Convenient KI-catalyzed regioselective synthesis of 2-sulfonylindoles using water as solvent

Article abstract of DOI:10.1039/c7nj00474e

A convenient procedure is developed for the preparation of 2-sulfonylindoles from indoles and sodium sulfinates catalyzed by KI in water. This environmentally benign 2-sulfonylation of indoles proceeds efficiently under mild conditions, affording the products with high regioselectivity and in moderate to good yields.

Full text of DOI:10.1039/c7nj00474e

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The role of atropisomers on the photo-reactivity and fatigue of
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DOI: 10.1039/C7NJ00474E
Convenient KI-Catalyzed Regioselective Synthesis of
2-Sulfonylindoles Using Water as Solvent
Hongjie Li, Xiaolong Wang and Jie Yan*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310032, P. R. of China
Corresponding author, Fax: +86(571)88320238; E-mail addresses: jieyan87@zjut.edu.cn
Abstract: A convenient procedure is developed for the preparation of 2-sulfonylindoles from
indoles and sodium sulfinates catalyzed by KI in water. This environmentally benign
2-sulfonylation of indoles proceeds efficiently under mild conditions, affording the products with
high regioselectivity and in moderate to good yields
.
Keywards: 2-Sulfonylation, Indole, Sodium sulfinate, Potassium iodide, Catalysis.
The indole nucleus is ubiquitous in a wide range of natural products, pharmaceuticals and fine
chemicals, and consequently, much attention has been paid to the synthesis of substituted indoles.1
2-Sulfonylindoles are a significant class of indole compounds due to the sulfonyl moiety can enhance
the biological activity of these compounds2 and also serve as useful vehicles for the development of
new strategies and tactics for synthesis.3 Recently, using sodium sulfinates as sulfur-containing
reagents for a direct regioselective synthesis of 2-sulfonylindoles has attracted considerable attention.
Deng and co-workers in 2014 first reported on the facile 2-sulfonylation of indoles catalyzed by
molecular iodine using indoles, sodium sulfinates and oxidant TBHP in AcOH (Scheme 1, a).4 Then,
Kuhakarn’s group demonstrated the regioselective 2-sulfonylation of indoles from indoles and sodium
sulfinates mediated by I2 in MeOH (Scheme 1, b).5 Zhang and co-workers just reported the new
contribution on the selective synthesis of 2-sulfonylindoles and 3-sulfonylindoles, and they found that
in the presence of catalyst NH4I combined with oxidant TBHP, a regioselective 2-sulfonylation of
indoles was reached (Scheme 1, c).6 The above new approaches for synthesis of 2-sulfonylindoles have
some advantages over previous methods, such as simple, efficient, direct, regioselective and giving
good yields. However, these new methods were not effective in water. Therefore, an exploration of
more environmentally benign protocol for synthesis of 2-sulfonylindoles using water as solvent is
highly desirable. Herein, we wish to report a convenient 2-sulfonylation of indoles with sodium
sulfinates and Oxone® in water using KI as catalyst (Scheme 1, d). To the best of our knowledge, this
regioselective 2-sulfonylation of indoles in water has not been reported before.
1

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DOI: 10.1039/C7NJ00474E
Scheme 1 Methods for the 2-sulfonylation of indoles
The catalytic utilization of molecular iodine and its salts in organic synthesis is increasing in
importance, with growing interest in the development of environmentally benign synthetic
transformations.7 Due to the ease of handling, low toxicity, commercial availability and mild reactivity,
especially the metal-like behavior of iodine, a number of recent studies have demonstrated the utility of
iodine catalysis as an efficient and powerful tool for the formation of carbon-carbon and
carbon-heteroatom bonds.8 In order to explore the possibility for the regioselective 2-sulfonylation of
indoles in water, we first checked the reaction of indole 1a, sodium phenylsulfinate 2a and KI in water
at room temperature, and after long time stirring, only the substrate 1a was recovered in near
quantitatively. Then, a water-soluble oxidant Oxone® (2KHSO5-KHSO4-K2SO4) was added in and the
suspension was stirred for a short time, the desired product, 2-(phenylsulfonyl)-1H-indole 3a was
fortunately obtained as sediment. Encouraged by the result, the 2-sulfonylation of 1.0 equiv of 1a in
water with 2a and Oxone® in the presence of KI at room temperature over 1 h was optimized (Table 1).
It is obvious that the amount of oxidant has the influence on the yield and the most suitable amount of
it for the reaction is 2.5 equiv (Table 1, entries 1-6). The optimal amounts of 2a and KI were then
evaluated, 1.5 equiv for 2a and 0.2 equiv for KI proving to be the best choices consequently (entries 4,
7-14). Other iodine-containing iodides such as NaI, NH4I and Et4NI were all effective in the reaction,
resulting in the similar yields (entries 4, 15-17). Some oxidants such as mCPBA, TBHP and H2O2 were
also checked under the optimal reaction conditions; however, besides mCPBA gave a poor yield, other
two were not active in the reaction (entries 18-20). As the control experiment, it was found that in the
absent of Oxone® or KI, no desired product 3a was observed (entries 21-22). In order to explore the
mechanism, a radical scavenger, 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), was added in the
reaction. It is clear that when more TEMPO was added, the yield decreased sharply, meaning the
reaction may undergo a radical pathway (entries 23-29).5
Based on the extensive screening process, we arrived at the optimal reaction conditions. Next, the
2-sulfonylation of 1.0 equiv of a number of indoles 1 with 1.5 equiv of several sodium sulfinates 2 and
2.5 equiv of Oxone® in the presence of 0.2 equiv of KI in water at room temperature over 1 h was
investigated, and a series of corresponding 2-sulfonylindoles 3 were afforded. The results are
summarized in Table 2.
2

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Table 1 Optimization of the 2-sulfonylation of indoles catalyzed by KI
Entry
PhSO2Na (equiv)
KI (equiv)
Oxone® (equiv)
TEMPO (equiv)
Yield (%)a
1.5
1.5
1.5
1.5
1.2
2.0
2.3
2.5
1
2
0.2
0.2
0.2
0.2
-
-
-
-
35
53
74
74
76
59
62
74
70
47
49
72
74
72
74
76
68
30
0
3
4
5
1.5
1.5
1.0
2.0
3.0
4.0
1.5
1.5
1.5
1.5
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.3
0.5
1.0
2.7
3.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
-
-
-
-
-
-
-
-
-
-
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1.5
1.5
1.5
1.5
1.5
NaI (0.2)
NH4I (0.2)
Et4NI (0.2)
0.2
2.5
2.5
-
-
-
-
-
2.5
mCPBA (2.5)
TBHP (2.5)
0.2
1.5
0.2
H2O2 (2.5)
20
0
21
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.2
-
-
-
0
22
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
-
0
23
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.5
1.0
2.0
3.0
5.0
6.0
58
52
43
37
29
19
17
24
25
26
27
28
29
aIsolated yields.
Table 2 2-sulfonylation of indoles catalyzed by KI a,b
Me
SO2Ph
N
H
3c, 52%
3

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DOI: 10.1039/C7NJ00474E
Br
SO2
Me
N
H
3n, 43%
a
b
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Oxone® (0.5 mmol), KI(0.04 mmol) in water (3mL), stirred at r.t. for 1 h. Yield of the
isolated product 3.
As shown in Table 2, the KI-catalyzed 2-sulfonylation was compatible with the studied indoles when
they reacted with sodium phenylsulfinate 2a, affording the corresponding 2-sulfonylindoles 3a-3i in
good yields. It is obvious that the substituents on indole ring, whether they were electron-donating
(methyl and methoxy) or electron-withdrawing (fluoro and bromo) groups, usually had no significant
influence on the yields. In the similar manner, 2-methylindole was checked; however, only the
corresponding 3-sulfonylindole6 was obtained with much poor yield. 5-Nitrolindole was also examined
in the reaction, but no product was observed. To investigate the scope of sodium sulfinates, indole 1a
and 5-substituent indoles 1e, 1g-1i were used as the representatives of indoles to react with sodium
p-toluenesulfinate 2b and sodium p-chlorophenylsulfinate 2c, respectively. Similarly, the reaction
proceed smoothly in water and gave the corresponding 2-sulfonylindoles 3j-3s in yields ranging from
36-66%. From the results it seems that the electron-donating groups on indole ring led to higher yields
than those with electron-withdrawing groups. Sodium methylsulfinate 2d, an aliphatic sulfinate, can
also react with indoles; however, the given yields were somewhat lower then aromatic sulfinates.
According to the above results and control experiments, similar to literatures,4-6 a plausible radical
addition mechanism catalyzed by KI is supported in Scheme 2. Thus, KI is first oxidized by Oxone® to
form molecular iodine, the fresh molecular iodine reacts quickly with sodium sulfinate to produce the
active sulfonyl iodide.9 Then, a radical addition of the sulfonyl iodide on indole occurs and generates
an intermediate. Finally, a HI elimination takes place to provide the 2-sulfonylindole. Meanwhile, the
molecular iodine can be re-generated via the oxidation of HI by oxidant.
4

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DOI: 10.1039/C7NJ00474E
R2SO2
I
R1
R2SO2Na
N
H
Oxone
SO2R2
R1
I2
KI
N
H
Oxone
HI
R2SO2I
or I2
I
SO2R2
R1
N
SO2R2
H
R1
N
H
Scheme 2 Proposed mechanism for KI-catalyzed 2-sulfonylation of indoles
In summary, we have developed a convenient procedure for preparation of 2-sulfonylindoles from
indoles and sodium sulfinates catalyzed by KI in water at room temperature. This regioselective
2-sulfonylation of indoles using water as solvent is an environmentally benign protocol, which has mild
reaction conditions and simple procedure. Furthermore, this reaction will extend the application scope
of inorganic iodides in organic synthesis.
Notes and references
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Graphical abstract
Convenient KI-catalyzed regioselective synthesis of 2-sulfonylindoles using
water as solvent
An environmentally benign procedure is developed for the preparation of 2-sulfonylindoles
catalyzed by KI in water.