Iodine-catalyzed Direct Thiolation of Indoles with Thiols Leading to 3-Thioindoles Using Air as the Oxidant

Article abstract of DOI:10.1007/s10562-016-1798-2

Abstract: A simple and convenient method has been developed for the construction of 3-thioindoles via molecular iodine-catalyzed direct thiolation of indoles with thiols. The present protocol, which employs thiols as the thiolating agents, inexpensive mol

Full text of DOI:10.1007/s10562-016-1798-2

Catal Lett
DOI 10.1007/s10562-016-1798-2
Iodine-catalyzed Direct Thiolation of Indoles with Thiols Leading
to 3-Thioindoles Using Air as the Oxidant
Xiaoxia Liu1 Huanhuan Cui1 Daoshan Yang1 Shicui Dai1
•
•
•
•
Guoqin Zhang1 Wei Wei1 Hua Wang1
•
•
Received: 28 April 2016 / Accepted: 17 June 2016
Ó Springer Science+Business Media New York 2016
Abstract A simple and convenient method has been devel-
oped for the construction of 3-thioindoles via molecular iodine-
catalyzed direct thiolation of indoles with thiols. The present
protocol, which employs thiols as the thiolating agents, inex-
pensive molecular iodine as the catalyst, and environmentally
benignair as the oxidant, allows theregioselective generationof
3-thioindoles in good to excellent yields.
1 Introduction
Indole represents an important class of structural scaffold
omnipresent in various natural products, pharmaceutically
active compounds and materials [1–8]. In particular, 3-thioin-
doles constitute a permanent focus of scientific interest since
they have a broad spectrum of biological and pharmaceutical
activities, such as anti-cancer activity [9], anti-HIV activity
[10], anti-bacterial infection [11], anti-obesity [12, 13], and
inhibitory activity against tubulin polymerization [14]. For
example, compound I can be used as inhibitor against
5-lipoxygenase, which may increase the antitumor activity of
celecoxib in colorectal cancer [16]; compound II is a powerful
and selective CRTh2 antagonist [17]; compound III is a potent
inhibitor of tubulin polymerization, inhibiting the growth of
breast cancer cells (Fig. 1) [14, 15, 18].
Graphical Abstract
Because of the importance of such compounds, numer-
ous synthetic methods have been successfully established.
Among them, the C3-thiolation of indoles has been
exhibited to be the most efficient and extensively explored
one. So far, a variety of thiolating agents such as aryl-
sulfenyl halides [19, 20], arylsulfonyl chlorides [21–23],
sulfonyl hydrazides [24, 25], diaryl disulfides [26–33], N-
thiophthalimides [34–37], O,S-acetals [38, 39], arylsulfo-
nium salts [40, 41], sulfinic acids [42] and Bunte Salts [43]
have been employed for C3-thiolation of indoles. Despite
the merits of these methods, most of these reactions require
an additional step for the synthesis of thiolating reagents.
From a synthetic standpoint, the direct use of thiols as
thiolating reagents is an effective strategy for constructing
3-thioindoles because of its advantages of low cost, easy
availability, and high atom economy. Up to date, a few
methods have been reported to synthesize 3-thioindoles
from thiols [44–50]. Nevertheless, most of these methods
suffer from some limitations such as the need for toxic
Keywords Molecular iodine Á Thiolation Á 3-Thioindoles Á
Indoles Á Thiols
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-016-1798-2) contains supplementary
material, which is available to authorized users.
& Wei Wei
weiweiqfnu@163.com
& Hua Wang
huawang_qfnu@126.com
1
The Key Laboratory of Life-Organic Analysis and Key
Laboratory of Pharmaceutical Intermediates and Analysis of
Natural Medicine, School of Chemistry and Chemical
Engineering, Qufu Normal University,
Qufu 273165, Shandong, China
123

X. Liu et al.
25 mL round-bottomed flack at room temperature under
air. The reaction vessel was allowed to stir at 80 °C for
16 h. After the reaction, the solvent was then removed
under vacuum. The residue was purified by flash column
chromatography using a mixture of petroleum ether and
ethyl acetate as eluent to give the desired 3-thioindoles 3.
The characterization of the corresponding products was
shown in Supporting Materials.
Fig. 1 Biologically active 3-thioindoles
3 Results and Discussions
In an initial experiment, indole 1a and 4-methylben-
zenethiol 2a were chosen as the model substrates to opti-
mize the reaction conditions in the presence of various
iodine reagents (Table 1, entries 1–4). Among the iodide-
containing reagents (20 mol%) examined, molecular iodine
was found to be the most efficient catalyst for mediating
the formation of product 3aa in 65 % yield (Table 1, entry
4), others such as NaI, KI, and TBAI did not promote this
reaction (Table 1, entries 1–3). Further optimization of
catalyst loading showed that 5 mol % of iodide was the
best choice, giving the corresponding product 3aa in 87 %
yield (Table 1, entry 8). Moreover, none of product was
detected when the reaction was conducted in the absence of
molecular iodine (Table 1, entry 10). The screening of
various solvents found that CH3CN was the optimal reac-
tion medium (Table 1, entries 8, 11–17). In contrast, only a
trace amount of product 3aa was detected when reaction
was performed in THF, EtOH, or DMF (Table 1, entries
15–17). In addition, the reaction efficiency was obviously
low with the decreasing of reaction temperature (Table 1,
entries 18–19), and only 17 % yield was obtained when
reaction was conducted at room temperature. The appro-
priate proportion of the indole 1a and 4-methylben-
zenethiol 2a was 1:1.5 (Table 1, entries 20–22).
Scheme 1 Molecular iodine-catalyzed regioselective synthesis of
3-thioindoles
metal catalysts, relatively harsh reaction conditions, poor
substrate scope, and the use of stoichiometric amounts of
base or potentially dangerous oxidants. Therefore, it is still
a highly desirable task to develop a convenient and effi-
cient approach to 3-thioindoles directly from thiols.
With our continuous interests in the synthesis of sulfur-
containing compounds [51–61], here, we wish to present a
simple and efficient synthesis method for the direct thio-
lation of indoles with various thiols in the presence of
inexpensive and environmentally friendly iodine under air
conditions (Scheme 1). The present protocol provides a
convenient and highly attractive approach to a variety of
3-thioindoles in good to excellent yields, and does not
require any metal catalyst, base, or peroxide oxidants.
2 Experimental
2.1 General Information
Under the optimized conditions, we then examined the
scope of the thiolation reactions. As shown in Table 2,
generally, aryl thiols bearing an electron-donating group or
an electron-withdrawing group on the aryl rings could react
smoothly to give the corresponding products in good to
excellent yields (3aa–3an). It should be noted the steric
effect of aryl thiols did not affect the yields significantly.
The ortho- or meta-substituted aryl thiols were effectively
reacted with indole to deliver the desired products (3ac–
3aj) in good yields. Moreover, functionalities such as
amino and halogen groups were compatible with this
reaction leading to the products 3ag–3am, which are the
potential substrates for further transformations. As expec-
ted, 2-naphthalenethiol was also tolerated in this process to
afford desired product 3ao obtained in 82 % yield. Nota-
bly, various alkyl thiols such as thiophen-3-ylmethanethiol,
phenylmethanethiol and 2-phenylethanethiol were
All commercially available reagents and chemicals were
purchased from chemical suppliers and used as received
without further purification. All reactions were carried out
under air. Column chromatography was performed on silica
1
gel (200–300 mesh). H NMR (500 MHz) and 13C NMR
(125 MHz) spectra were recorded of samples dissolved in
CDCl3 with TMS as internal standard at room temperature.
Mass analyses and HRMS were obtained on a Finnigan-
LCQDECA mass spectrometer and a Bruker Daltonics Bio-
TOF-Q mass spectrometer by the ESI method, respectively.
2.2 General Procedure for Regioselective Synthesis
of 3-Thioindoles Under Air
Acetonitrile (2 mL) was added into a mixture of indoles 1
(0.25 mmol), thiols 2 (0.375 mmol) and I2 (5 mol %) in a
123

Iodine-catalyzed Direct Thiolation of Indoles with Thiols Leading to 3-Thioindoles Using Air…
Table 1 Screening of the reaction conditions
Entry
Catalyst (mol%)
Solvent
T (oC)
Yield (%)a
1
NaI (20)
KI (20)
TBAI(20)
I2(20)
I2(30)
I2(40)
I2(10)
I2(5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
1,4-Dioxane
DMSO
Toluene
DME
80
0
2
80
0
3
80
0
4
80
65
5
80
40
6
80
38
7
80
68
8
80
87
9
I2(2)
80
72
10
11
12
13
14
15
16
17
18
19
20
21
22
I2(0)
80
0
I2(5)
80
29
I2(5)
80
77
I2(5)
80
14
I2(5)
80
10
I2(5)
THF
Reflux
Reflux
80
Trace
Trace
Trace
17
I2(5)
EtOH
I2(5)
DMF
I2(5)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
25
I2(5)
60
66
I2(5)
80
73b
83c
55d
I2(5)
80
I2(5)
80
Reaction conditions 1a (0.25 mmol), 2a (0.375 mmol), Iodine reagent (0–40 mol%), solvent (2 mL), 25–80 °C, 16 h, under air
a
Isolated yields based on 2a
b
1a (0.5 mmol), 2a (0.5 mmol)
c
1a (0.5 mmol), 2a (0.6 mmol)
d
1a (0.5 mmol), 2a (1 mmol)
suitable for this reaction, with the desired products
obtained in good yields (3ap–3ar). With respect to indoles,
in addition to 1-H indole, some substituted indoles such as
reaction pathway was proposed as shown in Scheme 2.
Initially, the interaction of thiol 2 with molecular iodine
would give electrophilic species R3-SI 4 with the con-
comitant generation of HI [66–71]. Subsequently, the
intermediate 5 could be produced by a direct electrophilic
substitution of indole 2 with R3-SI at the C-3 position.
Next, the loss of HI from 5 led to the formation of desired
product 3. Finally, the formed two equivalents of HI would
be oxidized by air oxygen into molecular iodine to
accomplish the catalytic cycle.
N-methylindole,
2-methylindole,
2-phenylindole,
5-methylindole, and 7-methylindole worked well with this
thiolation reaction to generate the corresponding products
in good yields (3ba–3ei).
Although the detailed reaction mechanism is still
unclear at the present stage, based on the above experi-
ments and previous studies [44–51, 62–71], a possible
123

X. Liu et al.
Table 2 Results for iodine-catalyzed regioselective synthesis of 3-thioindoles
Reaction conditions 1 (0.25 mmol), 2 (0.375 mmol), I2 (5mol%), CH3CN(2 mL), 80 °C, 16 h
Isolated yields based on 1
123

Iodine-catalyzed Direct Thiolation of Indoles with Thiols Leading to 3-Thioindoles Using Air…
11. Khandekar SS, Gentry RD, Van Aller GS, Doyle ML, Chambers
PA, Konstantinidis AK, Brandt M, Daines RA, Lonsdale JT
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In conclusion, a simple and efficient method has been
successfully developed for the synthesis of 3-thioindoles
via molecular iodine-catalyzed direct thiolation of indoles
with thiols using air as the oxidant. In comparison with
previous methods, the present protocol, which possesses
some advantages of cheap and metal-free catalysts, readily-
available starting materials, mild and environmentally
friendly reaction conditions. Further studies on the scope
and application of this reaction are underway.
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