ORGANIC
LETTERS
2004
Vol. 6, No. 24
4587-4590
A General Palladium-Catalyzed Coupling
of Aryl Bromides/Triflates and Thiols
Takahiro Itoh* and Toshiaki Mase
Process Research, Process R & D, Banyu Pharmaceutical Co. Ltd., 9-1,
Kamimutsuna 3-Chome, Okazaki, Aichi 444-0858, Japan
Received September 30, 2004
ABSTRACT
We have developed an efficient palladium-catalyzed carbon−sulfur bond formation reaction of aryl bromides, triflates, and activated aryl
chloride. Using this protocol, we have shown tolerance to a wide variety of aryl thiols and alkyl thiols that can also be used as sulfide
equivalents.
Aryl sulfides are a common functionality found in numerous
pharmaceutically active compounds.1 Indeed, a number of
drugs in therapeutic areas such as diabetes and inflammatory,
immune, Alzheimer’s, and Parkinson’s diseases contain the
aryl sulfide functionality.2 The traditional method3 for
forming an aryl-sulfur bond is a substitution reaction via
an addition-elimination mechanism. However, these reac-
tions often require high temperature and long reaction times
for nonactivated haloarenes. Recently, Kang and co-workers
reported the synthesis of alkyl aryl sulfides via lithium aryl
thiolates that are prepared from aryl bromide and n-BuLi in
the presence of sulfur.4 In 1980, Migita and co-workers first
reported the Pd-catalyzed cross-coupling reaction of aryl
bromides with thiols.5 Since then, many reports have
appeared in the literature describing the formation of aryl
sulfides using transition-metal catalysts (Pd, Ni, Cu).6 The
substantial contributions by Venkataraman,7 Buchwald,8 and
Palomo9 have demonstrated the combination of aryl iodides
with thiols using copper catalyst. In contrast to the more
widely investigated cross-coupling of thiol with aryl halides,
(5) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi,
M. Bull. Chem. Soc. Jpn. 1980, 53, 1385-1389.
(6) (a) Kondo, T.; Shimizu, T. Chem. ReV. 2000, 100, 3205-3220. (b)
Rane, A. M.; Miranda, E. I.; Soderquist, J. A. Tetrahedron Lett. 1994, 35,
3225-3226. (c) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-860. (d)
Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598-11599. (e)
Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937-2938. (f)
Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei, I. A. J.
Am. Chem. Soc. 1998, 120, 9205-9219. (g) Ciattini, P. G.; Morera, E.;
Ortar, G. Tetrahedron Lett. 1995, 36, 4133-4136. (h) Zheng, N.; McWil-
liams, J. C.; Fleitz, F. J.; Armstrong, J. D.; Volante, R. P. J. Org. Chem.
1998, 63, 9606-9607. (i) Scho¨pfer, U.; Schlapbach, A. Tetrahedron 2001,
57, 3069-3073. (j) Foa`, M.; Santi, R.; Garavaglia, F. J. Organomet. Chem.
1981, 206, C29-C32. (k) Herradura, P. S.; Pendola, K. A.; Guy, R. K.
Org. Lett. 2000, 2, 2019-2022. (l) Savarin, C.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2002, 4, 4309-4312. (m) Cristau, H. J.; Chabaud, B.; Christol,
H. Synthesis 1981, 11, 892-894. (n) Li, G. Y. Angew. Chem., Int. Ed. 2001,
40, 1513-1516. (o) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem.
2001, 66, 8677-8681. (p) Li, G. Y. J. Org. Chem. 2002, 67, 3643-3650.
(7) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4,
2803-2806.
(1) (a) Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen, M.-H.; Singh, S.
B.; Schwartz, C. D.; Fitzgerald, C. E.; O’Keefe, S. J.; Zaller, D. M.; Schmatz,
D. M.; Doherty, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 3979-3982. (b)
Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.;
Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson,
D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.;
Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979-3985.
(2) (a) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries,
P.; Leitza, S.; Reilly, E. B.; Okasinski, G. F.; Fesik, S. W.; von Geldern, T.
W. J. Med. Chem. 2001, 44, 1202-1210. (b) Nielsen, S. F.; Nielsen, E.
Ø.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med. Chem. 2000, 43, 2217-
2226.
(3) (a) Kwart, H.; Evans, E. R. J. Org. Chem. 1966, 31, 410-413. (b)
Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31, 3980-3984. (c)
Delogu, G.; Fabbri, D.; Dettori, M. A. Tetrahedron: Asymmetry 1998, 9,
2819-2826.
(8) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517-3520.
(9) Palomo, C.; Oiarbide, M.; Lo´pez, R.; Go´mez-Bengoa, E. Tetrahedron
Lett. 2000, 41, 1283-1286.
(4) Ham, J.; Yang, I.; Kang, H. J. Org. Chem. 2004, 69, 3236-3239.
10.1021/ol047996t CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/28/2004