A simple and efficient approach for the sulfonylation of indoles catalyzed by CuI

Article abstract of DOI:10.1080/17415993.2012.740672

In this paper, a simple and efficient protocol for the chemoselective sulfonation of indoles using aryl sulfonyl chlorides in the presence of CuI is reported. The reaction proceeds under mild conditions and is applicable to indoles bearing a selection of functional groups without NH protection.

Full text of DOI:10.1080/17415993.2012.740672

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A simple and efficient approach for the
sulfonylation of indoles catalyzed by
CuI
Matiur Rahman a , Monoranjan Ghosh a , Alakananda Hajra a &
Adinath Majee a
a Department of Chemistry, Visva-Bharati University, Santiniketan,
731235, India
Published online: 03 Dec 2012.
To cite this article: Journal of Sulfur Chemistry (2012): A simple and efficient approach
for the sulfonylation of indoles catalyzed by CuI, Journal of Sulfur Chemistry, DOI:
10.1080/17415993.2012.740672
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Journal of Sulfur Chemistry, 2012
http://dx.doi.org/10.1080/17415993.2012.740672
SHORT COMMUNICATION
A simple and efficient approach for the sulfonylation of indoles
catalyzed by CuI
Matiur Rahman, Monoranjan Ghosh, Alakananda Hajra∗ and Adinath Majee*
Department of Chemistry, Visva-Bharati University, Santiniketan 731235, India
(Received 28 July 2012; final version received 13 October 2012)
In this paper, a simple and efficient protocol for the chemoselective sulfonation of indoles using aryl
sulfonyl chlorides in the presence of CuI is reported. The reaction proceeds under mild conditions and is
applicable to indoles bearing a selection of functional groups without NH protection.
O
O
S
R
R
CuI (5 Mol%)
CH3CN, reflux
R2
SO2Cl
R1
N
H
R1
R2
N
H
R2 = H, Me, Cl, OCH3
R = H, Br, OMe
R1 = H, Me
11 Examples
Upto 90% yield
Keywords: sulfonylation; copper iodide; sulfonyl chlorides; indoles
1. Introduction
Sulfonylation is one of the most important and common reactions among aromatic electrophilic
substitutions (1). The sulfonyl group is a widely used synthon for synthetic organic chemistry
(2), and sulfone derivatives have many industrial applications (3). In particular, aryl sulfones
have received much attention as powerful anti-HIV-1 agents (4) and also possess high antifungal,
antibacterial, and antitumoral activities (5, 6). Indole-3-yl and pyrrol-2-yl aryl sulfones are novel
non-nucleoside reverse-transcriptase inhibitors, for example, PAS and L-737, 126 (7, 9).
O
O
O
O
O
O
NH2
Me
S
Cl
S
N
O
N
H
NH2
PAS
L-737, 126
Oxidation of indol-3-yl sulfides to the corresponding sulfones is the common method used
for its preparation (7, 8). Alternative methods, such as chlorosulfination and direct mesylation of
*Corresponding authors. Emails: adinath.majee@visva-bharati.ac.in, alakananda.hajra@visva-bharati.ac.in
© 2012 Taylor & Francis

2
M. Rahman et al.
more substituted indoles, have also been reported (9–12). For the sulfonylation of simple aromatic
compounds, the most effective reported catalysts are bismuth(III) triflate (13, 14), indium(III) tri-
flate (15), sodium perchlorate (16), Fe-PILC (17), graphite/MeSO3H (18), and silica-supported
AlCl3 (19). Though all these methods have their own advantages, in light of the current working
practice to emphasize green chemistry, they also have several disadvantages, such as the use of
toxic, expensive, less accessible, or thermally unstable reagents or the formation of by-products.
It should also be pointed out that all these reported methods have been restricted to the study of
the sulfonylation of simple aromatic species and as a consequence are not general for indoles.
The only well-studied method for indole sulfonylation is that using InBr3 (20), but InBr3 is
expensive. In light of this, a better methodology for this important reaction using an inexpensive
catalyst and a mild procedure is in demand. In continuation of our efforts to search for better
methodologies (21–29) in organic synthesis, we report the preparation of 3-alkylated indole (30)
and 3-alkenylated indole (31) derivatives. Here, we report our efforts to improve the method-
ology using a simple, inexpensive, and fast CuI catalytic system for the synthesis of indolyl
aryl sulfone derivatives. CuI as a catalyst is less expensive than InBr3 and highly stable in air
(Scheme 1).
O
O
R
S
R
CuI (5 mol%)
CH3CN, reflux
R2
SO2Cl
R1
R1
N
H
R2
N
H
1
2
3
R2 = H, Me, Cl, OCH3
R = H, Br, OMe
R1 = H, Me
Scheme 1. Synthesis of indolyl aryl sulfones.
2. Results and discussions
We investigated the reaction with a variety of indoles with a series of sulfonyl chlorides refluxing
in acetonitrile. The reaction is 100% chemoselective; no N-substituted products were observed
under these reaction conditions. This is probably due to the stabilization of the imine–enamine
complex by the CuI during sulfonylation (20). To optimize the reaction conditions, the reaction
of 2-methyl indole and p-TsCl was selected as a model to examine the effects of different metal
catalysts. The reaction is applicable for only the aromatic sulfonyl chloride. The best result was
achieved by carrying out the reaction with 2:2.2 molar ratios of 2-methyl indole and p-TsCl in
the presence of 5 mol% CuI in CH3CN (10 ml) under reflux conditions for 5 h (Entry 6, Table 1).
No substantial yield enhancement was realized with a higher catalysis loading or increasing
reflux time.
Accordingly, in a typical experimental procedure, a mixture of indole or substituted indole
(2 mmol) and aryl sulfonyl chloride (2.2 mmol) in CH3CN was refluxed in the presence of 5 mol%
CuI for a certain period of time to complete sulfonylation (TLC). A large number of structurally
diverse indoles were subjected to this procedure to give the corresponding indolyl aryl sulfone
products. The experimental procedure is very simple, requiring reflux at atmospheric pressure
without the need of an inert atmosphere. In general, the reactions are very clean without the
formation of any isolable by-product. In addition, our new methodology does not require any
additives or anhydrous conditions and no precautions are needed to exclude moisture from the
reaction media. An activated indole (Entries 4, 5, and 6) gave the sulfonylated product in an

Journal of Sulfur Chemistry
3
Table 1. Optimization of the reaction conditions.
O
S
O
Catalyst
Me
SO2Cl
CH3
Me
N
CH3CN (10 ml)
reflux
Me
N
H
H
2 mmol
2.2 mmol
Catalyst
Entry
Time (h)
Yield (%)a
1
2
3
4
5
6
7
ZnI2 (5 mol%)
ZnCl2 (5 mol%)
FeCl3 (5 mol%)
CuCl2 (5 mol%)
Cu(OAc)2 (5 mol%)
CuI (5 mol%)
5
5
5
5
5
5
5
65
45
76
78
80
90
92
CuI (10 mol%)
Note: aIsolated yield.
excellent yield for a variety of different aryl sulfonyl chlorides. In addition, substituents on the
aromatic ring such as Br (Entries 7 and 8) and OMe (Entries 9 and 10) also underwent smooth
conversion to the corresponding sulfonyl derivative. The results are summarized in Table 2.
3. Conclusion
In conclusion, we have developed a remarkably simple and highly efficient methodology for the
direct synthesis of 3-arylsulfonyl indole derivatives from indoles and aryl sulfonyl chlorides under
mild reaction conditions. We believe that this will present a better and more practical alternative
to the existing methodologies for the direct synthesis of 3-arylsulfonyl indole derivatives from
indoles and aryl sulfonyl chlorides.
4. Experimental
4.1. General
Chemicals were either prepared in our laboratory or purchased from Sigma-Aldrich and Spec-
trochem. 1H NMR and 13C NMR spectra were run in CDCl3 solution. IR spectra were taken using
KBr plates.
4.2. Typical experimental procedure
A mixture of indole or substituted indoles (2 mmol) and aryl sulfonyl chloride (2.2 mmol) in
CH3CN was refluxed in the presence of 5 mol% CuI for the time indicated in Table 2. The
progress of the reaction was monitored by TLC. After completion of the reaction, the mixture
was cooled to room temperature and extracted with ethyl acetate (10 ml). The resulting organic
layer was washed with brine (2 × 5 ml) and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to obtain the crude indolyl aryl sulfone product, which was
subjected to column chromatography to obtain the pure product. New compounds were properly
characterized by their spectral and analytical data. 3-(4-Methoxyphenylsulfonyl)-2-methyl-1H-
indole (Entry 11, Table 2): brown gummy liquid; IR (KBr): 3390, 3094, 2833, 2038, 1882, 1585,

4
M. Rahman et al.
Table 2. Copper iodide-catalyzed sulfonation of indoles.
Entry
1
R
H
R1
H
R2
H
Product
Time (h)
4.3
Yield (%)a
84
References
O
O
(19)
S
N
H
O
O
2
H
H
H
H
Me
Cl
5
6
4
5
6
6
7
5
6
5
86
81
85
90
84
78
75
85
81
84
(17)
(20)
(20)
(17)
(20)
(20)
(20)
(20)
(20)
–
S
Me
Cl
N
H
O
O
3
S
N
H
O
O
4
H
Me
Me
Me
H
H
S
N
H
Me
O
O
5
H
Me
Cl
S
Me
Cl
N
H
Me
O
O
6
H
S
N
H
Me
O
O
O
7
Br
Me
Cl
S
Br
Br
Me
N
H
O
8
Br
H
S
Cl
N
H
O
O
9
OMe
OMe
H
H
Me
Cl
S
MeO
MeO
Me
Cl
N
H
O
O
O
10
11
H
S
N
H
O
Me
OMe
S
OMe
N
Me
H
Note: aIsolated yield.

Journal of Sulfur Chemistry
5
1491, 1022, 746 cm−1; 1H NMR (500 MHz, CDCl3): δ 8.25 (s, 1H), 7.55–6.67 (m, 8H), 3.65 (s,
3H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 157.6, 140.8, 138.4, 135.5, 133.3, 129.9, 127.9
(2C), 122.0, 120.5, 118.9, 115.0 (2C), 113.9, 55.5, 12.2.
Acknowledgements
A.H. and A.M. thank DST (Grant No. SR/S5/GC-05/2010) for the financial support. M.R. and M.G. thank CSIR and
UGC, respectively, for their fellowship. The authors thank DST-FIST and UGC-SAP.
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