Metal-free, iodine-catalyzed regioselective sulfenylation of indoles with thiols

Article abstract of DOI:10.1016/j.tetlet.2016.03.073

An iodine-catalyzed regioselective sulfenylation of indoles in the presence of DMSO has been presented. Various indoles can react with aryl thiols or alkyl thiols to afford their corresponding 3-sulfenylindoles in good to excellent yields. The notable fea

Full text of DOI:10.1016/j.tetlet.2016.03.073

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Metal-free, iodine-catalyzed regioselective sulfenylation of indoles
with thiols
⇑
⇑
Shanli Yi, Meichao Li , Weimin Mo, Xinquan Hu, Baoxiang Hu, Nan Sun, Liqun Jin, Zhenlu Shen
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An iodine-catalyzed regioselective sulfenylation of indoles in the presence of DMSO has been presented.
Various indoles can react with aryl thiols or alkyl thiols to afford their corresponding 3-sulfenylindoles in
good to excellent yields. The notable features of this protocol include easy operation, metal-free reaction
conditions, and excellent functional group tolerance.
Received 26 December 2015
Revised 15 March 2016
Accepted 22 March 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Thiols
Sulfenylation
Iodine
DMSO
The formation of C–S bonds represents a key step in general
organic synthesis as well as in the pharmaceutical industry and
in material science.1 Consequently, the development of efficient
strategies for the formation of C–S bonds has stimulated consider-
able interest. In recent years, the direct sulfenylation via C–H func-
tionalization has emerged as a highly attractive and powerful
strategy to construct complicated organosulfur compounds.
The substituted indole is widespread in a large number of nat-
ural products and is extremely significant in medicinal chemistry.2
The development of general protocol for 3-sulfenylindoles forma-
tion has received significant attention because of their therapeutic
value in the treatment of cancer,3 HIV,4 allergies,5 heart disease,6
and bacterial infection.7 During the synthetic efforts, two major
synthetic strategies have been developed in the preparation of
3-sulfenylindoles. The first route is achieved by cyclization reac-
tions of o-ethenylaryl isocyanides,8 2-alkynylanilines,9 phenylhy-
drazine hydrochloride10 or 2-(gem-dibromovinyl) anilines,11
whereas the other protocol involves the direct sulfenylation of
indoles.12–20 A variety of sulfenylating reagents have been shown
as the reaction partners such as O,S-acetals,12 arylsulfenyl
halides,13 aryl-N-thioimides,14 sulfonyl hydrazides,15 sulfinic
acids,16 arylsulfonium salts,17 arylsulfonyl chlorides,18 disulfides,19
and thiols.20 However, these reported sulfenylation reactions all
have some drawbacks: (i) some of them should be catalyzed by
VO(acac)2, FeCl3, MgBr2, PdCl2, CuI, CeCl3, or other metal catalysts;
(ii) some of them need excess additives or harsh reaction condi-
tions, and suffer from a narrow substrate scope; (iii) many of these
sulfenylation reagents either need for moisture-free reaction con-
ditions or are difficult to obtain. It should be noted that although
most of sulfenylation reagents showed excellent activities in
sulfenylation reactions of indoles, they have to be prepared from
thiols or disulfides frequently. On the other hand, thiols and
disulfides have been utilized as attractive starting materials for
sulfenylation reactions due to their ready availability. The main
disadvantage of using disulfide as the sulfenylating reagent is that
disulfides should be synthesized from thiols via the oxidative cou-
pling reaction. This protocol means an additional operation step
and low atom economics. Therefore, there is a growing demand
to develop an efficient and metal-free method for synthesis of
3-sulfenylindoles from indoles. Obviously, directly using thiols as
sulfenylating reagents for the reaction is most preferred.
Recently, molecular iodine has attracted much attention as a
metal-free, inexpensive, non-toxic, and readily available catalyst
for various organic transformations. Especially, iodine has been
known as an important oxidation catalyst for the C–S cross-
coupling reactions.21 Herein, we report a new efficient protocol
for the synthesis of 3-sulfenylindoles based on direct C–H bond
functionalization of indoles with thiols to form C–S bonds using
I2 as the catalyst and DMSO as the oxidant. It is worth mentioning
that not only aryl thiols but also alkyl thiols are successfully
applied in the sulfenylation reaction under present catalytic condi-
tions. Indeed, DMSO has already been utilized in the sulfenylation
of indoles with thiols in the presence of NaOH.21i However,
⇑
Corresponding authors. Tel.: +86 571 88320416; fax: +86 571 88320103.
E-mail addresses: limc@zjut.edu.cn (M. Li), zhenlushen@zjut.edu.cn (Z. Shen).
http://dx.doi.org/10.1016/j.tetlet.2016.03.073
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Yi, S.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.073

2
S. Yi et al. / Tetrahedron Letters xxx (2016) xxx–xxx
R
sulfenylation reactions using aliphatic thiols or N-methylindole as
substrates were not successful under reported catalytic conditions.
In order to achieve the optimized conditions, the sulfenylation
of indole (1a) with thiophenol (2a) was selected as the model reac-
tion. Then, systematic investigation has been conducted. As out-
lined in Table 1, the influence of different solvents was studied.
Among them, 1,2-dichloroethane showed good performance for
this transformation while other solvents such as methanol, ethyl
acetate, acetonitrile, toluene, hexane, and H2O were low in effec-
tiveness (entries 1–7). To our surprise, the reaction almost did
not proceed when DMSO was used as the solvent (entry 8). Subse-
quent attempt on reducing the amount of catalyst and oxidant was
found to be negative to the reaction (entries 9–11). Notably, the
desired product was not obtained in the absence of iodine (entry
9). These results indicated that iodine should play a predominate
role in this reaction. In the absence of DMSO, 16% conversions of
1a was achieved under air atmosphere with 5 mol% of iodine
(entry 12). Meanwhile, under oxygen and nitrogen atmosphere
the conversions of 1a were 18% and 5%, respectively (entries 13
and 14). It was deducible that the oxygen could promote this
sulfenylation to a certain extent. When the reaction time was
extended from 3 h to 8 h, the conversion of 1a did not increase
obviously at 40 °C (entry 15).
S
I
2 (5 mol%)
DMSO (3 equiv.)
DCE, 60 o
+
RSH
N
H
C
N
H
1a
2
3
Cl
F
S
S
S
Cl
Br
N
N
H
H
N
H
3ab, 6 h, 88%
3ac, 6 h, 84%
3aa, 6 h, 92%
S
S
S
Cl
N
H
N
H
N
H
3af
, 6 h, 90%
3ad, 6 h, 96%
3ae
, 6 h, 96%
CH3O
OCH3
S
S
S
OCH3
N
H
N
H
N
H
3ag, 6 h, 88%
3ah, 6 h, 96%
3ai, 6 h, 89%
Then the effect of reaction temperature was further examined
(entries16–19). The reaction carried out at 60 °C led to the forma-
tion of the 3-sulfenyl indole (3aa) in a higher conversion of 1a
(entry 17). 98% Conversion of 1a and 98% selectivity to 3aa could
be obtained when the reaction time was prolonged to 6 h (entry
18). By contrast, a significant decrease in the conversion of 1a
was observed when the reaction was performed at room tempera-
ture (entry 16). Although 1a could be converted completely at
80 °C in 3 h, the selectivity to 3aa was dropped to 88% (entry 19).
Some by-products could be observed, and a small amount of
C12H25
S
S
S
N
N
H
N
H
H
3aj, 6 h, 89%
3ak, 7 h, 92%
3al, 10 h, 91%
C4H9
S
S
N
H
N
H
3am
, 8 h, 81%
3an
, 8 h, 74%
Table 1
Scheme 1. Reaction of indole (1a) with various thiols. The reactions were carried
out with 2 mmol of 1a, 2 mmol of thiols, 5 mol% of I2, and 6 mmol of DMSO in
10 mL of DCE at 60 °C. Yield of isolated product 74–96%.
Optimization on reaction conditionsa
S
SH
+
bis-sulfenylation product was detected. Thus, we chose 5 mol% of
I2 in the presence of 3.0 equiv of DMSO in 1,2-dichloroethane at
60 °C as the optimal reaction conditions.
N
N
H
H
1a
2a
3aa
In an endeavor to expand the scope of the methodology, the
reactivities of various thiol derivatives were investigated. The
results in Scheme 1 demonstrate that most of the thiols tested
underwent smooth transformations to afford the corresponding
3-sulfenylindoles in good to excellent yields (3aa–3an).22 The reac-
tion tolerated various thiophenols bearing electrondonating (Me,
OMe, isopropyl) and withdrawing groups (F, Cl, Br) in ortho, meta
and para positions. The electronic effect and steric effect did not
play great important roles in the isolated yield of the desired pro-
duct (3ab–3ak). We were delighted to disclose that similar
sulfenylation reactions, using aliphatic thiols including 1-dode-
canethiol, benzyl mercaptan, and 1-butanethiol as sulfenylating
agents, were also performed successfully under present reaction
conditions (3al–3an).
Having established the scope with respect to the thiol moiety,
subsequently, we turned our attention to the indole derivatives.
The reactions of various indoles with different coupling partners
proceeded in excellent yields (3bb–3fg, Scheme 2). 2-Methylindole
could react with para-substituted thiophenols steadily, and the iso-
lated yields of corresponding 3-(arylthio)-2-methylindoles were
higher than 90% (3bb–3bj). The presence of an electron donating
group (OMe) and electron withdrawing groups (Br, CN) on the
benzene ring of indoles did not prevent the smooth formation of
Entry I2
(mol%) (equiv)
DMSO T (°C) Solvent Time (h) Conv.b,c (%) Select.c (%)
1
5
3
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
rt
CH3OH
EtOAc
CH3CN
Toluene
Hexane
DCE
H2O
DMSO
DCE
DCE
DCE
DCE
DCE
3
3
3
3
3
3
3
3
3
3
3
3
3
3
8
3
3
6
3
29
62
72
48
Trace
87
8
Trace
N.R.
55
66
16
18
5
93
67
96
99
95
98
—
99
98
—
2
5
3
3
4
5
6
7
8
9
10
11
12
13d
14e
15
16
17
18
19
5
5
5
5
5
5
0
3
5
5
5
5
5
5
5
5
5
3
3
3
3
3
3
3
1.5
0
0
0
3
3
3
—
99
99
98
96
95
98
99
99
98
88
DCE
DCE
DCE
60
60
80
DCE
DCE
DCE
94
98
>99
3
3
a
b
c
Reaction conditions: 1a (1 mmol), 2a (1 mmol), solvent (5 mL).
Conversion of indole.
Determined by GC with area normalization method.
Under oxygen atmosphere.
d
e
Under nitrogen atmosphere.
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S. Yi et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
R
S
I2 (5 mol%)
R3
R2
R3
R2
DMSO (3 equiv.)
+
RSH
DCE, 60 o
C
N
N
R1
R1
1
2
3
OCH3
Br
Cl
S
S
S
N
N
N
H
H
H
3bg, 4 h, 92%
3bf
3bb
, 4 h, 93%
, 4 h, 96%
F
OCH3
S
S
S
Br
Br
N
H
N
H
N
H
3bj, 4 h, 91%
3ce, 6 h, 93%
3cg
, 6 h, 95%
F
F
OCH3
S
S
S
NC
CH3O
CH3O
N
N
N
H
H
H
3ee
, 7 h, 85%
3dg, 6 h, 90%
3de
, 4 h, 93%
OCH3
F
OCH3
S
N
S
S
NC
N
N
H
3eg, 10 h, 95%
3fg
, 6h, 93%
3fe
, 6 h, 89%
S
COOEt
N
H
3ga, 44 h, 67%
Scheme 2. Scope of indole derivatives. The reactions were carried out with 2 mmol of 1, 2 mmol of 2, 5 mol% of I2, and 6 mmol of DMSO in 10 mL of DCE at 60 °C. Yield of
isolated product 67–96%.
the expected products (3ce–3eg). In addition, no steric hindrance
SH
S
was observed even when a phenyl group was introduced in the
C-2 position of indoles (3fe and 3fg). However, when 2-car-
bethoxylindole was used as the substrate, only 67% yield of sulfeny-
lation product 3ga could be obtained even the reaction time was
prolonged to 44 h.
standard condition
5 min
S
(1)
(2)
2
4
2a
Yield: 99%
standard condition
3 h
3aa
4
+
N
H
To gain some insight into the possible reaction mechanism, sev-
eral control experiments were then carried out (Scheme 3).
I2/DMSO is well known to oxidize thiols into disulfides.23 Thiophe-
nol (2a) could be converted to 1,2-diphenyldisulfane (4) com-
pletely in the presence of 5 mol% of I2 and 3 equiv of DMSO at
60 °C in 5 min (Eq. 1). The sulfenylation of indole (1a) with 4 could
be successfully catalyzed by I2 in the presence of DMSO (Eq. 2),
implying 2a might be converted to 4 firstly in the iodine-catalyzed
sulfenylation of 1a with 2a. As blank reaction of 1a and 4 without
iodine catalyst could not afford any product (Eq. 3), we thought
iodine played an important role in this reaction. When stoichio-
metric radical-trapping reagent TEMPO was added into the
reaction of 1a and 4, the yield of 3aa reduced from 97% to 30%
(Eq. 4), indicating that this transformation might proceed via a rad-
ical pathway.
1a
Yield: 97%
standard condition
X
(3)
(4)
1a
1a
+
+
4
4
3aa
no I2
3 h,
N.R.
standard condition
1 eq. TEMPO
3aa
3 h,
Yield: 30%
Scheme 3. Control experiments for mechanism studies. Standard reaction condi-
tions: 1a or 2a (2 mmol), 4 (1 mmol), I2 (0.1 mmol), DMSO (6 mmol), DCE 10 mL,
60 °C. Yield of 3aa was determined by GC internal standard method.
the presence of I2 and DMSO (Scheme 4a).23 Subsequently, thio
radical A is formed from disulfide. The radical A reacts with indole
giving intermediate B,17a which loses hydrogen atom to release the
product 3-sulfenylindole (Scheme 4b, path a). However, multiple
pathways may be involved in this transformation. As references
According to the literatures and our observations, a plausible
reaction mechanism for 3-sulfenylation of indole has been pro-
posed (Scheme 4). Initially, disulfide is generated from thiol in
Please cite this article in press as: Yi, S.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.073

4
S. Yi et al. / Tetrahedron Letters xxx (2016) xxx–xxx
I2/DMSO
Ph
S
(a)
(b)
2PhSH
Ph
S
SPh
SPh
H
2
2
N
H
I2
+ 2 HI
2 PhS
2
2
2
path a
N
N
H
H
A
B
Ph
S
Ph
S
SPh
SPh
N
H
path b
+ 2 HI
2 PhSI
I
2
I2
N
H
N
H
C
OH2
S
OH
S
I
O
S
HI
S
+ H2O + I2
+ HI
H3C
CH3
(c)
H3C
CH3
I
I
D
E
Scheme 4. Proposed reaction mechanism.
reported,17b,19b,20f,20h disulfide can react with I2 to produce PhSI,
which attack on the C-3 position of indole to produce
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3-sulfenylindole is generated (Scheme 4b, path b). Then HI
produced in path or path reacts with DMSO to form
C is deprotonated, and the desired product
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a
b
intermediate D. Protonation of D gives intermediate E, which is
nucleophilic attacked by IÀ on the iodide atom to regenerate I2
and release dimethylsulfane and H2O (Scheme 4c).
In conclusion, we have successfully applied the I2/DMSO sys-
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sulfenylation of indoles with thiols to the corresponding
3-sulfenylindoles. Under the optimal reaction conditions, a variety
of indoles can react with aryl thiols or alkyl thiols to afford their
corresponding 3-sulfenylindoles in good to excellent yields, with
excellent functional group tolerance. The features of this protocol
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21376224, 21206147).
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22. Typical procedure for sulfenylation of indoles (Scheme 1, 3aa): A sealed tube
(90 mL) equipped with magnetic stirring bar was charged with 0.234 g of
indole (1a, 2 mmol), 0.220 g of thiophenol (1b, 2 mmol), 0.468 g of DMSO
(6 mmol, 3 equiv), 25.4 mg I2 (0.1 mmol, 5 mol%) and 10 mL of DCE. Then the
tube was placed in an oil bath, which was preheated to 60 °C. The mixture was
stirred for 6 h until starting material was complete consumed as monitored by
TLC. The reaction mixture was washed by H2O (10 mL Â 3) to remove excess of
DMSO and then organic layer was separated, dried (Na2SO4), filtered and
concentrated under reduced pressure. The crude product was purified by
chromatography on silica gel to afford 92% isolated yield of 3aa as a white
solid. 1H NMR (CDCl3): d = 8.43 (s, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.51 (d,
J = 2.6 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.32–7.28 (m, 1H), 7.21–7.16 (m, 3H),
7.15–7.11 (m, 2H), 7.06–7.09 (m, 1H). 13C NMR (125 MHz, CDCl3): d = 139.2,
136.5, 130.7, 129.1, 128.7, 125.9, 124.8, 123.1, 121.0, 119.7, 111.6, 102.9. MS
(EI): m/z 224.96 (M+).
23. Aida, T.; Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem. Soc. Jpn. 1976, 49, 1441.
Please cite this article in press as: Yi, S.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.073