with sulfur. This reaction proceeded smoothly at 90 °C to
give aryl disulfides exclusively, which underwent reductive
cleavage when treated with triphenylphosphine or sodium
borohydride to afford aryl thiols. Although two metal-
catalyzed methods for the synthesis of aryl thiols have been
reported,2,3 our method has the advantages in generality and
using an inexpensive coupling reagent. Herein, we wish to
detail our results.
Table 1. CuI-Catalyzed S-Arylation of 4-Iodoanisole and
Subsequent Reduction under Different Conditionsa
Recently, we found that under the catalysis of CuI, metal
sulfides such as Na2S·9H2O or K2S could couple with
2-haloanilides to produce substituted benzothiazoles, after
treatment with HCl.7 Inspired by this encouraging result, we
decided to explore if aryl thiol synthesis could be achieved
via direct coupling reaction of metal sulfides with simple
aryl halides.8 Accordingly, a reaction of 4-iodoanisole with
K2S in the presence of 10 mol % of CuI was conducted.
The reaction was found to be completed after 12 h at 80 °C
in DMF, providing a mixture of 4-methoxybenzenethiol 4a
(80% yield) and bis(4-methoxyphenyl)sulfane 3a (11% yield)
upon direct reduction of the coupling mixture with triph-
enylphosphine and 12 N HCl (Table 1, entry 1). Changing
the reducing agent to NaBH4 gave a similar result (entry 2).
To inhibit the formation of the diaryl sulfide 3a, we attempted
to introduce sulfur to the coupling reaction system because
it can promote the formation of metal disulfides. To our
delight, this measure led to isolation of the aryl thiol 4a as
a single product with an increased yield (entry 3). Further
investigations indicated that a combination of sulfur with
Na2CO3 or K2CO3 could give a similar outcome (entries 4
and 5). The presence of both base and copper catalyst is
essential for this transformation because no coupling occurred
if they were removed from the reaction system, respectively
(entries 6 and 7). Noteworthy is that after quenching the
coupling reaction with HCl, 2a could be obtained as an
inseparable mixture, indicating that several polysulfides with
different numbers of sulfur were formed.
sulfur
source
temp
(°C)
reduction
conditionb
yield
(%)c
entry
base
1
2
3
4
K2S
K2S
K2S/S
S
S
S
80
80
80
90
90
90
90
A
B
B
B
B
80d
79d
89
Na2CO3
K2CO3
89
5
90
e
6f
7g
-
e
S
K2CO3
-
a Reaction conditions: 1a (1 mmol), K2S or sulfur power (3 mmol),
CuI (0.1 mmol), base (2 mmol), DMF (2 mL), 80-90 °C, 12 h. b Condition
A: PPh3 (3 mmol), HCl (12 M, 0.2 mL), dioxane (3 mL), H2O (1 mL), 40
°C, 5 h. Condition B: NaBH4 (3 mmol), 40 °C, 5 h. c Isolated yield for 4a.
d 3a was isolated in about 11% yield. e No coupling reaction occurred as
monitored by TLC. f K2CO3 was not used. g CuI was not used
(entries 1 and 3), and a wide range of functional groups are
tolerated in this process. The groups include methoxy,
hydroxyl, carboxylate, amido, keto, bromo, fluoro, and nitro
moieties. Thus, we concluded that this method provided a
general approach to prepare aryl thiols.
When 4-bromoiodobenzene was utilized, aryl thiol 4m was
isolated in 90% yield (entry 12), which indicated that
disulfide and polysulfides were formed exclusively in the
coupling reaction step. This observation is inconsistent with
Taniguchi’s report in which this substrate gave rise to the
corresponding aryl disulfide as a major product. Obviously,
the different coupling reaction conditions could be used to
account for this phenomenon.
When some aryl iodides bearing a strong withdrawing
group were used, it was found that simple nucleophilic
substitution could take place easily and the presence of the
catalyst was not required. For example, in the absence of
CuI, 1-(4-iodophenyl)ethanone and 4-nitroiodobenzene pro-
duced thiol 4t and 4u in 73-84% yields at 60 °C (entries
19 and 20). However, for other electron-deficient aryl iodides,
CuI is still helpful as a catalyst, as evident from that for
both 3-nitroiodobenzene and 4-iodobenzoic acid, where better
yields were observed if CuI was added (entry 21 vs. entry
22, entry 17 vs. entry 23).
After the optimized reaction conditions were established,
a number of aryl iodides were examined to explore the scope
and limitation of this method. As summarized in Table 2,
both electron-rich and electron-deficient aryl iodides worked
well for this process, giving the corresponding aryl thiols in
good to excellent yields. Noteworthy is that sterically
hindered substrates also provided high yields of aryl thiols
(7) Ma, D.; Xie, S.; Xue, P.; Zhang, X.; Dong, J.; Jiang, Y. Angew.
Chem., Int. Ed. 2009, 48, 4222.
(8) For recent studies on copper-catalyzed S-arylation and S-vinylation,
see: (a) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002,
4, 2803. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (c)
Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X. Synlett 2004, 7, 1254.
(d) Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 2696. (e) Lv, X.; Bao, W. J.
Org. Chem. 2007, 72, 3863. (f) Zhang, H.; Cao, W.; Ma, D. Synth. Commun.
2007, 37, 25. (g) Kabir, M. S.; Van Linn, M. L.; Monte, A.; Cook, J. M.
Org. Lett. 2008, 10, 3363. (h) Gonzalez-Arellano, C.; Luque, R.; Macquarrie,
D. J. Chem. Commun. 2009, 1410. (i) Jammi, S.; Sakthivel, S.; Rout, L.;
Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, P.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 1971. (j) Basu, B.; Mandal, B.; Das, S.; Kundu, S.
Tetrahedron Lett. 2009, 50, 5523. (k) Prasad, D. J. C.; Naidu, A. B.; Sekar,
G. Tetrahedron Lett. 2009, 50, 1411. (l) Herrero, M. T.; SanMartin, R.;
Dom´ınguez, E. Tetrahedron 2009, 65, 1500. (m) Xu, H.-J.; Zhao, X.-Y.;
Deng, J.; Fu, Y.; Feng, Y.-S. Tetrahedron Lett. 2009, 50, 434. (n) Gan, J.;
Ma, D. Org. Lett. 2009, 11, 2788.
We next attempted to use aryl bromides as coupling
partners and observed low conversion for electron-rich aryl
bromides in the coupling step even though the reaction
temperature was increased to 140 °C. Only 1-(4-bromophe-
Org. Lett., Vol. 11, No. 22, 2009
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