substrates involving the oxidative addition/transmeta-
lation/reductive elimination sequence have been per-
formed using several organometals.7 However, the reac-
tion has limited synthetic scope, probably due to the slow
rate of the reductive elimination step.8
Palladium-Catalyzed Cross-Coupling
Reactions of Allylic Halides and Acetates
with Indium Organometallics†
David Rodr´ıguez, Jose´ Pe´rez Sestelo,* and
Luis A. Sarandeses*
In the past decade, indium and organoindium reagents
have proven to be useful in organic synthesis due to
their high chemoselectivity, low toxicity, and tolerance
to aqueous media.9 In 1999, we discovered the metal-
catalyzed cross-coupling reaction using indium organo-
metallics.10 In this reaction, triorganoindium compounds
(R3In) react efficiently under palladium catalysis with
alkenyl or aryl halides and triflates. The whole process
has a high atom economy, with all three groups attached
to indium being efficiently transferred to the electrophile
(eq 1). Since then, we have been interested in extending
the synthetic scope of this reaction to encompass new
scenarios.11
Departamento de Quı´mica Fundamental,
Universidade da Corun˜a, E-15071 A Corun˜a, Spain
Received May 19, 2004
Abstract: The palladium(0)-catalyzed cross-coupling reac-
tion of allylic halides and acetates with indium organome-
tallics is reported. In this synthetic transformation, trior-
ganoindium compounds and tetraorganoindates (aryl, alkenyl,
and methyl) react with cinnamyl and geranyl halides and
acetates to afford the SN2 product regioselectively and in
good yield. The reaction proceeds with net inversion of the
stereochemical configuration.
R3In + 3 R′-X Pd or Ni catalyst8 3 R′-R
(1)
THF
Recently, we discovered that triorganoindium com-
pounds react regioselectively with allylic halides and
acetates under copper catalysis to afford the SN2′ product
in good yield.12 We report here our results on the
palladium-catalyzed reaction of indium organometallics
with allylic electrophiles.13
As a starting point for our investigation, and in
accordance with literature precedents,14 we initially
studied the reactivity of Ph3In with cinnamyl chloride
under palladium(0) catalysis [Pd2(dba)3] without ligands.
Under these conditions, we observed that Ph3In (40 mol
%) reacted with cinnamyl chloride (1a, 100 mol %) in the
presence of Pd2(dba)3 (5 mol %) under reflux in THF to
afford the SN2 product (2a) regioselectively in 53% yield
(Table 1, entry 1). In the reaction, isomerization of the
alkene was not observed, but starting cinnamyl chloride
The metal-catalyzed cross-coupling reaction of orga-
nometallic reagents with organic halides and related
electrophiles is one of the most convenient methodologies
for carbon-carbon bond formation.1 A variety of organo-
metallic reagents (Mg, Zn, Cu, B, Sn, Si, In) and
unsaturated electrophiles (vinyl or aryl halides or
pseudohalides) can be used in conjunction with palladium
or nickel catalysis, and only alkyl and allyl electrophiles
suffer from limitations.2 Allylic substrates represent a
particular class of organic compounds due to their high
reactivity and bidentate electrophilicity. The control of
both the regio- and stereochemistry in allylic substitution
reactions are fundamental aspects of the reactivity of
such systems.3 Reactions involving allylic electrophiles
have been traditionally performed using organocopper
species4 (or copper-catalyzed reactions using other orga-
nometallics)5 and, more recently, using soft nucleophiles
under palladium catalysis (Tsuji-Trost reaction).6 Tran-
sition-metal-catalyzed cross-coupling reactions of allylic
(7) Negishi, E.; Liu, F. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; Vol.
1, Chapter III.2.9, pp 551-589.
(8) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules, 2nd ed.; University Science Books: Sausalito, CA,
1999; Chapter 9, pp 245-285. (b) Brown, J. M.; Cooley, A. M. Chem.
Rev. 1988, 88, 1031-1046. (c) Albe´niz, A. C.; Espinet, P.; Mart´ın-Ruiz,
B. Chem.sEur. J. 2001, 7, 2481-2489.
(9) (a) Cintas, P. Synlett 1995, 1087-1096. (b) Li, C.-J.; Chan, T.-
H. Tetrahedron 1999, 55, 11149-11176. (c) Ranu, B. C. Eur. J. Org.
Chem. 2000, 2347-2356. (d) Pae, A. N.; Cho, Y. S. Curr. Org. Chem.
2002, 6, 715-737. (e) Podlech, J.; Maier, T. C. Synthesis 2003, 633-
655.
(10) (a) Pe´rez, I.; Pe´rez Sestelo, J.; Sarandeses, L. A. Org. Lett. 1999,
1, 1267-1269. (b) Pe´rez, I.; Pe´rez Sestelo, J.; Sarandeses, L. A. J. Am.
Chem. Soc. 2001, 123, 4155-4160.
(11) (a) Pe´rez, I.; Pe´rez Sestelo, J.; Maestro, M. A.; Mourin˜o, A.;
Sarandeses, L. A. J. Org. Chem. 1998, 63, 10074-10076. (b) Pena, M.
A.; Pe´rez, I.; Pe´rez Sestelo, J.; Sarandeses, L. A. Chem. Commun. 2002,
2246-2247. (c) Pena, M. A.; Pe´rez Sestelo, J.; Sarandeses, L. A.
Synthesis 2003, 780-784.
(12) Rodr´ıguez, D.; Pe´rez Sestelo, J.; Sarandeses, L. A. J. Org. Chem.
2003, 68, 2518-2520.
(13) During the preparation of this manuscript, the first examples
of a palladium-catalyzed allylic substitution reaction using triorga-
noindium reagents were published: Baker, L.; Minehan, T. J. Org.
Chem. 2004, 69, 3957-3960.
(14) (a) Sheffy, F. K.; Godschalx, J. P.; Stille, J. K. J. Am. Chem.
Soc. 1984, 106, 4833-4840. (b) Del Valle, L.; Stille, J. K.; Hegedus, L.
S. J. Org. Chem. 1990, 55, 3019-3023.
† Dedicated in memoriam to Dr. Juan Carlos del Amo (Universidad
Complutense de Madrid, Spain), victim of the terrorism in Madrid on
March 11, 2004.
(1) Diederich, F.; Stang, P. J., Eds. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998.
(2) (a) Luh, T.-Y.; Leung, M.; Wong, K.-T. Chem. Rev. 2000, 100,
3187-3204. (b) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-
387.
(3) For a general overview: Tsuji, T. Transition Metal Reagents and
Catalysts; Wiley: New York, 2000; Chapter 4, pp 109-168.
(4) Lipshutz, B. H. In Comprehensive Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon: Oxford,
UK, 1995; Vol. 12, Chapter 3.2, pp 59-130.
(5) (a) Yanagisawa, A.; Yamamoto, H. In Transition Metal Catalysed
Reactions; Murahashi, S.-I., Davies, S. G., Eds.; Blackwell Science:
Oxford, UK, 1999; Chapter 11, pp 225-240. (b) Sofia, A.; Karlstro¨m,
E.; Ba¨ckvall, J.-E. In Modern Organocopper Chemistry; Krause, N.,
Ed.; Wiley-VCH: Weinheim: 2002; Chapter 8, pp 259-288.
(6) (a) Godleski, S. A. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, Chapter
3.3, pp 585-661. (b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395-422. (c) Heumann, A. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998;
Chapter 2.15, pp 251-264.
10.1021/jo0491511 CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/19/2004
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J. Org. Chem. 2004, 69, 8136-8139