Table 1. Heteroaryl Thioether-Organostannane Coupling
Scheme 2. Control Experiment
3 2 2 3 4
and PdCl(PPh ) (CH Ph) was replaced with Pd(PPh ) , which
is a more stable palladium source over prolonged reaction
times. The switch from heteroaryl-SMe ethers to hetero-
aryl-SAr ethers was predicated on the presumption that a
sluggish copper-mediated transmetalation from tin to the
heteroaryl-PdL -SMe intermediate was the cause of the
2
low yields. In both systems a variety of heteroaromatic
sulfides and organostannanes were cross-coupled when
CuMeSal was present as an activator (Table 1). No coupling
reactions were observed with either allyltri-n-butylstannane
or tetra-n-butylstannane.
Copper(I) 3-methylsalicylate was superior to copper(I)
7
f
I
thiophene-2-carboxylate, the only other Cu source inves-
tigated in this study. A control experiment demonstrated the
crucial importance of copper to a successful reaction. No
coupling occurred between 2-thiophenylpiperazine and 4-
chlorophenyltri-n-butylstannane in the presence of 5% Pd-
3 4
(PPh ) in THF after 65 h, but a 93% yield of the coupling
product was obtained within 21 h when 2.2 equiv of
CuMeSal was present in the reaction mixture (Scheme 2).
In summary, a palladium-catalyzed, copper-mediated
coupling of heteroaromatic thioethers with aryl, heteroaryl,
1
0
and alkenylstannanes has been described. The reaction
provides a useful complement to the recently described and
related coupling of heteroaromatic thioethers with boronic
acids. A related study of the coupling of thiol esters with
organostannanes to give ketones has been completed and will
be published shortly.
a
Catalyst: 5% PdCl(PPh3)2(CH2Ph), 2.2 equiv of CuMeSal. b Catalyst:
5
% Pd(PPh3)4, 2.2% equiv of CuMeSal.
Acknowledgment. The National Cancer Institute, DHHS,
supported this investigation through Grant CA40157. We
thank Dr. Jiri Srogl for his insight and for his preparation of
some of the heteroaromatic thioethers used in this study.
Ph) as the palladium source. In some cases, however, the
reactions were quite sluggish and significant quantities of
starting materials were recovered from the attempted cou-
plings. In these cases, the thiomethyl ethers were replaced
with the heteroaromatic thiophenyl (or thio-p-tolyl) ethers
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(
6) Alphonse, F. A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guillaumet,
G. Synlett 2002 (3), 447-450.
7) (a) Liebeskind, L. S.; Srogl, J.; Savarin, C.; Polanco, C. Pure Appl.
Chem. 2002, 74, 115-122. (b) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002,
OL0273497
(
4
, 979-981. (c) Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. L. Org.
(10) . Typical Experimental Procedure. CuMeSal (100 mg, 0.466
mmol, 2.2 equiv) and Pd(PPh3)4 (12.3 mg, 0.011 mmol, 0.05 equiv) were
added to a solution of 2-(phenylthio)pyrimidine (40.0 mg, 0.212 mmol,
1.0 equiv) and 2-(tri-n-butylstannyl)furan (83.5 mg, 0.234 mmol, 1.1 equiv)
in THF (2.6 mL). The reaction mixture was stirred under nitrogen at 50 °C
for 18 h, and then 5% aqueous NH4OH (10 mL) was added and the mixture
was stirred for an additional 10 min. The reaction mixture was filtered
through a plug of Celite, and the filtrate was extracted with Et2O. The
organic layer was washed with brine (5 mL), dried over MgSO4, and
evaporated. Purification by SiO2 column chromatography with CH2Cl2 gave
2-(furan-2-yl)pyrimidine (24.6 mg, 79%) as white crystals. Full details are
available in Supporting Information.
Lett. 2002, 4, 983-985. (d) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org.
Lett. 2001, 3, 91-93. (e) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2
2
000, 2, 3229-3231. (f) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc.
000, 122, 11260-11261. (g) Zhang, S.; Marshall, D.; Liebeskind, L. S. J.
Org. Chem. 1999, 64, 2796-2804. (h) Srogl, J.; Liu, W.; Marshall, D.;
Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 9449-9450.
(8) We thank Professor G. Guillaumet for informing us of his related
study of copper-mediated heteroaromatic thioether-organostannane cross-
coupling. See the following Letter in this issue.
(9) See Supporting Information for: Savarin, C.; Srogl, J.; Liebeskind,
L. S. Org. Lett. 2001, 3 (1), 91-93.
802
Org. Lett., Vol. 5, No. 6, 2003