisdiene 35 also cyclizes smoothly under the conditions employed for 32b and affords compound 36 in high yield (95%), and with good diastereoselectivity ( 90% diastereomeric purity). Thus, bisdienes bearing an ester substituent undergo facile Pd-catalyzed cycloisomerization via a pathway that complements that found for substrates without the ester substituent. This defines a new bond construction that is inaccessible by classical
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1587
methods. The cyclization proceeds with good to excellent levels of stereoinduction relative to a resident asymmetric center in the bisdiene substrate and defines another control element that efficiently directs the cyclization of an unsymmetrical substrate. B.v. A Novel Formal [3 2] Cycloaddition Mode Bergamini et al.[52] reported an unusual variation on the linear dimerization, wherein Pdcatalyzed dimerization in acetonitrile/water and in the presence of CO2 affords 37 selectively (52% yield, turnover number (TON) 420). Under these conditions, only small amounts of the water-trapped product and 1,3,7-octatriene are observed as side products (Scheme 11). The formal intramolecular [3 2] cycloaddition product 37, particularly the 1,4-diene subunit imbedded in it, is reminiscent of the products obtained from cyclization of 3-allylpalladium intermediates onto pendant alkenes, a process termed a “palladium-ene reaction” by Oppolzer and Gavdin,[53] which has also been investigated by Negishi et al.[54] and Trost and Luengo.[55] One can account for the formation of 37 from the chelated -allylpalladium intermediate 39 by ligand insertion to 40 followed by -hydride elimination. A similar cyclization mode has been observed in the intramolecular reaction of an ester-substituted bisdiene. Treatment of bisdiene 41 with 0.05 equiv of [Pd(OAc)2 / 2 Ph3P] and 5 equiv of acetic acid (THF / 65 °C) affords the acetic acid-trapped product 42 (25% yield) and the [3 2] cycloaddition product 43 (45% yield) (Scheme 12).[56] H 0.02 [Pd(acac)2 /12 (o-tol)3P3] MeCN/H2O 5:1, CO2 (3 atm), 90 °C, 72 h
37 (52%) – H+
H H+
Pd
Ln
+ SE2′
PdLn
ligand insertion
PdLn 38
39
40
Scheme 11 CO2Et
OAc 0.05 equiv [Pd(OAc)2 / 3Ph3P]
CO2Et
H
5 equiv HOAc THF, 65 °C
+ EtO2C 42 (25%)
41 Scheme 12
H 43 (45%)
1588
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
C. DIENE DIMERIZATION WITH INCORPORATION OF A PROTIC H—Y TRAPPING REAGENT C.i. Introduction Simple 1,3-dienes, such as 1,3-butadiene and isoprene, undergo efficient metal-catalyzed linear dimerization with incorporation of an appropriate protic H—Y trapping reagent to afford functionalized octadienes, typically as a mixture of predominantly the 1substituted 2,7-octadiene 44 and minor amounts of the 3-substituted 1,7-octadiene isomer 45 (Scheme 13). The process, originally termed diene telomerization, was discovered in 1967 independently by Smutny[57] and by Hagihara and co-workers.[38] The original reports employed soluble palladium complexes as the metal catalyst precursor; however, subsequently a variety of metals, including nickel, platinum, cobalt, rhodium, and iridium, have been shown to catalyze this mode of diene dimerization.[28],[29] However, among these, palladium is generally the metal catalyst of choice. Y HaY
2
Y +
Pd catalyst
Ha
Ha 44
45
Scheme 13
In exploring this mode of dimerization a number of issues have attracted significant attention. These include (i) the search for new protic trapping reagents (H—Y); (ii) the search for new catalysts and catalyst precursors, including enantioselective catalysts; (iii) studies directed toward defining the factors controlling the distribution of regioisomeric products 44 and 45 and controlling the distribution; (iv) studies directed toward defining the factors controlling the distribution of head-to-head, head-to-tail, tail-to-head, and tail-to-tail regioisomeric products 46 (Scheme 14) obtained from the intermolecular dimerization of unsymmetrical dienes and controlling their distribution; (v) studies directed toward defining the factors controlling the intermolecular dimerization of bisdienes; and (vi) using the Pd-catalyzed linear dimerization reaction in natural products synthesis. Recent progress toward addressing each of these issues will be discussed in the sections below, organized according to the nature of the protic H—Y trapping reagent employed: alcohols and phenols; water; carboxylic acids; formic acid; amines, amides, imides, and sulfonamides; sulfinic acids; doubly activated C—H acidic compounds; enamines; nitroalkanes; and carbon monoxide/alcohol (“H—CO2R”).
Y HaY
2
Pd catalyst
R
R
R 46
Scheme 14
head-to-head, head-to-tail, tail-to-head, or tail-to-tail dimers possible
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1589
C.ii. Alcohols and Phenols as H—Y Trapping Reagents: Intermolecular Diene Dimerization The Pd-catalyzed telomerization of butadiene and isoprene with alcohols, diols, and phenols continues to attract significant attention.[58] – [64] A recent detailed study by Beller and co-workers offers new insights into the reaction of butadiene with methanol and highly optimized conditions for the selective formation of 1-methoxy-2,7-octadiene (Scheme 15, 47).[16] The authors find that palladium(0) complex 49[17] is an excellent catalyst for the dimerization – trapping reaction of butadiene with methanol, the catalyst being active even at 10 °C. Finding a convenient source of a palladium(0) – monophosphine complex is a very significant advance in this field, and one can expect that this catalyst system will find widespread use. OMe MeOH 49
2
OMe
+ 47
H
Pd
O
O
48
H
Me
?
PdPPh3
PPh3
+ Ph3P
O
Me
PdPPh3 Ph3P
49
51
50 Scheme 15
Beller and co-workers find that the ratio of 47 to 48 is influenced by the reaction temperature, the ligand to metal ratio, and the ratio of methanol to butadiene. A high 47/48 ratio can be obtained at relatively low temperature with one phosphine per palladium and a 1:2 methanol/butadiene ratio. For example, at 30 °C (2.5 h, 36% conversion, TON 1376, turnover frequency (TOF) 556 h1), the 49-catalyzed reaction affords 34% combined yield of 47 and 48 in a 36:1 ratio. Addition of a second equivalent of phosphine per palladium decreases the regioselectivity (12:1 47/48). The authors suggest that disruption of the chelated -allylpalladium intermediate 50 by displacement of the complexed alkene by the second phosphine to 51 accounts for the lower regioselectivity. At 90 °C, impressive TON of 10,500 and TOF of 21,000 h1 are observed, although at higher temperature formation of 1,3,7-octatriene competes more effectively and comprises 23% of the product mixture. Carlini and co-workers carefully studied the influence of a series of mono- and diphosphines on the Pd(dba)2-catalyzed reaction of butadiene and methanol.[22] With monophosphines (2:1 phosphine:Pd(dba)2) it was found that more basic ligands afford more active catalysts; for example, the catalyst activity increases in the series: Ph3P Ph2PBu PhPBu2 PBu3. Bu3P, (C6H11)3P, and (i-Pr)3P afford catalysts of comparable activity;
1590
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
however, steric effects influence the ratio of trapping to formation of 1,3,7-octatriene. The latter two ligands afford about 80% trapping, while Bu3P affords 97% trapping product. In each case, the regioselectivity of trapping is high. A series of bidentate diphosphine ligands (dppm, dppe, dppp, and dppb) were also examined. The most strongly chelating ligands (dppe and dppp) gave the least active catalysts. In comparing the weakly chelating ligand dppb to the bridging ligand dppm, the former gives a higher TON and TOF (3310 and 1240 h1, respectively). Using the dppb catalyst, other primary alcohols (ethanol, n-propanol, n-hexanol) also react with butadiene; albeit somewhat slower (25–50% slower than methanol) and with lower selectivity for trapping relative to 1,3,7octatriene formation. In addition to the Beller catalyst system discussed above, several new catalysts have been introduced for the reaction of butadiene with methanol. For example, a number of cationic palladium complexes have been investigated. Basato and co-workers found that [(3-allyl)Pd((o-C6H4NMe2)PPh2)]PF6 and [Me(Ph3P)Pd(o-C6H4NMe2)PPh2)]OTf afford good catalysts, the former slightly better for the dimerization of butadiene with trapping by methanol.[21] Good TON and TOF numbers (1700 and 466 h1, respectively) were observed for the former catalyst when activated by the addition of sodium methoxide. The aminophosphine ligand ((o-C6H4NMe2)PPh2)) is thought to play an important role in catalyst stability, and the 1:1 combination of Pd(dba)2 plus (o-C6H4NMe2)PPh2) affords an even more active catalyst. A similar conclusion regarding ligands was reached by Carlini and co-workers in comparing a series of P—O, N—N, and P—N bidentate ligands to diphosphines. For the butadiene–methanol reaction, these authors found the P—N ligands to be the best, and, in particular, a 1:1 combination of Pd(dba)2 plus 2-diethylphosphino-1methyl-imidazole was especially promising.[65] Tkatchenko and co-workers reported that other cationic palladium complexes (e.g., [(3-allyl)Pd(ligand)2] X (X PF6, ClO4, BF4) afford a greater percentage of higher oligomers (principally C16 and C24) from the reaction of butadiene with alcohols and other protic trapping reagents.[66],[67] Certain cationic palladacyclic complexes behave similarly.[68] Water-soluble[63],[69],[70] or polymer-bound phosphorus ligands have been examined for their potential use as recoverable metal catalysts for diene dimerization.[71]–[78] For example, diphenylphosphinite functionalized cellulose binds palladium(II) chloride, which upon reduction with hydrazine forms a polymer-bound reduced palladium catalyst suitable for the linear dimerization of butadiene with methanol in benzene (97% yield).[72] A recent study by Carlini and co-workers into the potential of polymer-bound diphosphines showed that while a polymer-bound dppp catalyst system exhibited modest catalytic activity, an analogous polymer-bound dppm catalyst system showed quite good activity for the Pd-catalyzed reaction of butadiene with methanol (TON 199 h1). The activity is comparable to that of the corresponding soluble catalyst system (TON 217 h1).[79],[80] The authors conclude the catalyst is working as a real heterogeneous catalyst with significant potential for dimerization – trapping as well as for other Pd-catalyzed reactions. The linear dimerization of isoprene with alcohols also continues to be of interest.[27],[81] – [85] A rough correlation between the yield of octadienyl ether and the acidity of the alcohol was noted.[84] Thus, trifluoroethanol (pKa 12.39) and methanol (pKa 15.09) give high yields; ethanol (pKa 15.93), n-propanol (pKa 16.1), and n-butanol (pKa 16.1) give moderate yields; while tert-butyl alcohol (pKa 19) does not afford a linear dimer. C.ii.a. Polyols. cis-1,2-Cyclohexanediol reacts with excess butadiene in the presence of the catalyst system [Pd(acac)2-Ph3P-Et3Al] in (tert-BuOH, 100 °C, 10 h) to afford the
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1591
hydroxy ether 51 (Scheme 16) in 93% yield. Surprisingly, no bis(ether) formation is observed, and under forcing conditions the 2,7-isomer apparently isomerizes to the 1,7isomer.[60] The reaction with ethylene glycol proceeds similarly.[71] Two recent studies have examined the selective monoalkylation and polyalkylation of sucrose (Scheme 17, 52). Using Pd(acac)2/Ph3P, sucrose was efficiently polyalkylated with butadiene in 4:1 isopropanol/water to give a mixture of 2,7-octadienyl ethers averaging 4 – 5 ether linkages per sucrose.[86] While conditions for polyalkylation were found, Mortreux and co-workers also reported an alternative set of conditions that favor selective monoalkylation.[69] Treatment of sucrose (52) with Pd(OAc)2/3 TPPTS (TPPTS tris(msulfonatophenyl)phosphine) in 5:2 isopropanol/1 M NaOH (80 °C, 30 min, 73% conversion) afforded a 2:1 mixture of mono- and diethers, from which monoethers 53a (65%) and 53b (18%) were isolated. The reaction is of interest for its selective alkylation, the use of a water-soluble catalyst system, and the observation that NaOH acts as a strong activator for the reaction. HO
O
1,3-butadiene catalyst
HO
HO
51 Scheme 16
H OH OH
HO
HO HO
H HO H
O H HO
H
H
Pd(II)/TPPTS i-PrOH, 1 M NaOH
O H
HO
OH
52 H OH OR1
HO
HO HO
H
H HO H
O H R2 O
H
O HO
H
OH
53a: (R1 = C8H12, R2 = H) (65%) 53b: (R1 = H, R2 = C8H12) (18%) Scheme 17
C.ii.b. Enantioselective Catalysis. Hidai et al.[87] reported enantiomeric excesses of up to 35% in a widely cited study on the influence of certain chiral phosphines in the linear dimerization of isoprene with methanol. The tail-to-head product 54 (Scheme 18) predominates (2–5:1) over the tail-to-tail isomer 55. According to the model presented above, in this case the enantiomer ratio is set in the protonation step of the catalytic cycle
1592
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Me Me
Me
H OMe
+
[(CH2CHCH2)PdCl]2 L*
OMe
Me 54
OMe
Me 55
Me Br Pd 2
N
56 Me
Ph
Me 57 Scheme 18
(i.e., Schemes 3, 10, and 11). Menthyldiisopropylphosphine affords the highest enantioselectivity in this reaction (MenP(i-Pr)2, 2:1 54/55, 35% ee for 54), although the yield of dimers is low (14%). MenPPh2 gives higher yields (93%) and 29% ee for 54 (2:1 54/55). MenP(OPh)2 gives an 8% ee (60% yield, 5:1 54/55), and neo-MenPPh2 gives 13% ee (58% yield, 4:1 54/55). Dupont and co-workers reported similar studies on the dimerization of isoprene with trapping by methanol (isoprene, methanol, dichloromethane, 0.1% [Pd–phosphine catalyst]; 1.3 mol% NaOMe, 25 °C, 72 h).[88] Modest levels of enantiomeric excess were observed. These workers investigated a series of chiral ligands (i.e., ()-neomenthyldiphenylphosphine (()-nmdpp) Ph2P(O-menthyl); (S)-1-[(R)-2-diphenylphosphino)ferrocenyl]ethyl dimethylamine ((S,R)-ppfa), (R)-BINAP, (S,S)-DIOP, and sparteine) with four different catalyst precursors (i.e., [(MeCN)4Pd][BF4]2, [(PhCN)2PdCl2], Pd(dba)2, and the novel palladacycle 56). None of the catalyst/ligand combinations surveyed gave acceptable TOFs, rates ranging from only 0.6 to 18.1 h1, and the results were largely independent of catalyst precursor. In general, the selectivity for 54 over 55 was greater than 4:1, but the enantioselectivity for the formation of 54 was always low. The ligand ()-nmdpp achieved the highest ee, 10 – 12% when used in combination with [(MeCN)4Pd][BF4]2, [(PhCN)2PdCl2], or Pd(dba)2. Sparteine in combination with [(MeCN)4Pd][BF4]2 gave only 2% conversion and afforded predominantly 2,7-dimethyl-1,3,7-octatriene (57) rather than methyl ethers. Palladacycle 56 was said to be an efficient catalyst only in the presence of added phosphine; for example, in the presence of Ph3P (21% conversion, 67:22 54/55 (plus octatrienes), 54 in 2% ee). Recent studies have also been reported by Keim et al.[89] – [91] C.iii. Alcohols and Phenols as H—Y Trapping Reagents: Intramolecular Diene Coupling Bisdiene 58 undergoes Pd-catalyzed cyclization and trapping by phenol (0.05 [Pd(OAc)2 /2 Ph3P], 5 PhOH, THF, 65 °C) to give 59a in 94% yield.[92] Note the regioselective
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1593
formation of the terminal double bond, the stereoselective formation of the trans-configurated internal double bond, and the regioselective incorporation of the alkoxy group (OR) at the allylic terminus in 59. These results are fully consistent with those observed in the intermolecular linear dimerization of simple 1,3-dienes discussed above. Similarly, amide 60 cyclized with the incorporation of phenol to afford pyrrolidine 61 in good chemical yield (73%) (Scheme 19).
E
+ ROH
E
+ PhOH
N
E
THF
E
E = CO2Et
58
Bz
Pd(OAc)2 / 2 Ph3P
Pd(OAc)2 / 2 Ph3P THF, 65 °C, 12 h
OR
59a: R = Ph (94%, 15:1 trans/cis) 59b: R = Bn (88%, 7:1 trans/cis)
Bz
N
OPh
61 (73%, >20:1 trans/cis)
60 Scheme 19
The ratio of trans- to cis-3,4-disubstituted cyclopentanes 59a or pyrrolidines 61 is in the range of 15 to 20:1. The origin of the stereoselectivity is at this point unclear. Certain literature data obtained for the intermolecular linear dimerization of isoprene[11] and piperylene[93],[94] suggest that the corresponding oxidative cyclization of the bisdiene substrate to the intermediate fused-bicyclic palladacycle (the stereochemically determining step in the proposed mechanism) should be reversible under the cyclization conditions. Consequently, the relative stability of the diastereomeric trans/cis-metallacycles and/or their relative rates of trapping by H—Y may determine the diastereoselectivity of the cyclization. It was found that the trans/cis ratio of cyclized products is sensitive to the nature of the bisdiene substrate (e.g., 58 versus 60), the nature of the trapping reagent (e.g., PhOH versus BnOH), and the reaction temperature. For example, the Pd-catalyzed cyclization of bisdiene 58 with benzyl alcohol at 65 °C gave a 3:1 trans/cis ratio as compared to the 7:1 ratio observed when the reaction was carried out at ambient temperature. However, trapping the same substrate with phenol (65 °C) gave the product with a 15:1 trans/cis diastereoselectivity. Intramolecular six-membered ring formation is also efficient. Treatment of bisdiene 62a with 0.05 equiv of a [Pd(OAc)2 /3 Ph3P] mixture in THF (65 °C, 24 h) affords the cyclized and intramolecularly trapped diene 63a in good chemical yield (82%) and with good diastereoselectivity (9:1 mixture of two diastereomers) (Scheme 20).[95] The conversion of 62a to 63a is a unique cascade cyclization in that it constructs two new sixmembered rings via the net 1,4-addition of the elements carbon and oxygen across a diene subunit. Three stereochemical elements are controlled in the cyclization of 62a to 63a. Two of these elements, the (E)-configuration of the double bond and the trans
1594
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
HO E
0.05 equiv [Pd(OAc)2 / 3 Ph3P]
E
O
H
E E
THF, 65 °C (73−82%)
R
R
62a: (R = H, E = CO2Et) 62b: (R = Me, E = CO2Et) Me
HO
H
63a: (R = H, E = CO2Et) 63b: (R = Me, E = CO2Et)
0.05 equiv [Pd(OAc)2 / 3 Ph3P]
Me
O
THF, 65 °C (65%)
64
65 Scheme 20
relationship between the substituents on the newly formed cyclohexane ring, are easily established on the basis of spectral data and their control is consistent with results obtained in other Pd-catalyzed bisdiene cyclizations with intermolecular trapping by alcohols. The third element, the relative orientation between the newly formed carbon–carbon and carbon–oxygen bonds, could arise either via the net anti- 1,4-addition (as depicted in 5) or the net syn-1,4-addition of carbon and oxygen across the internal diene moiety. The sense of the 1,4-stereochemical control was established by the Pd-catalyzed cyclizations of the chiral bisdienes 62b and 64 (Scheme 20). The Pd-catalyzed cascade cyclization of the racemic bisdiene 62b (0.05 [Pd(OTFA)2/3 Ph3P], THF, 65 °C) gives comparable results to that obtained for 62a. The cyclized product 63b is obtained in 73% yield. Cyclization of 62b also proceeds with the Pd(OAc)2 catalyst mixture, but a relatively large amount (ca. 30%) of the enediene cycloisomerization product (Scheme 8) is formed. It is possible that the less basic trifluoroacetate counterion suppresses the competing cycloisomerization pathway. The stereocenter in bisdiene 62b resides adjacent to the lower diene subunit, and the cyclization proceeds with a high level of 1,2-stereoinduction ( 20:1) relative to that resident stereocenter. Similarly, Pd-catalyzed cyclization of (S)-64 (0.05 [Pd(OAc)2 /3 Ph3P], THF, 65 °C, 24 h) proceeds with a high level of 1,2-stereoinduction ( 20:1) from the resident methyl-bearing stereocenter. The only cyclized product isolated is 65 (65% yield), although under these conditions 35% unreacted starting material is recovered. Nonracemic 65 was used to establish the net anti sense of 1,4-stereocontrol during the Pd-mediated cyclization. Ozonolysis (CH2Cl2/EtOH, 78 °C) followed by treatment with NaBH4 (CH2Cl2/EtOH, 25 °C) yielded tetrahydropyran-2-methanol for which the sign of the optical rotation indicated the (R) absolute configuration. The catalytic cycle in Scheme 21 is adapted from that proposed by Jolly et al.[11] for the dimerization of 1,3-butadiene with intermolecular trapping as discussed above. In the model the bisdiene coordinates around a reduced palladium center (e.g., 66) and undergoes oxidative addition with cyclization (oxidative coupling) via the syn-addition of carbon and palladium across the diene to afford the intermediate palladacycle 68. Protonation of the 1-allyl in an SE2 fashion leads to the alkene complex 69, and stereospecific anti-addition
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
HO
O
H
Pd Ln
1595
H
HO O Pd Ln
Pd Ln
66
67
syn-oxidative cyclization
antiaddition
HO
HO
H
Pd Ln
Pd Ln
68
69 +
H (SE ) 2′
Scheme 21
of the oxygen nucleophile to the 3-allylpalladium moiety to 67 completes the catalytic cycle. To account for the net anti-1,4-addition of carbon and oxygen across the diene, the addition of the oxygen nucleophile to the 3-allyl in 69 must be fast relative to the rearrangement of palladium between the diastereomeric faces of the 3-allylpalladium complex. It is speculated that the alkene complexed to palladium in the intermediate 69 plays a crucial role in slowing the rate of isomerization. Metal-mediated cyclizations that rely on the initial complexation of an alkene or alkyne around a low oxidation state metal center are often sensitive to the presence of additional substituents (particularly electron-donating substituents), and relatively more stringent reaction conditions are often required for successful cyclization. This effect was noted in the Ni-catalyzed formal [4 4] cycloaddition reactions developed by Wender and Tebbe[3] and is apparent when one compares the reported facility of Pd-catalyzed linear dimerization of 1,3-butadiene versus that of substituted 1,3-dienes.[96] Similarly, the initial attempts at Pd-catalyzed cyclization of bisdiene 70a (Scheme 22) were rather disappointing. Using 0.05 equiv of [Pd(OAc)2 /3 Ph3P] (THF, 65 °C, 12 h), only a small
1596
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
HO E
0.05 equiv [Pd(OAc)2 / 2 Ph3P]
E R1
THF, 65 °C
E E
H
O
H H
R1 R2
R2 70a: (R1 = Me, R2 = H) 70b: (R1 = H, R2 = Me)
E = CO2Et
71a: (R1 = Me, R2 = H) (65%) 71b: (R1 = H, R2 = Me) (65%)
Scheme 22
percentage reacted, and starting material was largely recovered unchanged. However, it is known that coordinately unsaturated palladium catalyst systems turn over faster in Stille coupling reactions,[97] and the use of 2 equiv rather than 3 equiv of triphenylphosphine per palladium affords a more active cyclization catalyst. Bisdiene 70a undergoes smooth cyclization (0.05 equiv [Pd(OAc)2 /2 Ph3P], THF, 65 °C, 12 h) affording cyclized product 71a in 65% isolated yield and 95% diastereomeric purity.[98] The remaining 35% of the mass is isolated as a mixture of isomeric products resulting from the bisdiene to enediene cycloisomerization pathway. The (E)-configuration of the newly formed trisubstituted double bond in 71a was assigned on the basis of NOE studies. It should also be noted that the (E)-configuration is consistent with the working model for the catalytic cycle (Scheme 21), which assumes transoid 3-allyl-containing metallacyclic intermediates. Upon treatment with 0.05 equiv of the [Pd(OAc)2 /2 Ph3P] mixture in refluxing THF, bisdiene 70b cyclizes to afford product 71b in 65% yield (97% diastereomeric purity).[98] The methyl substitution pattern in 70b leads to the formation of a fourth stereocenter in the cyclized product 71b (Scheme 22). Based on the results of deuteration studies,[99] it was anticipated that this new methyl-bearing center would be generated in a stereochemically controlled fashion. This indeed proved to be the case; the product possessed the relative configuration shown. Remarkably, the cyclization of the acyclic bisdiene 70b generates four new stereocenters in a highly selective fashion, two of which reside exocyclic to the initially formed cyclohexane ring. The stereocontrolled generation of quaternary centers remains a significant synthetic problem in organic synthesis.[100] A new solution to this problem via Pd-mediated bisdiene cyclization could lead to a novel method for ultimately setting the angular methyl group at the ring fusion of a bicyclic ring system—a common structural element present in a variety of natural products. Upon treatment with 0.05 equiv of the [Pd(OAc)2 /2 Ph3P] mixture in THF (65 °C), 72 cyclizes to 73 in 68% isolated yield (94% diastereomeric purity) (Scheme 23). The successful cyclization of 72 demonstrates two important extensions of the methodology: (i) that the formation of a five-membered carbocyclic ring is efficient and (ii) that the formation of the quaternary methyl-bearing stereocenter is accomplished in a stereoselective fashion. C.iv. Water as the H—Y Trapping Reagent The Pd-catalyzed dimerization of butadiene[101]–[103] or isoprene[75],[101],[104]–[106] with trapping by water is of exceptional interest. This is especially true in the patent literature,
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
HO E E
E
THF, 65 °C
E
Me
O
Me
0.05 equiv [Pd(OAc)2 / 2 Ph3P]
1597
H 73 (68%)
E = CO2Et
72
Scheme 23
given the potential for a commercial route to n-octanol.[107] – [113] The addition of carbon dioxide is reported to facilitate the reaction with water.[101] The current postulate is that the direct addition of water to the chelated -allylpalladium intermediate 75 is slow. The rapid equilibrium reaction between CO2 and water affords carbonic acid and carbonate ion, and it is speculated that the carbonate ion adds to 75 to form a carbonic acid ester (e.g., 76), which suffers decarboxylation to afford the observed 2,7-octadien-1-ol (74, Scheme 24). Minor amounts of the 1,7-octadien-3-ol isomer, 1,3,7-octatriene, and lactones are usually observed as side products.
OH
Pd catalyst H2O, CO2
74
H2O + CO2
HOCO2– + H+
HOCO2H
– CO2
O Pd Ln
via
O
+ (HOCO2–)
Pd
75
OH
Ln
76 Scheme 24
Several interesting variations on the reaction have recently been introduced. While the reaction with water is often carried out using a sulfonated, and hence water-soluble, triarylphosphine, the use of a palladium(0) complex of 1,3,5-triaza-7-phosphaadamantane (77, Scheme 25) was recently reported.[114] Monflier and co-workers reported that in addition to running the reaction under a CO2 atmosphere, the reaction of butadiene with water is facilitated by the use of cationic[115] or neutral (nonionic) surfactants.[116] The role of cationic surfactants such as dodecylammonium hydroxide is conceived to be threefold:
1598
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
N
N P N
Pd 4
N
(CH2)4CH3
X 78a: (MBIBF4, X = BF4) 78b: (MBIPF 6, X = PF6) 78c: (MBICl, X = Cl)
77
2 78c + PdCl2
Me N
[(MBI)2PdCL4]
H2O MBIBF4 (78a)
Me N
Cl N Pd N
Me N
Cl 80
79 Scheme 25
(i) to increase transport between the aqueous and the organic phase; (ii) to increase the concentration of carbonate in the organic phase; and (iii) to stabilize the palladium catalyst. In the case of the neutral surfactant, the amphiphilic nature of the addend is important. For example, reaction in the presence of C18H37(OCH2CH2)20OH is superior to the reaction with no addend, CH3(OCH2CH2)20OH or the PEG dimethyl ether (CH3(OCH2CH2)8OCH3). With the addition of C18H37(OCH2CH2)20OH, conversion of butadiene reached 70% and the turnover number reached 230 h1. At concentrations above the critical micelle concentration, the efficiency of the surfactant-assisted reaction can be correlated to the amount of butadiene solubilized in water and, according to the authors, may result from surfactant-induced liquid–crystalline phases, association colloids, or microemulsions. Dupont and co-workers published a very interesting study on the Pd-catalyzed reaction of butadiene with water in an ionic liquid solvent (e.g., 78a, Scheme 25).[117] 1-n-Butyl-3methylimidazolium tetrafluoroborate (BMIBF4, 78a) is partially miscible with water at temperatures above 5 °C; water is less soluble in the corresponding PF6 salt, 78b. In addition, several common palladium(II) salts, for example, common diene dimerization catalyst precursors such as Pd(OAc)2, are soluble in 78a. Dimerization–trapping occurs in this solvent, better in 78a than 78b, and the dimerization products, 2,7-octadien-1-ol and 3,6octadien-1-ol, are immiscible below 5 °C, making the product isolation via phase separation very easy. The dimerization reaction using the common palladium catalyst precursors is complicated by precipitation of palladium metal toward the end of the reaction. The authors found, however, that a new dimerization catalyst eliminates this problem. Reaction of PdCl2 with 78c affords complex 79. Dissolution of 79 in ionic liquid 78a and addition of water forms palladium complex 80, which serves as their new dimerization catalyst. Using 79, butadiene (28% conversion, 70 °C, homogeneous reaction mixture) reacts with a TOF of 118 h1 to afford 94% of the octadienol. Running the reaction under a CO2 atmosphere (5 atm) gives 49% conversion (TOF 204 h1) and 84% of octadienol. Given the practical advantages of this approach and the fact that the catalyst mixture was reused several times without loss of activity, the potential of this methodology seems very high. Heterogeneous catalysis is also a very attractive alternative from an industrial perspective. Lee and co-workers reported a novel montmorillonite-supported palladium catalyst for butadiene dimerization with trapping by water.[118] Simple solid-supported palladium(0) catalysts, such as 5% Pd/C and Pd/Al2O3, were modestly effective catalysts for
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1599
butadiene dimerization with tapping by water (surface Pd TOFs of 50 – 80 h1) as compared to 259 h1 for a solution phase reaction catalyzed by [Pd(OAc)2/Ph3P] (65 °C). Montmorillonite is a swelling-type layered silicate clay. Palladium was anchored onto montmorillonite by treating the commercially available sodium form with HCl and reacting the so-derived H – montmorillonite with 3-aminopropylethoxysilane. The resulting silane-exchanged montmorillonite was treated with Pd(OAc)2. The resulting Pd – montmorillonite was a good catalyst for butadiene dimerization – trapping (butadiene, water, DMF, Ph3P, CO2 (200 psi), 65 °C, 10 h, 91% conversion) affording 77% of 1,2,7octadienol with a TOF of 277 h1. Examining the reaction mixture after the dimerization reaction showed less than 1% palladium loss to solution, and the catalyst could be reused. C.v. Carboxylic Acids as the H—Y Trapping Reagent: Intermolecular Diene Dimerization Butadiene reacts with carboxylic acids, even relatively labile carboxylic acids such as 81, to form unsaturated esters (Scheme 26).[61],[71],[119],[120] For example, methacrylic, ,dimethylacrylic, and crotonic acid react with butadiene under palladium catalysis (Pd(acac)2 /Ph3P/Et3Al) in THF to afford predominantly the 2,7-octadienyl esters 82 in high yields (90–95%).[119] O
O R1
HO
1,3-butadiene
R1
O
catalyst
R2
R3 81
82a: (R1 = Me, R2, R3 = H) 82b: (R1, R3 = H, R2= Me) 82c: (R1 = H, R2, R3 = Me)
R3
R2
Scheme 26
The product of the reaction of butadiene with acetic acid has found use in natural products synthesis. Spur and co-workers reported the total synthesis of leukotrienes starting from butadiene via its Pd-catalyzed linear dimerization with trapping by acetic acid (0.2% Pd(acac)2, 0.2% tri(o-tolyl)phosphite, 3% NaOAc, 25 °C) (Scheme 27).[121] These are comparatively mild conditions for butadiene dimerization; elevated temperatures are more commonly employed, but the authors report the formation of a mixture of products (90% yield) consisting of (E)-2,7-octadien-1-yl acetate (83, 76%), (Z)-2,7-octadien-1-yl acetate (84, 11%), and 1,7-octadienyl-3-acetate (85, 13%). It has previously been noted that, among the protic H—Y trapping reagents, carboxylic acids often give rise to a greater percentage of the isomer arising from trapping at the 3-position, and that the percentage of this isomer increases with reaction time. Observing the formation of a significant amount of (Z)-2,7-octadien-1-yl acetate is less common. The mixture of isomeric acetates is converted to the corresponding mixture of alcohols and that mixture subjected to Sharpless asymmetric epoxidation. From this reaction, the chiral nonracemic epoxide 87 is isolated in 60% yield ( 94% ee). Compound 87 is converted by standard transformations to 88 and 89, ultimately affording the leukotriene methyl ester LTA4-Me (90) (Scheme 27). A number of other leukotrienes (e.g., LTC4, LTD4,
1600
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
(90%)
HOAc
AcO
H AcO
+ H H
H 84 (11%)
83 (76%) K2CO3 MeOH
H2C
+
OAc 85 (13%) H Sharpless AE
HO
O
HO
[(+)-tartrate]
H 86 (plus isomers, 95%)
87
O
O
CO2Me H
O
H
CO2Me O
88
89 O
H
CO2Me 90 (LTA4-Me)
H Scheme 27
LTE4, and (14S,15S)-LTA4 methyl ester) were also prepared from 86. In addition, Spur and co-workers reported a conceptually similar route to lipoxins A4 and B4 from 86.[122] C.vi. Carboxylic Acids as the H—Y Trapping Reagent: Intramolecular Diene Coupling Due of the potential for subsequent Pd-catalyzed reaction of the allylic carboxylate product and the relatively low trapping regioselectivity reported for the intermolecular linear dimerization carboxylic acid trapping, few examples of the analogous intramolecular diene coupling followed by carboxylic acid trapping have been examined. Bisdiene 91 undergoes Pd-catalyzed cyclization in the presence of (Et3NH)OAc and HOAc to afford predominantly the trans-disubstituted cyclopentane 92 (80%) (Scheme 28). No evidence was found for the formation of a regioisomeric allylic acetate.[92]
1601
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
0.05 equiv [Pd(OAc)2 / 2 Ph3P]
PhO2S PhO2S
(Et3NH)OAc HOAc, THF, 65 °C
OAc
PhO2S PhO2S
91
92 (80%, 5:1 trans/cis) Scheme 28
C.vii. Formic Acid as the H—Y Trapping Reagent: Intermolecular Diene Dimerization Employing formic acid or one of its carboxylate salts as the trapping reagent effects reductive dimerization of the diene, although formation of the formate addition product has also been seen.[123] The reaction may involve, at least under certain conditions, formation of an intermediate -allylpalladium hydride intermediate (e.g., 97), possibly generated from the decarboxylation of the -allylpalladium formate 96. For butadiene, dimerization conditions have been identified that afford either 1,7-octadiene (93) or 1,6-octadiene (94) as the reaction product (Scheme 29). 1,7-Octadiene is reported to be the near exclusive product when a phosphinated polystyrene-bound palladium(0) catalyst was used[71] or when the reaction was carried out in solution phase using [Pd(OAc)2/Et3P].[35] When Et3P was omitted from the latter catalyst system or when [Pd(OAc)2 /Et3N], [Pd(OAc)2 /DMF],[124],[125] or [Pd(acac)2 /Amberlyst A-21][123] was employed, the near exclusive product was 1,6-octadiene. While the reasons for the unusual regiocontrol in these variants is unclear, it can be suggested that recent work by Tsuji and co-workers on Pd-catalyzed reduction of allylic formates may offer some insight.[126],[127] The linear dimerization of isoprene often affords mixtures of head/tail dimers. For example, [Pd(OAc)2, P(CH2CH2CN)3] catalyzes dimerization of isoprene with triethylammonium formate in dimethylacetamide (55 °C, 3 h), affording dimers in 97% yield as a 10:49:37 98/99/100 mixture of head/tail coupling regioisomers (Scheme 30).[128] It is interesting to note that, as in the case of butadiene and formic acid in the presence of phosphinemodified Pd(OAc)2, only 1,7-dienes are formed in this reaction of isoprene with formic acid.
93
94 reductive
elimina
O H
+ H+
Pd 95
L
Pd O
– CO2
PdH
SE2′
96 Scheme 29
97
1602
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Me 98 (Tail−Tail) Me Me
Me
H2CO2H, Et3N
Me 99 (Tail−Head)
Pd(OAc) 2, P(CH2CH2CN)3
Me 100 (Head−Head) Me Scheme 30
C.viii. Amines, Amides, Imides, and Sulfonamides as the H—Y Trapping Reagents: Intermolecular Diene Dimerization Butadiene undergoes efficient Pd-catalyzed linear dimerization followed by trapping with many primary and secondary amines to give predominantly 1-amino-2,7-octadienes.[129]–[133] Generally, more basic amines react better.[134] Among the more unusual amines that serve as suitable amine trapping reagents are amino alcohols,[135] amino acids,[136] hydroxylamines,[137] hydrazine,[138] aziridines,[139],[140] imidazoles,[141]–[143] triazoles,[141] and pyrazolines.[144] A range of nonbasic amine derivatives, including phthalimides,[145]–[147] formamide,[148],[149] and aryl- or alkylsulfonamides[150]–[152] can also serve as nitrogen trapping reagents. There are a number of features within this variant of protic H—Y trapping reagents that have attracted significant interest. For example, Antonsson et al.[153] carefully examined the stereochemistry of the C2"C3 double bond as a function of catalyst composition using a [Pd(OAc)2, phosphine, Et3Al] catalyst system. Using [Pd(OAc)2, 2 Ph3P] without the addition of Et3Al, a mixture of 101 and 102 with an (E)/(Z) ratio of 96:4 was obtained in 93% yield. The catalyst system [Pd(OAc)2, 2 Ph3P, 2 Et3Al] affords 99% (E)-product 101 in 75% yield (Scheme 31). The amount of butadiene is also important as a large excess leads to an increased amount of a C16 product, and a catalyst using polymer-bound phosphine gives a good (E)/(Z) ratio when the Al/Pd ratio is high. It is not clear whether
NEt2
+ HNEt2
[Pd(OAc)2 / Ph3P/Et3Al]
101 (major)
102 (minor) Scheme 31
NEt2
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1603
the role of Et3Al is solely that of a reducing agent for the reduction of Pd(II) to Pd(0) or if its Lewis acidity is an important component to its success. However, other workers have found that the Pd(acac)2-catalyzed reaction of butadiene with a variety of secondary amines (including diethylamine) is greatly facilitated by the addition of BF3.[154],[155] For example, a catalyst system derived from 1:15 (Pd(acac)2)/BF3 exhibits a TOF of greater than 625 h1 at 70 °C and an 80% yield of 101 after 7 h at 50 °C. Generally, more basic amines are better trapping reagents than less basic ones, and consequently, the reaction of ammonia or a primary amine does not stop after the addition of one octadienyl moiety; the resulting monooctadienylated amine product reacts faster than the starting amine. Thus, for ammonia, one typically forms the tertiary octadienylamine ((C8H13)3N) as the major product. For example, butadiene and ammonia (10:1) undergo Pd-catalyzed reaction (1 mol % (relative to NH3) [Pd(OAc)2, 3.4 Ph3P], t-BuOH, 100 °C, 1 h) to afford 1:2:31 ratio of mono/di/tri(octadienyl)amine (21% total yield based on ammonia) (Scheme 32). To improve selectivity of the mono(octadienyl)amine, Prinz et al.[156] examined the corresponding liquid/liquid two-phase reaction. The idea behind their study is that, using a water-soluble phosphine (3,3,3 -phosphinidynetris(benzenesulfonic acid) trisodium salt, TPPTS), the palladium catalyst can be sequestered in an aqueous ammonia phase, while the mono(octadienyl)amine (and higher amines) will be sequestered in the organic phase. The strategy shows good potential. The biphasic reaction of butadiene and ammonia (10:1) under conditions similar to those above (1 mol % (relative to NH3) [Pd(OAc)2, 4 TPPTS], 2:1 H2O/CH2Cl2, 100 °C, 1 h) afforded a 21:17:1 ratio of mono/di/tri(octadienyl)amine (24% yield). Optimized conditions (75 mmol butadiene, 300 mmol ammonia, 0.15 mmol Pd(OAc)2, 0.6 mmol TPPTS, 20 mL H2O, 12.5 mL toluene, 80 °C, 1.5 h) afford a 13:1:0 ratio of mono/di/tri(octadienyl)amine in 55% yield.
1,3-butadiene + NH3
Pd catalyst
(C8H13)NH2 + (C8H13)2NH + (C8H13)3N Scheme 32
As noted above, certain protic H—Y trapping reagents (e.g., carboxylic acids) can give rise to a significant percentage of the isomer arising from trapping at the 3-position of the octadienyl chain. Prinz and Driessen-Hölscher [157] examined the liquid/liquid two-phase reaction of butadiene with ammonia (a water/liquid butadiene biphasic mixture) in an effort to optimize for the selective formation of 1-amino-2,7-octadiene (103). They found that the reaction rate and regioselectivity (103/104) are a function of ammonia concentration, catalyst concentration, Pd/ligand ratio, and the nature of the ligand. A series of water-soluble ligands were screened under a standard set of reaction conditions (1:1 [Pd(OAc)2 /ligand], 80 °C) (Scheme 33). The authors find a trade-off between regioselectivity and reaction rate (TOF) in this series: p-F -TPPDS (105, 1.4:1 103/104, TOF 357 h1); TPPTS (106, 3.0:1 103/104, TOF 252 h1); BOM-TPPTS (107, 13:1 103/104, TOF 128 h1); and TOM-TPPTS (108, 36:1 103/104, TOF 47 h1). They conclude that both steric and electronic factors influence the regioselectivity. The reactions are run under the author’s biphasic conditions, and as expected from their prior studies, they proceed with high selectivity for the mono(octadienyl)amine (i.e., 103 or 104); each of the four catalyst systems shows 6% or less of the di(octadienyl)amine product.
1604
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
NH2
103 (major)
Pd(OAc) 2, TPPTS
+ NH3
H2O, butadiene (biphasic)
NH2
104 (minor) F SO3Na
NaO3S P
F
SO3Na NaO3S
F
NaO3S 106 (TPPTS)
105 ( p-F-TPPDS)
Me
Me O
NaO3S
P
SO3Na P
O NaO3S
O Me NaO3S
SO3Na P
O Me
O Me NaO3S
107 (BOM-TPPTS)
108 (TOM-TPPTS) Scheme 33
The linear dimerization of isoprene with amines continues to be of interest; particularly with respect to controlling the four possible modes of coupling, tail-to-tail 109, tailto-head 110, head-to-tail 111, or head-to-head 112 (Scheme 34).[154],[158]–[164] With amine trapping reagents the tail-to-tail mode is typically preferred, but ligands can strongly influence the ratio. For example, the linear dimerization of isoprene with N-methylaniline mediated by [Pd(acac)2-P(OBu)3] in acetonitrile affords a 48% yield of trapped dimers of which 85% is the tail-to-tail isomer (85:5.5:9.5:1 109/110/111/112 (R1 Me, R2 Ph)). In contrast, the same reaction mediated by [Pd(acac)2/Ph3P] in methanol affords a 52% yield of linear dimers of which 89% is the tail-to-head isomer (10:89:1:1 109/110/111/112 (R1 Me, R2 Ph)).[159]
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1605
Me + R1N(R2)H
N(R1)R2
Pd catalyst
Me
Me 109 (tail-to-tail) Me
N(R1)R2
Me N(R1)R2
110 (tail-to-head)
Me
Me
111 (head-to-tail) Me N(R1)R2 Me 112 (head-to-head) Scheme 34
The head-to-head isomer 112 can be favored by appropriate combinations of cationic palladium catalysts and ligand. Röper and co-workers had shown that cationic palladium complexes were particularly active catalyst precursors for linear diene dimerization, and the cationic palladium complex [Pd(dppe)(py)2 (BF4)2] affords a 7:43:8:39 109/110/111/112 (R1, R2 Et) ratio in 81% yield (0.5 mol % catalyst, acetonitrile, 25 °C) (Scheme 34).[163] The addition of a Lewis acid[154],[165] as a cocatalyst also influences the isomer distribution; carbon dioxide and Brønsted acids act similarly. For example, the reaction of isoprene with diethylamine and the catalyst system [Pd(acac)2, 4 P(c-C6H11)3, 20 BF3-OEt2] in acetonitrile (70 °C, 16 h) affords a 91% yield of dimers of which 60% is the head-to-head isomer (4:32:3:60 109/110/111/112 (R1, R2 Et)).[162] A recent study by Maddock and Finn is particularly striking.[166] A large number of ligands was screened in the reaction of isoprene with diethylamine; other secondary amines were also examined. The combination of a cationic palladium complex [(C3H5)Pd(cod)BF4] and tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP) affords a 93% yield of the head-to-head isomer 112 as a mixture of (E)and (Z)-isomers with only 6.1% of the tail-to-head isomer 110 (5 mmol isoprene, 4.8 mmol Et2NH, 0.025 mmol [(C3H5)Pd(cod)BF4 /1.5 TTMPP], 1 mL methanol, 25 °C, 72 h). The beneficial effect of TTMPP is thought to be a result of both steric and electronic effects; tris(o-tolyl)phosphine, a ligand that is sterically similar to TTMPP, shows poor activity and poor selectivity. C.ix. Amines as the H—Y Trapping Reagent: Intramolecular Diene Coupling The intramolecular diene dimerization with trapping by amines has also been shown to be viable.[92] Bisdiene 113 is trapped by diethylamine (0.05 [Pd(OAc)2/2 Ph3P], THF, 65 °C) to afford allylic amine 114 (73%, 20:1 trans/cis ring substitution) (Scheme 35).
1606
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
NEt2 E
+ Et2NH
E
Pd(OAc)2 / 2Ph3P THF, 65 °C, 12 h
E = CO2Et
113
E E 114 (76%, 20:1 trans/cis)
Scheme 35
C.x. Sulfinic Acids as the H—Y Trapping Reagents: Inter- and Intramolecular Diene Coupling Sulfinic acids, or their alkali metal salts, add to butadiene after dimerization to form octadienyl sulfone derivatives.[167] For example, butadiene reacts with cyclohexylsulfinic acid (115) under palladium catalysis [Pd(acac)2-Ph3P -Et3Al] in a toluene–water mixture to afford the allylic sulfone 116 in 95% yield and high isomeric purity (Scheme 36).[168]–[170] Under these conditions, isoprene, piperylene, cyclopentadiene, and cyclohexadiene give 1:1 and/or bis-sulfones, not linear dimerization products.[168],[169] Carbon dioxide reportedly promotes the Pd-catalyzed reaction of dienes with sulfinic acids.[171] Sulfides such as benzyl, phenyl, and ortho-tolyl sulfides react with butadiene to give a mixture of butenylsulfide, octadienylsulfide, and disulfide.[172] O +
HO
SO2C6H11
S [Pd(acac)2 / Ph3P/Et3Al] toluene, water
115
116 SO2Ar
E
+ ArSO 2H
E
117
Pd(OAc)2 / Ph3P
E
C6H6, 70 °C, 12 h
E
E = CO2Et
118 (50%, 13:1 trans/cis)
Scheme 36
The intramolecular diene coupling with trapping by sulfinic acid has also been shown to be viable.[92] Bisdiene 117 is trapped by p-toluenesulfinic acid (0.05 [Pd(OAc)2/2 Ph3P], benzene, 70 °C) to afford allylic sulfone 118 in moderate yield (50%, 13:1 trans/cis ring substitution). C.xi. Doubly Activated Methylene and Methines (C—H Acidic Compounds) as the H—Y Trapping Reagent: Inter- and Intramolecular Diene Coupling A number of types of carbon nucleophiles participate as protic H—Y trapping reagents in Pd-catalyzed linear diene dimerization. Among these, doubly activated methylene and
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1607
methine C—H acidic compounds ((EWG)2C(R)H; e.g., malonates, substituted malonates, -ketoesters) are particularly well-covered in the older literature.[8],[29],[93] While there have been relatively few recent innovations reported (vide infra), the chemistry appears to be quite generally applicable for a wide range of such compounds. A few examples will illustrate the chemistry. Butadiene reacts with the active methine compound (-sulfonyl ester 119, R1 Me) to afford the trapped linear dimer 121a (R1 Me, R2 H) in 95% yield (Scheme 37). Reaction of 119 with isoprene affords the tail-to-tail dimer 121b (R1 Me, R2 Me) in 60% yield.[173],[174] In the case of C—H acidic methylene rather than methine trapping agents (e.g., 119, R1 H) double addition can compete. For example, under the conditions described above, the reaction of butadiene with ethyl acetoacetate affords both the mono- (78% yield) and disubstituted (12% yield) derivatives. Ketosulfones, nitrosulfonyl, and the vinylogous sulfonyl ester ArSO2CH2CH"CHCO2Me give similar results. The 1:1 butadiene/active methylene products can be obtained selectively when bidentate ligands are employed.[175],[176]
MeO2C
SO2Ar R1
R1 CO2Me (Ph3P)2PdCl2, NaOPh
+
R2
SO2Ar
R2 R2
119 (R1 = Me, H)
121
120 (R2 = H, Me)
EtO2C
+ CH2(CO2Et)2
PhC(O)N
Pd(OAc)2 / Ph3P THF, 65 °C, 12 h
CO2Et
PhC(O)N
123 (73%, >20:1 trans/cis)
122 Scheme 37
The intramolecular diene coupling with trapping by C—H acidic methylene compounds has also been shown to be viable.[92] Bisdiene 122 is trapped by diethyl malonate (0.05 [Pd(OAc)2/2 Ph3P], THF, 65 °C) to afford the disubstituted pyrrolidine 123 (73%, 20:1 trans/cis ring substitution). C.xi.a. Enantioselective Catalysis. The influence of certain chiral bidentate diphosphine ligands (L*) was examined in the [Pd(OAc)2-L*]-catalyzed reactions of butadiene with two cyclic -ketoesters.[76],[90],[91],[177] The reaction of butadiene with 2-(methoxycarbonyl)cyclohexanone (124a) using a 1:1 ratio of Pd(OAc)2/BPPM (BPPM (2S, 4S)-N-tbutoxycarbonyl-2,4-bis(diphenylphosphino)methylpyrrolidine) in isopropanol (10 °C, 20 h) gave product 125a (86% yield and 46% ee) (Scheme 38). Note that the new chiral center is on the trapping reagent, not the dienes, and arises from asymmetric alkylation of the -allylpalladium moiety. Under similar conditions, 2-(methoxycarbonyl)cyclopentanone gave comparable results (86% yield, 41% ee).[177] DIOP, NORPHOS, and
1608
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
O +
O
0.25 mol % [Pd(OAc)2 / BPPM]
( )n
MeO
MeO2C
O ( )n
NaOH, i-PrOH –10 °C, 20 h
124a (n = 1)
125 PPh2 BPPM =
BocN PPh2
Scheme 38
(2R, 3R)-2,3-bis(diphenylphosphino)butane gave ees values of 10% or less. Heterogeneous versions of this reaction gave similar results.[91] C.xii. Enamines as the H—Y Trapping Reagent: Inter- and Intramolecular Diene Coupling Under certain conditions less activated ketones (e.g., acetone, cyclopentanone, cyclohexanone, and cyclohexenone) can participate in the reaction with butadiene[178] or isoprene,[179],[180] but more commonly enamine derivatives are employed. For example, Tsuji reported that butadiene undergoes Pd-catalyzed linear dimerization with trapping by the pyrrolidoyclohexene 126 (Scheme 39) (Pd(OAc)2, Ph3P, CH3CN, 80 °C, 3 h) to afford the octadienyl derivative 127 in 66% yield after hydrolysis (aq. HCl, 50 °C, 0.5 h).[181] In addition, 22% of the , -dialkylated product was isolated.
O N +
1. [Pd(OAc)2 / Ph3P] CH3N, 80 °C, 3 h 2. aq. HCl, 50 °C, 0.5 h
126
127 (66%)
H N +
H Pd(acac)2, Ph3P
N
Et3Al
128 Scheme 39
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1609
In a sense, pyrrole can be considered enamine-like in its reactivity, and Dzhemilev and co-workers reported that it acts as a carbon nucleophile, reacting twice with butadiene under palladium catalysis to afford 128.[141],[182] C.xii.a. Enantioselective Trapping. Keim et al.[90],[177] evaluated the influence of chiral trapping reagents and chiral ligands on the formation of a new stereogenic center at the site of reaction on the trapping nucleophile. For example, the [Pd(OAc)2/Ph3P]-catalyzed reaction of butadiene with the (S)-2-(methoxymethyl)pyrrolidine-derived enamine of cyclohexanone 129 affords, after hydrolysis, the 2-(2,7-octadienyl)cyclohexanone (130) with 72% ee (Scheme 40). Note that the new chiral center is generated on the trapping reagent, not the dienes, and arises from asymmetric alkylation of the chiral trapping reagent by the -allylpalladium moiety. HO N +
O
1. [Pd(OAc)2 / Ph3P] MeCN, 10 °C 2. aq. HCl
129
130 (72% ee) Scheme 40
C.xii.b. Intramolecular Diene Coupling. Treatment of the simple bisdiene derivatives 131a – c with 2 equiv of 1-pyrrolidino-1-cyclohexene and 5 mol % [Pd(OAc)2 /2 Ar3P (Ar C6H5 or o-CH3C6H4)] in refluxing methylene chloride solution effects facile carbocyclization with incorporation of the enamine trapping reagent. Hydrolysis of the crude reaction mixture yields the -alkylated cyclohexanones 132 in good to excellent yields (131a 90%, 131b 72%, 131c 83%) as mixtures of epimers with respect to the stereogenic center in the cyclohexyl ring (Scheme 41). The chemical yield and diastereoselectivity for the cyclization of bisdiene 131a are highly dependent on the solvent, ligand, and nature of the enamine. In THF or benzene solution, cycloisomerization to an enediene competes with trapping by the enamine. This side reaction is suppressed in dichloromethane, chloroform, or acetonitrile. With respect to chemical yield and reaction time required for the cyclization, triarylphosphines are superior ligands to trialkylphosphines or to phosphites. Finally, the pyrrolidinocycloalkene is superior to the morpholino derivative as the trapping reagent in trapping by either cyclohexanone- or cyclopentanone-derived enamines.
R R
+
N
1. 5 mol % Pd(OAc) 2 2. Ar 3P, CH 2Cl2, 40 °C 2. 10% aq. HCl, 25 °C, 1 h 72−90% overall
131a (R = CO2Et) 131b (R = SO2Ph) 131c (R = CN)
O R R 132
Scheme 41
1610
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
With regard to the intramolecular reaction, it is conceivable that catalytic amounts of acetate ion in this [Pd(OAc)2 /2 Ar3P]-catalyzed carbocyclization reaction serve to shuttle the bisdiene to an intermediate allylic acetate, which subsequently undergoes Pdcatalyzed reaction with the enamine. The action of the enamine trapping reagent could, in principle, be entirely independent from the carbocyclization event. In fact, treatment of the independently prepared allylic acetate 133 under the enamine carbocyclization conditions (2 equiv of 1-pyrrolidino-1-cyclohexene, 5 mol % [Pd(OAc)2 /2 (o-CH3C6H4)3P], CH2Cl2, 40 °C, 5 h) gave 132a in 96% yield after hydrolysis (Scheme 42). However, the presence of acetate ion is not required for successful allylation of the enamine. Treatment of bisdiene 131a with 1-pyrrolidino-1-cyclohexene in the presence of 5 mol % Pd(acac)2 (i.e., an acetate-free palladium catalyst used in place of Pd(OAc)2) still gives 132a in 81% yield (2 (o-CH3C6H4)3P, CH2Cl2, 40 °C, 25 h). Thus, reaction via allylic acetate 133 is a viable, but not an obligatory, pathway for the conversion of bisdiene 131a to 132a.
OAc E E
+
133
N
1. 5 mol % Pd(OAc) 2 2. Ar 3P, CH 2Cl2, 40 °C, 4 h 2. 10% aq. HCl, 25 °C, 1 h 96% overall
O E E 132a
E = CO2Et Scheme 42
The benzamide bisdiene 134 proved to be a particularly good substrate for the carbocyclization with 1-pyrrolidino-1-cyclohexene. Its cyclization using 2 equiv of triphenylphosphine or tris(o-tolyl)phosphine or 1 equiv of diphenylphosphinoethane (dppe) in conjunction with Pd(OAc)2 proceeds in about 90% overall yield to the substituted Nacylpyrrolidine 135 (Scheme 43). Notably, indole also proves to be an effective trapping reagent in the reaction of 134. The adduct 136 is obtained in 91% yield from the palladium acetate-catalyzed reaction in the presence of tris(o-tolyl)phosphine.
O 1. 0.05 Pd(OAc) 2, Ar3P
1-(pyrrolidino) cyclohexene
CH2Cl2, 40 °C 2. 10% aq. HCl, 25 °C, 1 h
BzN 135
BzN 134 indole
0.05 Pd(OAc) 2, Ar3P CH2Cl2, 40 °C
BzN 136
Scheme 43
N H
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1611
C.xiii. Nitroalkanes as the H—Y Trapping Reagent: Inter- and Intramolecular Diene Coupling While relatively few examples have been reported, nitroalkanes can serve as efficient carbon nucleophiles in the Pd-catalyzed linear dimerization reaction.[183] For example, butadiene reacts with 2-nitropropane (137, (Ph3P)2PdCl2, KOH, i-PrOH, 50 °C, 4 h) to afford 9methyl-9-nitro-1,6-decadiene (138 R1, R2 Me) in 89% yield (Scheme 44). Nitromethane or primary nitroalkanes also react but can give a mixture of polyalkylation products. Keim and co-workers found that butadiene undergoes [(DIOP)Pd(OAc)2]-catalyzed dimerization with trapping by 1-nitropropane to afford 138 (R1 H, R2 CH2CH3) with 16% ee.[177] The intramolecular diene coupling with trapping by nitromethane has also been shown to be viable.[92] Using an excess of nitromethane, polyalkylation is not a problem. Bisdiene 139 is trapped by nitromethane (0.05 [Pd(OAc)2 /2 Ph3P], CH3NO2 (solvent), 60 °C) to afford cyclopentane 140 (79%, 9:1 trans/cis ring substitution). R2 R1 Me
Me
+ NO2
NO2
(Ph3P)2PdCl2, NaOPh i-PrOH, 50 °C, 4 h
138 R1,R2 = Me (89%)
137
NO2 E
Pd(OAc)2, 2Ph3P
E
E
MeNO2, 60 °C, 12 h
E
139
E = CO2Et
140 (79%, 9:1 trans/cis)
Scheme 44
C.xiv. CO/ROH, an Equivalent of “H—CO2R”as the H—Y Trapping Reagent: Intermolecular Diene Dimerization Butadiene reacts with carbon monoxide and alcohols[184],[185] or amines[186] to form 3,8nonadienoic acid derivatives. A variety of alcohols, even relatively bulky ones, can be used. For example, reaction of butadiene with CO (50 atm) in tert-butyl alcohol (Pd(OAc)2/4 Ph3P, 110 °C, 16 h) affords the , -unsaturated tert-butyl ester 141 in 92% yield (Scheme 45).[187] CO pressures greater than 50 atm slow the reaction as do Ph3P/Pd ratios greater than or less than 4:1.
OCMe3 [Pd(OAc) 2/4 Ph3P], CO (50 atm) t-BuOH, 110 °C, 16 h
O 141 (92%)
Scheme 45
1612
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
D. DIENE DIMERIZATION WITH INCORPORATION OF SILANES, DISILANES, AND RELATED COMPOUNDS D.i. Intermolecular Diene Dimerization Butadiene undergoes Pd-catalyzed linear dimerization with trapping by silanes, disilanes, and distannanes to afford 2,6-octadiene derivatives (e.g., Schemes 2 and 6).[29] For example, reaction of butadiene with triethylsilane catalyzed by a phosphinated polystyrenebound palladium(0) complex affords the 1-silyl-2,6-octadiene derivative 142 (85%) (Scheme 46).[71] The highly selective formation of the 2,6- rather than 2,7-octadiene is what differentiates this class of trapping agents from the protic H—Y trapping reagents discussed above.[188]–[194] The change in regioselectivity may reflect a change in mechanism for this class of Pd-catalyzed linear dimerization reactions with subsequent trapping (vide infra). Substituted 1,3-dienes (e.g., isoprene, piperylene) give predominantly to exclusively simple hydrosilylation products rather than linear dimerization products.
SiEt3
Pd catalyst Et3SiH, 25 °C, 20 h
142 (85%) Scheme 46
Disilane trapping reagents behave in a conceptually similar fashion.[195] Tsuji and coworkers found that a variety of simple dienes (143, e.g., butadiene, isoprene, 2-phenyl-1,3butadiene, 2-trimethylsilyloxy-1,3-butadiene) undergo efficient Pd(dba)2-catalyzed linear dimerization disilane trapping with a variety of simple disilanes 144 to afford bis(allylsilane) products 145 (41–92% yield) (Scheme 47).[196] Cyclic disilanes afford macrocyclic bis(allylsilane) products.[197] 144 (R1 = Me, Ph, CH=CH2, CH2CH=CH R1Me2Si
R2
SiMe2R1 +
5 mol % Pd(dba)2 DMF or dioxane, 25 °C
SiMe2R1
R1Me2Si
R2
R2 145 (head-to-head dimer)
143 (R2 = H, Me, Ph, OSiMe3) Scheme 47
There are a number of remarkable features in this very facile linear dimerization reaction with trapping by disilanes. (i) In contrast to silanes with which substituted 1,3dienes (e.g., isoprene, piperylene) give predominantly to exclusively simple hydrosilylation products rather than linear dimerization products, disilanes afford only disilylated linear dimers—no disilylated monomer. (ii) Only the head-to-head dimerization products
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1613
(i.e., (E,E)-145) are observed from 2-substituted dienes (Scheme 47); this is in contrast to many other dimerization – trapping reactions of substituted dienes in which mixtures of head-to-tail dimers are formed. (iii) It is of particular note that 2-substituted 1,3-diene derivatives other than isoprene can successfully be dimerized under these conditions; for example, the 2-phenyl derivative (82% yield, R1 Me, DMF) and the 2-trimethylsilyloxy derivative (63% yield, R1 Me, DMF) afford linear dimers. However, it is reported that 2,3-dimethyl-1,3-butadiene, 1,3-pentadiene, and 1,3-cyclohexadiene do not react under these or even more vigorous reaction conditions. (iv) Other palladium catalysts work as well (e.g., Ph4Pd, (PhCN)2PdCl2, [(C3H5)Pd(cod)BF4], [(C3H5)Pd(Cl]), but Pd(dba)2 shows the highest activity. (v) DMF and dioxane are superior to benzene, toluene, THF, HMPA, or dichloromethane as reaction solvent. (vi) Finally, no crossover products are observed when reacting an equimolar mixture of disilanes 144 (R1 Me and R1 Ph) with isoprene. Both silicon atoms of the disilane trapping reagent are transferred to the same isoprene dimer, a remarkable observation given the facile Pd-catalyzed metathesis of disilanes.[198] Tsuji and Kakehi reported the analogous linear dimerization of 1,3-dienes with subsequent trapping by distannanes.[199] For example, 1,3-butadiene undergoes efficient Pd(dba)2-catalyzed linear dimerization trapping with hexamethyldistannane (0 °C, 0.05 h) to afford 146a (78% yield) (Scheme 48). Isoprene reacts analogously (25 °C, 5 h) to afford (E,E)-146b (62% yield). Again, only the head-to-head dimerization product is observed. When the hexabutyldistannane is used in place of the hexamethyl derivative dimeric products are not formed.
R 5 mol % Pd(dba)2
R
SnMe3
Me3Sn
(Me3Sn)2, toluene
R (head-to-head dimer) 146a (R = H) 146b (R = Me)
a (R = H) b (R = Me) Scheme 48
D.ii. Intramolecular Diene Coupling Treatment of bisdiene 147 with 1.5 equiv of triphenylsilane in the presence of a palladium catalyst (3 mol % Pd2(dba)3, THF, 25 °C, 1 – 2 h) effects rapid cyclization of the bisdiene.[200] A 6:1 mixture of two diastereomeric cyclopentanes, 148a and 149a, is obtained in excellent yield (94%) (Scheme 49). Similar products are obtained when dimethylphenylsilane (95%) or triethylsilane (95%) is employed. The reactions of three related bisdiene substrates have been investigated. The N-acylpyrrolidine precursor 150 (Ph3SiH, 82%), the six-membered ring precursor 151 (Ph3SiH, 80%), and the methylsubstituted bisdiene 152 (Ph3SiH, 57%) also undergo Pd-catalyzed cyclization. About 65% of the products obtained in the cyclization of 152 are derived from addition of the silyl group to the less substituted diene subunit. The structures of diastereomers 148 and 149 are related in an unusual way. Six contiguous stereochemical centers are formed as a consequence of the carbocyclization. Yet,
1614
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
SiR3 E
cat. Pd2(dba)3
E
1.5 equiv HSiR3 E THF, 25 °C, 2 h
E
147 (E = CO2Et)
H Me
R = Ph (94%) R = Et (95%)
Me
E +
H R3Si
H
148a (R = Ph) 148b (R = Et)
E
6 : 1
H
149a (R = Ph) 149b (R = Et)
E E
BzN
Me
E E
150
151 (E = CO2Et)
152 (E = CO2Et)
Scheme 49
out of the multitude of possible stereoisomeric products, the overall configuration of the carbon skeleton is identical in both diastereomeric products. Structures 148 and 149 differ only with respect to which of the termini in the newly formed carbon skeleton the triphenylsilyl group and the hydrogen, respectively, become attached. In essence, while 148 and 149 are formally stereoisomers, they result from regioisomeric modes of H—Si addition. The Pd-catalyzed carbocyclization to assemble the carbon skeleton of the product apparently proceeds with very high levels of relative diastereoselectivity and alkene stereoselectivity. This curious relationship between 148 and 149 must somehow relate to the role of the metal in the catalytic process leading to the cyclization. It has long been a puzzle as to why linear dimerization of butadiene with hydrosilane trapping gives 2,6-octadienes while protic H—Y trapping reagents give 2,7-octadienes. To explain the formation of 1-silyl-2,6-octadiene, it is generally postulated that the reaction proceeds via the initial partial hydrosilylation of one butadiene molecule followed by capture of the intermediate -allylpalladium complex (i.e., [-(CH2CHCHCH3)]Pd(SiR3)Ln) by insertion of another butadiene unit. This mechanism is in contrast to the one discussed in the introductory section that has been postulated for the reaction with protic trapping reagents, that is, C—C bond formation via initial oxidative coupling of two molecules of butadiene. The Pd-catalyzed reaction of bisdiene 147 with [D]-triphenylsilane gives the regiospecifically monodeuterated products corresponding to 148 and 149 (i.e., 153a (X D, Y SiPh3) and 154a (X D, Y SiPh3)); that is, the cyclized product picks up its hydrogen (deuterium) from the silane trapping reagent. When admixed in the absence of bisdiene 147, Pd2(dba)3 catalyzes the rapid H/D exchange and competitive dehydrogenative coupling of a mixture of deuterosilane and hydrosilane (0.03 mmol (Pd2(dba)3/0.75 mmol Ph3SiD / 0.75 mmol Me2PhSiH / 5 mL THF/25 °C/0.5 h). Nonetheless, a competition experiment in which a limiting amount of bisdiene 147 is reacted under otherwise standard conditions with a mixture of [D]-triphenylsilane and dimethylphenylsilane yields only four cyclized products (0.03 mmol (Pd2(dba)3/1.0 mmol 147 / 0.75 mmol Ph3SiD/0.75 mmol Me2PhSiH/5 mL THF / 25 °C/3 h/98% combined yield of products). Triphenylsilyl-containing products are separated from dimethylphenylsilyl-containing products by chromatography
1615
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
on silica. Analysis of the product mixture containing the triphenylsilyl moiety shows that this material also has stoichiometric deuterium incorporation; that is, a mixture of 153a (X D, Y SiPh3) and 154a (X D, Y SiPh3) is isolated (46%) (Scheme 50). Products containing the dimethylphenylsilyl moiety show no deuterium incorporation; only 153b (X H, Y SiMe2Ph) and 154b (X H, Y SiMe2Ph) are isolated (52%). This experiment shows that no crossover products are formed; both the hydrogen (or deuterium) and the silyl group come from the same molecule of silane.
147
cat. Pd2(dba)3
E
YX
E
Y H X
+
E
H Y
H
153a (X = D, Y = SiPh3) 153b (X = H, Y = SiMe 2Ph)
E = CO2Et
X
E
H
154a (X = D, Y = SiPh3) 154b (X = H, Y = SiMe2Ph)
Scheme 50
The results of the crossover experiments argue against a mechanism initiated by hydrosilylation. An alternative mechanistic possibility, which is consistent with all of the data and which adequately accounts for the stereoselective formation of only diastereomers 148 and 149, is given in Scheme 51. Complexation of the silane to an initially formed palladacycle such as 155 would afford a complex such as 156. Sigma bond metathesis to a mixture of -allylpalladium complexes 157 (presumed major) and 158 (presumed minor) followed by reductive elimination from each of these would generate the observed products 148 (major) and 149 (minor).
Pd-Ln
Pd
Ln
155 HSiR3 coordination
and Pd
SiR3 H
156
Pd
SiR3
Ln 157 (major)
148 Scheme 51
Pd H L SiR3 n 158 (minor)
149
1616
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
The Pd-catalyzed reaction of bisdiene 147, using tributylstannane in place of the hydrosilane, provides one example where tin can be used in place of silicon. The mixture of allylstannanes 159 and 160 is obtained in excellent yield (96%) (Scheme 52). SnBu3 cat. Pd2(dba)3 1.5 equiv HSnBu3 E
E
THF, 25 °C, 2 h (96%)
E 147
E = CO2Et
Me
E
E
H Me
+
H 159
E
H Bu3Sn
H 160
Scheme 52
E. DIENE DIMERIZATION WITH INCORPORATION OF A R1(R2)C"Y TRAPPING REAGENT E.i. Introduction At first glance the products obtained from the dimerization of dienes with R1(R2)C"Y trapping reagents (e.g., aldehydes, ketones, imines, carbon dioxide, and isocyanates),[29] especially those obtained via the cycloaddition mode, look quite different from those obtained via the other three trapping modes. Nonetheless, as illustrated in Scheme 53 for the reaction of 1,3-butadiene with a hypothetical R1(R2)C"Y trapping reagent (for simplicity, R1 R2), the products can be thought of as arising via a mechanism that is conceptually quite similar to that discussed in Sects. A–C. Pd-catalyzed oxidative coupling of butadiene to the palladacycle 163 followed by addition of the carbon electrophile to the 1-allyl moiety in an SE2 fashion (i.e., a reaction akin to SE2 protonation in the case of proton H—Y trapping reagents) leads to a chelated allylpalladium intermediate such as 164. At this juncture, one option is deprotonation, that is, the same pathway postulated in Sect. B to account for the intermolecular linear dimerization with trapping. Loss of the proton labeled Ha would lead to chelate 165, and upon decomplexation, triene 162. In practice, products of this sort are seen when the Pd/phosphine ratio is less than 2 (vide infra). The more common reaction mode (favored when the Pd/phosphine ratio is greater than 2) leads to the cyclized product 161. Its formation can be rationalized via decomplexation of chelate 164 to 166 followed by addition of the newly generated nucleophile Y to the 3-allylpalladium, a pathway akin to that postulated in Sect. C for trapping by protic H—Y trapping reagents, but here an intramolecular variation. The following discussion is organized according to the nature of the R1(R2)C"Y trapping reagent employed: aldehydes and ketones, imines, and carbon dioxide and isocyanates. E.ii. Aldehydes and Ketones as Trapping Agents: Intermolecular Diene Dimerization A variety of aldehydes (formaldehyde, aliphatic, and aromatic aldehydes) and some electrophilic ketones (e.g., -diketones and hexafluoroacetone) have been shown to serve as
1617
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
+ R2C = Y
oxidative
Pd
Y
catalyst
+/or
C R R
R C YH R 162
161
coupling
Ha PdLn + (R2C = Y)
Pd
SE2′
Ln
– Ha+ E2
R C YH R 165
R C – Y R 164
163
PdLn
+L
162 –Y
PdLn 161
C R R 166 Scheme 53
trapping reagents.[201]–[204] The formation of linear or cyclic products depends on the Pd/phosphine ratio. For example, the reaction of butadiene with acetaldehyde (Pd(acac)2, n Ph3P, 25 °C, 60 h, ca. 0.5–2.0 mmol Pd/mol butadiene) in the presence of 4 equiv of Ph3P per Pd affords predominantly 167 (70% yield) (Scheme 54).[201] The same reaction run in the presence of 1 equiv of Ph3P per Pd affords predominantly 168 (70% yield). The reaction is said to be more facile when run in an alcohol solvent, as illustrated by the following two sets of reaction conditions: (i) (Pd(acac)2, 4 Ph3P, EtOH, 80 °C, 2 h) yields 167 (74%) and 168 (6%); and (ii) (Pd(acac)2, 1 Ph3P, i-PrOH, 80 °C, 3 h) yields 167 (8%) and 168 (75%).
H +
O Me
Pd
O
or
catalyst
Me Me 167 Scheme 54
OH 168
1618
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
In general, when the reaction is run so as to favor formation of the cyclic (here, divinyltetrahydropyran) product, a mixture of four racemic diastereomers is formed. For example, butadiene reacts with aromatic aldehydes such as 3,4-(methylenedioxy)benzaldehyde to afford a 33:33:24:10 mixture of substituted divinylpyrans (169–172) in high yield (70–95%) (Scheme 55).[205],[206]
O O O
Ar H
1,3-butadiene
Ar
O 169
O 170
[Pd(OAc)2 / Ph3P] i-PrOH (95%)
Ar
Ar
O 171
O 172
Scheme 55
E.ii.a. Enantioselective Catalysis. Keim and co-workers examined the enantioselective butadiene dimerization with aldehyde trapping. For example, Pd-catalyzed reaction of butadiene with formaldehyde (0.02 mol % Pd(OAc)2, 0.03 mol % chiral diphosphine, i-PrOH, 20 °C, 40 h) affords a mixture of cis- and trans-divinyltetrahydropyrans, 173 and 174, respectively.[177],[207] (The absolute configurations of 173 and 174 were not assigned by the authors; the configurations illustrated in Scheme 56 were chosen arbitrarily.) Table 1 summarizes the results obtained for several chiral phosphines. The reaction with formaldehyde affords a 2.6–5.6:1 ratio of trans- and cis-2,5-divinyltetrahydropyran in 25–65% chemical yield. Among the chiral ligands examined, DIOP (173 18% ee; 174 26% ee), NORPHOS (173 3% ee; 174 36% ee), and neo-MenPPh2 (173 13% ee; 174 30% ee) gave the highest levels of enantioselectivity.
TABLE 1. Enantioselective Dimerization of Butadiene Followed by Trapping with Formaldehyde Chiral Ligand a
Yield (%)
173/174
173 ee (%)
174 ee (%)
()-DIOP ()-DIOP BPPM CIRA NORPHOS NMDPP PHEN
65 64 45 30 55 25 45
5.0 : 1 5.5 : 1 2.6 : 1 3.6 : 1 5.6 : 1 3.9 : 1 3.9 : 1
18 17 2 15 3 13 5
26 25 5 20 36 30 24
BPPM (2S,4S )-N-t-butoxycarbonyl-2,4-bis(diphenylphosphino)methylpyrrolidinone; CIRA (2R,3R)-2,3bis(diphenylphosphinobutane); NORPHOS (2R,3R)-2,3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene; NMDPP (1R,2R,5S)-neomenthyldiphenylphosphine; PHEN (R)-1,2-bis(diphenylphosphino)-3-phenylpropane.
a
1619
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
0.02 mol % Pd(OAc) 2 0.03 mol % chiral diphosphine
O + H
O
i-PrOH, 20 °C, 40 h (25−65%)
H
O
+
173
174
Scheme 56
As shown above, the reaction with an aldehyde other then formaldehyde can form four chiral diastereomers. Keim and Mastrorilli examined the reaction of butadiene with acetaldehyde using chiral diphosphine ligands (0.1 mmol Pd(OAc)2, 0.15 mmol chiral diphosphine or 0.3 mmol chiral monophosphine, 20 mmol acetaldehyde, 42 mmol 1,3butadiene, i-PrOH).[208] The products 175–178 are shown in Scheme 57 with the correct relative configuration within each structure, but arbitrarily chosen absolute configuration. The authors state that the ratio of chiral diastereomers is typically found to be 48:35:5:12 (175/176/177/178). It seems difficult to draw many conclusions from the numbers in Table 2, given the mixture of products. The authors report that BINAP and CHIRAPHOS did not afford active catalysts, and among the bidentate ligands that were successful, DIOP was the best. The best enantiomeric excesses were obtained with chiral monophosphines, but these gave significant amounts of the triene product. In one case, Pd(acac)2 was substituted for Pd(OAc)2 with similar results, but Pd(dba)2 failed to give an active catalyst with DIOP.
TABLE 2. Enantioselective Dimerization of Butadiene Followed by Trapping with Acetaldehyde Ligand a
Time
Temperature (°C)
Yield (%)
175 ee (%)
176 ee (%)
177 ee (%)
178 ee (%)
BPPM BPPM ()-NORPHOS ()-NORPHOS ()-NORPHOS ()-NORPHOS ()-DIOP ()-DIOP ()-DIOP NMDPP NMDPP TMP TMP
66 h 13 d 3d 14 d 12 d 12 d 5d 14 d 66 h 4d 9d 4d 9d
21 0 45 15 21 10 21 15 21 21 0 21 0
58 3 55 9 23 5 75 77 52 5 28 42 3
21 62 10 10 52 60 47 50 1 63 37 23 1
21 29 33 46 2 6 2 1 27 77 47 50 76
25 23 25 26 27 32 7 7 7 16 33 35 8
6 22 11 22 7 7 0 4 1 48 16 10 61
BPPM (2S,4S )-N-t-butoxycarbonyl-2,4-bis(diphenylphosphino)methylpyrrolidinone; CIRA (2R,3R)-2,3bis(diphenylphosphinobutane); NORPHOS (2R,3R)-2,3-bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene; NMDPP (1R,2R,5S)-neomenthyldiphenylphosphine; PHEN (R)-1,2-bis(diphenylphosphino)-3-phenylpropane; TMP trimenthylphosphite.
a
1620
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
O
0.1 mmol Pd(OAc) 2
+ H
Me
O
0.15 mmol chiral diphosphine or 0.3 mmol chiral monophosphine (see Table 2)
+
O
Me
Me
175
176
O
+
O
Me
177
Me
178
Scheme 57
Peiffer and co-workers found an unusual variation in which butadiene dimerization was coupled to incorporation of separate R1(R2)C"Y and protic H—Y trapping reagents.[209] Treatment of butadiene and paraformaldehyde in isopropanol (50 mmol paraformaldehyde, 97 mmol butadiene, 0.1 mmol Pd(OAc)2, 0.15 mmol diphosphine or 0.3 mmol monophosphine chiral ligand, i-PrOH (10 mL), 25 °C, 24 h) in the presence of aminophosphinephosphinite (AMPP) 181 (IleNOP) affords mostly 2,5-divinyltetrahydropyran (179, 74% yield , 5:1 trans/cis, 1– 4% ee) along with minor amounts of linear dimers; 180 is formed in 13% yield (3% ee). In contrast, when aminophosphinite 182 (IleOP) is used, the major product is the linear dimer 180 (66% yield, racemic); 179 is formed in 13% yield under these conditions (3:1 trans (3% ee)/cis (36% ee)). In compound 180 two molecules of formaldehyde have been incorporated, one as a R1(R2)C"Y trapping reagent and one that has condensed with a molecule of i-PrOH to form a novel protic H—Y trapping reagent (i-PrOCH2OH). Formation of 180 can be rationalized via the addition of i-PrOCH2OH to an intermediate such as 184 (Scheme 58). Surprisingly, AMPPs other than the one derived from isoleucine (i.e., IleNOP, 181) were found to afford mostly the linear dimer 180. Of these, the AMMP derived from leucine (i.e., LeuNOP, 183) gave 180 with the highest ee (20% ee, 54% yield). E.iii. Aldehydes and Ketones as Trapping Agents: Intramolecular Diene Coupling Preliminary studies into the doubly intramolecular variant of the linear diene dimerization with aldehyde trapping show promise.[56] Two versions of the reaction have been demonstrated. Because of the ring constraints, it is unlikely that the aldehyde oxygen can add to the -allylpalladium, and, therefore, the cycloisomerization reaction was investigated. Bisdiene 185 undergoes Pd-catalyzed cyclization to afford the bicyclic ring system 186 (Scheme 59). A 6:6:1 mixture of three diastereomers was obtained in 76% yield. Bisdiene 187 undergoes Pd-catalyzed cyclization in the presence of the external protic H—Y
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
O O
cat. Pd, i-PrOH
+ H
O
1621 Oi-Pr
+
(54−87% yield) (up to 36% ee)
H
OH 179 Me
Me Me
OPPh2 Me
180
N
Me Me
PPh2
i-PrOCH2OH
OPPh2
181
N
H
182 PdLn
Me
OPPh2 Me
Me
N
O
PPh2
183
184 Scheme 58 5 mol % [Pd(OAc)2 / 3Ph3P] THF, i-PrOH 65 °C, 24 h
CHO
OH 186 (76%, 3 isomers: 6:6:1)
185
OPh 5 mol % [Pd(OAc)2 / 3Ph3P] THF, PhOH 65 °C, 24 h
CHO
OH 188 (67%, 2 isomers: 1:1)
187 Scheme 59
trapping reagent phenol to the doubly cyclized and trapped product 188 (67%, 1:1 mixture of diastereomers). E.iv. Imines as the Trapping Agent: Intermolecular Diene Dimerization The reaction of dienes with imines has not been widely studied.[210] The results obtained thus far are very similar to those obtained with aldehydes. For example, the reaction of
1622
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
butadiene with imine 189 (Pd(NO3)2, 3 Ph3P, DMF, 80 °C, 10 h) affords a mixture of divinylpiperidines 190 – 193 (73%) in a ratio of 37:11:17:34 (Scheme 60). At longer reaction times (40 h, 91% yield), the ratio of products is 45:40:9:6, suggesting that the products equilibrate. This was verified independently by resubjecting the isolated products to the catalyst system. The authors report that Pd(acac)2 is not a suitable catalyst precursor and that other simple imines behave similarly to 189.
N
Me +
N
Ph N
Me Ph
Me 1,3-butadiene [Pd(NO3)2 / 3Ph3P]
H
190
191
DMF, 80 °C, 10 h (73%)
189
N
Me +
N
Ph
192
Me Ph
193
Scheme 60
E.v. Carbon Dioxide and Isocyanates as Trapping Agents: Intermolecular Diene Dimerization As discussed above, carbon dioxide plays an important role in facilitating the reaction of dienes with water. In the absence of water, CO2 reacts with butadiene to afford a number of addition products.[211] – [213] Given the potential commercial importance of CO2 as a C1 building block,[214] – [216] the diene dimerization–CO2 trapping reaction has been examined in great detail in an effort to optimize the selectivity.[20],[217],[218] Much progress has been made, and now high selectivity for formation of the -lactone and yields approaching 60% have been reported. For example, Behr and co-workers reported the reaction catalyzed by [Pd(OAc)2, 3 P(i-Pr)3] (MeCN, 90 °C) affords the -lactone 195 in 48% yield (Scheme 61).[217] The reaction presumably involves the intermediacy of the divinyl derivative 194, but it isomerizes under the reaction conditions to the more stable ,unsaturated derivative 195. Nonetheless, the scope of the CO2-trapping reaction is still rather limited. Under conditions such as those described above, isoprene fails to react or reacts to only very low conversion.[20],[219] The corresponding reaction with isocyanates has been less widely studied but overall seems to be qualitatively similar. For example, the reaction of butadiene with phenyl isocyanate (0.05 mol % [Pd(cod)2, Ph3P (1:1)], 60 °C, 48 h) affords a 1:1 mixture of 196a (R H) and 197 in quantitative yield (Scheme 62).[204] In contrast to the reaction of CO2, phenyl isocyanate is reported to readily react with isoprene to afford 196b (R Me, 1:1 cis/trans).[220]
1623
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
O
[Pd(OAc) 2, 3 P(i-Pr)3]
+
MeCN, 90 °C
O O
CO2
O Me
194
H
195 (48%)
Scheme 61
R
R 0.05 mol % [Pd(cod)2 / Ph3P]
+ N C
O
N
60 °C, 48 h, (100%)
Ph
N
+
O
O
Ph
R 196a (R = H) 196b (R = Me)
Ph
Me
H 197
Scheme 62
F. MISCELLANEOUS TRAPPING MODES: INTERMOLECULAR DIENE DIMERIZATION F.i. Oximes as the Trapping Reagent The reaction of dienes with oximes has not been extensively investigated[221]; however, it has been shown that the reaction mode depends on the nature of the oxime 198. Oximes derived from aromatic aldehydes or from ketones afford mixtures of 1-substituted 2,7octadienyl (e.g., 199) and 3-substituted 1,7-octadienyl oxime ethers. Such oxime trapping reagents apparently function as typical protic H—Y trapping reagents. For example, butadiene undergoes a Pd-catalyzed reaction with methyl ethyl ketone oxime (180 mmol butadiene, 30 mmol oxime 198, 0.3 mmol Pd(Ph3P)4 or [1:1 Pd(NO3)2-Ph3P], THF (10 mL), 110 °C, 4–12 h) to afford 199 and its 3-substituted isomer (9:1, 58%) (Scheme 63). In contrast, the reaction of butadiene with the oxime derived from an aliphatic aldehyde (e.g., 198 R1 Me, R2 H) affords the isoxazolidine containing product 201 (63%). Its formation can be rationalized via initial alkylation on nitrogen, generating a 1,3-dipole (i.e., 200), which under the reaction conditions undergoes [3 2] cycloaddition with a third molecule of butadiene to give the observed product 201. F.ii. Hydrazones as the Trapping Reagent The reaction of dienes with hydrazones has not been extensively investigated. Nonetheless, the results obtained to date show an unusual dependency on the nature of the substituents.
1624
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
HO
1 mol % (Ph3P)4Pd THF, 110 °C, 24 h
N
+
R1
R2
R1
N
O
R2
(R1,R2 = alkyl or R1 = aryl, R2 = H)
199 R1 = Me, R2 = Et (58%)
198 alipahtic aldoximines
R1
H + N
R1
N
O-
[3 + 2]-cycloaddition
O 201 R1 = Me(63%)
200 Scheme 63
Methylhydrazones act just like protic H—Y trapping reagents.[222] For example, the methylhydrazone of acetaldehyde 202 undergoes Pd-catalyzed reaction with butadiene to afford linear dimer 203 (1 mol % (Ph3P)4Pd, THF, 110 °C, 24 h, 89%) (Scheme 64). Methylhydrazones derived from propanal, acetone, and methyl ethyl ketone behave similarly (80–86% yield). Me +
H
N
N
H
1 mol % (Ph3P)4Pd
N
THF, 110 °C, 24 h
Me
N
Me
Me 203 (89 %)
202 Scheme 64
Phenylhydrazones exhibit another mode of reaction (Scheme 65).[223] The reaction of butadiene with the phenylhydrazone of acetaldehyde 204 (1 mol % (Ph3P)4Pd, THF, 110 °C, 24 h) affords a 2:1 mixture of 205 and 206 (86%). A small amount of the protic (H— Y) trapping product was also observed. The formation of 205 can be rationalized by addition of the phenylhydrazone in the fashion of a R1(R1)C"Y-type electrophile to a palladacycle in an SE2 fashion to 208 followed by hydride transfer to 209. Reductive elimination could account for the formation of 205. Thus, 206 could be formed via a similar pathway, by addition of the phenylhydrazone in an SE2 rather than SE2 fashion. The proposed hydride transfer invoked to rationalize the formation of the observed products offers interesting possibilities and appears worthy of further investigation. Phenylhydrazones derived from propanal, acetone, and methyl ethyl ketone behave similarly (60–95% yield), although the ratio of 205/206 and the proportion of the protic (H—Y-type) trapping product vary.
1625
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
Ph N
+ H
N
H
1 mol % (Ph3P)4Pd
+
THF, 110 °C, 24 h
Me
Me
SE2′
Pd
N
Ph Ph
205 (58%)
204
via (?)
N
N
N
206 (29%)
Pd L
(or SE2)
L Me
N
CH2 N(H)Ph
207
208
Me
Pd H
Me
N
N
Ph
209
Scheme 65
F.iii. Dimethylallylamine as the Trapping Reagent The [(Ph3P)2PdCl2-Et3Al]-catalyzed reaction of butadiene with N,N-dimethylallylamine is a particularly intriguing linear dimerization reaction.[224] It appears to involve a carbon electrophile (allyl cation or an equivalent). The reaction affords a 1:9 mixture of 1-(N,Ndimethylamino)-2,7-octadiene (211) and 212 in 79% yield (Scheme 66). The formation of 211 requires dimethylamine and hence requires that N,N-dimethylallylamine must decompose under the reaction conditions. Its decomposition could liberate allyl cation or an equivalent (e.g., a -allylpalladium). The formation of 212 could arise via addition of the allyl electrophile to the palladacycle 213 in an SE2 fashion to afford 214 and be completed by subsequent addition of dimethylamine. The adduct 212 has been used as an intermediate in the synthesis of the diquinane 215[225] and the natural product ()-sativene (216).[226]
G. CONCLUDING REMARKS Diene telomerization has attracted much attention over the years, perhaps not surprisingly so. The reaction can be quite efficient, even industrially practical. It uses relatively stable unactivated substrates and a catalyst to effect bond formations between two, three, or even four components, with considerable flexibility in the choice and combination of those components. These are very desirable features. A number of recent advances hold significant promise for the future. The use of ionic liquids, biphasic conditions, and heterogeneous catalyst systems are exciting developments to the field, as are the discoveries of new, more efficient homogeneous catalysts, a better understanding of the mechanism, and new ligands and catalyst systems that render the reaction more selective. The use of chiral catalysts is as yet modestly effective, but this area is sure to attract much more research. The intramolecular diene coupling and the intramolecular diene coupling with intramolecular trapping constitute a relatively new direction for this chemistry and promise to offer novel ways to efficiently assemble complex ring systems. These advances mark
1626
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
N Me
(Ph3P)2PdCl2
+ NMe2
Et3Al (79%)
210
211
Me
N
Me
Me
+
10:90
212
Me2NH
+ “C3H5+” Pd
Ln
PdLn
SE2′
213
214
O O
H 215
Me
H
216 Me
Scheme 66
growth areas for the chemistry and suggest it will continue to attract intense research efforts in the coming years.
REFERENCES [1] F. Agbossou, J.-F. Carpentier, F. Hapiot, I. Suisse, and A. Mortreux, Coord. Chem. Rev., 1998, 178 – 180, 1615. [2] P. Brun, A. Tenaglia, and B. Waegell, Tetrahedron Lett., 1985, 26, 5685. [3] P. A. Wender and M. J. Tebbe, Synthesis, 1991, 1089. [4] P. A. Wender, J. Nuss, D. B. Smith, A. Suarez-Sobrino, J. Vgberg, D. Decosta, and J. Bordner, J. Org. Chem., 1997, 62, 4908. [5] P. W. Jolly, in Comprehensive Organometallic Chemistry, G. Wilkinson, F. G. A. Stone, and E. W. Abel, Eds., Pergamon Press, New York, 1982, Vol. 8, 671 – 711. [6] F. R. Hartley, in Comprehensive Organometallic Chemistry, G. Wilkinson, F. G. A. Stone, and E. W. Abel, Eds., Pergamon Press, New York, 1982, Vol. 6, 471 – 762. [7] R. Baker and D. E. Halliday, Tetrahedron Lett., 1972, 2773. [8] R. Baker, A. Onions, R. J. Popplestone, and T. N. Smith, J. Chem. Soc., Perkin Trans. 2, 1975, 1133.
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1627
[9] G. K. Baker, M. Green, J. A. K. Howard, J. L. Spencer, and F. G. A. Stone, J. Chem. Soc. Dalton Trans., 1978, 1839. [10] R. Benn, P. W. Jolly, T. Joswig, R. Mynott, and K. P. Schick, Z. Naturforsch., 1986, 41b, 680. [11] P. W. Jolly, R. Mynott, B. Raspel, and K. P. Schick, Organometallics, 1986, 5, 473. [12] R. Benn, G. Gabor, P. W. Jolly, R. Mynott, and B. Raspel, J. Organomet. Chem., 1985, 296, 443. [13] R. Benn, P. W. Jolly, R. Mynott, B. Raspel, G. Schenker, K.-P. Schick, and G. Schroth, Organometallics, 1985, 4, 1945. [14] R. Benn, P. W. Jolly, R. Mynott, and G. Schenker, Organometallics, 1985, 4, 1136. [15] G. Wilke, B. Bogdanovich, P. Hardt, P. Heimbach, W. Keim, M. Kroner, W. Oberkirch, K. Tanaka, E. Steinrucke, D. Walter, and H. Zimmerman, Angew. Chem. Int. Ed. Engl., 1966, 5, 151. [16] F. Vollmüller, J. Krause, S. Klein, W. Magerlein, and M. Beller, Eur. J. Inorg. Chem., 2000, 1825. [17] J. Krause, G. Cestaric, K. J. Haack, K. Seevogel, W. Storm, and K. R. Porschke, J. Am. Chem. Soc., 1999, 121, 9807. [18] A. Behr, G. V. Ilsemann, W. Keim, C. Krueger, and Y. H. Tsay, Organometallics, 1986, 5, 514. [19] N. Heldt, K. Heldt, H. Anderson, and W. Gaube, J. Therm. Anal., 1993, 40, 1213. [20] E. Dinjus and W. Leitner, Appl. Organomet. Chem., 1995, 9, 43. [21] M. Basato, L. Crociani, F. Benvenuti, A. M. R. Galletti, and G. Sbrana, J. Mol. Catal., 1999, 145, 313. [22] F. Benvenuti, C. Carlini, M. Lami, M. Marchionna, R. Patrini, A. M. Raspolli Galletti, and G. Sbrana, J. Mol. Catal., 1999, 144, 27. [23] R. Benn, P. Betz, R. Goddard, P. W. Jolly, N. Kokel, C. Krueger, and I. Topalovic, Z. Naturforsch. B, 1991, 46, 1395. [24] B. Barnett, B. Buessemeier, P. Heimbach, P. W. Jolly, C. Krueger, I. Tkatchenko, and G. Wilke, Tetrahedron Lett., 1972, 1457. [25] P. W. Jolly, Angew. Chem. Int. Ed. Engl., 1985, 24, 283. [26] H. M. Buech, P. Binger, R. Benn, C. Krueger, and A. Rufinska, Angew. Chem. Int. Ed. Engl., 1983, 22, 774. [27] H. Anderson, N. Heldt, and K. Heldt, Chem. Ing. Tech., 1994, 66, 69. [28] J. M. Takacs, in Comprehensive Organometallic Chemistry II, E. W. Abel, F. G. A. Stone, and G. Wilkinson, Eds., Pergamon Press, Oxford, 1995, Vol. 12, 785 – 796. [29] W. Keim, A. Behr, and M. Röper, in Comprehensive Organometallic Chemistry, G. Wilkinson, F. G. A. Stone, and E. W. Abel, Eds., Pergamon. Press, New York, 1982, Vol. 8, 371–462. [30] J. Tsuji, Palladium Reagents and Catalysts: Innovations in Organic Synthesis, Wiley, Chichester, 1995. [31] N. Yoshimura, in Applied Homogeneous Catalysis with Organometallic Compounds, B. Cornils and W. A. Herrmann, Eds., VCH, Weinheim, 1996, Vol. 1, 351 – 358. [32] A. Behr, Aspects Homogeneous Catal., 1984, 5, 3. [33] A. Behr, in Industrial Applications of Homogeneous Catalysis, A. Mortreux and F. Petit, Eds., Reidel, Dordrecht, Netherlands, 1988, 141–175. [34] H. Kurosawa, J. Organomet. Chem., 1987, 334, 243. [35] C. U. Pittman, R. U. Hanes, and J. J. Yang, J. Mol. Catal., 1982, 15, 377. [36] D. Neibecker, M. Touma, and I. Tkatchenko, Synthesis, 1984, 1023. [37] A. D. Josey, J. Org. Chem., 1974, 39, 139.
1628 [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70]
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
S. Takahashi, T. Shibano, and N. Hagihara, Tetrahedron Lett., 1967, 2451. P. Denis, A. Mortreux, F. Petit, G. Buono, and G. Peiffa, J. Org. Chem., 1984, 48, 5276. W. J. Richter, J. Mol. Catal., 1986, 34, 145. T. Bartik, P. Hermback, T. Himmler, and R. Mynott, J. Organomet. Chem., 1988, 348, C37. H. tom Dieck, C. Mueller, E. T. K. Haupt, and K. D. Bolze, Z. Naturforsch. B, 1987, 42, 853. P. Denise, A. Jean, J. F. Croiyz, A. Mortreux, and F. Petit, J. Am. Chem. Soc., 1990, 112, 1292. M. A. Vardanyan and L. K. Freidlin, Neftekhimiya, 1989, 29, 502. J. M. Takacs, J. Zhu, and S. Chandramouli, J. Am. Chem. Soc., 1992, 114, 773. J. M. Takacs, F. Clement, J. Y. Zhu, S. V. Chandramouli, and X. P. Gong, J. Am. Chem. Soc., 1997, 119, 5804. M. Sugiura, M. E. Krafft, and K. A. Abboud, in Book of Abstracts, 219th ACS National Meeting, San Francisco, CA, March 26 – 30, 2000; ORGN063. M. E. Krafft, Z. Fu, M. J. Procer, A. M. Wilson, O. A. Dasse, and C. Hirosawa, Pure Appl. Chem., 1998, 70, 1083. J. M. Takacs, E. C. Lawson, and F. Clement, J. Am. Chem. Soc., 1997, 119, 5956. A. Tenaglia, P. Brun, and B. Waegell, Tetrahedron Lett., 1985, 26, 3571. J. M. Takacs, M. R. Jaber, and A. V. Strakhov, in Book of Abstracts, 215th ACS National Meeting, Dallas, March 29–April 2, 1998; ORGN146. F. Bergamini, F. Panella, R. Santi, and E. Antonelli, Chem. Commun., 1995, 931. W. Oppolzer and J. M. Gaudin, Helv. Chim. Acta, 1987, 70, 1477. E. Negishi, S. Iyer, and C. J. Rousset, Tetrahedron Lett., 1989, 30, 291. B. M. Trost and J. I. Luengo, J. Am. Chem. Soc., 1988, 110, 8239. J. M. Takacs and R. V. Athalye, unpublished results. E. Smutny, J. Am. Chem. Soc., 1967, 89, 6793. L. I. Zakharkin and E. A. Petrushkina, Zh. Org. Khim., 1982, 18, 1623. U. M. Dzhemilev, R. V. Kunakova, N. Z. Baibulatova, G. A. Tolstikov, and A. A. Panasenko, Zh. Org. Khim., 1980, 16, 1157. U. M. Dzhemilev, R. V. Kunakova, N. Z. Baibulatova, G. A. Tolstikov, and L. M. Zelenova, Izv. Akad. Nauk SSSR Ser. Khim., 1981, 8, 1837. U. M. Dzhemilev, R. V. Kunakova, and N. Z. Baibulatova, Zh. Org. Khim., 1986, 22, 1591. Y. Xie and R. He, Dalian Ligong Daxue Xuebao, 1991, 31, 647. G. Peiffer, S. Chhan, A. Bendayan, B. Waegell, and J. P. Zahra, J. Mol. Catal., 1990, 59, 1. R. Patrini, M. Lami, M. Marchionna, F. Benvenuti, A. M. Raspolli Galletti, and G. Sbrana, J. Mol. Catal., 1998, 129, 179. F. Benvenuti, C. Carlini, M. Marchionna, R. Patrini, A. M. Raspolli Galletti, and G. Sbrana, J. Mol. Catal., 1999, 140, 139. F. Bouachir, P. Grenouillet, D. Neibecker, J. Poirier, and I. Tkatchenko, J. Organomet. Chem., 1998, 569, 203. P. Grenouillet, D. Neibecker, J. Poirier, and I. Tkatchenko, Angew. Chem. Int. Ed. Engl., 1982, 21, 767. M. Camargo, P. Dani, J. Dupont, R. F. de Souza, M. Pfeffer, and I. Tkatchenko, J. Mol. Catal., 1996, 109, 127. I. Pennequin, J. Meyer, I. Suisse, and A. Mortreux, J. Mol. Catal., 1997, 120, 139. D. L. Deng, K. W. Liu, T. B. Pang, H. F. Zhou, C. Q. Ye, and T. L. Wang, Yu Chi Hua Hsueh, 1981, 3, 184.
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1629
[71] K. Kaneda, H. Kurosaki, M. Terasawa, T. Imanaka, and S. Teranishi, J. Org. Chem., 1981, 46, 2356. [72] K. Kaneda, H. Yamamoto, T. Imanaka, and S. Teranishi, J. Mol. Catal., 1985, 29, 99. [73] K. Kaneda, M. Higuchi, and T. Imanaka, Chem. Express, 1988, 3, 335. [74] U. Schuchardt, E. Nicolau dos Santos, and F. S. Dias, J. Mol. Catal., 1989, 55, 340. [75] J. P. Bianchini, E. M. Gaydou, B. Waegell, A. Eisenbeis, and W. Keim, J. Mol. Catal., 1985, 30, 197. [76] W. Keim, P. Mastrorilli, C. F. Nobile, N. Ravasio, B. Corain, and M. Zecca, J. Mol. Catal., 1993, 81, 167. [77] G. P. Potapov, V. V. Punegov, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1985, 1468. [78] D. E. Bergbreiter and R. Chandian, J. Org. Chem., 1986, 51, 4754. [79] F. Benvenuti, C. Carlini, A. M. Raspolli Galletti, G. Sbrana, M. Marchionna, and R. Patrini, J. Mol. Catal., 1999, 137, 49. [80] F. Benvenuti, C. Carlini, M. Marchionna, R. Patrini, A. M. Raspolli Galletti, and G. Sbrana, J. Mol. Catal., 1999, 139, 177. [81] L. I. Zakharkin, V. N. Medvedkov, and E. A. Petrushkina, Zh. Obshch. Khim., 1982, 52, 2118. [82] R. Berger and W. Gaube, J. Prakt. Chem., 1985, 327, 643. [83] W. Gaube and H. Stegemann, J. Prakt. Chem., 1984, 326, 729. [84] A. Behr and W. Keim, Chem. Ber., 1983, 116, 862. [85] C. Moberg, T. Antonsson, L. Tottie, and A. Heumann, Chem. Scr., 1987, 27, 507. [86] K. Hill, B. Gruber, and K. J. Weese, Tetrahedron Lett., 1994, 35, 4541. [87] M. Hidai, H. Mizuta, H. Yagi, Y. Nagai, K. Hata, and Y. Uchida, J. Organomet. Chem., 1982, 232, 89. [88] P. Dani, J. Dupont, and A. L. Monteiro, J. Braz. Chem. Soc., 1996, 7, 15. [89] W. Keim, A. Koehnes, and T. Roethel, in Proc. Symp. 3rd Org. Synth. Organomet., K. H. Doetz and R. W. Hoffmann, Eds., Vieweg, Braunschweig, Germany, 1991, 15–31. [90] W. Keim, A. Kuster, T. Roethel, D. Vogt, and P. Mastrorilli, Bull. Pol. Acad. Sci. Chem., 1994, 42, 487. [91] W. Keim, D. Schwarzer, and D. Vogt, Chem. Ing. Tech., 1995, 67, 903. [92] J. M. Takacs and J. Zhu, J. Org. Chem., 1989, 54, 5193. [93] G. Hata, K. Takahashi, and A. Miyake, J. Org. Chem., 1971, 36, 2116. [94] J. Beger, C. Duschek, and H. Reichel, J. Prakt. Chem., 1973, 315, 1077. [95] J. M. Takacs and S. Chandramouli, J. Org. Chem., 1993, 58, 7315. [96] J. Tsuji, Adv. Organomet. Chem., 1979, 17, 141 – 193. [97] V. Farina and K. Bala, J. Am. Chem. Soc., 1991, 113, 9585. [98] J. M. Takacs and S. V. Chandramouli, Tetrahedron Lett., 1994, 35, 9165. [99] J. M. Takacs, S. V. Chandramouli, and R. Shoemaker, Tetrahedron Lett., 1994, 35, 9161. [100] K. Fuji, Chem. Rev., 1993, 93, 2037 – 2066. [101] J. P. Bianchini, B. Waegell, E. M. Gaydou, H. Rzehak, and W. Keim, J. Mol. Catal., 1981, 10, 247. [102] U. M. Dzhemilev, V. V. Sidorova, and R. V. Kunakova, Izv. Akad. Nauk SSSR Ser. Khim., 1983, 3, 584. [103] L. Y. Gubaidullin, E. I. Logunov, and V. P. Yur’ev, Zh. Org. Khim., 1985, 21, 1131. [104] R. Berger, L. Klimke, P. Schroeder, and W. Gaube, Z. Chem., 1985, 25, 226.
1630
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
[105] R. V. Kunakova, V. V. Sidorova, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1985, 2624. [106] Y. Inoue, M. Sato, M. Satake, and H. Hashimoto, Bull. Chem. Soc. Jpn., 1983, 56, 637. [107] M. Röper, W. Bertleff, and D. Koeffer, in Ger. Offen., BASF A.-G., Fed. Rep. Ger., 1989; CA112:98016. [108] E. Drent, in Eur. Pat. Appl., Shell Internationale Research Maatschappij B.V., Neth., 1993; CA120:31538. [109] K. Koga, T. Noda, and M. Oguri, in Jpn. Kokai Tokkyo Koho, Tosoh Corp., Japan, 1993; CA119:249575. [110] R. Patrini and M. Marchionna, in Eur. Pat. Appl., SNAM Progetti S.p.A., Italy, 1994; CA122:291749. [111] B. Driessen-Hoelscher, W. Keim, T. Prinz, H.-J. Traenckner, and J.-D. Jentsch, in Eur. Pat. Appl., Bayer A.-G., Germany, 1997; CA127:33850. [112] A. Tafesh, M. Beller, and J. Krause, in PCT Int. Appl., Hoechst Research & Technology Deutschland G.m.b.H. & Co. K.-G., Germany, 1998; CA128:181829. [113] H.-J. Traenckner, J. Jentsch, T. Prinz, B. Driesser-Hoelscher, and W. Keim, in Ger. Offen., Bayer A.-G., Germany, 1999; CA131:186549. [114] J. Cermak, M. Kvicalova, and V. Blechta, Collect. Czech. Chem. Commun., 1997, 62, 355. [115] E. Monflier, P. Bourdauducq, J.-L. Couturier, J. Kervennal, and A. Mortreux, J. Mol. Catal., 1995, 97, 29. [116] E. Monflier, P. Bourdauducq, J.-L. Couturier, j. Kervennal, I. Suisse, and A. Mortreux, Catal. Lett., 1995, 34, 201. [117] J. E. L. Dullius, P. A. Z. Suarez, S. Einloft, R. F. deSouza, J. Dupont, J. Fisher, and A. DeCian, Organometallics, 1998, 17, 815. [118] B. I. Lee, K. H. Lee, and J. S. Lee, J. Mol. Catal., 2000, 156, 283. [119] N. Z. Baibulatova, R. V. Kunakova, S. I. Lomakina, and U. M. Dzhemilev, Zh. Org. Khim., 1982, 18, 46. [120] T. Takahashi, I. Minami, and J. Tsuji, Tetrahedron Lett., 1981, 22, 2651. [121] A. Rodriguez, M. Nomen, B. W. Spur, J.-J. Godfroid, and T. H. Lee, Eur. J. Org. Chem., 2000, 2991. [122] A. Rodriguez, M. Nomen, B. W. Spur, J. J. Godfroid, and T. H. Lee, Tetrahedron Lett., 2000, 41, 823. [123] J. J. Lin and J. F. Knifton, Catal. Lett., 1996, 37, 199. [124] S. Grardnev and D. Wright, Tetrahedron Lett., 1972, 163. [125] R. Roffia, G. Gregorio, F. Conti, G. F. Pregaglia, and R. Ugo, J. Organomet. Chem., 1973, 55, 3455. [126] T. Mandai, T. Matsumoto, M. Kawada, and J. Tsuji, Tetrahedron, 1994, 50, 475. [127] T. Mandai, T. Matsumoto, M. Kawada, and J. Tsuji, Tetrahedron, 1993, 49, 5483. [128] A. J. Chalk and S. A. Magennis, Ann. N.Y. Acad. Sci., 1980, 333, 286. [129] J. Tsuji and M. Takahashi, J. Mol. Catal., 1980, 10, 107. [130] J. Beger and F. Meier, J. Prakt. Chem., 1980, 322, 69. [131] U. M. Dzhemilev, F. A. Selimov, and G. A. Tolstikov, Izv. Akad. Nauk SSSR Ser. Khim., 1980, 348. [132] R. N. Fakhretdinov, R. N. Khusnitdinov, I. B. Abdrakhmanov, and U. M. Dzhemilev, Zh. Org. Khim., 1984, 20, 1101. [133] G. P. Chiusoli, M. Costa, L. Pallini, and G. Terenghi, Transition Met. Chem. (Weinheim, Ger.), 1982, 7, 304.
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1631
[134] U. M. Dzhemilev, G. A. Tolstikov, A. G. Telin, M. Y. Dolomatov, E. G. Galkin, and G. A. Tolstikov, Izv. Akad. Nauk SSSR Ser. Khim., 1980, 163. [135] A. Groult and A. Guy, Tetrahedron, 1983, 39, 1543. [136] U. M. Dzhemilev, R. N. Fakhretdinov, and A. G. Telin, Zh. Org. Khim., 1986, 22, 1610. [137] R. N. Fakhretdinov, A. G. Telin, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1986, 10, 2254. [138] A. G. Telin, R. N. Fakhretdinov, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1986, 2474. [139] U. M. Dzhemilev, R. I. Khusnutdinov, Z. S. Muslimov, G. A. Tolstikov, and O. M. Nefedov, Izv. Akad. Nauk SSSR Ser. Khim., 1980, 220. [140] R. N. Fakhretdinov, A. A. Turchin, and U. M. Dzhemilev, Zh. Org. Khim., 1987, 23, 890. [141] A. G. Telin, R. N. Fakhretdinov, G. A. Tolstikov, and U. M. Dzhemilev, Zh. Org. Khim., 1987, 23, 289. [142] E. A. Petrushkina and V. I. Bregadze, Metalloorg. Khim., 1991, 4, 473. [143] E. A. Petrushkina, V. V. Gavrilenko, Y. F. Oprunenko, and N. G. Akhmedov, Zh. Obshch. Khim., 1996, 66, 1864. [144] U. M. Dzhemilev, F. A. Selimov, G. A. Tolstikov, E. A. Galkin, and V. I. Khvostenko, Izv. Akad. Nauk SSSR Ser. Khim., 1980, 652. [145] Y. Inoue, M. Taguchi, M. Toyofuku, and H. Hashimoto, Bull. Chem. Soc. Jpn., 1984, 57, 3021. [146] U. M. Dzhemilev, R. N. Fakhretdinov, and R. M. Safuanova, Izv. Akad. Nauk SSSR Ser. Khim., 1985, 9, 2098. [147] M. I. Zakharkin, V. V. Guseva, D. D. Sulaimankulova, and E. A. Petrushkina, Zh. Org. Khim., 1987, 23, 1654. [148] R. M. Safuanova, R. N. Fakhretdinov, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1984, 3, 703. [149] R. M. Safuanova, R. N. Fakhretdinov, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1988, 4, 821. [150] U. M. Dzhemilev, R. V. Kunakova, and M. M. Sirazova, Izv. Akad. Nauk SSSR Ser. Khim., 1985, 12, 2766. [151] U. M. Dzhemilev, M. M. Sirazova, R. V. Kunakova, A. A. Panasenko, and L. M. Khalilov, Izv. Akad. Nauk SSSR Ser. Khim., 1985, 2, 372. [152] E. A. Petrushkina, V. I. Bregadze, Y. F. Oprunenko, T. M. Shcherbina, and A. P. Laretina, Metalloorg. Khim., 1991, 4, 1336. [153] T. Antonsson, A. Langlet, and C. Moberg, J. Organomet. Chem., 1989, 363, 237. [154] M. L. Chernyshev, V. S. Tkach, T. V. Dmitrieva, G. V. Ratovskii, S. V. Zinchenko, and F. K. Shmidt, React. Kinet. Catal. Lett., 1992, 48, 291. [155] M. L. Chernyshev, V. S. Tkach, T. V. Dmitrieva, G. V. Ratovskii, S. V. Zinchenko, and F. K. Shmidt, Kinet. Catal. (Transl. of Kinet. Katal.), 1997, 38, 527. [156] T. Prinz, W. Keim, and B. Driessen-Hoelscher, Angew. Chem. Int. Ed. Engl., 1996, 35, 1708. [157] T. Prinz and B. Driessen-Hölscher, Eur. J. Chem., 1999, 5, 2069. [158] L. I. Zakharkin, E. A. Petrushkina, and L. S. Podvisotskaya, Izv. Akad. Nauk SSSR Ser. Khim., 1983, 4, 886. [159] L. I. Zakharkin and E. A. Petrushkina, Izv. Akad. Nauk SSSR Ser. Khim., 1986, 6, 1344. [160] W. Keim and M. Röper, J. Org. Chem., 1981, 46, 3702. [161] W. Keim, K. R. Kurtz, and M. Röper, J. Mol. Catal., 1983, 20, 129. [162] W. Keim, M. Röper, and M. Schieren, J. Mol. Catal., 1983, 20, 139.
1632
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
[163] M. Röper, R. He, and M. Schieren, J. Mol. Catal., 1985, 31, 335. [164] H. Zhang, Yingyong Huaxue, 1988, 5, 87. [165] V. S. Tkach, F. K. Shmidt, U. M. Dzhemilev, G. V. Ratovskii, M. L. Chernyshev, and O. I. Burlakova, Koord. Khim., 1989, 15, 1395. [166] S. M. Maddock and M. G. Finn, Organometallics, 2000, 19, 2684. [167] R. V. Kunakova, R. L. Gaisin, G. A. Tolstikov, L. M. Zelenova, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR Ser. Khim., 1980, 11, 2610. [168] U. M. Dzhemilev, R. V. Kunakova, R. L. Gaisin, and G. A. Tolstikov, Izv. Akad. Nauk SSSR Ser. Khim., 1979, 2702. [169] U. M. Dzhemilev, R. V. Kunakova, R. L. Gaisin, G. A. Tolstikov, R. V. Talipov, and S. I. Lomakina, Zh. Org. Khim., 1981, 17, 763. [170] U. M. Dzhemilev, R. V. Kunakova, R. L. Gaisin, F. G. Valyamova, and G. A. Tolstikov, Izv. Akad. Nauk SSSR Ser. Khim., 1990, 5, 1146. [171] Y. Inoue and H. Hashimoto, Bull. Chem. Soc. Jpn., 1986, 59, 3705. [172] U. M. Dzhemilev, R. V. Kunakova, and N. Z. Baibulatova, Izv. Akad. Nauk SSSR Ser. Khim., 1986, 1, 128. [173] G. A. Tolstikov, O. A. Rozentsvet, R. V. Kunakova, and N. N. Novitskaya, Izv. Akad. Nauk SSSR Ser. Khim., 1983, 589. [174] G. A. Tolstikov and O. A. Rozentsvet, Izv. Akad. Nauk SSSR Ser. Khim., 1983, 1647. [175] P. W. Jolly and N. Kokel, Synthesis, 1990, 771. [176] B. M. Trost and L. Zhi, Tetrahedron Lett., 1992, 33, 1831. [177] W. Keim, A. Koehnes, T. Roethel, and D. Enders, J. Organomet. Chem., 1990, 382, 295. [178] R. Bortolin and A. Musco, J. Mol. Catal., 1984, 22, 319. [179] A. Citterio, E. Comunale, and A. Musco, J. Chem. Res. Synop., 1984, 3, 77. [180] A. Citterio, P. De Angelis, P. Longo, and A. Musco, J. Chem. Res. Synop., 1985, 10, 316. [181] J. Tsuji, Bull. Chem. Soc. Jpn., 1973, 46, 1896. [182] U. M. Dzhemilev, F. A. Selimov, and G. A. Tolstikov, Izv. Akad. Nauk SSSR Ser. Khim., 1979, 2652. [183] T. Mitsuyasu and J. Tsuji, Tetrahedron, 1974, 30, 831. [184] N. T. Byrom, R. Grigg, B. Kongkathip, G. Reimer, and A. R. Wade, J. Chem. Soc. Perkin Trans 1, 1984, 1643. [185] W. E. Billups, W. E. Walker, and T. C. Shields, Chem. Commun., 1971, 1067. [186] U. M. Dzhemilev, R. V. Kunakova, and V. V. Sidorova, Izv. Akad. Nauk SSSR Ser. Khim., 1987, 403. [187] J. Tsuji, Y. Mori, and H. Hara, Tetrahedron, 1972, 28, 3721. [188] V. Vaisarova, J. Schraml, and J. Hetflejs, Collect. Czech. Chem. Commun., 1978, 43, 265. [189] J. Langova and J. Hetflejs, Collect. Czech. Chem. Commun., 1975, 40, 420. [190] J. Langova and J. Hetflejs, Collect. Czech. Chem. Commun., 1975, 40, 432. [191] J. Tsuji, M. Hara, and K. Ohno, Tetrahedron, 1974, 30, 2143. [192] M. Hara, K. Ohno, and J. Tsuji, Chem. Commun., 1971, 247. [193] S. Takahashi, T. Shibano, and N. Hagihara, Chem. Commun., 1969, 161. [194] S. Takahashi, T. Shibano, H. Kojima, and N. Hagihara, Organomet. Chem. Synth., 1970, 1, 193. [195] H. Sakura, Y. Eriyama, Y. Kamiyama, and Y. Nakadaira, J. Organomet. Chem., 1984, 264, 229. [196] Y. Obora, Y. Tsuji, and T. Kawamura, Organometallics, 1993, 12, 2853. [197] C. W. Carlson and R. West, Organometallics, 1983, 2, 1801. [198] Y. Uchimaru and M. Tanaka, J. Organomet. Chem., 1996, 521, 335.
IV.10.1 Pd-CATALYZED OLIGOMERIZATION AND POLYMERIZATION
1633
[199] Y. Tsuji and T. Kakehi, Chem. Commun., 1992, 1000. [200] J. M. Takacs and S. V. Chandramouli, Organometallics, 1990, 9, 2877. [201] R. M. Manyik, W. E. Walker, K. E. Atkins, and E. S. Hammack, Tetrahedron Lett., 1970, 3813. [202] P. Haynes, Tetrahedron Lett., 1970, 3687. [203] K. Ohno, T. Mitsuyasu, and J. Tsuji, Tetrahedron, 1972, 28, 3705. [204] M. Green, G. Sholes, and F. G. A. Stone, J. Chem. Soc. Dalton Trans., 1978, 309. [205] F. Dallacker, R. Semmler, K. Hartmann, W. Keim, and G. Von Ilsemann, Chem. Ztg., 1988, 112, 223. [206] R. Bortolin, G. Gatti, and A. Musco, J. Mol. Catal., 1982, 14, 95. [207] W. Keim, W. Meltzow, A. Koehnes, and T. Roethel, J. Chem. Soc. Chem. Commun., 1989, 16, 1151. [208] W. Keim and P. Mastrorilli, Gazz. Chim. Ital., 1993, 123, 401. [209] C. Siv, G. Peiffer, and A. Bendayan, J. Organomet. Chem., 1996, 525, 151. [210] J. Kiji, K. Yamamoto, H. Tomita, and J. Furukawa, Chem. Commun., 1974, 506. [211] Y. Sasaki, Y. Inoue, and H. Hashimoto, Chem. Commun., 1976, 605. [212] Y. Inoue, Y. Sasaki, and H. Hashimoto, Bull. Chem. Soc. Jpn., 1978, 51, 2375. [213] A. Musco, J. Chem. Soc. Perkin Trans. 1, 1988, 693. [214] A. Behr, Aspects Homogeneous Catal., 1988, 6, 59. [215] A. Behr, Angew. Chem. Int. Ed. Engl., 1988, 27, 661. [216] P. Braunstein, D. Matt, and D. Nobel, Chem. Rev., 1988, 88, 747 – 764. [217] A. Behr, R. He, K.-D. Juszak, C. Krueger, and Y.-H. Tsay, Chem. Ber., 1986, 119, 991. [218] P. Braunstein, D. Matt, and D. Nobel, J. Am. Chem. Soc., 1988, 110, 3207. [219] H. Hoberg and M. Minato, J. Organomet. Chem., 1991, 406, C25. [220] K. Ohno and J. Tsuji, Chem. Commun., 1971, 247. [221] R. Baker and M. S. Nobbs, Tetrahedron Lett., 1977, 3759. [222] R. Baker, M. S. Nobbs, and P. W. Winton, J. Organomet. Chem., 1977, 137, C43. [223] R. Baker, M. S. Nobbs, and D. T. Robinson, Chem. Commun., 1976, 723. [224] T. Antonsson and C. Moberg, Organometallics, 1985, 4, 1083. [225] C. Moberg, K. Nordstroem, and P. Helquist, Synthesis, 1992, 7, 685. [226] T. Antonsson, C. Malmberg, and C. Moberg, Tetrahedron Lett., 1988, 29, 5973.
Pd(0)
IV.10.2 Palladium-Catalyzed Benzannulation Reactions of Conjugated Enynes and Diynes SHINICHI SAITO and YOSHINORI YAMAMOTO
A. INTRODUCTION As shown in the previous section and in other sections, palladium complexes are good catalysts for the activation of conjugated dienes, allenes as well as alkynes, and the Pd-catalyzed dimerizations and/or oligomerizations of such compounds are observed. Since no by-products (inorganic salt, etc.) are produced in these reactions, and new carbon–carbon bonds are formed from relatively inert compounds, which are not activated by leaving groups and so on, it is highly desirable to develop such types of reactions. Compared to the frequent use of conjugated dienes for Pd-catalyzed reactions, conjugated enynes were not employed as substrates for Pd-catalyzed oligomerization. In an initial study of a Ni-catalyzed reaction, conjugated enynes cyclotrimerized to give trisubstituted benzenes and therefore conjugated enynes were considered as “substituted alkynes.”[1] Though conjugated enynes have been reported to undergo Lewis-acid-catalyzed and thermal [4 2] cycloaddition reactions,[2] the oligomerization of conjugated enynes in the presence of Pd catalysts has never been mentioned. In 1996, a new type of Pd-catalyzed reaction of unsaturated hydrocarbons was discovered.[3] Conjugated enynes cyclodimerize in the presence of Pd(0) catalysts to give disubstituted benzenes in high yields (benzannulation). Later, it was found that conjugated enynes undergo cross-benzannulation with conjugated diynes.[4] In most cases, these reactions give single products and no by-products are produced (Scheme 1). These reactions were applied to the preparation of many oligosubstituted aromatic compounds, which are not easily accessible by other synthetic methodologies.
B. CYCLODIMERIZATION OF CONJUGATED ENYNES (HOMOBENZANNULATION) Conjugated enynes cyclodimerize in the presence of Pd(PPh3)4 to give substituted benzenes. The mode of the cyclodimerization is strictly controlled as shown in Scheme 2, with 1,4-disubstituted benzenes obtained as the sole products. Though it has been
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1635
1636
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION 2 3 4
1
Pd(0)
+
Scheme 1 R
R
Pd(0)
R
R
R 2
R
R
R
not formed
R
Scheme 2
shown that some Pd compounds are efficient catalysts for the cyclotrimerization of alkynes,[5] the cyclotrimerization of conjugated enynes was not observed. It is also noteworthy that the reaction proceeded only in the presence of some Pd catalysts, and the reaction was not promoted by other transition metal catalysts such as CpCo(CO)2[6] or RhCl(PPh3)2,[7] which are effective catalysts for the cyclotrimerization of alkynes. Substituents could be introduced at the 2- or 4-position of the enynes, and 2-substituted enynes showed the highest reactivity. The reactions of 2-substituted enynes are summarized in Table 1, and the reactions of 4-substituted enynes are summarized in Tables 2 and 3. As shown, many functional groups including carbonyl groups, hydroxyl groups, and amino groups are tolerated for this reaction. A substituted phenol was obtained when an oxygen atom was introduced at the 2-position (Scheme 3).[8] At present, the scope of this reaction is limited to 2- or 4-substituted enynes, and the homobenzannulation of other substituted enynes has not been reported: the reactivity of the conjugated enynes becomes lower when the number of substituents becomes larger or a substituent is attached at the 1-position. The attempts to carry out the cross-benzannulation between different conjugated enynes turned out to be unsuccessful, giving mixtures of isomers in most cases (Table 4).[9] OMe
OMe
OMe
silica gel
Pd(0)
OMe Scheme 3
O 52%
1637
IV.10.2 Pd-CATALYZED BENZANNULATION REACTIONS
TABLE 1. Pd-Catalyzed Homobenzannulation of 2-Substituted Conjugated Enynes R R 2 mol % Pd(PPh3)4
1
toluene, 65 °C, 1 h
R 2
Enyne
Yield (%)
n-C6H13
77
CH3
70 a
81
HO O
a
82
The reaction was carried out with 2 mmol of the enyne in the presence of 1 mol % of Pd(PPh3)4.
TABLE 2. Pd-Catalyzed Homobenzannulation of 4-Substituted Conjugated Enynes (Alkyl Group) cat. Pd(0)
R
THF, 100 °C
3 (R = alkyl group) Enyne
R
R 4
Catalyst
Time (h)
Yield (%)
1 mol % Pd(PPh3)4 10 mol % COD
24
86
1 mol % Pd(PPh3)4 10 mol % COD
10
92
1 mol % Pd(PPh3)4 10 mol % COD
22
30
O
1 mol % Pd(PPh3)4
72
51
1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3
66
81
HO
24
100
MeO
1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3 1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3
24
100
Et2N
n-C6H13 n-C10H21
Cl
1638
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 3. Pd-Catalyzed Homobenzannulation of 4-Substituted Conjugated Enynes (Aryl Group) cat. Pd(0) THF, 100 °C
R
R
R
3 (R = alkyl group)
4
Enyne
Catalyst
Time (h)
Yield (%)
5 mol % Pd(PPh3)4
48
71
1 mol % Pd(PPh3)4 10 mol % COD
84
71
1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3
96
40
1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3
48
80
1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3
24
69
1 mol % Pd(PPh3)4 10 mol % P(o-Tol)3
48
81
MeO
F
O
S
TABLE 4. Pd-Catalyzed Cross-Benzannulation Between 4-Substituted Conjugated Enynes 1 mol % Pd(PPh3)4− 10 mol % P(o-Tol)3
+ n-C6H13
n-C6H13
n-C6H13
+
Ph MeOCH2 t-Bu Me3Si -Naphthyl
n-C6H13
R 6
5
R
THF, 100 °C
R
Yield of 5 (%) 13 5 36 0 25
+
R
R 7
Yield of 6 (%) 19 15 0 0 23
Yield of 7 (%) 23 80 0 0 0
1639
IV.10.2 Pd-CATALYZED BENZANNULATION REACTIONS
TABLE 5. Synthesis of [n]Paracyclophanes 9 (n m 1) from Bis-enynes 8 a
(CH2)m
toluene, 100 °C, high dilution
8 (m = 7−14) Reaction Pd(PPh3)4 (mol %)
8a (m 7) 8b (m 8) 8c (m 9) 8d (m 10)
40 40 40 40 20 20 40 10 40 10 40 10
8f (m 12) 8g (m 14)
9 (m = 7−14)
Conditions
Enyne
8e (m 11)
(CH2)m
cat. Pd(PPh3)4
Concentration of 8 (mM)
Time (min)
2.5 2.5 2.5 2.5 8.3 25 2.5 2.5 5 5 5 5
Yield of 9 (%)
20 30 15 15 90 60 15 25 15 15 10 15
1.7 18 36 47 28 a, b 7 a, c 61 51 71 59 71 67
a
The reaction was carried out at 80 °C. An inseparable mixture of cyclic dimers (M 484) was obtained in 27% yield. c A mixture of cyclic dimers was obtained in 7% yield. b
This reaction was also carried out in an intramolecular fashion, yielding a series of cyclophanes (Table 5).[10] Even strained [n]paracyclophanes could be prepared by this procedure, and the thermodynamically more stable metacyclophanes were not isolated. This result indicates that the regiochemistry of this reaction is strictly controlled. In these cases the intramolecular reaction competed with the intermolecular one; therefore, the reaction should be carried out under high dilution conditions, especially when the number m of the methylene groups of the bis-enyne becomes smaller (Table 5). The prepared strained [n]paracyclophanes possess some interesting properties. [n]Oligooxacyclophanes 11 could also be prepared by this procedure (Table 6).[11] It is noteworthy that the yields TABLE 6. Synthesis of [n]Oligooxaparacyclophanes 11 from 10 (n 3m 5) (OCH2CH2)m Pd(PPh3)4 -ligand (OCH2CH2)m CH2
(CH2)3 10 (m = 2−5)
DMSO, 100 °C 15−30 min high dilution
11 (m = 2−5)
Reaction
Conditions
Enyne
Pd(PPh3)4 (mmol)
Concentration of 10 (mM)
Ligand
Amount of Ligand (mol %)
Yield of 11 (%)
10a (m 2) 10b (m 3) 10c (m 4) 10d (m 5)
4 5 4 10
20 15 7 5
PPh3 PPh3 P(-Tol)3 P(-Tol)3
50 40 12 30
34 100 95 a 50 a
a
Yield determined by NMR spectroscopy.
1640
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
of the oxacyclophanes are higher compared to those of their hydrocarbon analogs. The higher yields were explained in terms of the coordination of the oxygen atoms to the palladium catalyst. C. CYCLOTRIMERIZATION OF CONJUGATED DIYNES Another type of benzannulation, which might be related to the benzannulation of conjugated enynes, is the Pd-catalyzed cyclotrimerization of 1,3-diynes (Scheme 4).[12] 1,3-Diynes cyclotrimerize in the presence of a Pd catalyst to give 1,3,5-trisubstituted benzene derivatives. In this reaction, too, the regioselectivity is perfectly controlled as shown in Scheme 4, and other products were never isolated. The reaction of various diynes is summarized in Table 7. Some functional groups such as olefins and ether linkages may be present in the side chain. An example for the cross-cyclotrimerization of a diyne and an alkyne has also been reported (Scheme 5).[12] TABLE 7. Pd-Catalyzed Cyclotrimerization of Conjugated Diynes
R Pd(0)
R 12
THF, reflux 15 h
R 13
Diyne
R
Catalyst
Yield (%)
n-C6H13
5 mol % Pd(dba)2 20 mol % PPh3
64
n-C10H21
5 mol % Pd(dba)2 20 mol % PPh3
46
p-Tolyl
5 mol % Pd(dba)2 20 mol % PPh3
46
TrO(CH2)2
5 mol % Pd(dba)2 20 mol % PPh3
65
MOMO(CH2)4
5 mol % Pd(dba)2 20 mol % PPh3
43
MOMO(CH3)2C
5 mol % Pd(dba)2 20 mol % PPh3
56
Ph(CH2)2
5 mol % Pd(PPh3)4
51
tert-Bu
5 mol % Pd(PPh3)4
21
1-Cyclohexenyl
5 mol % Pd(PPh3)4
40
1641
IV.10.2 Pd-CATALYZED BENZANNULATION REACTIONS
R R H
Pd(0)
R R
R R R
R R Scheme 4
Ph
n-C6H13
(1.0 mmol) + n-C6H13
H
cat. Pd(PPh3)4 THF, 65 °C 15 h
Ph
(0.5 mmol)
n-C6H13
n-C6H13
n-C6H13 + Ph n-C6H13 21%
n-C6H13
24%
n-C6H13
Scheme 5
D. [4 2] ANNULATION OF CONJUGATED ENYNES WITH DIYNES (CROSS-BENZANNULATION) The scope of the reaction discussed in Sect. B is somewhat limited since the only practical synthetic procedure consists of the cyclodimerization of the two identical enynes, and therefore the same substituents are attached at the phenyl group and the vinyl group of the reaction product. The attempted cross-annulation of conjugated enynes with alkynes or dienes turned out to be unsuccessful. However, the scope of the benzannulation reaction could be extended significantly by introducing conjugated
1642
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
diynes, which are highly reactive hydrocarbons in the presence of Pd catalysts (see Sect. C), as substrates for the reaction (Scheme 6). Thus, 2-substituted conjugated enynes reacted with conjugated diynes in the presence of Pd(0) catalysts to give 1,2,4trisubstituted benzene derivatives in good yields (Table 8).[4] In this case, too, the product was formed in a highly regioselective manner, and other isomeric benzenes were not isolated. This reaction has been applied to the synthesis of oligosubstituted phenols (Table 9).[8] Unlike other reactions described in this section, some highly substituted R1
R1
R2
Pd(0)
R1
R2
R2
+
R
R2
1
R
1
R2
R2 R2 R2 not formed
R2
R2
Scheme 6 TABLE 8. Pd-Catalyzed Cross-Benzannulation of Conjugated Enynes with Diynes (1)
R1 R
1
R2
+ R2 14
5 mol % Pd(PPh3)4 THF, 100 °C 15 h
15
1.5−5 equiv
R2
Enyne CH3
Diyne
n-C4H9
PhCH2
16 Yield (%)
n-C4H9
89
Ph
>99
Me3Si
SiMe3
92
n-C4H9
n-C4H9
60
n-C4H9
n-C4H9
89
Ph
86
SiMe3
80
Ph
n-C6H13
R2
Ph
Me3Si
1643
IV.10.2 Pd-CATALYZED BENZANNULATION REACTIONS
TABLE 9. Pd-Catalyzed Cross-Benzannulation of Conjugated Enynes with Diynes (2) OR2 R
1Z
+R
R1E
R3
4
R
4
THF, 100 °C, 12 h
18
17
OR2
2 mol % Pd(PPh3)4 _ 20 mol % P(o-Tol)3
R1 R4
R3
OH
TBAF (R2 = TBS) or BBr3 (R2 = Me)
R1 R4 R
3
R
R4
19
4
20
R1Z
R1E
R2
R3
R4
Methoda
Yield of 19 (%)
Yield of 20 (%)
H H H H H H H Me H H H
H H H H H H Me H H H H
TBS TBS TBS TBS TBS TBS TBS TBS Me Me Me
n-Hex n-Hex Ph Ph Ph Ph Ph Ph H H H
n-Bu Ph n-Bu n-Bu Ph Ph n-Bu n-Bu n-Bu Ph Me3Si
Stepwise Stepwise Stepwise One-pot Stepwise One-pot Stepwiseb Stepwise Stepwise Stepwise Stepwise
83 70 79 — 61 — 66 0 73(18)c 75 41(36)c
94 77 86 73 89 57 92 — 75 81 —
a
“Stepwise” corresponds to the stepwise reaction; that is, the protected phenol was isolated and then subjected to the deprotection. “One-pot” corresponds to the one-pot procedure; that is, the protected phenol was not isolated and was directly deprotected. b The reaction was carried out in the presence of 5 mol % Pd(PPh3)4. c Yield of the homodimerized product.
enynes such as 1,4-disubstituted, 2,4-disubstituted, and 1,2,4-trisubstituted enynes could be used as substrates for this reaction (Table 10).[13] The reactivity of the Z enynes or enynes containing an ester group appears to be higher compared to that of E enynes or enynes that do not contain an ester group.[14]
E. A MECHANISTIC RATIONALE OF THE BENZANNULATION REACTIONS Currently, the mechanism of these reactions is unclear, though some proposals appear in the literature without having decisive experimental evidence (Schemes 7–9).[3],[4] The initial step of this reaction should be the coordination of the alkyne moiety of the enyne or diyne to the Pd complex, since the coordinating ability of an alkyne is higher compared to that of an alkene. The Pd species formed via the insertion of the Pd into the acetylenic C—H bond cannot be an intermediate since the reaction of 4-substituted enynes proceeded smoothly (see Tables 2 and 3). Another enyne molecule might regioselectively
1644
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 10. Pd-Catalyzed Cross-Benzannulation of Conjugated Enynes with Diynes (3)
R2 R2 4 + R
R
3
R
21
R4
R1
5 mol % Pd(PPh3)4 toluene or THF, ∆
R4
R3
22
1
23 R4 Conditions
a
R1
R2
R3
R4
Temperature (°C)
Time (d)
Yield (%)
H H H Me (88%-Z) Me (84%-Z) Me (Z) COOMe(Z) COOMe(E) H H H
Me Me Me H H Me Me Me Me Me Me
n-Hex Ph 1-Cyclohexenyl n-Hex Ph Ph Ph Ph n-Hex Ph 1-Cyclohexenyl
n-Bu n-Bu n-Bu n-Bu n-Bu n-Bu n-Bu n-Bu Ph Ph Ph
100 100 100 120 120 120 120 120 100 100 100
3 3 3 5 5 5 2 2 3 3 3
95 79 89 45a 95a 43a 88 42 84 80 68
TDMPP (tris(2,6-dimethoxyophenyl)phosphine) was used as an additive (20 mol %).
R
R
R
Pd(0)
Pd
+
R
• Pd
Pd
H
R
H
R
1,3-H shift
Pd
Scheme 7 R
R
+
Pd(0)
Pd
R Diels-Alder-type reaction
Scheme 8
R H
Pd
H
formal 1,3-H shift
IV.10.2 Pd-CATALYZED BENZANNULATION REACTIONS
1645
interact with the Pd – alkyne complex to give a palladacyclopentadiene. Metallacyclopentadienes are widely accepted intermediates in some transition-metal-catalyzed reactions of alkynes such as cyclotrimerizations.[6] A subsequent intramolecular insertion of the alkene moiety into the metallacycle followed by a formal 1,3-hydrogen shift and reductive elimination would give the aromatized product. The 1,3-rearrangement of the proton was confirmed by deuteration experiments (Scheme 7).[3],[4] Alternatively, the enyne might react as a “diene” to give a Diels – Alder-type adduct, followed by the 1,3-hydrogen shift and reductive elimination (Scheme 8). The observed high regioselectivity reminds one that this type of mechanism might be operating. Another pathway, which involves an initial C — C bond formation between the alkene moiety and the alkyne moiety, has also been proposed (Scheme 9). It would be very important to study, in depth, the mechanism of this benzannulation reaction, which has some unique characteristics. R
R
R
• +
Pd(0)
Pd
Pd
R
R H
reductive elimination
H
Pd
Scheme 9
F. SUMMARY 1. Conjugated enynes cyclodimerize in the presence of Pd(0) catalysts to give di- or trisubstituted benzene derivatives with high regioselectivity. This reaction could be carried out in an intramolecular fashion to give [n]paracyclophanes. 2. Conjugated enynes react with conjugated diynes in the presence of Pd(0) catalysts to give tri-, tetra-, and pentasubstituted benzene derivatives with high regio- and chemoselectivity. This reaction was applied to the synthesis of oligosubstituted phenols. These transformations should be useful synthetic methods for the preparation of oligosubstituted benzenes.
REFERENCES [1] L. S. Meniwether, E. C. Colthup, G. W. Kennerly, and R. N. Reusch, J. Am. Chem. Soc., 1961, 83, 5155. [2] R. L. Danheiser, A. E. Gould, R. F. Pradilla, and A. L. Helgason, J. Org. Chem., 1994, 59, 5514.
1646
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
[3] S. Saito, M. M. Salter, V. Gevorgyan, N. Tsuboya, K. Tando, and Y. Yamamoto, J. Am. Chem. Soc., 1996, 118, 3970. [4] V. Gevorgyan, A. Takeda, and Y. Yamamoto, J. Am. Chem. Soc., 1997, 119, 11313. [5] J. Tsuji, Palladium Reagents and Catalysts, Wiley, New York, 1995, 476. [6] K. P. C. Vollhardt, Angew. Chem. Int. Ed. Engl., 1984, 23, 539–556. [7] S. J. Neeson and P. J. Steverson, Tetrahedron, 1989, 45, 6239. [8] V. Gevorgyan, L-.G. Quan, and Y. Yamamoto, J. Org. Chem., 1998, 63, 1244. [9] V. Gevorgyan, K. Tando, N. Uchiyama, and Y. Yamamoto, J. Org. Chem., 1998, 63, 7022. [10] S. Saito, N. Tsuboya, and Y. Yamamoto. J. Org. Chem., 1997, 62, 5042. [11] D. Weibel, V. Gevorgyan, and Y. Yamamoto, J. Org. Chem., 1998, 63, 1217. [12] A. Takeda, A. Ohno, I. Kadota, V. Gevorgyan, and Y. Yamamoto, J. Am. Chem. Soc., 1997, 119, 4547. [13] V. Gevorgyan, N. Sadayori, and Y. Yamamoto, Tetrahedron Lett., 1997, 38, 8603. [14] For the recent developments in this field, see the following reviews and articles. V Gevoegyan and Y. Yamamoto, J. Organomet. Chem., 1999, 576, 232. S. Saito and Y. Yamamoto, Chem. Rev., 2000, 100, 2901. S. Saito and Y. Yamamoto, J. Syn. Org. Chem. Jpn., 2001, 59, 346.
Pd (II or IV)
Pd
IV.10.3 Other Reactions Involving Palladacyclopropanes and Palladacyclopropenes ARMIN DE MEIJERE and OLIVER REISER
Although palladacyclopropanes and palladacyclopropenes can be postulated as intermediates when palladium in the oxidation state 0 or 2 interacts with an alkene or an alkyne, there is very little evidence that Pd-catalyzed reactions of alkenes and alkynes actually proceed this way. In principle, a palladacyclopropane might be generated starting from palladium(0) or palladium(II) 1 and an alkene 2 (Scheme 1): after coordination to form a -complex 3, oxidative addition would yield a -complex 4, a pallada(II)- or pallada(IV)cyclopropane. Likewise, the analogous reaction with an alkyne 5 would lead to a palladacyclopropene 7. 0 or +2
Pd
+
1
2
0 or +2
Pd 1
+ 5
0 or +2
+2 or +4
Pd
Pd
3
4
0 or +2
+2 or +4
Pd
Pd
6
7
Scheme 1
Conclusive evidence for palladacyclopentanes[1] and palladacyclopentadienes[2],[3] as potentially stable intermediates has been put forward, and they have a close analogy to such metallacycles with other metals.[4],[5] They frequently are intermediates in metalcatalyzed or -mediated formal [2 2 2] cyclotrimerizations of alkynes and strained alkenes. It is plausible to assume that palladacyclopropanes or -cyclopropenes also play a role in such formal [2 2 2] processes catalyzed by palladium(0), for example, in the type of Pd-catalyzed cyclotrimerization of 3,3-dimethylcyclopropene reported by Binger et al.[6] (see also Sect. IV.2.4), for which a palladacyclopentane as intermediate was already isolated.[7] Moreover, dimethyl 3,3-dimethylcyclopropenedicarboxylate 8 has recently been shown to form the tricyclic palladacyclopentane derivative 10, the structure Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1647
1648
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATIONS
of which was proved by X-ray analysis of its 1,1-bis(diphenylphosphinyl)ferrocene adduct 11 (Scheme 2).[1] It is most reasonable that 10 is formed via carbopalladation of 8 by the palladacyclopropane derivative 9. Pd(dba)2 reacts rapidly with dimethyl acetylenedicarboxylate (DMAD) to form the polymeric palladacyclopentadiene TCPC(13),[2] which could be fully characterized as diazadiene complexes 14 (Scheme 3).[3] The palladacyclopropene 12 would most probably be an intermediate en route to 13, and, indeed, 1:1 complexes of palladium and DMAD have been obtained and characterized by 1H NMR and IR spectroscopy with stabilizing ligands such as triphenylphosphine[2] and N,N-di-tert-butyl-1,4-diaza-1,3-diene[3] present (Scheme 4). Unfortunately, however, it was
E
E
E [Pd2(dba)3] CHCl3
E
8
Pd E
Pd
E
E 9
8
E
10 PPh2 PPh2
E
E
Fe
Pd E E Ph2P PPh2 Fe 11 Scheme 2
E
E
E
E DMAD
Pd
Pd
+ Pd(dba) 2
E
E
E E = CO 2Me
E 12
13
E R N
N R
E
Scheme 3
E R N Pd N E R 14
n
IV.10.3 REACTIONS OF PALLADACYCLOPROPANES AND PALLADACYCLOPROPENES
E
E + Pd(dba)2
E PPh3
2 PPh3
PPh3 E
15
16
t-Bu
E
t-Bu
E
N
N
or
Pd N t-Bu
Pd
PPh3
E = CO2Me
t-Bu N
PPh3 or
Pd E
E
1649
Pd
N E
t-Bu 17
N E
t-Bu 18
Scheme 4
not possible to distinguish whether their structures are best described as -complexes 15 and 17 or as palladacyclopropenes 16 and 18, respectively, but the latter seem plausible by analogy to platinacyclopropenes being well established via similar pathways.[8] In enyne cycloisomerizations developed by Trost (see Sect. IV.2.5 and IV.3.1), palladacycles are also likely intermediates (Scheme 5).[9] In the palladium(II)-initiated cyclization of an enyne 19, the palladacyclopentene 21 has been postulated, requiring palladium to adopt the formal oxidation state 4. Catalytic cycles involving Pd(II) – Pd(IV) are not well precedented; however, by now several reactions have been reported in which Pd(IV) intermediates are most likely,[10] – [16] and one palladium(IV)
H 4+
H
Pd H Pd2+
4+
20
Pd 21
19
H Pd2+ 22
4+
Pd H 23
Scheme 5
24
1650
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATIONS
complex has been fully characterized by an X-ray crystal structure analysis.[17] Most probably, 21 would be formed from the -complex 22 via the palladacyclopropene 20 by intramolecular carbopalladation of the double bond.
REFERENCES [1] A. S. K. Hashmi, F. Naumann, R. Probst, and J. W. Bats, Angew. Chem. Int. Ed. Engl., 1997, 34, 104. [2] K. Moseley and P. M. Maitlis, J. Chem. Soc. Dalton Trans., 1974, 169. [3] H. tom Dieck, C. Munz, and C. Müller, J. Organomet. Chem., 1990, 384, 243. [4] E. Negishi, Acc. Chem. Res., 1987, 20, 65–78. [5] N. E. Schore, Chem. Rev., 1988, 88, 1081–1119. [6] P. Binger, J. McMeeking, and U. Schuchardt, Chem. Ber., 1980, 113, 2372. [7] P. Binger, H. M. Bück, R. Benn, and R. Mynott, Angew. Chem. Int. Ed. Engl., 1982, 21, 62. [8] G. B. Young, in Comprehensive Organometallic Chemistry II: A Review of the Literature 1982–1994, Vol. 9, E. W. Abel, F. G. A. Stone, and G. Wilkinson, Eds., Pergamon Press, Oxford, 1995, 533–588. [9] B. M. Trost, Acc. Chem. Res., 1990, 23, 34–42. [10] A. J. Canty, Acc. Chem. Res., 1992, 25, 83–90. [11] M. Catellani, G. P. Chiusoli, and C. Castagnoli, J. Organomet. Chem., 1991, 407, C30. [12] O. Reiser, M. Weber, and A. de Meijere, Angew. Chem. Int. Ed. Engl., 1989, 28, 1037. [13] K. Albrecht, O. Reiser, M. Weber, B. Knieriem, and A. de Meijere, Tetrahedron, 1994, 50, 383. [14] T. Ito, H. Tsuchiya, and A. Yamamoto, Bull. Chem. Soc. Jpn., 1977, 50, 1319. [15] A. Moravskiy and J. K. Stille, J. Am. Chem. Soc., 1981, 102, 4182. [16] M. K. Loar and J. K. Stille, J. Am. Chem. Soc., 1981, 103, 4174. [17] M. Catellani and M. C. Fagnola, Angew. Chem. Int. Ed. Engl., 1995, 33, 2421.
RI + Et2Zn
cat. Pd
RZnI
IV.11
Palladium-Catalyzed Carbozincation
PAUL KNOCHEL
A. INTRODUCTION The carbopalladation is a central reaction in organopalladium chemistry and is extensively presented in Part IV. In most reactions, a discrete organopalladium intermediate adds to a double or triple bond. In this section, the reaction of an alkyl iodide with diethylzinc in the presence of a palladium(0) catalyst is presented. Such reaction conditions generate an alkyl radical that readily adds intramolecularly to a double bond, leading to an organozinc derivative (Scheme 1). The combination of a radical cyclization with the formation of an organometallic product allows new synthetic applications that will be discussed. Closely related Ni-catalyzed cyclizations will also be briefly presented.
B. MECHANISTIC STUDIES The iodine–zinc exchange[1],[2] is a convenient method for preparing diorganozincs. It is catalyzed by copper(I) salts[2] and proceeds at temperatures between 50 and 60 °C. Other metallic salts catalyze this exchange reaction and especially palladium(II) salts give excellent results, allowing the conversion of octyl iodide to octylzinc iodide (and not dioctylzinc as shown by gravimetric analysis)[3] (Scheme 2). Functionalized primary alkyl iodides such as EtO2C(CH2)3I or NC(CH2)3I react within 1 0 – 30 min at 25 °C (90% yield) without the formation of any -hydride elimination product. In order to clarify the mechanism of the reaction, other precursors were used. It was found that alkyl tosylates or mesylates do not react. The reaction is inhibited by small amounts of nitrobenzene and does not proceed with Me2Zn. The exchange reaction is also very slow in ether. The treatment of either exo- or endo-7-iodobicyclo[2.1.0]heptane[4] with Et2Zn (ca. 2 equiv) in the presence of PdCl2(dppf) in THF furnishes the exo-substituted bicyclic organozinc reagent, which was allylated in a stereoconvergent manner, suggesting a radical to be a reaction intermediate (Scheme 3). The insertion of Pd(0) into an alkyl iodide may therefore proceed via a radical pathway.[5],[6] The fast oxidative insertion may also indicate that a palladate species[7] such as 1 may be responsible for an electron transfer reaction[8] (Scheme 4). By using 5-hexenyl
Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.
1651
1652
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
I
Et2Zn
ZnI
PdCl2L2
Scheme 1 Et2Zn, 50 °C, 12 h
Oct2Zn
Et2Zn, THF, 25 °C, 2 h
Oct-I
CuI (0.3 mol %)
Oct-ZnI
PdCl2(dppf) (1.5 mol %) −H2C=CH 2 −H3C CH3
Scheme 2 H
I
H Et2Zn, Pd(0) cat.
Et2Zn, Pd(0) cat.
ZnI
H
I
H
H H
H endo
H exo/endo = 96:4
exo
1. CuCN ⴢ 2 LiCl 2.
H
COOEt Br
H
COOEt
H 60%
H Scheme 3
Et2Zn
Pd(0)
R
EtPd ZnEt 1
−EtZnI
EtPd + R
EtPd R
Scheme 4
iodide as a substrate, a radical cyclization occurs, affording cyclopentylmethylzinc iodide (Scheme 1). This synthetic procedure allows one to perform radical ring closures[9] but affords as a product an organometallic species (organozinc halide) that can be used to form further carbon–carbon bonds. The stereoselectivity observed in the ring closure follows Beckwith rules[10] and is also stereoconvergent. Thus, the cyclization of the iodides 2a and 2b provides only the trans-product via a chair transition state such as 4 (Scheme 5). A complete trans-stereoselectivity is observed between C(1) and C(2) of products 3a-b. The cyclization leads as expected[10] to lower stereoselectivity for the ring closure, affording the allylated product 5 as a cis/trans mixture of 78:22. This selectivity can dramatically be improved by using the 3-substituted secondary alkyl iodide 6. Although
1653
IV.11 PALLADIUM-CATALYZED CARBOZINCATION
EtO2C 99:1
H
H I Et2Zn (2 equiv)
RO
RO
H
PdCl2(dppf) 1.5 mol % 25 °C, 20 h
H
1. CuCN • 2 LiCl 2.
H
RO
COOEt
67%
Br
3a: R = Bn 73% 3b: R = Bz 47%
4
2a: R = Bn 2b: R = Bz
Scheme 5
6 is used as a 1:1 mixture of diastereoisomers, only one stereoisomer 7 is obtained. Its formation is easily rationalized by assuming a chair transition state such as 8 (Scheme 6).[4],[11] The stereoconvergence of the reaction supports the radical mechanism of the ring closure.
EtO2C Et2Zn (2 equiv)
Me I
1. CuCN • 2 LiCl
Me
PdCl2(dppf) 1.5 mol % 25 °C, 2 h
H
2.
H
78:22
COOEt
Me
Br
5 80%
EtO2C 99:1
H BnO
I Me 6
Et2Zn (2 equiv) PdCl2(dppf) 1.5 mol % 25 °C, 5 h
BnO
Me H
1. CuCN • 2 LiCl 2.
H
COOEt
95:5 Me
BnO
Br
7 67%
8 Scheme 6
C. SCOPE AND LIMITATION OF THE CYCLIZATION The cyclization of 4-substituted 5-hexenyl iodides proceeds well, leading to cyclopentylzinc iodides that can be trapped with various electrophiles such as 3-iodo-2-cyclohexenone, iodine, acid chlorides, allylic halides, and ethyl propiolate (carbocupration) (Scheme 7).[4] Various substitution patterns allow a successful cyclization. Also, a range of functional groups like esters or nitriles are tolerated in the ring closure (Scheme 8). The presence of an oxygen functionality (O-centered leaving group) is also compatible with the reaction conditions and the 2-pivaloyloxyalkyl iodide 9 leads after allylation to the expected cyclopentane derivative 10 (Scheme 9).[4]
1654
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Ph O 1. CuCN • 2 LiCl 2.
Ph
O
I
I2
I
90% Et2Zn, THF
Ph
Ph 25 °C, 2h
PdCl2(dppf) 1.5 mol %
I
Ph
1. CuCN • 2 LiCl
ZnI
CO2Et
CO2Et
2.
>98% trans
64% >95% E 1. CuCN • 2 LiCl 2.
CO2Et Br
1. CuCN • 2 LiCl 2. PhCOCl
Ph CO2Et
Ph
O
73%
76% Scheme 7
I Et2Zn (2 equiv)
ZnI
PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
FG
1. CuCN • 2 LiCl 2.
CO2Et
CO2 Et
Br
FG
FG FG = CN 83% FG = OCOt-Bu 62%
I Bu
ZnI 1. CuCN • 2 LiCl
Et2Zn (2 equiv) PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
Bu
Ph
2.
Bu
Ph
NO2
NO2
81% Scheme 8
1655
IV.11 PALLADIUM-CATALYZED CARBOZINCATION
I
E
Et2Zn (2 equiv) PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
E
E
1. CuCN • 2 LiCl CO2Et 2. Br
E
E = CO2Et R
E = CO2Et R
I Et2Zn (2 equiv) PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
1. CuCN • 2 LiCl
O
2.
O
R = Me, Et, c-Hex R
62−81% cis/trans ca. 70:30
I
R
I Et2Zn (2 equiv)
1. CuCN • 2 LiCl
PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
2.
COOEt Br
CO2Et 75−87% cis/trans ca. 78:22
R = (CH2)4OAc, Et, (CH 2)3CN R
73% CO2 Et
R
I Et2Zn (2 equiv)
1. CuCN • 2 LiCl
PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
2.
CO2Et
CO2Et
51−71% cis/trans ca. 78:22
R = (CH2)4OAc, (CH 2)3CN OAc
OAc
I Et2Zn (2 equiv) PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
1. CuCN • 2 LiCl 2. Cl
OAc
AcO 52% cis/trans 77:23
Scheme 8 (Continued )
EtO2C I
Et2Zn
OPiv
PdCl2(dppf ) 1.5 mol % 25 °C, 2 h
ZnI OPiv
80:20
1. CuCN • 2 LiCl 2.
CO2Et
OPiv
Br
9 10 87% Scheme 9
1656
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Various domino cyclizations using substrates like 1 1–13 have been used successfully (Scheme 10).[4],[11] The intramolecular addition to unsaturated esters was also possible. Best results are obtained with a t-amyl ester, which leads to a product that is less prone to undergo Claisen condensation. The same reaction is observed with the corresponding acetylenic ester (Scheme 11).[4]
I
1. Et2Zn
CO2Et
PdCl2(dppf ) cat. 25 °C, 2 h 2. CuCN • 2 LiCl COOEt
90%
endo/exo 80:20
Br
1. Et2Zn PdCl2(dppf ) cat. 25 °C, 2 h 2. CuCN • 2 LiCl CO2Et
I 11 n
1. Et2Zn (2 equiv) Ni(acac)2 (2.5 mol %) 0 °C, 3h 2. CuCN • 2 LiCl
I
CO2Et 70% endo/exo 80:20
EtO2C
CO2Et Br
12 n = 1 13 n = 2
n = 1: 85 % endo/exo 1:2 n = 2: 63 % endo/exo 1:2
Scheme 10
CO2R
I
Et2Zn, THF PdCl2(MeCN)2 (1.5 mol %) −78 °C to 25 °C, 4 h
R = Et R = t-Am
R = Et 57% R = t-Am 74%
CO2Me I
CH2 CO2R
CO2Me
Et2Zn ( 2 equiv), THF PdCl2(MeCN)2 ( 1.5 mol % ) 25 °C, 4 h
73% Scheme 11
IV.11 PALLADIUM-CATALYZED CARBOZINCATION
1657
The reactivity observed with acetylenic ketones is more complex and the two iodoalkynyl ketones 14 and 15 behave in a different way (Scheme 12). Thus, the phenyl ketone 14 undergoes carbopalladation of the triple bond followed by a reductive elimination, furnishing the exo-alkylidenecyclopentane derivative 16. On the other hand, the methyl ketone 15 undergoes, after carbopalladation, a subsequent Michael addition, leading to the ketone 17 in 52% yield. COPh I
COPh
Et2Zn, THF PdCl2(MeCN)2 (1.5 mol %) 25 °C, 4 h
Et
14
16 60% COMe I
COMe
Et2Zn, THF PdCl2(MeCN)2 (1.5 mol %) 25 °C, 4 h
Et
15
17 52% Scheme 12
The scope of the reaction can be extended to unsaturated alkyl bromides as substrates by using Ni(acac)2 as a catalyst[12],[13] instead of Pd(II) complexes. The use of Ni(acac)2 as a catalyst even with several polyfunctional alkyl iodides gives better results. Thus, in the key step for the synthesis of methyl epijasmonate 18, the alkyl iodide 19 undergoes a smooth cyclization using Ni(acac)2 and Et2Zn (Scheme 13).[12] OBn 1. Et2Zn, Ni(acac)2 cat THF, 25 °C
I
CO2Me
OBn
2. CuCN • 2 LiCl 3. Br Et −55 °C, 48 h
CO2Me
Et
86% 95:5
19 O
Et CO2Me 18 epijasmonate Scheme 13
Polyfunctional alkyl bromides have been cyclized with Ni(acac)2/Et2Zn for the construction of various heterocycles[13] as well as for the antitumor antibiotic ()-methylenolactocin 20. In this case, the alkyl bromide 21 is cyclized and selectively oxidized to the aldehyde 22, which is converted in a standard way to the natural product 20 (Scheme 14).
1658
IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
Me3Si Br
Pent
O
OBu
1. Et2Zn, LiI Ni(acac)2 THF, 40 °C
ZnX O
SiMe3
O
C
OHC
2. O2, TMSCl THF, −5 °C
Pent Pent
21
OBu
O
OBu
O
22 55% HO2C
HO2C
Jones reagent acetone, 0 °C, 15 min
Pent
O 90 %
O
Pent
O
O
20: (−)-methylenolactocin
Scheme 14
D. SUMMARY 1. The treatment of an alkyl iodide with Et2Zn in the presence of catalytic amounts of palladium(II) salts leads to the corresponding organozinc iodide. 2. The reaction proceeds via a radical intermediate and can be used to perform radical cyclizations affording five-membered rings. However, the products of these reactions are organozinc reagents, which can be reacted with a wide range of electrophiles. 3. The cyclizations are stereoselective following the Beckwith rules and allow the elaboration of highly substituted cyclopentane derivatives. 4. Domino cyclizations can be performed. 5. Unsaturated alkyl bromides can be used as substrates if the Pd(II) catalyst is replaced by Ni(acac)2. REFERENCES [1] M. J. Rozema, S. AchyuthaRao, and P. Knochel, J. Org. Chem., 1992, 57, 1956. [2] M. J. Rozema, C. Eisenberg, H. Lütjens, R. Ostwald, K. Belyk, and P. Knochel, Tetrahedron Lett., 1993, 34, 3115. [3] H. Stadtmüller, R. Lentz, W. Dörner, T. Stüdemann, C. E. Tucker, and P. Knochel, J. Am. Chem. Soc., 1993, 115, 7027. [4] H. Stadtmüller, A. Vaupel, C. E. Tucker, T. Stüdemann, and P. Knochel, Chem. Eur. J., 1996, 2, 1204. [5] A. V. Kramer, J. A. Labinger, J. S. Bradley, and J. A. Osborn, J. Am. Chem. Soc., 1974, 96, 7145. [6] A. V. Kramer and J. A. Osborn, J. Am. Chem. Soc., 1974, 96, 7832. [7] C. Amatore, E. Carré, A. Jutand, H. Tanaka, Q. Ren, and S. Torii, Chem. Eur. J., 1996, 2, 957. [8] M. Chanon, Bull. Soc. Chim. Fr., 1982, 2, 197. [9] D. P. Curran, in Comprehensive Organic Chemistry, Vol. 4, B. M. Trost and I. Fleming, Eds., Pergamon Press, New York, 1991, 779.
IV.11 PALLADIUM-CATALYZED CARBOZINCATION
1659
[10] A. L. J. Beckwith, T. Lawrence, and A. K. Serehis, J. Chem. Soc. Chem. Commun., 1980, 484. [11] H. Stadtmüller, C. E. Tucker, A. Vaupel, and P. Knochel, Tetrahedron Lett., 1993, 34, 7911. [12] H. Stadtmüller and P. Knochel, Synlett, 1995, 463. [13] A. Vaupel and P. Knochel, J. Org. Chem., 1996, 61, 5743.
