K2CO3 promoted direct sulfenylation of indoles: A facile approach towards 3-sulfenylindoles

Article abstract of DOI:10.1039/c3gc40724a

An efficient and convenient method was developed for the preparation of 3-sulfenylindoles via a K₂CO₃ promoted direct sulfenylation of indoles with disulfides. The method is applicable to a wide range of indoles containing different

Full text of DOI:10.1039/c3gc40724a

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K2CO3 promoted direct sulfenylation of indoles: a facile
approach towards 3-sulfenylindoles†
Cite this: DOI: 10.1039/c3gc40724a
Received 17th April 2013,
Accepted 2nd June 2013
Peng Sang,a Zhengkai Chen,a Jianwei Zoua,b and Yuhong Zhang*a,c
DOI: 10.1039/c3gc40724a
www.rsc.org/greenchem
An efficient and convenient method was developed for the prepa- from limitations, such as low yield or low functional group tol-
ration of 3-sulfenylindoles via a K2CO3 promoted direct sulfenyla- erance. It is desirable to develop new methods for the syn-
tion of indoles with disulfides. The method is applicable to a wide thesis of 3-sulfenylindoles from simple and readily available
range of indoles containing different functional groups furnishing precursors under mild reaction conditions with regard to
good to excellent yields. This synthetic strategy features environ- green chemistry and synthetic practice.
mental friendliness, easy operation, and mild reaction conditions.
As part of our continuing effort to construct bioactive mole-
cules by developing cheap, green and sustainable methods,17
our group took an interest in the 3-sulfenylindoles. Herein, we
wish to report the cheap K2CO3 promoted direct C(3)–H sulfe-
nylation of free (N–H) indoles with disulfides. The protocol
here has a broad substrate scope, simple reaction conditions,
and excellent yields. Notably, in this transformation, no noble
metal salts, ligands or additives were added and without exclu-
sion of air and moisture.
Introduction
3-Sulfenylindoles represent pharmaceutically and biologically
important structures with their therapeutic value in the treat-
ment of heart disease,1 allergies,2 cancer,3 HIV4 and obesity.5
They are also used as potent inhibitors of tubulin polymeri-
zation.6 The fascinating biological profiles of this group of com-
pounds stimulated researchers to explore efficient methods for
the synthesis of 3-sulfenylindoles and their structural ana-
logues. In the past few decades, a number of significant syn-
thetic methods for the construction of 3-sulfenylindoles have
been developed. Among these approaches, the direct sulfenyla-
tion of the indole ring by various sulfenylating agents such as
sulfenyl halides,7 N-thioimides,8 sulfonium salts,9 thiols,10 di-
sulfides,11 quinone mono-O,S-acetals,12 arylsulfonyl chlorides13
and sulfonyl hydrazides14 is the most common. However, in
many of these transformations, harsh reaction conditions
(such as a stoichiometric strong base), toxic reagents and
oxygen-free techniques are required. An alternative method is
the annulation of 2-(1-alkynyl)-benzenamines with sulfenylat-
ing agents such as disulfides and arylsulfenyl chlorides, which
is performed with the aid of transition-metal catalysts15 or a
stoichiometric amount of n-Bu4NI.16 But these methods need
preparation steps of the starting materials and often suffer
Results and discussion
The development of economical and environmentally benign
strategies for the construction of useful molecular skeletons is
an important goal in contemporary organic synthesis. Our
initial attempts started with the reaction of simple and readily
available 1H-indole 1a and 1,2-diphenyldisulfane 2a (0.5
equiv.) in the presence of K2CO3 (1 equiv.) at 100 °C under air
(Table 1, entry 1). To our delight, the sulfenylation product 3a
was obtained in 84% yield. Increasing the amount of 1,2-
diphenyldisulfane (2a) improved the yield of the product
(entries 6 and 7). Screening of the solvents (Table 1, entries
1–5) revealed that DMSO was optimal. A relatively lower yield
was obtained when the reaction was carried out by the use of
DMF as the solvent (Table 1, entry 2). The use of NMP deli-
vered the product with moderate yield (Table 1, entry 3), and
the reaction was sluggish in toluene and 1,4-dioxane (Table 1,
entries 4 and 5). The effect of bases was also investigated, and
the commonly used inorganic bases such as K2CO3, Cs2CO3,
K3PO4 and KOH all gave excellent results (Table 1, entries
7–10). KOAc gave a moderate yield (Table 1, entry 11). No reac-
tion was observed in the absence of base. We also examined
organic bases such as Et3N and DBU, but no product was
aDepartment of Chemistry, ZJU-NHU United R&D Center, Zhejiang University,
Hangzhou 310027, China. E-mail: yhzhang@zju.edu.cn
bNingbo Institute of Technology, Zhejiang University, Ningbo 315104, China
cState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
†Electronic supplementary information (ESI) available: Experimental details,
spectral data and other ESI. See DOI: 10.1039/c3gc40724a
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Table 1 Optimization of reaction conditionsa
Table 2 The effect of transition-metal saltsa
Entry
2a (equiv.)
Base (equiv.)
Solvent
Yieldb (%) Entry
TM salt
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
0.75
1
1
1
1
1
1
1
1
1
1
1
1
1
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
K2CO3 (1)
Cs2CO3 (1)
K3PO4 (1)
KOH (1)
DMSO
DMF
NMP
84
80
63
nr
nr
96
99
99
99
99
68
nr
1
2
3
4
5
6
7
None
None
CuI
Pd(OAc)2
NiCl2(PCy3)2
Fe(acac)3
[Cp*RhCl2]2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
77
77c
Trace
19
Toluene
1,4-Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
nr
nr
Trace
a Reaction conditions: 1H-indole (0.5 mmol), 1,2-diphenyldisulfane
(1.0 mmol), K2CO3 (0.025 mmol), DMSO (2 mL) under air. b Isolated
yield. c K2CO3 with 99.997% purity was from Alfa Aesar Co.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
KOAc (1)
Et3N (1)
DBU (1)
nd
99
K2CO3 (0.8)
K2CO3 (0.5)
K2CO3 (0.4)
K2CO3 (0.3)
K2CO3 (0.2)
K2CO3 (0.1)
K2CO3 (0.05)
K2CO3 (0.5)
K2CO3 (0.5)
sulfenylation reaction. Furthermore, we purchased K2CO3 with
99.997% purity from Alfa Aesar Co. and used new glassware
and a new magnetic stirring bar to avoid the involvement of
other metals in the reaction. The result shows that the reaction
outcome was not affected (Table 2, entry 2), indicating that the
reaction might not be related to transition metals and K2CO3
determines the rate of the reaction.
With our optimal reaction conditions in hand, the substrate
scope of the free (N–H) indoles was investigated as shown in
Table 3. The indoles containing both electron-donating substi-
tuents (Me and OMe) and electron-withdrawing substituents
(NO2, CN, F, Cl and Br) in the benzene ring tolerated the reac-
99 (78c)
95
95
89
81
1
1
1
77
76d
54e
a Reaction conditions: 1H-indole (0.5 mmol), 1,2-diphenyldisulfane
(0.5–1 equiv.), base (0.05–1 equiv.), solvent (2 mL) under air. b Isolated
yield. c Under a nitrogen atmosphere (exclusion of air). d The reaction
was carried out at 90 °C. e The reaction was carried out at 80 °C.
detected (Table 1, entries 12 and 13). Considering the cost and tion conditions well to give 3-arylthioindoles in good to excel-
corrosivity, K2CO3 was selected for further studies. In addition, lent yields (Table 3, 3b–3k). The electronic properties of the
the amount of K2CO3 was examined (entries 14–20) and we substituents in the benzene ring exerted a very limited influ-
found that a small amount of K2CO3 also afforded the target ence on the reactivity. As for substitution patterns, 6-substi-
product (3a) in higher yields. It is important to note that a tuted and 7-substituted indoles delivered a relatively low yield
77% yield of 3a could be obtained even if 0.05 equiv. of K2CO3 compared with their 3- or 4-analogues (Table 3, 3b–3e).
was employed (Table 1, entry 20). When the reaction was sub- Encouraged by this successful C(3)–H sulfenylation of indoles
jected to a nitrogen atmosphere, a relatively lower yield was with substituents in the benzene ring, we next examined
obtained (Table 1, entry 15). The reaction afforded the highest various indoles with C-2 functional groups. It was found that
yield when performed at 100 °C. A temperature lower than that the desired products were also obtained in good to excellent
was deleterious to the reaction (Table 1, entries 21 and 22). yields (Table 3, 3l–3p). We were delighted to find that C-2
Therefore, the standard reaction conditions for the synthesis naphthyl- and heteroaryl-substituted indoles were also toler-
of 3-sulfenylindoles were obtained: 1,2-diphenyldisulfane 2a ated in this process to provide the corresponding 2-(naphtha-
(1.0 equiv.), K2CO3 (0.5 equiv.) under air in DMSO (2 mL) at len-2-yl)-3-(phenylthio)-1H-indole 3o and 2-(furan-2-yl)-3-
100 °C for 9 h.
(phenylthio)-1H-indole 3p. Notably, 1H-pyrrolo[2,3-b]pyridine
The observation of the direct C(3)–H sulfenylation product participated in the reaction easily with 1,2-diphenyldisulfane
3a in the absence of any added metal catalyst concerned us, to afford the 3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine deriva-
and our initial thoughts were whether the transformation was tive 3q in excellent yield (Table 3).
being induced by metal impurities in the K2CO3. To explore
We next examined the scope of variously substituted disul-
this possibility, we examined the K2CO3. Indeed, 10 ppb– fides (Table 4, 3r–3v). All of the substrates provided good to
10 ppm of Cu, Pd, Fe and other metal species were contained excellent yields, showing good functional group tolerance. A
in the K2CO3. Therefore, we subjected 10–1000 times these variety of substituted aromatic disulfides participated in the
amounts of various metal salts to the reaction system and we reaction smoothly to give the desired products, including elec-
found that the addition of these metal salts decreased the tron-withdrawing fluoro and chloro, as well as electron-donat-
efficiency of this reaction (Table 2, entries 3–7). This result ing methyl and benzamido groups. But disulfides with strong
reveals that transition metals may play a minor role in this electron-withdrawing-substituted groups such as a nitro group
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Table 3 Scope of free (N–H) indolesa
Table 3 (Contd.)
Entry
12
1
3
Yieldb (%)
99
Entry
1
1
3
Yieldb (%)
99
13
14
94
99
2
3
4
5
92
93
85
82
15
16
98
88
6
7
94
92
17
96
a Reaction conditions:
1 (0.5 mmol), 2a (0.5 mmol), K3CO3
(0.25 mmol), DMSO (2 mL) under air. b Isolated yield.
8
95
93
92
failed to give the 3-arylthioindole product. It is noteworthy
that the introduction of functional groups, such as F, Cl, Br
and CN, adds flexibility to further elaborate the 3-arylthio-
indole products that are formed.
9
To demonstrate the synthetic utility of the new method, the
reaction was carried out on
a gram scale (Scheme 1;
10.0 mmol of 1H-indole (1a) in the presence of 10.0 mmol of
1,2-diphenyldisulfane (2a) and 5 mmol of K2CO3 in 40 mL of
DMSO). The reaction could afford 2.07 g of 3a in 92% yield.
Therefore, this protocol could be used as a practical method to
synthesize the precursors of some important bioactive
molecules.
10
11
93
The reaction mechanism was also investigated. In Table 1,
entries 2 and 3 indicate that DMSO (as an oxidant) is not
required by the reaction; entry 15 demonstrates that oxygen is
not required but could facilitate the reaction; entries 15–20
suggest that K2CO3 could work under catalytic loading. We
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Table 4 Scope of disulfidesa
In conclusion, we have demonstrated an easy and efficient
K2CO3-promoted C(3)–H sulfenylation of free (N–H) indoles. In
the presence of K2CO3, the reactions performed well under
mild conditions without exclusion of air and moisture, and
the corresponding 3-sulfenylindoles were obtained in good to
excellent yields. This novel method provides a complementary,
environment-friendly, and easy operation approach to acces-
sing 3-sulfenylindole derivatives.
We gratefully acknowledge the National Basic Research
Program of China (No. 2011CB936003), the NSFC (No.
21272205), and the Program for Zhejiang Leading Team of S&T
Innovation for their financial support.
Entry
1
2
3
Yieldb (%)
99
2
3
4
95
98
95
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