Efficient copper(I)-catalyzed C-S cross coupling of thiols with aryl halides in water

Article abstract of DOI:10.1002/ejoc.200700978

CuI efficiently catalyzes the C-S cross coupling of thiols with aryl halides in the presence of tetrabutylammonium bromide in water. The reactions with aryl thiols that have electron-withdrawing and -donating substituents are comparable and afford C-S cross-coupling products in high yield. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700978

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200700978
Efficient Copper(I)-Catalyzed C–S Cross Coupling of Thiols with Aryl Halides
in Water
Laxmidhar Rout,[a] Prasenjit Saha,[a] Suribabu Jammi,[a] and
Tharmalingam Punniyamurthy*[a]
Keywords: C–S Cross-coupling reactions / Copper catalyst / Thiols / Aryl halides
CuI efficiently catalyzes the C–S cross coupling of thiols with
aryl halides in the presence of tetrabutylammonium bromide
in water. The reactions with aryl thiols that have electron-
withdrawing and -donating substituents are comparable and
afford C–S cross-coupling products in high yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
al. reported the formation of thioethers by using copper
salts and 1,2-diamine derivatives in water.[6n]
Introduction
The formation of C–S bonds is a powerful means for
the preparation of numerous compounds of biological and
pharmaceutical interest and for use in the material sci-
ences.[1] The traditional methods available for this purpose,
however, often require harsh reaction conditions – the use
of polar solvents such as HMPA, high temperatures around
200 °C, and the reduction of sulfones or sulfoxides with
strong reducing agents such as DIBAL-H or LiAlH4.[2] To
overcome these drawbacks, considerable attention has re-
cently been focused on the development of catalytic systems
for the cross coupling of thiols with aryl halides. In 1980,
Migita and co-workers first reported the cross coupling of
aryl halides with thiols in the presence of [Pd(PPh3)4] as the
catalyst and NaOtBu as the base, in polar solvents such as
ethanol heated at reflux or dimethyl sulfoxide (DMSO) at
90 °C.[3] Palladium-,[4] nickel-,[5] copper-,[6] and cobalt-
based[7] catalytic systems have since been studied for this
purpose. These reactions are effective in anhydrous solvents
under inert conditions.
The use of water as a solvent for organic reactions has
been extensive in recent years.[8,9] Because water is cheap,
nontoxic, safe, and environmentally benign relative to or-
ganic solvents. Herein we report that CuI efficiently cata-
lyzes the C–S cross coupling of thiols with aryl halides in
the presence of tetrabutylammonium bromide (TBAB) in
water. These reactions are effective in air in the presence of
KOH at moderate temperature. During this study, Carril et
Results and Discussion
First, we studied the cross coupling of thiophenol with
iodobenzene as the model substrate (Table 1). The reaction
afforded the desired C–S cross-coupling diphenylsulfide in
98% yield when the substrate was stirred in water at 80 °C
for 10 h in the presence of 1 mol-% CuI, 1.1 equiv. iodo-
benzene, 1.5 equiv. KOH, and 1 equiv. TBAB in air. Among
the bases studied Ϫ KOH, K2CO3, Cs2CO3, pyridine, and
DIPA (diisopropylamine) Ϫ the first provided the best re-
sult. Of the copper catalysts investigated, CuI was superior
to CuSO4·5H2O, Cu(OAc)2·2H2O, CuCl2·2H2O, Cu(NO3)2·
3H2O, and CuO. Iodobenzene was more reactive than
bromo- and chlorobenzene. The presence of TBAB is essen-
tial and in its absence no reaction was observed.
To study the scope of the procedure, the reactions of
other thiols with iodobenzene were then studied (Table 2).
The reactions with 2-methyl-, 4-methyl-, 4-nitro-, 2-bromo-,
4-bromo-, 4-chloro-, and 4-methoxybenzenethiol afforded
cross-coupling products in 91–99% yield in 9–15 h. Similar
results were observed with 2-naphthalenethiol and phenyl-
methanethiol; however, 1-butanethiol was less reactive, and
the C–S cross-coupling product was obtained in 15% yield.
These reaction conditions are also suitable for the C–
S cross coupling of thiols with chloro- and bromobenzene
(Table 3). For example, the reactions with 4-methoxy-, 4-
methyl-, and 4-nitrobenzenethiol afforded cross-coupling
products in 30–60% yield in 14–15 h. Similar results were
obtained with 2-naphthalenethiol and phenylmethane-
thiol – the C–S cross-coupling products were obtained in
21–48% yield in 18–19 h. Bromobenzene was more reactive
than chlorobenzene.
[a] Department of Chemistry, Indian Institute of Technology
Guwahati,
Guwahati 781039, India
Fax: +91-361-2690762
E-mail: tpunni@iitg.ernet.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 640–643

Copper(I)-Catalyzed C–S Cross Coupling of Thiols with Aryl Halides
Table 1. Cross coupling of thiophenol with aryl halides in water.
Table 3. Reaction of thiols with chloro- and bromobenzene.
Catalyst
X
Base
T [°C]
Time [h]
Yield [%][a,b]
CuCl2·2H2O
CuSO4·5H2O
Cu(OAc)2·H2O
CuO
I
I
I
I
I
I
I
I
I
I
I
Br
Cl
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
Cs2CO3 80
DIPA 80
pyridine 80
KOH
KOH
80
80
80
80
80
80
r.t.
80
10
10
10
10
10
10
12
10
10
8
90
76
88
72
85
98
Cu(NO3)2·3H2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
no reaction
75
88
65
8
12
12
75
80
80
52[c]
32[c]
[a] The catalyst (1 mol-%), thiophenol (1 mmol), aryl halide
(1.1 mmol), base (1.5 mmol), and TBAB (1 mmol) were stirred in
water (1 mL) in air. [b] Isolated yield. [c] 5 mol-% catalyst used.
Table 2. The reaction of various thiols with iodobenzene in water.
[a] CuI (5 mol-%), thiol (1 mmol), iodobenzene (1.1 mmol), KOH
(1.5 mmol), and TBAB (1 mmol) were stirred in water at 80 °C in
air. [b] Isolated yield.
zene afforded the product in a 95% yield in 6 h, while the
reactions of 1-iodo-4-methoxybenzene and 1-iodo-2,4-di-
methylbenzene required 12 h to provide the cross-coupling
products in 75% and 85% yield, respectively. These results
suggest that the reaction occurs by oxidative addition fol-
lowed by reductive elimination (Scheme 1). The oxidative
addition of the aryl halide with catalyst a can give interme-
diate b, which can undergo reaction with a thiol to afford
intermediate c. Intermediate c can provide the C–S cross-
coupling product by reductive elimination, where TBAB
presumably acts as the phase-transfer catalyst, solubilizing
the organic substrates in water.[9]
Table 4. The cross coupling of thiols with substituted aryl iodides.
[a] CuI (1 mol-%), thiol (1 mmol), iodobenzene (1.1 mmol), KOH
(1.5 mmol), and TBAB (1 mmol) were stirred in water at 80 °C in
air. [b] Isolated yield.
Finally, the reactions of thiophenol with aryl iodides that
have electron-donating and -withdrawing substituents were
[a] CuI (1 mol-%), thiophenol (1 mmol), aryl iodide (1.1 mmol),
KOH (1.5 mmol), and TBAB (1 mmol) were stirred at 80 °C in
investigated (Table 4). The reaction with 1-iodo-4-nitroben- water (1 mL) in air. [b] Isolated yield.
Eur. J. Org. Chem. 2008, 640–643
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641

L. Rout, P. Saha, S. Jammi, T. Punniyamurthy
SHORT COMMUNICATION
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In conclusion, a simple and efficient procedure is de-
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with aryl halides by using a combination of CuI and TBAB
in water. These reactions do not require an inert atmo-
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Experimental Section
Materials and Methods: Thiols, bromobenzene (99%), chloroben-
zene (99%), iodobenzene (98%), CuCl2·2H2O (99%), CuSO4·5H2O
(98%), Cu(OAc)2·H2O (99%), CuO (99.99%), Cu(NO3)2·3H2O
(98%), and CuI (99.99%) were purchased from Aldrich. NMR
spectra (400 MHz for 1H and 100 MHz for 13C) were recorded with
a DRX-400 Varian spectrometer by using CDCl3 as solvent and
Me4Si as internal standard. Flash column chromatography was
performed on silica gel (230–400 mesh) with ethyl acetate and hex-
ane as eluent. Melting points were determined by using a Büchi B-
540 melting point apparatus and are uncorrected.
General Procedure for the C–S Cross-Coupling Reaction: CuI
(1 mol-%) was added to a stirred solution of thiol (1 mmol), aryl
halide (1.1 mmol), TBAB (1 mmol), and KOH (1.5 mmol) in water
(1 mL). The solution was heated at 80 °C in air for the appropriate
time. The progress of the reaction was monitored by TLC. The
reaction mixture was then cooled to room temperature and treated
with diethyl ether (10 mL). The aqueous layer was separated and
extracted with diethyl ether (3ϫ5 mL). The combined organic
solution was successively washed with brine (3ϫ5 mL) and water
(1ϫ5 mL), dried (Na2SO4), and passed through a short pad of
silica gel by using ethyl acetate and hexane as eluent to afford ana-
lytically pure cross-coupling products.
[5]
[6]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR data and spectra of all the C–S cross-cou-
pled products.
Acknowledgments
This work was supported by the Department of Science and Tech-
nology, New Delhi and the Council of Scientific and Industrial
Research, New Delhi.
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Eur. J. Org. Chem. 2008, 640–643

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Received: October 16, 2007
Published Online: December 12, 2007
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