Copper-Catalyzed Cross-Coupling of Aryl Halides and Thiols Using Microwave Heating

Article abstract of DOI:10.1055/s-2003-41407

The copper-catalyzed cross-coupling of aryl halides and thiols using microwave heating is described.

Full text of DOI:10.1055/s-2003-41407

LETTER
1789
Copper-Catalyzed Cross-Coupling of Aryl Halides and Thiols Using
Microwave Heating
C
Y
opper-Catalyzed
o
Cross-Coup
n
A
ryl
H
g
alides and
T
-
hiols
U
s
J
ing Micro
i
w
ave
H
n
e
ating Wu,* Huan He
Department of Neuroscience Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT,
6492, USA
0
Fax +1(203)6777702; E-mail: Yong-Jin.Wu@bms.com
Received 28 May 2003
mol%) and cesium carbonate (2 equiv) in N-
methylpyrrolidinone (NMP) at 195 °C for 2 hours under
microwave irradiation provided 1-tert-butyl-4-(phenyl-
thio)benzene in 89% yield after purification of the crude
product using silica gel flash chromatography (entry 1,
Table 1). As a control experiment, the same reaction mix-
ture was heated at 195 °C for 2 hours in a sealed tube using
an oil bath, and the product was obtained in 67% yield.
This observation demonstrates the advantage of micro-
wave radiation over conventional heating techniques. As
shown in Table 1, these conditions worked well for a va-
riety of aryl iodides (entries 2, 3) and bromides (entries 4–
Abstract: The copper-catalyzed cross-coupling of aryl halides and
thiols using microwave heating is described.
Key words: copper(I) iodide, copper-catalyzed, cross-coupling,
microwave heating, aryl halide
Aryl sulfides are valuable intermediates in organic
1
synthesis and are of great importance to pharmaceutical
industry. A number of them have been reported to have
significant biological activity as, for example, antagonists
of leukocyte function-associated antigen-1/intracellular
2
molecule-1 interaction (LFA-1/ICAM-1), M muscarinic
2
6
5
). The coupling of unactivated aryl bromides (entries 4,
) required longer reaction times and gave slightly lower
3
receptor antagonists, nonsteroidal antiinflammatory
4
5
agents, and HIV protease inhibitors. Numerous method-
ologies have been developed for synthesizing aryl sul-
fides, typically involving the condensation of activated
aryl halides with thiols under strongly basic conditions.6
Recently, the conversion of unactivated aryl halides or tri-
flates to aryl sulfides has been realized using stoichio-
metric amounts of copper or catalysis by palladium. Guy
and co-workers developed the synthesis of aryl sulfides
through copper-mediated cross-coupling of aryl boronic
yields than that of the corresponding iodides (entries 1, 2).
The good yields obtained for the coupling of unactivated
bromides (entries 4, 5) are particularly noteworthy, since
10
the Buchwald methodology for aryl sulfide synthesis ap-
plies only to the coupling of aryl iodides. To expand the
scope of this methodology, 1-tert-butyl-4-iodobenzene
was treated with a variety of aryl thiols (entries 7–12) and
benzyl mercaptan (entry 13) and 6-mercapto-1-hexanol
7
8
(
entry 14) under the above conditions, and the yields were
9
10
acids and thiols. Buchwald and co-workers reported
copper(I)-catalyzed coupling of aryl iodides and thiols us-
ing potassium carbonate as a base and ethylene glycol as
an additive in 2-propanol at 80 °C. Even with these recent
developments, a need for improved methods for the prep-
aration of aryl sulfides remains. In a recent medicinal
chemistry program, we found that microwave heating can
be used to facilitate the cross-coupling of aryl halides and
thiols using a methodology which we utilized in the syn-
obtained in the range of 64–88%. It should be pointed out
that the yield of the reaction was not greatly influenced by
the presence of electron-donating or electron-withdraw-
ing groups on the aryl halides or thiol substrates. Ho-
wever, this type of coupling reaction does not seem to
work well on aryl chlorides. For example, only 39% con-
version (HPLC analysis) was observed from the reaction
of chlorobenzene with benzenethiol in the presence of
copper(I) iodide and cesium carbonate in NMP at 195 °C
under microwave irradiation for 10 hours.
1
1
thesis of diaryl ethers. Microwave irradiation has be-
come increasingly popular in recent years to improve
yields and shorten reaction times in a variety of reac-
In summary, we have developed an operationally simple
and efficient method for the cross-coupling of aryl bro-
mides and iodides with thiols using microwave heating.
This methodology is complimentary with a similar one we
recently disclosed that affords diaryl ethers from phenols
and aryl iodides and bromides.11
1
2–14
tions.
However, to our knowledge, the microwave-
mediated methodology has not been applied to the cross-
coupling of aryl halides and thiols. This report describes
the microwave-assisted synthesis of aryl sulfides using
copper(I) iodide and cesium carbonate in the absence of
ethylene glycol as the additive.
Treatment of 1-tert-butyl-4-iodo-benzene with 1 equiva-
lent benzenethiol in the presence of copper(I) iodide (10
Representative Procedure
To a solution of 1-tert-butyl-4-iodo-benzene (130 mg, 0.5 mmol)
and benzenethiol (51 mL, 0.5 mmol) in NMP (0.67 mL) in a micro-
wave vial were added cesium carbonate (325 mg, 1 mmol) and cop-
per(I) iodide (9.5 mg, 0.05 mmol). The vial was sealed and heated
Synlett 2003, No. 12, Print: 29 09 2003. Web: 28 08 2003.
Art Id.1437-2096,E;2003,0,12,1789,1790,ftx,en;S04303ST.pdf.
DOI: 10.1055/s-2003-41407
®
in a Smith Creator at 195 C for 2 h. The temperature of the contents
of the vessel was monitored using a calibrated infrared temperature
©
Georg Thieme Verlag Stuttgart · New York

1
790
Y.-J. Wu, H. He
LETTER
control mounted under the reaction vessel. The cooled reaction mix- References
ture was passed through a 2 g silica gel cartridge eluting with hex-
(
1) Tiecco, M. Synthesis 1988, 749.
anes to give 1-tert-butyl-4-(phenylthio)benzene (108 mg, 89%) as a
colorless oil.15
(2) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen,
B.; Marsh, K. C.; Okasinski, G. F.; Geldern, T. W.; Ormes,
M.; Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025.
Table 1 Coupling of Thiols and Aryl Halides
(
3) Wang, Y.; Chackalamannil, S.; Hu, Z.; Clader, J. W.;
Greenlee, W.; Billard, W.; Binch, H. III; Crosby, G.;
Ruperto, V.; Duffy, R.; McQuade, R.; Lachowicz, J. E.
Bioorg. Med. Chem. Lett. 2000, 10, 2247.
CuI (10 mol%)
Cs2CO3 (2 equiv.)
R-SH + Ar-X
R-S-Ar
microwave
heating
(4) Nagai, Y.; Irie, A.; Nakamura, H.; Hino, K.; Uno, H.;
Nishimura, H. J. Med. Chem. 1982, 25, 1065.
Entry R-SH
Ar-X
Time Yield
(%)a
(5) 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.
(
h)
1
2
PhSH
PhSH
2
2
89
tBu
I
88
(
(
(
6) Sasaki, N. A.; Hashimoto, C.; Potier, P. Tetrahedron Lett.
I
1987, 28, 6039.
7) Hickman, R. J. S.; Christie, B. J.; Guy, R. W.; White, T. J.
Aust. J. Chem. 1985, 38, 899.
8) (a) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001,
3
PhSH
MeO
tBu
2
77
66, 8677. (b) Li, G. Y. Angew. Chem. Int. Ed. 2001, 40,
1513. (c) Schopfer, U.; Schlapbach, A. Tetrahedron 2001,
57, 3069. (d) Ciattini, P. G.; Morera, E.; Ortar, G.
I
4
5
PhSH
PhSH
4
6
74
73
Tetrahedron Lett. 1995, 36, 4133. (e) Zheng, N.;
McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D. III;
Volante, R. P. J. Org. Chem. 1998, 63, 9606. (f) Kosugi,
M.; Ogata, T.; Terada, M.; Sano, H.; Migita, T. Bull. Chem.
Soc. Jpn. 1985, 58, 3657.
Br
Br
(
9) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000,
2, 2019.
(
(
(
10) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
11) Wu, Y.J.; He, H. Tetrahedron 2003, 44, 3445.
12) For a review, see: Perreux, L.; Loupy, A. Tetrahedron 2001,
57, 9199.
6
7
8
9
0
PhSH
2
2
2
2
2
74
87
88
88
67
NC
tBu
tBu
tBu
tBu
Br
tBu
MeO
F
SH
I
I
I
I
(13) For a copper(II)-mediated N-arylation of N-H containing
heteroarenes with arylboronic acids under microwave
irradiation, see: Combs, A. P.; Saubern, S.; Rafalski, M.;
Lam, P. Y. S. Tetrahedron Lett. 1999, 40, 1623.
SH
(
14) For a microwave-assisted Goldberg reaction, see: Lange, J.
H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.; Osnabrug, S. J. M.;
Verveer, P. C.; Kruse, C. G.; Feenstra, R. W. Tetrahedron
Lett. 2002, 43, 1101.
SH
SH
1
(
15) All new compounds have spectral and analytical data in
agreement with the indicated structures. 1-tert-Butyl-4-
1
(
(
phenylthio)benzene: H NMR (400 MHz, CDCl ): d = 1.31
3
MeO
1
3
s, 9 H), 7.15–7.35 (m, 9 H). C NMR (100 MHz, CDCl ) :
3
1
1
1
2
3
2
88
84
d (attached H’s) = 31.3 (3), 34.6 (0), 126.3 (1), 126.6 (1),
tBu
I
I
1
1
29.1 (1), 130.3 (1), 131.5 (1), 131.6 (0), 136.7 (0), and
50.6 (0). The spectroscopic data are in full agreement with
SH
SH
those described in the literature, see: Nakayama, J.; Fujita,
T.; Hoshino, M. Chem. Lett. 1983, 249.
tBu
1
1
3
4
2
2
64b
76
CH2SH
tBu
tBu
I
I
HO(CH ) SH
2
6
a
Isolated yields.
b
2
Equiv of thiol was added.
Synlett 2003, No. 12, 1789–1790 © Thieme Stuttgart · New York