Synthesis of 3-sulfenylated indoles by a simple NaOH promoted sulfenylation reaction

Article abstract of DOI:10.1039/c4ra05206d

The C-3 sulfenylation reaction of indoles has been achieved under mild reaction conditions by simply employing NaOH as promoter and thiols as thiolating reagents. This simple method allows for easy and rapid synthesis of various 3-sulfenylated indoles wit

Full text of DOI:10.1039/c4ra05206d

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Synthesis of 3-sulfenylated indoles by a simple
NaOH promoted sulfenylation reaction†
Cite this: RSC Adv., 2014, 4, 35528
a
a
b
a
b
*
*
Yunyun Liu, Yi Zhang, Changfeng Hu, Jie-Ping Wan and Chengping Wen
Received 1st June 2014
Accepted 6th August 2014
DOI: 10.1039/c4ra05206d
www.rsc.org/advances
The C-3 sulfenylation reaction of indoles has been achieved under disuldes11 and thiols12 are still the most frequently employed
mild reaction conditions by simply employing NaOH as promoter and thiolating reagents in the preparation of sulfenylated indoles.
thiols as thiolating reagents. This simple method allows for easy and The main advantages of thiols and disuldes are the easy
rapid synthesis of various 3-sulfenylated indoles with generally good availability, low cost as well as general functional group toler-
to excellent yields. Primary attempts in scale-up synthesis give satis- ance. The main problem of disulde-based synthesis are that
factory result.
disuldes need to be prepared via the oxidative coupling of
thiols, which means additional operation step and low atom
economics.13 In this regard, directly using thiols as thiolating
reagents for the transformation is more favorable. On the other
hand, in those presently known thiol-based indole sulfenylation
methods, either transition metal catalyst or harsh heating
conditions are required. In this context, a mild and generally
applicable, transition metal free protocol for the 3-sulfenylation
of indoles using thiols is still highly demanding. Following our
recent interests in sulfur-based coupling chemistry,13,14 we
report herein a facile NaOH promoted, thiol-based approach for
the 3-sulfenylation of indoles under mild and transition metal
free conditions.
Introduction
Sulfenylated indoles consist of an important class of indole
derivatives and have been discovered as scaffolds possessing
versatile biological relevance. According to known results, 3-
sulfenylated indoles, for example, has displayed a broad spec-
trum of biological and pharmaceutical activities, including anti-
HIV activity,1 inhibitory activity against tubulin polymeriza-
tion,2 anti-cancer activity,3 anti-obesity activity,4 to name but a
few. In the known methods for synthesizing these valuable
molecules, the catalytic C3-sulfenylation of indoles has been
found to be the most efficient and extensively explored one.
During the synthetic efforts, a variety of thiolating reagents have
been discovered as reaction partners. For examples, sulfonyl
hydrazides could regioselectively couple indoles to give 3-sul-
fenylated indoles using simply molecular iodine as catalyst.5
Other thiol sources such as arylsulfonyl chlorides,6 N-thio-
phthalimides,7 O,S-acetals8 and sodium sulnates9 etc. have
also been discovered as effective thiolating reagents in the
synthesis of 3-sulfenylated indoles and other related heterocy-
cles.10 While these thiolating reagents have all been found to be
capable of efficiently provide 3-sulfenylated indoles, however,
Results and discussion
The investigation began from the model reaction of indole 1a
and p-tolyl thiol 2a. In tentative study, K2CO3 was employed as
the base to promote the reaction in DMSO and heating of
100 ꢀC. The result from the entry showed the production of
target sulfenylated product 3a with moderate yield (entry 1,
Table 1). Subsequently, systematic investigation has been con-
ducted to enhance the efficiency of the reaction. As outlined in
Table 1, initial attempt on increasing the amount of thiol
component was found to be effective to enhance the yield of 3a,
and using 2 equivalent moles of 2a led to signicant improve-
aKey Laboratory of Functional Small Organic Molecules, Ministry of Education, College
of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang ment by giving 3a with 76% yield (entries 1–4, Table 1). Further
330022, P. R. China. E-mail: chemliuyunyun@gmail.com; Fax: +86 7918812 0380;
examination on reaction media of different polarity, including
water, EtOH, DMF, toluene and MeCN disclosed that DMSO was
Tel: +86 7918812 0380
bCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou
amongst the best solvent (entries 5–9, Table 1). Subsequent
310053, P R China. E-mail: cpwen.zcmu@yahoo.com
screening on base promoters suggested that inorganic bases
could generally promote the reaction, while organic base such
as Et3N failed to initiated the expect reaction. The highest yield
† Electronic supplementary information (ESI) available: Experimental
information, 1H and 13C NMR spectra copies for all products. See DOI:
10.1039/c4ra05206d
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Table 1 Optimization on reactions conditionsa
Table 2 Synthesis of various 3-sulfenylated indolesa
Entry
Base
Solvent
T (ꢀC)
Yieldb (%)
R1
R2
Z
Product
Yieldb (%)
1c
2d
3e
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
no
Na2CO3
KOH
NaOH
Et3N
t-BuOK
NaOH
NaOH
NaOH
NaOH
DMSO
DMSO
DMSO
DMSO
H2O
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
47
53
66
76
nr
40
20
nr
50
nr
70
94
95
nr
76
94
95
85
83
H
H
H
H
H
H
H
H
4-Me
4-Cl
4-Br
4-F
4-i-Pr
H
2-Me
2-Cl
2-NH2
3-Me
4-Me
4-Me
2-Me
4-Cl
3-Me
2-Cl
4-Me
4-Cl
4-Br
3-Me
4-Me
3-Me
4-Cl
4-Br
4-Me
4-Me
4-Cl
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
95
94
85
95
95
85
92
90
95
86
93
87
95
76
96
75
78
86
89
96
67
89
75
72
85
75
71
EtOH
DMF
Toluene
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
H
H
H
2-Me
2-Me
2-Me
2-Me
2-Me
5-Br
5-Br
5-Br
5-Br
5-OMe
5-OMe
5-OMe
5-OMe
5-CN
5-CO2Me
5-CO2Me
70
60
40
3s
3t
a
General conditions: 1a (0.25 mmol), 2a (0.5 mmol), base (0.5 mmol),
b
solvent (2 mL), stirred at 70 ꢀC for 6 h. Yield of isolated product.
c
d
e
3u
3v
3w
3x
3y
3z
3aa
0.25 mmol 2a was employed. 0.3 mmol 2a was employed. 0.4
mmol 2a was employed.
of 3a was obtained from the entry using NaOH (entries 10–15,
Table 1). Finally, variation on the reaction temperature proved
that heating at 70 ꢀC gave equally excellent result as 100 ꢀC,
further lowering the temperature, however, led to evident
decrease in the product yield (entries 16–19, Table 1).
a
General conditions: 1 (0.25 mmol), 2 (0.5 mmol), NaOH (0.5 mmol),
b
DMSO (2 mL), stirred at 70 ꢀC for 6 h. Yield of isolated yield.
Aer optimization study on the model reaction, the appli-
cation scope of this facile catalytic protocol was conducted. The
results from this section demonstrated that the present method
was broadly applicable for the synthesis of sulfenylated indoles
of type 3. Functional groups such as alkyl, alkoxyl, halide, cyano
and ester all displayed satisfactory tolerance to the protocol and
provided corresponding products with good to excellent yields.
Generally, electron enriched indoles, for example, 2-methyl
indole and 5-methoxyl indole underwent the transformation to
provide corresponding products with slightly lower yields when
coupling with electron decient thiols, which could be attrib-
uted to the hindrance effect of the electron intensity in indole
component and the electron decience in thiol component to
the nucleophilicity of thiols (3n, 3p, 3w, 3n). Most of other
entries, on the other hand, provided thiolated indoles with
excellent yields without showing evident impact from the
substrates. Similar sulfenylation reaction using aliphatic thiols,
including isobutyl thiol, benzyl mercaptan and cyclo-
hexanethiol, however, was not successful under present cata-
lytic conditions. In addition, N-methylindole and 3-
methylindole failed to undergo any sulfenylation trans-
component, respectively. While no additional oxidant was
employed in all these sufenylating reactions, as the case in other
related indole sulfenylation process employing either thiols or
disuldes,11a,12d it was deducible that the oxygen in the air was
the main oxidant to promote this sulfenylation process in our
work (Table 2).
Being inspired by the simplicity of the synthetic method, we
then attempted to conduct scale-up experiments to examine the
synthetic efficiency. When 5 mmol indole was subjected for the
reaction with p-chlorothiophenol 2b, corresponding product 3b
has been afforded with satisfactory yield of 82% (1.06 g),
demonstrating the great potential of the present method for large
scale synthesis of 3-sulfenylated indole products (Scheme 1).
formation either when they were employed as the heterocycle Scheme 1 Gram scale synthesis of 3-sulfenylated indoles.
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Conclusions
In conclusion, we have established a facile and atom econom-
ical synthetic method towards the synthesis of 3-sulfenylated
indoles under transition metal free conditions. A variety of
indoles and thiols have been efficiently transformed to struc-
turally diverse products by mild heating in the presence of
NaOH. In addition, the present protocol is advantageous for
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Acknowledgements
This work is nancially supported by NSFC of China (no.
21202064), NSF of Jiangxi Province (20142BAB213007), a Spon-
sored Program for Cultivating Youths of Outstanding Ability in
Jiangxi Normal University (Y. Liu) and a program Sponsored by
Zhejiang Provincial Program for the Cultivation of High-level
Innovative Health talents (C. Wen).
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