ORGANIC
LETTERS
2
005
Vol. 7, No. 13
719-2722
Solid-Phase Synthesis of Diaryl
Sulfides: Direct Coupling of
2
Solid-Supported Aryl Halides with Thiols
Using an Insoluble Polymer-Supported
Reagent
Fabrice Gendre, Mathieu Yang, and Philippe Diaz*
Galderma R&D, Les Templiers, 2400 route des Colles 06410 Biot,
Sophia Antipolis Cedex, France
Received April 27, 2005
ABSTRACT
Diaryl sulfides have been prepared by direct nickel(II)-catalyzed coupling of thiols with iodoaryl bound to SynPhase polystyrene lanterns in
the presence of polymer-supported borohydride.
The solid-phase synthesis of nonpeptide compounds has
1
become a standard tool of the drug discovery process. On
Scheme 1. Nickel-Catalyzed Carbon-Sulfur Formation
the other hand, the use of insoluble polymer-bound reagents
2
for organic synthesis has increased in the past few years.
Metal-catalyzed synthesis of aryl sulfides is of current
interest. Efficient copper- or palladium-catalyzed C-S bond
3
formations under mild conditions have been described.
Recently, we reported a very useful method for coupling
selenolates as well as thiolates with aryl halides in solution
commercially available thiols with aryl halides grafted on
polystyrene SynPhase lanterns using the mix and sort
phase using polymer-supported borohydride.4
5
In the course of our parallel synthesis programs, we sought
approach.
to apply this methodology for coupling a large number of
We report here, the first application, to the best of our
knowledge, using a mixture of supported reactant and
(
1) (a) Lebl, M. J. Comb. Chem. 1999, 1, 3-24. (b) Dolle, R. E. J. Comb.
supported reagent. We have investigated the scope and
limitation of this new preparative method for obtaining a
small library of diaryl sulfides by reacting commercially
available thiols with aryl or heteroaryl halides bound to HMP
or RAM polystyrene SynPhase lanterns in the presence of
Chem. 2004, 6, 623-679. (c) Hall, D. G.; Manku, S.; Wang F. J. Comb.
Chem. 2001, 3, 125-150. (d) Franzen, R. G. J. Comb. Chem. 2000, 2,
95-214.
1
(
2) (a) Ley, S. V. Nat. ReV. Drug DiscoVery 2002, 1, 573-586. (b)
Bhalay, G.; Dunstan, A.; Glen, A. Synlett 2000, 12, 1846-1859. (c)
Thompson, L. A.; Curr. Opin. Chem. Biol. 2000, 4, 324-337. (d) Kim,
K.; McComas W. Comb. Chem. High Throughput Screening 2000, 3, 125-
6
IRA 400 borohydride resin using nickel bipyridine dibro-
1
29.
7
(
3) (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517-3520.
b) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti, B. Tetrahedron,
002, 58, 2041-2075. (c) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara,
J.-i.; Kato, Y.; Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385-1389.
d) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 915-920. (e)
Taniguchi, N. J. Org. Chem. 2004, 69, 6904-6906.
4) Millois, C.; Diaz, P. Org. lett. 2000, 2, 1705-1708.
mide as a catalyst (Scheme 1).
(
2
(5) Provided by Mimotopes. http://www.mimotopes.com.
(6) Gibson, H. W.; Bailey, F. C. Chem. Commun. 1977, 817.
(7) Cristau, H. J.; Chabaud, B.; Labaudiniere, R.; Christol, H Organo-
metallics 1985, 4, 657-661.
(
(
1
0.1021/ol050939v CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/26/2005