Iodine-promoted selective 3-selanylation and 3-sulfenylation of indoles with dichalcogenides under mild conditions

Article abstract of DOI:10.1080/10426507.2014.999068

A simple method was developed for the synthesis of 3-chalcogen indoles via iodine-promoted direct 3-selanyl- and 3-sulfenylation of indoles with dichalcogenides. The reaction was carried out smoothly in EtOH under air at room temperature, selectively givi

Full text of DOI:10.1080/10426507.2014.999068

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Phosphorus, Sulfur, and Silicon and the Related
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Iodine-promoted selective 3-selanylation and 3-
sulfenylation of indoles with dichalcogenides under
mild conditions
Su-Qin Chena, Qian-Mei Wanga, Ping-Chuan Xua, Shao-Peng Gea, Ping Zhonga & Xiao-Hong
Zhanga
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035,
China
Accepted author version posted online: 16 Mar 2015.
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To cite this article: Su-Qin Chen, Qian-Mei Wang, Ping-Chuan Xu, Shao-Peng Ge, Ping Zhong & Xiao-Hong Zhang (2015): Iodine-
promoted selective 3-selanylation and 3-sulfenylation of indoles with dichalcogenides under mild conditions, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2014.999068
To link to this article: http://dx.doi.org/10.1080/10426507.2014.999068
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Iodine-promoted selective 3-selanylation and 3-sulfenylation of indoles with
dichalcogenides under mild conditions
Su-Qin Chen,a Qian-Mei Wang, a Ping-Chuan Xu, a Shao-Peng Ge, a Ping Zhong, a Xiao-Hong
Zhang,*a
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
kamenzxh@163.com.
Abstract: A simple method was developed for the synthesis of 3-chalcogen indoles via
iodine-promoted direct 3-selanyl- and 3-sulfenylation of indoles with dichalcogenides. The
reaction was carried out smoothly in EtOH under air at room temperature, selectively giving a
series of 3-chalcogen indoles bearing different functional groups in good to excellent yields. The
procedure has the merits of environmental friendliness, easy operation, wide substrate scope and
mild reaction conditions.
Keywords: Iodine-promoted, 3-selanyl- and 3-sulfenylation, indoles, dichalcogenides
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3-Selanyl- and 3-sulfenylindoles are an important class of heterocycles that were widely applied
in many major therapeutic fields, such as in the treatment of allergies, 1 heart disease, 2 cancer, 3
HIV 4 and obesity. 5 Their important pharmaceutical property encouraged researchers to develop
different and efficient methods for the synthesis of 3-chalcogen indoles. 6 Among these various
approaches, the most commonly used methods involved the direct sulfenylation of the indole
moieties with various electrophilic sulfur reagents, including sulfenyl chloride, 7 thiols, 8 quinine
mono-O,S-acetals, 9 N-thiophthalimides 10 and so on. However, most of them have one or more
disadvantages such as instability, difficult to be prepared, high volatility, unpleasant smelling,
incompatibility of the substrates, and generation of undesired byproducts or need of strictly
anhydrous reaction conditions.7-10 Moreover, despite the successful synthesis of 3-sulfenylindole
derivatives, the aforementioned sulfur reagents were limited to only give 3-selanylindoles
compounds. Therefore, alternative protocols were conducted with the disulfides / diselenides as
the sulfur /selenium sources using metal compounds as the catalysts (or the promoters), such as
NaH,11 FeCl3,12 CuI 13 and MgO.14 These reactions have been proved to be efficient for the
synthesis of a series of substituted 3-chalcogen indoles. Nonetheless, the usage of metal
compounds would inevitably result in environmental pollution. In addition, some additives or
high temperature are often required to achieve good yields. 12, 14 Further, some of these catalytic
systems were generally sensitive to the nature of indoles. For example, indoles with the strong
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12,14
electron-withdrawing groups (such as nitro group) kept intact in the reaction.
These
shortcomings would limit the scope of these methods and hardly made them attractive
procedures.
In recent years, with the urged requirement for green chemistry and economic/ sustainable
development, researchers paid much attention to search for metal-free, green and sustainable
protocols to provide 3-sulfenylindole compounds. 15 For instance, K2CO3 and Cs2CO3 promoted
direct sulfenylation of indoles with disulfides at high temperature to prepare 3-sulfenylindoles
16
were reported successively by Zhang
and Bolm groups.17 Wu and co-workers described a
18
metal-free sulfenylation of indoles using NBS (3 equiv) as the promoters.
I2-catalyzed
oxidative system using DMSO as oxidant for the synthesis of 3-sulfenylindole derivatives was
developed by Wei group. 19 However, there still have great spaces to make these reaction systems
more perfect, including lowering the reaction temperature and loading of the promoters, without
using any oxidant, adapting the sulfenylation to selanylation and so on. As part of our continuing
interest to seek for simple methodologies for the synthesis of 3-sulfenylindoles as well as
3-selanylindole derivatives, we found that 3-chalcogen indoles could be achieved in good to
excellent yields via iodine-promoted direct 3-selanyl- and 3-sulfenylation of indoles with
dichalcogenides in EtOH at room temperature. Herein, we reported the results in detail.
1. Results and Discussion
The reaction of 1H-indole (1a) with 1,2-diphenyldisulfide (2a) was chosen as a model
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system to determine the optimal reaction conditions (Table 1). The amounts of
1,2-diphenyldisulfide (2a) and I2 were firstly explored using EtOH as solvent at room
temperature. It can be seen that 1H-indole (1a) underwent the reaction with 1,2-diphenyldisulfide
(2a, 1.0 equiv) selectively to afford the 3-(phenylthio)-1H-indole (3) in 92% yield (entry 1),
which structure was identified by single crystal X-ray diffraction (see Fig.1 and Tables S 1
and S 2, Supplemental Materials). When lowing the amounts of 1,2-diphenyldisulfide to 0.55
equiv, 90% yield of the compound 3 can be achieved (entry 2). The results showed both of the
phenylthio groups from 1,2-diphenyldisulfide could involve in the reaction. No obvious yield
increasment can be observed when the amount of I2 was increased to 1.0 equiv (entry 3), whereas
the yield was sharply decreased to 50 % when lowering I2 loading to 0.3 equiv (entry 4). The
other iodine sources, such as ICl and NIS, were screened to give worse results than I2 (entries 5,
6). When the reaction temperature was raised to 60 oC, no higher yield can be obtained (entry 7).
Thus, the optimal reaction condition was identified as follows: 1 (1.0 equiv), 2 (0.55 equiv), I2
(0.5 equiv), and EtOH (3 mL) at room temperature under air for 12 h.
(Tables S 1 and S 2, Supplemental Materials contain the X-ray experimental summary and
selected bond lengths and angles)
With the optimal reaction condition in hand, the scope of the indoles (1a-1l) and disulfide
(2a-2m) for the sulfenylation reaction was investigated (Table 2). Initially, the sulfenylation of
substituted indoles (1a-1l) with 1,2-diphenyldisulfide (2a) was examined. The results
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demonstrated that indole derivatives, with either electron-donating (methyl and methoxyl) or
electron-withdrawing moieties (F, Cl, Br), underwent 3-sulfenylation with 1,2-diphenyldisulfide
(2a) smoothly to give their corresponding products in good to high yields (compounds 3-9).
However, it was found that 5-nitroindole kept intact at room temperature, giving
5-nitro-3-(phenylthio)-1H-indole (10) in 75% yield only if increasing the reaction temperature to
o
80 C. Encouraged by the successful synthesis of 3-(phenylthio)-1H-indoles with various groups
in the benzene ring, the indoles with C-2 functional substituents were next examined. We found
that C-2 methyl and ester groups-substituted indoles were also tolerated well in this procedure to
give the products 11 and 12 in 70% and 65% yields, respectively. Notably, the 3-sulfenylation of
N-methyl and N-benzyl indoles was also conducted smoothly, providing the target products 13
and 14 in moderate yields.
Subsequently, a variety of disulfide derivatives were examined with 1H-indole (1a). The
results showed good functional group tolerance. For example, the disulfides bearing
electron-donating groups (such as methyl and methoxyl groups), as well as electron-withdrawing
substituents (such as F, Cl, NO2) participated in the 3-sulfenylation with 1H-indole (1a) smoothly
to achieve the desired products (15-19) in good to high yields. We are pleased to find that
1,2-di(pyridine-2-yl)disulfane and 1,2-di(thiophen-2-yl)disulfane underwent the 3-sulfenylation
successfully, giving their corresponding products 20 and 21 in 95% and 85% yields, respectively.
It is noteworthy that the reaction conditions are compatible with dialkyl disulfides.
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1,2-dimethyldisulfane, 1,2-dicyclohexyldisulfane and 1,2-dibenzyldisulfane, for instance, could
underwent the reaction with 1H-indole (1a) to furnish the products 22-24 in good yields.
3-Selenylation of 1H-indole (1a) with 1,2-diphenyldiselane and 1,2-dibenzyldiselane were also
tested to give good results, showing the simple reaction conditions were also compatible with
3-selanylation reaction.
According to the results and the reported mechanisms,12, 20 the possible mechanism of the
iodine-promoted 3-selanylation and 3-sulfenylation of indoles was outlined in Scheme 1.
Initially, the reaction of RSSR with iodine affords RSI (A) in situ, which immediately reacts with
indoles by electrophilic addition to give intermediate B. Deprotonation of intermediate B gives
the target product. It is obvious that the strong electron-withdrawing groups in the phenyl ring of
indole will decrease the efficiency according to the mechanism. And the mechanism was in
accordance with the fact that the reaction of 5-nitroindole with 1,2-diphenyldisulfide undergoes
at a higher temperature.
In conclusion, we have developed a simple method for the synthesis of 3-chalcogen indoles
via iodine-promoted direct 3-selanyl- and 3-sulfenylation of indoles with dichalcogenides. The
3-selanyl- and 3-sulfenylation were conducted well in EtOH under air condition at room
temperature. And the reaction system has the merits of wide substrate scope, environmental
friendliness, easy operation and mild reaction conditions. Indoles and dichalcogenides with
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various substituted groups can participate in the reaction smoothly to furnish a series of
3-chalcogen indoles in good to excellent yields.
Experimental
Materials and methods
Chemicals were either purchased or purified by standard techniques. NMR spectroscopy was
performed on a Bruker Avance-300 spectrometer operating at 300, 500 MHz (1H NMR) and 125
MHz (13C NMR), using CDCl3 and Actone-D6 as the solvent with tetramethylsilane (TMS) as an
internal standard at room temperature. Melting points were determined on a digital melting-point
apparatus from Beijing TECH Instrument CO. LTD and are uncorrected. All reactions are
happened under air atmosphere. Column chromatography was performed using EM Silica gel 60
(300-400 mesh). The crystal was mounted on a Bruker APEX area-detector diffractometer
equipped with a graphite-monochromatic MoKα (λ = 0.71073Å) radiation. The structure of
compound 3 was solved by direct methods using the SHELXLS-97 program and refined by using
the SHELXL-97 program.21. Data collection parameters are provided in Table S 1.
Typical Experimental Procedure for the iodine-promoted direct 3-selanyl- and
3-sulfenylation of indoles with dichalcogenides
Indole (0.5 mmol), disulfide (0.28 mmol), I2 (0.25 mmol), and EtOH (3 mL) were added to a
Schlenk tube or round-bottomed flask and stirred at room temperature for 12 h. After the reaction
was finished, the reaction mixture was washed with sodium thiosulfate. Then the mixture was
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extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4,
concentrated under vacuum, and the resulting residue was purified by silica gel column
chromatography to afford the desired product. Complete characterization of the products and
selected 1H and 13C NMR spectra for 3, 4 and 5 are presented in the Supplemental Materials
(Figures S 1 – S 6)
The products formed are known compounds, viz 3-(phenylthio)-1H-indole (3)12,
5-methyl-3-(phenylthio)-1H-indole
5-methoxyl-3-(phenylthio)-1H-indole
5-chloro-3-(phenylthio)-1H-indole
(4)8b,
(6)8c,
(8)8b
7-methyl-3-(phenylthio)-1H-indole
5-fluoro-3-(phenylthio)-1H-indole
5-bromo-3-(phenylthio)-1H-indole
(5)8d,
(7)21,
(9)8b,
,
5-nitro-3-(phenylthio)-1H-indole (10)16, 2-methyl-3-(phenylthio)-1H-indole (11)12, Methyl
3-(phenylthio)-1H-indole-2-carboxylate (12)12, 1-methyl-3-(phenylthio)-1H-indole (13)12,
1-benzyl-3-(phenylthio)-1H-indole
3-(4-methoxyphenylthio)-1H-indole
3-(4-chlorophenylthio)-1H-indole
3-(pyridin-2-ylthio)-1H-indole
(14)20,
(16)12,
(18)12,
(20)12,
3-(4-methylphenylthio)-1H-indole
3-((4-fluorophenyl)thio)-1H-indole
3-((4-nitrophenyl)thio)-1H-indole
3-(thiophen-2-ylthio)-1H-indole
(15)12,
(17)12,
(19)12,
(21)6c,
3-(methylthio)-1H-indole (22)8c, 3-(cyclohexylthio)-1H-indole (23)12, 3-(benzylthio)-1H-indole
(24)12, 3-(phenylselanyl)-1H-indole (25)12 and 3-(benzylselanyl)-1H-indole (26)15b.
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Acknowledgements
The authors thank the National Natural Science Foundation of China (No. 21302144)
Supplementary data
Supplementary data associated with this article can be found online. CCDC1025473
contains the supplementary crystallographic data for compound 3. The data can be obtained free
of
charge
from
the
Cambridge
Crystallographic
Data
Centre,
via
www.ccdc.cam.ac.uk/data_request.cif.
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Table 1. Screening of the Optimal Conditionsa
Entry Iodine source 2a,
Temp
(°C)
Yield a(%)
( equiv)
equiv
1
2
3
4
5
6
7
I2 (0.5)
1.0
rt
rt
92
90
91
50
47
68
88
I2 (0.5)
I2 (1.0)
0.55
0.55
0.55
0.55
0.55
0.55
rt
I2 (0.3)
rt
ICl (0.5)
NIS (0.5)
I2 (0.5)
rt
rt
60
a Reaction conditions: 1a (0.5 mmol), 2a, iodine source
b
and EtOH (3 mL) at room temperature for 12 h. Yield
of isolated products.
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Table 2. Iodine-promoted selective 3-sulfenylation and 3-selanylation of indoles (1a-1l) with
dichalcogenides (2a-2m) a,b
SPh
SPh
SPh
SPh
H3C
H3CO
N
N
N
N
H
H
H
H
CH3
5
12
8b
8d
8c
3
4
6
(80 %)
(90 %)
(95 %)
(92 %)
SPh
SPh
SPh
SPh
F
Cl
Br
O2N
N
N
N
N
H
H
H
H
20
8b
8b
c, 16
7
8
9
%
(87 )
(85 %)
(88 %)
10
(75 %)
SPh
SPh
SPh
CH3
SPh
COOCH3
N
N
N
N
H
H
CH3
12
Ph
12
12
20
11
2
13
4
(70 %)
1 (65 %)
(80 %)
1 (78 %)
F
OCH3
Cl
CH3
S
S
S
S
N
N
N
H
N
H
H
H
15 (92 %) 12
16 (80 %) 12
17 (85 %) 12
18 (86 %) 12
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S
NO2
CH3
S
S
S
S
N
N
N
N
N
H
H
H
H
19 (79 %) 12
20 (95 %) 12
21 (85 %) 6c
22 (83 %) 8c
S
SePh
Se
S
Ph
Ph
N
H
N
H
N
H
N
H
23 (86 %) 12
24 (85 %) 12
25 (85 %) 12
26 (83 %) 15b
a Reaction conditions: 1 (0.5 mmol), 2 (0.28 mmol), I2 (0.25 mmol), and EtOH (3 mL)
at room temperature for 12 h. b Yield of isolated products. c at 80 oC
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Figure 1. Molecular structure of compound 3 shown at 30 % probability level.
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Scheme 1 the possible mechanism of the iodine-promoted 3-selanylation and
3-sulfenylation of indoles
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