An efficient synthesis of N-arylsulfonylindoles from indoles and arylsulfonyl chlorides in the presence of triethylbenzylammonium chloride (TEBA) and NaOH

Article abstract of DOI:10.1002/cjoc.201090028

An efficient synthesis of N-arylsulfonylindoles from indoles and arylsulfonyl chlorides in the presence of triethylbenzylammonium chloride (TEBA) and NaOH at room temperature is described.

Full text of DOI:10.1002/cjoc.201090028

NOTE
An Efficient Synthesis of N-Arylsulfonylindoles from Indoles
and Arylsulfonyl Chlorides in the Presence of Triethyl-
benzylammonium Chloride (TEBA) and NaOH
Xu, Hui*(徐晖)
Wang, Yangyang(王阳阳)
Laboratory of Pharmaceutical Design & Synthesis, College of Science, Northwest Agriculture & Forestry
University, Yangling, 712100 Shaanxi, China
An efficient synthesis of N-arylsulfonylindoles from indoles and arylsulfonyl chlorides in the presence of
triethylbenzylammonium chloride (TEBA) and NaOH at room temperature is described.
Keywords triethylbenzylammonium chloride (TEBA), N-arylsulfonylindole, indole, phase transfer catalyst
Introduction
Table 1 Preparation of 3a under different reaction conditions
N-Arylsulfonylindole subunits have gained wide-
spread interest due to their key role in medically impor-
tant species, such as those displaying potent and selec-
tive ligation for the human serotonin 5-HT6 receptor,1-3
and potent antagonism against the peptidoleukotrienes.4
Meanwhile, N-arylsulfonylindoles are often used as the
intermediates, because of their robust behavior under a
wide variety of reaction conditions, by protecting the
NH group of the indoles with arylsulfonyl chlorides.5,6
Some harsh reaction conditions for the synthesis of
N-arylsulfonylindoles have been described, such as
using lithium diisopropylamide (LDA)/THF at －78
℃,7 over excess NaOH (nearly 9—10 equiv.),8 and bu-
tan-2-one in reflux for long time.2 Therefore, the devel-
opment of mild and efficient methods for the synthesis
of N-arylsulfonylindoles is very desirable. In continua-
tion of our research interest in the development of mild
and efficient methods for the synthesis of biological
compounds,9-12 herein we wish to report the preparation
of N-arylsulfonylindoles from arylsulfonyl chlorides
and indoles in the presence of triethylbenzylammonium
chloride (TEBA) and NaOH.
Molar ratio
1a 2a NaOH
Isolated yield of 3a/
Entry
PTCa
%
1
2
3
4
5
6
7
8
9
1.1 1.0
1.1 1.0
1.1 1.0
1.1 1.0
1.1 1.0
1.1 1.0
1.1 1.0
1.1 1.0
1.1 1.0
1.5
0
0
60
82
68
93
70
81
82
87
86
71
1.75
1.5
0.1 (TEBA)b
1.75 0.1 (TEBA)
1.75 0.1 (CTAB)c
1.75 0.1 (β-CD)d
1.75 0.1 (PEG-600)e
1.75 0.1 (PEG-800)
1.75 0.1 (PEG-1000)
1.75 0.1 (TBAB)f
10 1.1 1.0
a PTC: phase transfer catalyst; b TEBA: triethylbenzylammonium
c
d
chloride; CTAB: hexadecyltrimethylammonium bromide; β-
CD: β-cyclodextrin; e PEG: poly(ethylene glycol); TBAB: tetra-
f
Results and discussion
butylammonium bromide.
Firstly, we investigated the synthesis of N-(p-tolue-
nesulfonyl)indole (3a) from p-toluenesulfonyl chloride
(1a) and indole (2a) at room temperature for optimizing
reaction conditions, and the results are summarized in
Table 1. When the molar ratio of 1a, 2a, and NaOH was
1.1/1.0/1.5, the yield of 3a was 60% after reaction for
1.5 h (Entry 1). When 0.1 equiv. of triethylbenzyl-
ammonium chloride (TEBA) was added as a phase
transfer catalyst to the above reaction, the corresponding
yield of 3a was increased to 68% (Entry 3). When the
equivalent of NaOH in the reaction was increased from
1.5 to 1.75, the corresponding yield of 3a was increased
from 60% to 82% (Entry 2). Especially when the molar
ratio of 1a, 2a, NaOH to TEBA was 1.1/1.0/1.75/0.1,
the corresponding yield of 3a was increased to 93%
(Entry 4). That is, the amount of NaOH and TEBA was
*
E-mail: orgxuhui@nwsuaf.edu.cn; Tel./Fax: 0086-029-87091952
Received May 23, 2009; revised and accepted October 9, 2009.
Project supported by the Program for New Century Excellent University Talents (NCET-06-0868), State Education Ministry of China.
Chin. J. Chem. 2010, 28, 125— 127 © 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
125

Xu & Wang
NOTE
very crucial to this reaction. Meanwhile, the influences
of other phase transfer catalysts, such as hexadecyl-
trimethylammonium bromide (CTAB, 70%, Entry 5),
β-cyclodextrin (β-CD, 81%, Entry 6), poly(ethylene
glycol)-600 (PEG-600, 82%, Entry 7), poly(ethylene
glycol)-800 (PEG-800, 87%, Entry 8), poly(ethylene
glycol)-1000 (PEG-1000, 86%, Entry 9), and tetrabu-
tylammonium bromide (TBAB, 71%, Entry 10), were
also examined. Obviously, TEBA was the most effec-
tive phase transfer catalyst for the synthesis of N-(p-
toluenesulfonyl)indole.
Based upon the above findings, we further studied
the synthesis of N-arylsulfonylindoles (3a—3l) from
different arylsulfonyl chlorides (1a—1e) and indoles
(2a—2e) in the presence of TEBA and NaOH at room
Table 2 Synthesis of N-arylsulfonylindoles in the presence of TEBA and NaOH
Entry
1
Arylsulfonyl chloride
Indole
Product
Yield/%
93
3a (1.5 h)a
2
3
1a
1a
3b (2 h)
100
91
3c (1.5 h)
4
5
1a
1a
3d (1.5 h)
3e (1.5 h)
99
100
6
2a
3f (2 h)
90
7
8
9
1b
1b
1b
2b
2c
2e
3g (1.5 h)
3h (1.5 h)
3i (1.5 h)
88
89
99
10
2a
3j (2 h)
92
11
12
2a
2a
3k (1.5 h)
3l (1.5 h)
89
95
a Values in parentheses represent the reaction time.
126
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Chin. J. Chem. 2010, 28, 125— 127

An Efficient Synthesis of N-Arylsulfonylindoles
1
temperature. As shown in Table 2, it can be seen that a
variety of indoles, including those having electron-
deficient and electron-rich substituents, were effective
for this N-arylsulfonylation with arylsulfonyl chlorides.
Good to excellent yields (88%—100%) were obtained
(Table 2, Entries 1—12). For example, when 3-methyl-
indole (2b) was reacted with 1a in the presence of
TEBA and NaOH for 2 h, the corresponding compound
3b was obtained in a quantitative yield (Entry 2).
All the compounds were characterized by H NMR,
EI-MS and melting points.13 The typical spectral data of
3a: white solid, m.p. 83—84 ℃ (lit.14 87—88 ℃); H
1
NMR (CDCl3, 400 MHz) δ: 2.33 (s, 3H), 6.65 (d, J＝
4.8 Hz, 1H), 7.20—7.33 (m, 4H), 7.51 (d, J＝10 Hz,
1H), 7.56 (d, J＝4.4 Hz, 1H), 7.75 (d, J＝10.8 Hz, 2H),
7.97 (d, J＝10.8 Hz, 1H); EI-MS m/z (%): 271 (M＋,
100).
In conclusion, we have described an efficient and
mild procedure for the synthesis of N-arylsulfonylin-
doles from indoles and arylsulfonyl chlorides in the
presence of TEBA and NaOH. Good to excellent yields
(88%—100%) and easy workup made it an attractive
approach to prepare such important molecules.
References
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Experimental
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1
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(104.8 mg, 0.55 mmol), indole 2a (58.6 mg, 0.5 mmol),
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(E0905232 Cheng, F.; Dong, H.)
Chin. J. Chem. 2010, 28, 125— 127
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