ORGANIC
LETTERS
2008
Vol. 10, No. 7
1413-1415
Palladium-Catalyzed
Oxindoles
r-Arylation of
Matthew J. Durbin† and Michael C. Willis*,‡
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, United Kingdom, and
Department of Chemistry, UniVersity of Oxford, Chemical Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, United Kingdom
Received January 21, 2008
ABSTRACT
A catalyst generated from Pd(dba)2 and the bulky electron-rich phosphine ligand 2-(dicyclohexylphosphino)-2′,4′, 6′-tri-i-propyl-1−1′-biphenyl
is effective for the
r-arylation of oxindoles. Generation of the potassium-enolates of a range of oxindoles allows coupling with aryl chlorides,
bromides, and triflates. Significant variation of the substitution pattern on both the oxindole and aryl halide is possible.
Oxindoles, specifically those with C-3 functionalization,
represent an important motif in a number of natural products1
and pharmaceutical targets. They display biological activity
against a variety of neurodegenerative disorders2 and exhibit
anti-tumor3 and anti-HIV properties.4 An important subclass
are the C-3 aryl oxindoles, which maintain an important role
in potassium channel modulation for the treatment of post-
stroke patients.5 Traditional methods for their preparation
include reduction of a parent isatin6 and palladium catalyzed
asymmetric intramolecular cyclization.7 However, such
protocols are unsuitable if the oxindole core is already present
in the substrate, and there remains a need for an efficient
process for intermolecular arylation of the C-3 position.8
Palladium-catalyzed R-arylations of carbonyl and related
compounds have been achieved with a range of nucleophiles
including enolates of ketones,9 aldehydes,10 malonates,9a
esters,11 silyl enol ethers,12 nitriles,13 and amides.7a,11b,14 The
arylation of amide enolates represents one of the most
challenging of this group of compounds due to the high pKa
(5) (a) Gribkoff, V. K.; Starrett, J. E., Jr.; Dworetzky, S. I.; Hewawasam,
P.; Boissard, C. G.; Cook, D. A.; Frantz, S. W.; Heman, K.; Hibbard, J. R.;
Huston, K.; Johnson, G.; Krishnan, B. S.; Kinney, G. G.; Lombardo, L.
A.; Meanwell, N. A.; Molinoff, P. B.; Myers, R. A.; Moon, S. L.; Ortiz,
A.; Pajor, L.; Pieschl, R. L.; Post-Munson, D. J.; Signor, L. J.; Srinivas,
N.; Taber, M. T.; Thalody, G.; Trojnacki, J. T.; Wiener, H.; Yeleswaram.
K.; Yeola, S. W. Nat. Med. 2001, 7, 471. (b) Hewawasam, P.; Gribkoff, V.
K.; Pendri, Y.; Dworetzky, S. I.; Boissard, C. G.; Martinez, E.; Post-Munson,
D. J.; Trojnacki, J. T.; Yeleswaram, K.; Pajor, L. M.; Knipe, J.; Gao, Q.;
Perrone, R.; Starrett, J. E., Jr. Bioorg. Med. Chem. Lett. 2002, 12, 1023.
(c) Hewawasam, P.; Gribkoff, V. K.; Erway, M.; Moon, S. L.; Knipe, J.;
Weiner, H.; Boissard, C. G.; Post-Munson, D. J.; Gao, Q.; Huang, S.;
Meanwell, N. A. J. Med. Chem. 2002, 45, 1487. (d) Jensen, B. S. CNS
Drug ReV. 2002, 8, 353.
(6) (a) Shintani, R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006,
45, 3353. (b) Hewawasam, P.; Erway, M. Tetrahedron Lett. 1998, 39, 3981.
(7) (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (b) Arao,
T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743. (c) Ku¨ndig,
E. P.; Seidel, T. M.; Jia, Y.; Bernardinelli, G. Angew. Chem., Int. Ed. 2007,
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† University of Bath.
‡ University of Oxford.
(1) (a) Bindra, J. S. In Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1973; Vol. 14, p 83. (b) Marti, C.; Carreira, E. M. Eur.
J. Org. Chem. 2003, 2209.
(2) Berg, S.; Bhat, R.; Edwards, P.; Hellberg, S. PCT Int. Appl. 2003,
(WO 2003055877 A1 20030710 CAN 139:101026).
(3) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.;
Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.;
Wang, S. J. Med. Chem. 2006, 49, 3432.
(8) During the preparation of this manuscript a report detailing the
R-vinylation of an oxindole derivative appeared: Huang, J.; Bunel, E.; Faul,
M. M. Org. Lett. 2007, 9, 4343.
(9) (a) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234. (b)
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108. (c)
Hamada, T.; Chieffi, A.; Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 1261. (d) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997,
38, 7581.
(4) Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.;
Bursulaya, B.; Wu, T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16,
2105.
(10) (a) Mart´ın, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46,
7236. (b) Terao, Y.; Fukuoka, Y.; Satoh, T.; Nomura, M.; Miura, M.
Tetrahedron Lett. 2002, 43, 101.
10.1021/ol800141t CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/06/2008