3
Figure 1. Substrate found to be incompatible under the present
We gratefully acknowledge the Council of Science & Industrial
reaction condition.
Research, New Delhi for financial support. K.G. is thankful to the
University Grand Commission, New Delhi for her research
fellowship and contingency grant. S.R. is thankful to the department
of Science and Technology (DST) for his INSPIRE fellowship. We
are also thankful to DST-FIST for financial support for establishing
NMR facility.
To gain an insight of the reaction mechanism, we carried out a
deuterium-leveling study in the reaction of 5a with d6-DMSO under
the standard reaction condition (Scheme 2, eq (1)). Complete
deuterium incorporation at the carbon of methylthio moiety was
observed by 1H NMR analysis, which confirmed that DMSO acts as
source of SMe moiety. No reaction was observed in the absence of
copper salt, suggesting that copper is involved in the reaction
mechanism (Table 1, entry 3). Meanwhile, when the reaction of 5a
with CuI / DABCO and DMSO was carried out in presence of 1
equiv. of TEMPO, a radical scavenger, the formation of sulfide 7a
was observed in 80% yield without significant change in reaction
rate, which indicates that the methylthiolation reaction does not
follow the radical pathway (Scheme 2, eq (2)).
References and notes
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O
S
CuI/DABCO
130 °C
O
O
(1)
D3C
CD3
D3CS
Br
O
(71%)
O
7n
5a
5a
O
CuI/DABCO
N
7a (80%)
(2)
(3)
DMSO/130 °C
S
CuI/DABCO
X
DMSO/130 °C
N
H
N
H
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S
Br
CuI/DABCO
X
130 °C
(4)
MeSSMe
7b
5b
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Scheme 2. Supporting experiments for mechanistic investigation.
In recent disclosure, the synthesis of 3-methylthiomethyl
a
substituted indole via CuBr(PPh3)3/NH4OAc induced intramolecular
Pummerer-type reaction of indole with DMSO was described by
Huang and co-workers.13
The authors have proposed that
methylthiomethanol (MeSCH2OH), formed from the activated
DMSO with AcO-, can be successfully transformed to the methyl-
methylene-sulfonium ion in a catalytic cycle of CuBr(PPh3)3. To
determine the identity of methyl-methylene-sulfonium ion
unambiguously, we carried out the same reaction with indole as a
substrate (Scheme 2, eq. 3). In this case, no reaction was observed
upon overnight heating at 130 oC temperature. Recently, Kantam
and coworkers have described the methylthiolation of aryl halides
using DMSO-CuI and Zn(OAc)2 as a promoters.10 The authors have
proposed that MeSSMe and MeSH are the two possible
intermediates for their desired transformations. In our method, when
aryl halide 5b was directly treated with MeSSMe under our reaction
condition, we observed the formation of a complex mixture of
unknown products as well as considerable precipitation, presumably
of copper salts (Scheme 2, eq 4). In view of these findings, we
believe that a mechanism involving Pummerer type intermediates is
highly unlikely. Further mechanistic investigations are currently
going on in our laboratory and will be published in due courses.
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In summary, we have established a convenient copper-mediated
method for the methylthiolation of haloarenes with inexpensive and
readily available DMSO as the source of SMe moiety. The protocol
demonstrates a practical approach to build up aryl methyl sulfides in
good to excellent yields with high selectivity and exhibits a good
functional tolerance with respect to both electron-donating and -
withdrawing groups. Thus, the protocol is a feasible and low-costing
alternative to the traditional methods for preparing of aryl methyl
sulfides.
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Acknowledgments