ORGANIC
LETTERS
2011
Vol. 13, No. 15
4052–4055
Palladium-Catalyzed Cross-Coupling of
Benzyl Thioacetates and Aryl Halides
Krista M. Wager† and Matthew H. Daniels*
Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur,
Boston, Massachusetts 02115, United States
Received June 10, 2011
ABSTRACT
A method for preparing benzyl aryl thioethers utilizing an in situ deprotection of benzyl thioacetates as an alternative to free thiols as starting
materials has been developed and optimized. Good to excellent yields of diverse benzyl aryl thioethers are obtained with air-stable, odor-free, and
easy to prepare thioesters. A one-pot protocol for forming benzyl aryl thioethers from a benzyl halide, potassium thioacetate, and an aryl bromide
has also been demonstrated.
The prevalence of alkyl aryl thioethers (and their
derivatives) in natural products and pharmaceuticals has
led to the development of many methods for CÀS bond
construction. Metal-catalyzed cross-coupling reactions
have proven to be a robust technique,1 with Pd2 and Cu3
emerging as excellent catalysts in various applications.
These methods, however, rely on the use of alkyl thiols,
which can be odorous and sensitive to oxidation. To
circumvent this issue, diaryl disulfides have been coupled
with alkyl halides.4 There have also been reports of in situ
cleavage of thioesters for use in SNAr reactions.5 Hartwig
and co-workers have used Pd coupling to prepare unsym-
metrical biaryl thioethers from aryl halides and TIPS-
thiol,6 while others have utilized copper and a xanthate
salt.7 Potassium thioacetate has also been employed in a
Cu-catalyzed coupling with an aryl halide followed by
hydrolysis and reaction with an alkyl halide.8
† Present address: Bioorganic and Medicinal Chemistry Laboratories,
Department of Chemistry and Chemical Biology, Northeastern University,
Boston, MA 02115.
(1) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205.
(2) (a) Fu, C.-F.; Liu, Y.-H.; Peng, S.-M.; Liu, S.-T. Tetrahedron
2010, 66, 2119. (b) Lee-Dutra, A.; Wiener, D. K.; Arienti, K. L.; Liu, J.;
Mani, N.; Ameriks, M. K.; Axe, F. U.; Gebauer, D.; Desai, P. J.;
Nguyen, S.; Randal, M.; Thurmond, R. L.; Sun, S.; Karlsson, L.;
Edwards, J. P.; Jones, T. K.; Grice, C. A. Bioorg. Med. Chem. Lett.
2010, 20, 2370. (c) Harris, R. N., Iii; Stabler, R. S.; Repke, D. B.; Kress,
J. M.; Walker, K. A.; Martin, R. S.; Brothers, J. M.; Ilnicka, M.; Lee,
S. W.; Mirzadegan, T. Bioorg. Med. Chem. Lett. 2010, 20, 3436. (d)
Hamada, M.; Nakamura, M.; Kiuchi, M.; Marukawa, K.; Tomatsu, A.;
Shimano, K.; Sato, N.; Sugahara, K.; Asayama, M.; Takagi, K. E. A. J.
(3) (a) Martinek, M.; Korf, M.; Srogl, J. Chem. Commun.
(Cambridge, U.K.) 2010, 46, 4387. (b) Feng, Y.-S.; Li, Y.-Y.; Tang,
L.; Wu, W.; Xu, H.-J. Tetrahedron Lett. 2010, 51, 2489. (c) Prasad,
D. J. C.; Sekar, G. Synthesis 2010, 1, 79. (d) Kabir, M. S.; Lorenz, M.;
Van Linn, M. L.; Namjoshi, O. A.; Ara, S.; Cook, J. M. J. Org. Chem.
2010, 75, 3626. (e) Xu, H.-J.; Zhao, X.-Y.; Deng, J.; Fu, Y.; Feng, Y.-S.
Tetrahedron Lett. 2009, 50, 434. (f) Feng, Y.; Wang, H.; Fangfang, S.; Li,
Y.; Fu, X.; Jin, K. Tetrahedron 2009, 65, 9737. (g) Prasad, D. J. C.;
Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2009, 50, 1441. (h) Xin, K.;
Huang, H.; Jiang, H.; Liu, H. J. Comb. Chem. 2009, 11, 338. (i) She, J.;
Jiang, Z.; Wang, Y. Tetrahedron Lett. 2009, 50, 593. (j) Clayden, J.;
Senior, J. Synlett 2009, 17, 2769. (k) Zhao, X.-Y.; Fu, Y.; Feng, Y.-S.
Synlett 2008, 3063. (l) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T.
Eur. J. Org. Chem. 2008, 640. (m) Lu, X.; Bao, W. J. Org. Chem. 2007,
72, 3863. (n) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (o) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(4) (a) Munbunjong, W.; Lee, E. H.; Ngernmaneerat, P.; Kim, S. J.;
Singh, G.; Chavasiri, W.; Jang, D. O. Tetrahedron 2009, 65, 2467. (b)
Peppe, C.; Borges de Castro, L. Can. J. Chem. 2009, 87, 678. (c) Tang, R.;
Zhong, P.; Lin, Q. Synthesis2007, 85. (d) Ranu, B. C.; Mandal, T. J. Org.
Chem. 2004, 69, 5793. (e) Fukuzawa, S.; Tanihara, D.; Kikuchi, S.
Synlett 2006, 2145.
ꢀ
Med. Chem. 2010, 53, 3154. (e) Fernandez-Rodriguez, M. A.; Hartwig,
J. F. J. Org. Chem. 2009, 74, 1663. (f) Eichman, C. C.; Stambuli, J. P. J.
Org. Chem. 2009, 74, 4005. (g) Hartwig, J. F. Acc. Chem. Res. 2008, 41,
1534. (h) Lee, J.-Y.; Lee, P. H. J. Org. Chem. 2008, 73, 7413. (i) Rabac-a,
ꢀ
S.; Duarte, M. C.; Santos, I. C.; Pereira, L. C. J.; Fourmigue, M.;
ꢀ
Henriques, R. T.; Almeida, M. Polyhedron 2008, 27, 1999. (j) Fernandez-
Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
ꢀ
2180. (k) Fernandez-Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. Chem.;
Eur. J. 2006, 12, 7782. (l) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio,
S.; Breslin, P. Tetrahedron 2005, 61, 5253. (m) Moreau, X.; Campagne,
J. M.; Meyer, G.; Jutand, A. Eur. J. Org. Chem. 2005, 3749. (n) Murata,
M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397. (o) Itoh, T.; Mase, T.
Org. Lett. 2004, 6, 4587. (p) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org.
Chem. 2001, 66, 8677. (q) Mann, G.; Baranano, D.; Hartwig, J. F.;
Rheingold, A. L.; Guzei, I. A. J. Am. Chem. Soc. 1998, 120, 9205.
r
10.1021/ol201564j
Published on Web 07/05/2011
2011 American Chemical Society