Visible-light promoted synthesis of 3-arylthioindoles from indoles and diaryl disulfides

Article abstract of DOI:10.1016/j.tetlet.2017.05.090

3-Arylthioindoles could be synthesized in good yields via the photoirradiation of indoles and disulfides. The reaction is efficiently promoted by the catalytic amount of sodium iodide. A reaction mechanism involving the electrophilic substitution of indol

Full text of DOI:10.1016/j.tetlet.2017.05.090

Accepted Manuscript
Visible-light promoted synthesis of 3-arylthioindoles from indoles and diaryl
disulfides
Lin-miao Ye, Jie Chen, Peng Mao, Xue-jing Zhang, Ming Yan
PII:
S0040-4039(17)30698-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.05.090
TETL 48983
Reference:
Tetrahedron Letters
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28 May 2017
31 May 2017
Please cite this article as: Ye, L-m., Chen, J., Mao, P., Zhang, X-j., Yan, M., Visible-light promoted synthesis of 3-
arylthioindoles from indoles and diaryl disulfides, Tetrahedron Letters (2017), doi:http://dx.doi.org/10.1016/j.tetlet.
2017.05.090
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Tetrahedron Letters
Visible-light promoted synthesis of 3-arylthioindoles from indoles and diaryl
disulfides
Lin-miao Ye, Jie Chen, Peng Mao, Xue-jing Zhang, and Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3-Arylthioindoles could be synthesized in good yields via the photoirradiation of indoles and
disulfides. The reaction is efficiently promoted by the catalytic amount of sodium iodide. A
reaction mechanism involving the electrophilic substitution of indoles with arylsulfenyl iodine
intermediates is suggested.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
photoirradiation
synthesis
3-arylthioindole
disulfide
Indoles are important heterocyclic compounds which are
widely found in natural products and pharmaceuticals1. Among
them, 3-thioindoles are of great interest due to their diverse
biological and pharmacological properties, such as antitumor2,
anti-HIV3, antiallergic4 and anticardiovascular5 activities. Thus,
the synthesis of 3-thioindoles has attracted great attentions over
the past decades. Thiols6, sulfonyl halides7, sulfonyl hydrazides8,
N-thioimides9 and sulfonium salts10 were used as the source of
organic sulfur moiety to synthesize 3-sulfenyl indoles. Disulfides
were also applied for the 3-sulfenylation of indoles in the
presence of metal catalysts11, iodine12, oxidants13 and bases14.
Microwave irradiation was reported to promote the reaction15.
Recently, Lei reported an electrocatalytic protocol for the
synthesis of 3-arylthioindoles from indoles and disulfides16.
added. The reaction conditions were further examined and the
results are summarized in Table 1. Among the tested iodide
sources, sodium iodide afforded the best yield (Table 1, entries 2-
6). The reaction could be conducted under argon or oxygen
atmosphere, however lower yields were obtained (Table 1,
entries 7-8 vs. entry 2).19 A screening of reaction solvents
demonstrated acetonitrile as the best choice (Table 1, entries 9-
13). Other lights with different wavelengths (254 nm, 365 nm
and 530 nm) could also promote the reaction, but low yields were
observed (Table 1, entries 14-16). The reaction did not occur
upon the exclusion of the photoirradiation (Table 1, entry 17).
The increase or the decrease of the loading of 2a led to lower
yields (Table 1, entries 18-19).
Table 1. Screening of reaction conditions.
In recent years, visible-light-mediated reactions have emerged
as one attractive strategy for organic synthesis17. The methods are
safer, cleaner and more environmentally friendly. Recently, we
developed the synthesis of benzothiophenes and benzothiazoles
via visible-light promoted reactions of diaryl disulfides18. The
generation of arylthiyl radical through the homolysis of
diaryldisulfides is proposed as the crucial initiation step. Herein,
we report an efficient synthesis of 3-arylthioindoles from diaryl
disulfides and indoles under the irradiation of visible light.
Entry
Solvent
Additive
(mol%)
-
Light source
Yield (%)a
1
2
3
4
5
6
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtOAc
DCM
450 nm
450 nm
450 nm
450 nm
450 nm
450 nm
450 nm
450 nm
450 nm
450 nm
0
NaI (20)
KI (20)
TBAI (20)
NaI (10)
NaI (30)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
89(83b)
76
13
85
88
23
43
42
61
Initially, the reaction of 2-methylindole 1a and diphenyl
disulfide 2a was examined with the irradiation of a 12 W blue
LED under an air atmosphere. No expected product 3a was
obtained after 18 h. To our delight, the product 3a was obtained
in a good yield when a catalytic amount of sodium iodide was
———
7 c
8 d
9
10
 Corresponding author. Tel.: +86-20-39943049; fax: ++86-20-39943049; e-mail: yanming@mail.sysu.edu.cn

Tetrahedron Letters
11
12
13
14
EtOH
THF
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
NaI (20)
450 nm
450 nm
450 nm
254 nm
365 nm
530 nm
-
52
15
65
42
31
8
N-methylindole 1g gave the product 4g in a moderate yield. The
reaction of N-methyl-2-phenyl-indole 1h delivered the product
4h in a low yield. The steric hindrance of 2-phenyl group may
affect the transformation. N-acetylindole 1i is unreactive in the
reaction. The reaction of unsubstituted indole 1j gave the product
4j in a moderate yield. 5-Methylindole 1k provided the desired
product 4k in a moderate yield. Unfortunately, indoles containing
electron-withdrawing groups such as chloro and cyano were
unreactive (4l-4m). Only trace amount of the product 4l was
detected by GC-MS.
Toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
15
16
17 e
18f
19g
0
80
88
450 nm
450 nm
Reaction conditions: indole 1a (0.3 mmol), disulfide 2a (0.3 mmol), solvent
a
(2 mL), photoirradiation with a 12 W blue LED, room temperature, 18 h.
GC yield with n-dodecane as the internal standard. b Isolated yields after the
Table 3. Scope of indoles.a,b
column chromatography. c Under an argon atmosphere. d Under an oxygen
atmosphere. e Reaction performed in the dark. 2a (0.25 mmol) was used. g 2a
f
(0.35 mmol) was used.
With the optimized reaction conditions in hand, the scope of
disulfides was examined and the results are summarized in Table
2. Diphenyl disulfides bearing with electro-donating groups such
as methyl, t-butyl and methoxyl were tolerated well. The
corresponding products (3b-3e) were obtained in good yields.
The substitutions with fluoro, chloro, and bromo did not affect
the yields (3f-3k). The substrate 2l containing a nitro group gave
the product 3l in a moderate yield. Functional groups such as
hydroxyl, amino and amide were also tolerated well. The
corresponding products 3m-3o were prepared in 70-82% yields.
The reaction of heteroaryl disulfides (2p-2r) provided the
products in good yields. However, dibenzyl disulfide 2s was
found to be unreactive. No expected product 3s was obtained.
Table 2. Scope of disulfides.a,b
aReaction conditions: 1b-1j (0.3 mmol), 2a (0.3 mmol), MeCN (2.0 mL),
photoirradiation with a 12 W blue LED, room temperature, 18 h. b Isolated
yields.
To gain the insight into the reaction mechanism, the radical
scavenger TEMPO was added. The reaction was completely
inhibited. The result supported a radical pathway (Scheme 1).
Scheme 1. Radical trapping experiment.
Furthermore, the effect of photoirradiation was examined
through the ON/OFF light experiment (Scheme 2). The reaction
proceeded smoothly under the irradiation of visible-light. The
conversion stopped when the light source was removed. The
result excluded a radical chain reaction mechanism.
aReaction conditions: 1a (0.3 mmol), 2a-2s (0.3 mmol), MeCN (2.0 mL),
photoirradiation with a 12 W blue LED, room temperature, 18 h. b Isolated
yields.
Scheme 2. ON/OFF light experiment.
Furthermore, a series of substituted indoles were examined
and the results are summarized in Table 3. Generally, the indoles
substituted with methyl, methoxy, and halogen reacted smoothly
to provide the corresponding products in moderate yields (4b-4f).
The UV-vis spectra of diphenyl disulfide, sodium iodide, 2-
methylindole, and the reaction mixture were examined under the
different concentrations (see support information for the details).
None of them showed the strong absorptions around 450 nm. The

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maximum absorption peaks of diphenyl disulfide solutions were
observed around 350 nm. As we also found in the other reactions
of diphenyl disulfide, the irradiation with the light of 450 nm
provided the best yields18. We speculated that the energy
provided by the light of 450 nm is appropriate for the break of
the S-S bond. The light of shorter wavelengths provides too
much energy to cause the side reactions. On the other hand, the
light of longer wavelengths cannot provide the enough energy to
break the S-S bond.
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A tentative reaction mechanism is outlined in Scheme 3. The
diphenyl disulfide is firstly activated under the photoirradiation.
A single electron transfer from iodide to the activated diphenyl
disulfide provides a diphenyl disulfide anion radical A. The
fragmentation of A generates a thiophenol anion and a
phenylthiyl radical B. The coupling of iodine radical and B gives
arylsulfenyl iodine C. The subsequent electrophilic substitution
with the indole affords the 3-arylthioindole product12.
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9.
Scheme 3. Proposed reaction mechanism.
In summary, we have developed a visible-light promoted
synthesis of 3-arylthioindoles from indoles and diaryl disulfides.
The reaction can be promoted by the catalytic amount of sodium
iodide. A series of 3-arylthioindoles were prepared in good yields.
The reaction is suggested to occur via electrophilic arylsulfenyl
iodine intermediates, which are formed after the photo promoted
single electron transfer from iodide to diphenyl disulfides. The
finding provides a practical strategy for the synthesis of 3-
arylthioindoles.
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Acknowledgments
We thank the National Natural Science Foundation of China (no.
21472248) for the financial support of this study.
Supplementary Material
Supplementary data associated with this article can be found in
the online version, at http://. These data include experimental
1
procedure, characterization data of products, UV-vis spectra, H
and 13C NMR spectra.
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19. The exact reason for the result is not clear so far. We speculated that
the by-product thiophenol can be oxidized to diphenyl disulfide by
oxygen under photoirradiation (see Kim, J. H.; Yoon, J. L.; Yoon, S.
J. Phys. Chem. A, 2010, 114, 12010). Small amount of oxygen is
helpful for increasing the yield. Because the reaction proceeds via a
radical pathway, high oxygen concentration can inhibit the radical
2.
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Tetrahedron Letters
process and lead to a low yield.
Highlights

An efficient and convenient synthesis of 3-
arylthioindoles from indoles and diaryl disulfides via
visible-light irradiation.


Sodium iodide was used as the catalyst.
A variety of indoles and diaryl disulfides are
applicable.
Graphical Abstract
Visible-light promoted synthesis of 3-
arylthioindoles from indoles and diaryl
disulfides
Leave this area blank for abstract info.
Lin-miao Ye, Jie Chen, Peng Mao, Xue-jing Zhang and Ming Yan*