Indium chloride: A versatile Lewis acid catalyst for the synthesis of 3-sulfenylindoles

Article abstract of DOI:10.1080/17415993.2013.879870

Indium chloride has been used as a versatile Lewis acid catalyst for the synthesis of 3-sulfenylindoles in good yields by the independent reaction of indoles and N-alkylindoles with N-(phenylthio)phthalimide in dimethyl formamide (DMF) at 100°C for about 5-6 h.

Full text of DOI:10.1080/17415993.2013.879870

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Indium chloride: a versatile Lewis
acid catalyst for the synthesis of 3-
sulfenylindoles
P. Praveen Kumara, Y. Dathu Reddya, Ch. Venkata Ramana Reddya,
B. Rama Devia & P.K. Dubeya
a Department of Chemistry, Jawaharlal Nehru Technological
University Hyderabad, Kukatpall-500 085, Hyderabad, Andhra
Pradesh, India
Published online: 31 Jan 2014.
To cite this article: P. Praveen Kumar, Y. Dathu Reddy, Ch. Venkata Ramana Reddy, B. Rama
Devi & P.K. Dubey (2014) Indium chloride: a versatile Lewis acid catalyst for the synthesis of 3-
sulfenylindoles, Journal of Sulfur Chemistry, 35:4, 356-361, DOI: 10.1080/17415993.2013.879870
To link to this article: http://dx.doi.org/10.1080/17415993.2013.879870
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Journal of Sulfur Chemistry, 2014
Vol. 35, No. 4, 356–361, http://dx.doi.org/10.1080/17415993.2013.879870
Indium chloride: a versatile Lewis acid catalyst for the synthesis
of 3-sulfenylindoles
P. Praveen Kumar∗, Y. Dathu Reddy, Ch. Venkata Ramana Reddy, B. Rama Devi and P.K. Dubey
Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpall-500 085,
Hyderabad, Andhra Pradesh, India
(Received 20 September 2013; accepted 30 December 2013)
Indium chloride has been used as a versatile Lewis acid catalyst for the synthesis of 3-sulfenylindoles in
good yields by the independent reaction of indoles and N-alkylindoles with N-(phenylthio)phthalimide in
dimethyl formamide (DMF) at 100◦C for about 5–6 h.
Keywords: InCl3; sulfenylation; alkylation; N-(phenylthio)phthalimide; 3-sulfenylindole
1. Introduction
The selective introduction of C–S bond into organic molecules, in particular in heterocycles,
has played a significant role in medicinal chemistry.[1–4] 3-Sulfenylindoles are a popular class
of compounds for their activity in the treatment of HIV,[5–7] obesity,[5–7] cancer,[5–7] heart
diseases [5–7] and allergies.[5–7] Several methods for the preparation of 3-sulfenylindoles
∗Corresponding author. Email: padampraveenku@gmail.com
© 2014 Taylor & Francis

Journal of Sulfur Chemistry 357
have been reported [8–26] in recent years. The synthesis of 3-sulfenylindoles included the
direct sulfenylation of the indole ring by disulfides,[8–10] quinone mono-O,S-acetals,[11,12]
sulfenyl halides,[13,14] N-(arylthio)succinimides,[15] N-(arylthio)phthalimides[16] and acti-
vatedthiols.[17–23]3-Sulfenylindoleshavealsobeenpreparedbypalladium-catalyzedannulation
of 2-(1-alkynyl)benzenamines with disulfides [24] and by tetra-n-butylammonium iodide-induced
electrophilic cyclization of the same starting materials with arylsulfenylchlorides.[25,26] On the
other hand, 3-substituted indols derivatives are very important compounds as they display various
biological and pharmaceuticals activities.[27–29]
At present, many synthetic methods are available for the 3-sulfenylation of indoles.[13,21] Still,
it is necessary to develop new methods that avoid the use of toxic and foul-smelling substances,
more particularly, the use of sulphenyl chlorides and activated thiols, respectively. Indium chloride
is one of the important Lewis acids employed in various chemical transformations over the past
few years.
In view of our interest in the synthesis of C–S containing organic compounds [30] and contin-
uation of our earlier work,[31,32] we wish to report electrophilic substitution on indoles at the
third position with N-(phenylthio)phthalimides using indium chloride as a catalyst.
2. Result and discussion
Treatment of indole 1a with N-(phenylthio)phthalimide 2 in the presence of indium chloride as
the Lewis acid catalyst in DMF at 100◦C for 5 h resulted in the formation of 3-sulfenylindole
3a in 80% yield. Previously, the product is known in the literature,[13,21] it has been fully
characterized in the present work by spectral methods. 3a was, independently, treated with each
of the alkylating agents, DMS and benzyl chloride, in the presence of K2CO3 (as a base) and
TBAB (as a phase transfer catalyst) in DMF for about 1–2 h to obtain the previously reported
[6,23] N-methyl-3-sulfenylindole 5a and N-benzyl-3-sulfenylindole 5b, respectively as products.
To find out the optimum conditions for the reaction of 1a with 2, the reaction was carried
out by treating 1a with 2 in the presence of InCl3 as catalyst in different solvents (DMF, DMA
and Acetonitrile [MeCN]) at different temperatures (Table 1). However, reaction with InCl3 as
a catalyst at 100◦C for 5 h in DMF gave the best yield (85%) of the product 3a (Table 1, Entry
3). For finding out the optimum amount of InCl3, the reaction was carried out by changing the
concentration of InCl3 as a catalyst (Table 2). Results indicated that 20 mol% (0.2 mmol) InCl3
at 100◦C for 5 h in DMF gave the best yield of the product 3a (80%) (Table 2, Entry 3). Further
increase in the amount of indium chloride did not have any significant effect on the product yield.
Table 1. Effect of solvent and temperature on reaction of
1a and 2 in the presence of 20 mol% InCl3 yielding 3a.
Entry
Solvent
Temperature
Time/h
3a (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMA
DMA
DMA
DMA
MeCN
MeCN
MeCN
RT
50
100
140
RT
50
100
140
RT
50
15
12
5
4.5
15
13
7
6.5
15
12
8
–
60
85
70
–
60
65
60
–
9
10
11
45
40
80

358 P. Praveen Kumar et al.
Table 2. The effect of the amount of InCl3 in the
preparation of 3a from 1a and 2 in DMF at 100◦C.
Entry
Mol % of InCl3
Time (h)
3a (%)
1
2
3
4
6
7
–
10
20
30
50
100
15
10
5
4.5
4.25
4
–
65
85
80
70
65
Having optimized the reaction conditions, the generality of the reaction 1a–3a and 3a–
5a was established by using different 2-substituted indoles such as 2-methylindole (1b)
and 2-phenylindole (1c) resulting in the formation of 2-substituted-3-sulfenylindoles (3b–
c) and N-alkyl-2-substituted-3-sulfenylindoles (5c–f), respectively (for details see Section 4)
(Scheme 1).
Scheme 1. Synthesis of 3-sulfenylindoles.
Alternatively, 5 could also be synthesized by the independent reaction of 1 with each of the
alkylating agents methyl iodide and benzyl chloride to yield N-methyl (4a) and N-benzyl (4b)
indoles 4, respectively, and subsequent treatment of the latter, with N-(phenylthio)phthalimide 2
in the presence of 20 mol% (0.2 mmol) indium chloride in DMF at 100◦C for about 5–6 h.
3. Conclusion
In conclusion, InCl3 has proved to be a useful and efficient Lewis acid for the sulfenyla-
tion of indoles at the 3-position. In addition, this method produces 3-sufenylindoles in good
yields in reasonable reaction times and provides easy access for the preparation of a range of
3-sulfenylindoles.

Journal of Sulfur Chemistry 359
4. Experimental section
Melting points are uncorrected and were determined in open capillary tubes in sulfuric acid bath.
TLC was run on silica gel-G and visualization was done using iodine or UV light. IR spectra were
recorded using a Perkin–Elmer 1000 instrument in KBr pellets. 1H NMR spectra were recorded
in DMSO-d6 using TMS as internal standard using a 400 MHz spectrometer. Mass spectra were
recorded on an Agilent-LCMS instrument. 2-Subtituted indoles and DMF were obtained from
commercial sources and used as such.
4.1. General procedure for the preparation of 3 from 1 and 2
A mixture of 1 (10 mM), 2 (10 mM), InCl3 (20 Mol%) and DMF (20 ml) was heated at 100◦C for
5–6 h. The reaction mixture was monitored by TLC for the disappearance of 1. On completion
Table 3. Characterization data, reaction time and yields of 3 and 5a–e.
Entry
Starting material used
Product obtained Time (h) Yield%
M.P (◦C) (Lit. M.P ◦C)
O
N
O
S
1
2
5
85
85
150–152 (149–151) [13,21]
112–114 (110–113) [6]
2
5.5
3
4
6
1
80
82
Liquid [6]
89–91 (86–87) [6]
5
6
1.5
1
85
80
Liquid [2,3]
116–118 (113–114) [11]
7
8
9
1.5
1
83
84
82
93–95 (94–96) [27]
108–110 (108) [11]
90–92
2

360 P. Praveen Kumar et al.
of the reaction, the mixture was cooled to RT, diluted with water (50 ml) and extracted with ethyl
acetate. The organic layer was separated, washed with a saturated solution of sodium hydrogen
carbonate (10 ml) followed by brineand thendried withNa2SO4.Thesolvent ethylacetate(EtOAc)
was evaporated to give a crude residue, which on purification by silica gel column chromatography
(hexane–ethyl acetate, 90:10) gave 3 (Table 3).
4.2. General procedure for the preparation of 5 from 3
A mixture of 3 (10 mM), alkylating agent (DMS or benzyl chloride) (11 mM), K2CO3 (10 mM),
catalytic amount of TBAB and DMF (20 ml) was stirred at RT for 1–2 h. At the end of this period,
the mixture was poured into cold-water (50 ml) and extracted with ethyl acetate. The organic layer
was separated, washed with a saturated solution of sodium hydrogen carbonate (10 ml) followed
by brine (10 ml) and then dried with Na2SO4. The solvent EtOAc was evaporated to give a residue
of crude 5. The products were recrystallized from a suitable solvent to obtain pure 5 (Table 3).
4.3. General procedure for the preparation of 5 from 4 and 2
A mixture of 4 (10 mM), 2 (10 mM), InCl3 (20 Mol%) and DMF (20 ml) was heated at 100◦C
for 5–6 h. The reaction mixture was monitored by TLC for the disappearance of 4. On comple-
tion of the reaction, the mixture was cooled to RT, diluted with the water (50 ml) and extracted
with ethyl acetate. The organic layer was separated, washed with a saturated solution of sodium
hydrogen carbonate (10 ml) followed by brine (10 ml) and then dried with Na2SO4. The solvent
was evaporated to obtain a residue which on purification by the silica gel column chromatography
(hexane–ethyl acetate, 90:10) gave 5 (Table 3).
Acknowledgements
Authors are thankful to the authorities of Jawaharlal Nehru Technological University Hyderabad, for providing laboratory
facilities and for constant encouragement.
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