Iodine-catalyzed oxidative system for 3-sulfenylation of indoles with disulfides using DMSO as oxidant under ambient conditions in dimethyl carbonate

Article abstract of DOI:10.1039/c2gc35337g

The iodine catalyzed oxidative system for 3-sulfenylation of indoles with disulfides using DMSO as oxidant has been achieved under ambient conditions, providing a convenient and efficient method for the synthesis of 3-sulfenylindoles in good to excellent

Full text of DOI:10.1039/c2gc35337g

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PAPER
Iodine-catalyzed oxidative system for 3-sulfenylation of indoles with disulfides
using DMSO as oxidant under ambient conditions in dimethyl carbonate†
Wenlei Ge and Yunyang Wei*
Received 7th March 2012, Accepted 10th May 2012
DOI: 10.1039/c2gc35337g
The iodine catalyzed oxidative system for 3-sulfenylation of indoles with disulfides using DMSO as
oxidant has been achieved under ambient conditions, providing a convenient and efficient method for the
synthesis of 3-sulfenylindoles in good to excellent yields and with high selectivity. The reaction was
carried out in a green solvent, DMC, under atmospheric conditions. Only 0.5 mmol of disulfide was
needed for the 3-sulfenylation of 1 mmol of indole because both the sulfenyl groups of a symmetric
disulfide take part in the reaction. The procedure is suitable for N-protected or unprotected indoles.
bistrifluoroacetate (PIFA) in 2004. In 2007, Yadav and co-
Introduction
workers11e described a rapid synthesis of 3-sulfenylindoles using
Substituted indole functionality exists in a variety of natural
Selectfluor™ under mild conditions.
products and synthetic drugs and plays a significant role in
medicinal chemistry for their biological activities.1 Among
indole derivatives, 3-sulfenylindoles are currently attracting con-
siderable attention due to their therapeutic value in the treatment
of HIV, cancer, obesity, heart disease and allergies.2 They are
also used as potent inhibitors of tubulin polymerization.3 There
has been long-standing interest in the development of new
methods for the synthesis of 3-sulfenylindoles due to their
important applications. A number of different strategies have
been devised for the 3-sulfenylation of indoles with thiols,
disulfides or activated sulfur reagents catalyzed by metal
compounds, such as VO(acac)2,4 MgBr2,5 FeCl3,6 FeF3,7
CeCl3,8 CuI,9 and PdCl2.10
In 2009, Richard Larock’s group reported an interesting pro-
cedure for the synthesis of 3-sulfenyl- and 3-selenylindoles via
n-Bu4NI-induced electrophilic cyclization.11h
In our continuous work on the C–S, C–N, and C–O bond
forming reactions,12 an efficient iodine catalyzed oxidative
system for the 3-sulfenylation of indoles with disulfides was
developed. The reaction was carried out in an environmentally
benign solvent dimethyl carbonate (DMC) in the presence of
more than one equivalent of oxidant, such as DMSO using
5 mol% of iodine as catalyst and without the need for oxygen
and moisture-free reaction conditions (Scheme 1).
With the development of green chemistry and the enhance-
ment of people’s awareness of environmental protection in
recent years, chemists have paid much attention to screening
various non-metal reagents and designing new sulfur reagents
for the synthesis of 3-sulfenylindoles.11 In 2001, Matsugi and
co-workers11a,b described a facile and efficient sulfenylation
method using quinone mono-O,S-acetals under mild conditions.
Schlosser and co-workers11c reported a highly efficient one-pot
procedure for the 3-sulfenylation of 2-carboxyindoles with
sulfenyl chlorides as reagents, which were generated in situ by
treatment of the thiols with N-chlorosuccinimide at −78 °C in
CH2Cl2. Subsequently, Campbell and co-workers11d reported a
nice protocol for the 3-arylthiolation of 2-substituted indoles
Results and discussion
In recent years, molecular iodine has drawn considerable
attention as an inexpensive, nontoxic, nonmetallic, and readily
available catalyst for effecting various organic transformations.13
However, to the best of our knowledge, there are no reports on
the sulfenylation of indoles with disulfides using an iodine–
DMSO oxidative system under green and ambient conditions.
Initially the 3-sulfenylation of 1H-indole was carried out with
phenyl disulfide in the presence of 10 mol% of iodine in THF
at r.t. for about 6 h. We were delighted to find that the product,
3-(phenylthio)-1H-indole, was obtained in 24% yield after
using
a
wide variety of benzenethiols as reagents
in (CF3)2CHOH in the presence of phenyliodine(III)
School of Chemical Engineering, Nanjing University of Science and
Technology, Nanjing 210094, P.R. China.
E-mail: ywei@mail.njust.edu.cn; Fax: +86(25)84317078
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2gc35337g
Scheme 1 Molecular iodine catalyzed 3-sulfenylation of indoles under
ambient conditions.
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Table 1 Optimization of reaction conditions for sulfenylation of
Having optimized the reaction conditions, a variety of indoles
and disulfides were tested to determine the scope and limitations
of the method. Results listed in Table 2 demonstrates that most
of the disulfides 2 tested underwent smooth transformations to
afford the corresponding 3-sulfenylindoles 3 in high yields
(Table 2, entries 1–7). The reactions of indole derivatives with a
variety of disulfide coupling partners proceeded in high
yields (Table 2, entries 10–15). In general, the disulfides bearing
electron-donating groups were more reactive than those with
electron-withdrawing groups (Table 2, entries 3 and 7). Based on
these results, we proposed that an electrophilic species RS+ may
be formed. An electron-withdrawing group attached to R would
be unfavorable for the formation of the species. We were
delighted to disclose that satisfactory yield was also obtained
from 3-sulfenylation of 1H-indole with benzyl disulfide (Table 2,
entry 8). However, the present iodine-catalyzed oxidative system
was not suitable for alkyl disulfides (Table 2, entry 9).
indolesa
Catalyst
Entry (mmol)
Oxidant
Solvent (equiv.)
Temp.
(°C)
Yieldb
(%)
1
2
3
4
5
6
7
8
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
TBAI
I2O5
DIB
PTSA
—
THF
THF
—
—
—
—
—
—
—
—
r.t.
40
40
40
40
40
40
40
40
40
40
40
40
40
40
30
40
40
40
40
40
40
40
24
35
49
16
41
7
Trace
46
22
58
71
68
65
95
96
85
86
73
0
DCM
EtOAc
CH3CN
EtOH
Toluene
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
DMC
9c
10
11
12
13
14
15d
16d
17d
18e
18
19
20
21
22
—
O2
To explore the catalytic mechanism, potassium iodide was
tested as catalyst instead of molecular iodine, the results are
listed in Table 3.
H2O2 (1)
Oxone (1)
TBHP (1)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (2)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
DMSO (3)
It was found that in the presence of 10 mol% of HCl, KI can
catalyze the 3-sulfenylation of 1H-indole with DMSO as oxidant
(Table 3, entry 2). Without the presence of HCl or DMSO, no
sulfenylation product was detected with KI as catalyst (Table 3,
entries 1 and 3). The reaction also proceed well in the presence
of HI and DMSO without I2 or KI (Table 3, entry 4). These
results demonstrated the essential role of an acid and DMSO for
the sulfenylation to proceed if potassium iodide was used as
catalyst.
Therefore, a plausible reaction mechanism for 3-sulfenylation
of indoles is depicted in Scheme 2.7,13c–f,14 Initially, RSSR reacts
with I2 to form an electrophilic species RSI (A), which can
provide the electrophile RS+ and react with indole moiety to
produce intermediate B.11g,15 Deprotonation of B gives the
desired product and HI. Addition of HI to the SvO double bond
of DMSO gave intermediate C. Protonation of the oxygen atom
of C gave intermediate D. Nucleophilic attack of I− on the
iodine atom of D regenerated I2 with the formation of water and
dimethyl sulfane.
Trace
Trace
0
0
a Reaction conditions: 1a (1 mmol), 2a (0.5 mmol), catalyst (10 mol%),
solvent (2 mL), 6 h, under an air atmosphere. b Yield of isolated product
after column chromatography. c Under nitrogen atmosphere. d Iodine
(5 mol%) was used. e Iodine (3 mol%) was used.
column chromatography. Encouraged by this result, the reaction
was optimized and the results are summarized in Table 1.
At first, several kinds of solvents were tested and the highest
yield of 49% was obtained in DCM. In DMC under air atmos-
phere the yield was 46% (Table 1, entry 8). To avoid the use of
environmental harmful halide solvent, the green solvent DMC
was chose for the next exploitation of optimal experimental con-
ditions. It was found that reaction under an oxygen atmosphere
increased the yield to 58% (Table 1, entry 10). However,
nitrogen protection decreased the yield to 22% (Table 1,
entry 9). Subsequently, several oxidants such as H2O2, Oxone,
TBHP and DMSO were tested for the reaction (Table 1, entries
11–14). It was found that the reaction could proceed well using
DMSO as oxidant. In the presence of other oxidants tested, the
yield of the sulfenylation product decreased due to the oxidation
of the disulfide to benzenesulfonothioate. The dosages of iodine
and DMSO were also tested, it was found that 5 mol% iodine
could give the highest yield of 96% with 3 equivalent DMSO at
40 °C (Table 1, entries 15–18). Based on this result, other
iodine-containing non-metal catalysts such as TBAI, I2O5, and
iodobenzene diacetate (DIB), were screened for the reaction and
no product was detected (Table 1, entries 18–20). Furthermore,
the protonic acid PTSA was tested which gave no product
(Table 1, entry 21). And no product was formed without the
presence of iodine catalyst (Table 1, entry 22).
Conclusions
In conclusion, a simple and efficient oxidative system for the
selective sulfenylation of indoles to the corresponding 3-sulfenyl-
indoles in the presence of catalytic amounts of iodine using
disulfides in DMC under ambient conditions has been devel-
oped. In comparison with reported procedures for sulfenylation
of indoles,4–11 the present procedure is not moisture sensitive,
and is carried out in green solvent DMC with high yields. More-
over, both N-protected and unprotected indoles can be tolerated
well. Relatively low reaction temperature (40 °C) and easy work-
up manipulation may decrease energy consumption and operat-
ing cost for large scale preparation.
All chemicals (AR grade) were obtained from commercial
sources and were used without further purification. Petroleum
ether (PE) refers to the fraction boiling in the 60–90 °C range.
The progress of the reactions was monitored by TLC (silica gel,
Polygram SILG/UV 254 plates). Column chromatography was
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Table 2 Iodine catalyzed 3-sulfenylation of indoles with disulfides under the optimum conditionsa
Entry
1
Indole
R
Product
Time (h)
6
Yieldb (%)
TON
19
Ph
96
2
1a
1a
1a
4-MeC6H4
4-MeOC6H4
2-H2NC6H4
6
96
19
19
9
3
6
97
88
4c
10
5
6
7
1a
1a
1a
4-ClC6H4
4-BrC6H4
4-O2NC6H4
6
94
95
92
19
19
18
6
10
8c
1a
1a
Bn
Et
12
20
6
89
0
9
9
0
10
Ph
97
19
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Table 2 (Contd.)
Entry
11
Indole
R
Product
Time (h)
4
Yieldb (%)
TON
19
Ph
95
96
93
94
96
12
13
14
15
1c
4-MeC6H4
4
6
6
6
19
19
19
19
Ph
1d
4-MeC6H4
Ph
a Reaction conditions: 1 (1 mmol), 2 (0.5 mmol), iodine (0.05 mmol, 5 mol%), DMSO (3 mmol) and DMC (2 mL), at 40 °C. b Isolated yield based
on substrate 1. c Iodine (10 mol%) was used.
Table 3 Reaction of phenyl disulfide with 1H-indolea
Entry
Catalyst
Acid
Oxidant
Yieldb (%)
1
2
3
4
KI
KI
KI
—
—
DMSO
DMSO
—
0
89
0
HCl
HCl
HI
DMSO
91
a Reaction conditions: KI (10 mol%), acid (20%, 10 mol%), DMSO
(3 equiv.). b Yield of isolated product after column chromatography.
performed on Silicycle silica gel (200–300 mesh). Melting
points were obtained using a Yamato melting point apparatus
Model MP-21 and are uncorrected. IR spectra were recorded on
a Shimadzu spectrophotometer using KBr discs. 1H and 13C
Scheme 2 Proposed mechanism for the iodine-catalyzed 3-sulfenyl-
ation of indoles.
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NMR spectra were obtained using
a Bruker DRX 500
(500 MHz) spectrometer in CDCl3 or DMSO-d6 with TMS as
the internal standard. All the products are known compounds
and they were identified by comparison of their physical and
spectral data with those reported in the literature.
Experimental
General procedure for the iodine-catalyzed 3-sulfenylation of
indoles with disulfides
A mixture of indole 1 (1 mmol), disulfide 2 (0.5 mmol) and
DMSO (3 mmol) were dissolved in DMC (2 mL) at 40 °C in a
flask, then iodine (0.05 mmol, 5 mol%) was added. The reaction
proceeded under an air atmosphere for the indicated time until
complete consumption of starting material as monitored by TLC.
The solution was diluted with DMC (8 mL), washed with H2O
(3 × 10 mL), and then the organic layer was separated and con-
centrated under vacuum and the crude product was purified by
column chromatography (PE–EtOAc, 15 : 1) or recrystallization
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Acknowledgements
We are grateful to Nanjing University of Science and Technology
for financial support.
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