pubs.acs.org/joc
have been used as key steps in the synthesis of numerous biolo-
Asymmetric 1,4-Addition of Arylboronic Acids to
2,3-Dihydro-4-pyridones Catalyzed by Axially Chiral
NHC-Pd(II) Complexes
gically active compounds.2 The piperidine ring is a key unit in
many natural products, biologically active molecules, and drugs.3
Piperidones serve a role as advanced intermediates to piperi-
dines.4 They are also attractive synthetic targets due to their
interesting pharmacological properties.5 Thus far, numerous
asymmetric synthetic routes have been developed for preparation
of substituted piperidones and piperidines, and many efforts have
been devoted to make short, versatile, stereocontrolled routes for
the synthesis of these compounds.4e,f,6 Enantioselective conjugate
addition to readily accessible N-substituted 2,3-dihydro-4-pyri-
dones7 is an attractive catalytic route toward enantiopure
piperidones. However, to the best of our knowledge, only a
few suitable procedures, with the exception of the elegant
works of Hayashi et al. and Vries et al. have been reported.8
N-Heterocyclic carbenes (NHC) have become a very im-
portant class of ligands in transition metal catalysis due to
their stability to air and in some cases to moisture, and their
strong σ-donor but poor π-acceptor abilities.9 Previously,
Qin Xu,† Rui Zhang,† Tao Zhang,† and Min Shi*,†,‡
†Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, School of Chemistry & Molecular Engineering, East
China University of Science and Technology, and 130 MeiLong
Road, Shanghai 200237, People’s Republic of China, and
‡State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, People’s Republic of China
Received April 1, 2010
(3) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetra-
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B. Org. Lett. 2000, 2, 3679–3681.
(4) (a) Mayers, A. I.; Shawe, T. T.; Gottlieb, L. Tetrahedron Lett. 1992,33, 867–
870. (b) Tawara, J. N.; Lorenz, P.; Stermitz, F. R. J. Nat. Prod. 1999, 62, 321–323.
(c) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–3681. (d) Brooks,
C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41, 3551–3553. (e) Weintraub, P. M.;
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(f) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1709.
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Aran, V. J.; Herradon, B. Chem. Med. Chem. 2006, 1, 710–714. (e) Pei, Z.; Li, X.;
von Geldern, T. W.; Longenecker, K.; Pireh, D.; Stewart, K. D.; Backes, B. J.; Lai,
C.; Libben, T. H.; Ballaron, S. J.; Beno, D. W. A.; Kempf-Grote, A. J.; Sham, H.
L.; Trevillyan, J. M. J. Med. Chem. 2007, 50, 1983–1987. (f) Jha, A.; Mukherjee, C.;
Prasad, A. K.; Parmar, V. S.; De Clercq, E.; Balzarini, J.; Stables, J. P.; Manavathu,
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(6) For reviews of the recent developments in asymmetric routes to
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P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998, 633–640.
(b) Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813. (c) Zhou, P.; Chen,
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Axially chiral cis-chelated bidentate bis(N-heterocyclic
carbene)-palladium(II) complexes are effective catalysts
for the asymmetric conjugate addition of arylboronic acids
to 2,3-dihydro-4-pyridones, producing the synthetically and
biologically important 2-aryl-4-piperidones in moderate-to-
high yields (up to 96%) along with excellent enantioselectivi-
ties (up to >99.5% ee) in most cases under mild conditions.
ꢀ
Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005,
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D. L.; Chung, G.; Foley, M. A. Heterocycles 1994, 37, 1121–1140.
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R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 6240–6241.
(c) Syebesta, R.; Pizzuti, M. G.; Boersma, A. J.; Minnaard, A. J.; Feringa, B. L.
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The asymmetric conjugate addition of organometallic reagents
to Michael acceptors is one of the most useful methods for the
construction of chiral C-C bonds.1 These addition reactions
*To whom correspondence should be addressed. Fax: 86-21-64166128.
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DOI: 10.1021/jo1006224
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Published on Web 05/06/2010
J. Org. Chem. 2010, 75, 3935–3937 3935
2010 American Chemical Society