Photocatalytic direct C-S bond formation: Facile access to 3-sulfenylindoles: Via metal-free C-3 sulfenylation of indoles with thiophenols

Article abstract of DOI:10.1039/c7ra08086g

An efficient and convenient photocatalytic direct C-3 sulfenylation of indoles with thiophenols has been developed for the construction of 3-sulfenylations. This protocol employs thiophenols as the sulfenylating agents, inexpensive rose bengal as the photocatalyst, and shows mild conditions, readily available starting materials, high atom and step atom economy, and environmental advantages. The representative method provides a straightforward approach for C-S bond formation, and has potential applications in the chemical and pharmaceutical industries.

Full text of DOI:10.1039/c7ra08086g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Photocatalytic direct C–S bond formation: facile
access to 3-sulfenylindoles via metal-free C-3
sulfenylation of indoles with thiophenols†
Cite this: RSC Adv., 2017, 7, 37739
*
Wei Guo, ‡ Wen Tan,‡ Mingming Zhao, Kailiang Tao, Lv-Yin Zheng,
* *
Deliang Chen and Xiao-Lin Fan
Yongquan Wu,
An efficient and convenient photocatalytic direct C-3 sulfenylation of indoles with thiophenols has been
developed for the construction of 3-sulfenylations. This protocol employs thiophenols as the
sulfenylating agents, inexpensive rose bengal as the photocatalyst, and shows mild conditions, readily
available starting materials, high atom and step atom economy, and environmental advantages. The
representative method provides a straightforward approach for C–S bond formation, and has potential
applications in the chemical and pharmaceutical industries.
Received 22nd July 2017
Accepted 25th July 2017
DOI: 10.1039/c7ra08086g
rsc.li/rsc-advances
For the past several years, more and more chemists gave
their attentions to the photocatalytic organic reaction for the
synthesis of useful products.17 The metal complexes
Introduction
3-Substituted indoles compose an important skeleton in natural
products, agrochemicals, and functional materials.1 More
specically, 3-sulfenylindoles have been explored for their
therapeutic worth in many elds, such as anti-bacterial infec-
tion2 and anti-allergy agents.3 Because of the importance of
such compounds, numerous synthetic approaches of 3-sulfe-
nylindoles have been successfully established in previous liter-
ature.4,5 Importantly, direct functionalization of indoles at the
C-3 position is a valuable approach for the effective preparation
of 3-sulfenylindoles. So far, a variety of sulfenylating agents
such as arylsulfenyl halides,6 arylsulfonyl chlorides,7 sulfonyl
hydrazides,8 diaryl disuldes,9 N-thiophthalimides,10 O,S-
acetals,11 arylsulfoniumsalts,12 sulnic acids,13 Bunte salts,14
and thiols15 have also been employed for C3-sulfenylation of
indoles. Although many 3-sulfenylindoles can be obtained
using these methods, most of the reactions mentioned above
suffered from one or more drawback such as stringent condi-
tions (transition metals (VO(acac)2),16a iodine,7c strong base,16b,c
high temperature or extreme low temperature16d) and unavail-
able starting materials (Scheme 1a). Therefore, the development
of simple and efficient procedures for the acquisition of 3-sul-
fenylindoles from easily available starting materials under mild
conditions continues to attract the interest of organic chemists
because of the remarkable application value of the target
products.
([Ru(bpy)3]2+, fac-[Ir(ppy)3]+) and organic dyes (eosin Y, rose
bengal) have been explored in photocatalytic radical reaction.
Zheng's group successfully developed a visible light mediated C-
3 sulfenylation of indole derivatives using [Ru(bpy)3]Cl2 as the
photocatalyst (Scheme 1b).7b Herein, we wish to present
a simple and efficient synthesis method for the direct sulfeny-
lation of indoles with various thiophenols in the presence of
inexpensive and environmentally friendly photocatalyst under
air conditions (Scheme 1c). The present protocol provides
a convenient and highly attractive approach to a variety of 3-
sulfenylindoles in good to excellent yields, and does not require
any metal catalyst, base, or peroxide oxidants.
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan
Normal University, Ganzhou 341000, China. E-mail: guoweigw@126.com;
deliang2211@hotmail.com; fanxl2008@gnnu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra08086g
‡ W. G. and W. T. contributed equally.
Scheme 1 Synthesis of 3-thioindole with different pairs.
RSC Adv., 2017, 7, 37739–37742 | 37739
This journal is © The Royal Society of Chemistry 2017

View Article Online
RSC Advances
Paper
nitrogen or vacuum atmospheres (Table 1, entries 14 and 15),
no desired product 3aa was formed. Further control experiment
indicated that no reaction took place at all in the absence of
light, which clearly showed that photoinduced irradiation was
necessary for this transformation (Table 1, entry 16). Gram scale
reaction was performed under the optimized reaction condi-
tions to afford the 3aa in 72% isolated yields.
Results and discussion
We started our investigation of light-mediated indole sulfeny-
lation reaction using 1-methyl-1H-indole (1a) and 4-methyl-
benzenethiol (2a) as the model substrates in the presence of 1
mol% Ru(phen)3Cl2 in CH3CN. The reaction was carried out
open to air, under irradiation with a 5 W compact 415 nm lamp.
The desired product 3-((4-methylphenyl)thio)-1-methyl-1H-
indole (3aa) was obtained in 47% yield aer 12 h (Table 1, entry
1). Inspired by this result, systematic investigation has been
conducted to enhance the efficiency of the reaction. Initial
attempt on changing photocatalysts was found to be effective to
enhance the yield of 3aa, and using rose bengal as the photo-
catalyst led to signicant improvement by giving 3aa with 77%
yield (Table 1, entries 2–5). Next, a number of solvents were
screened, such as DMF, DMSO, toluene, CH2Cl2 and EtOH
(Table 1, entries 6–10). To our delight, 3aa was obtained in 85%
yield in CH2Cl2 aer 12 h (Table 1, entry 9). No product was
formed in the absence of photocatalysts (Table 1, entry 11).
Furthermore, no product is produced when additional 1 eq.
base was added (Table 1, entry 12). To our delight, 3aa was
obtained in 78% yield with 10 W 415 nm lamp aer 12 h
(Table 1, entry 13). When the reaction was performed on
Under the optimized reaction conditions, the scope of the
substrates was investigated. Firstly, the reactions of 1-methyl-
1H-indole (1a) with a variety of thiophenols (2) were examined
and the results were shown in Scheme 2. Thiophenols bearing
an electron-donating group or an electron-withdrawing group at
p-, m-, o-position reacted smoothly to give the corresponding
products in moderate yields 3aa–3aj. However, the electron-
withdrawing group on thiophenols afforded lower yields,
which attributed to the worse activities of the corresponding
thioyl radical intermediates. Moreover, some difunctionalities
substituent thiophenols such as 3,4-dimethylbenzenethiol (2k),
2-chloro-4-uorobenzenethiol (2l), 2,5-dichlorobenzenethiol
(2m) were compatible with this reaction leading to the products
3ak–3am, which are the potential substrates for further trans-
formations. Notably, 3,5-bis(triuoromethyl)benzenethiol (2n)
and 2,3,4,5,6-pentauorobenzenethiol (2o) were suitable for
this reaction, with the desired products obtained in moderate
yields (3an, 3ao). Moreover, as expected, 2-naphthalenethiol
(2p) was also tolerated in this process to afford desired product
3ap obtained in 38% yield.
Table 1 Selected optimization studiesa
The scope of the indoles substrates is also crucial for the
extensive utility of this direct sulfenylation of indoles trans-
formation (Scheme 3). The listed results demonstrate that
various indole derivatives (1) reacted smoothly with 4-methyl-
benzenethiol (2a) to afford the corresponding 3-sulfenylindoles
Entry
Photocatalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Ru(phen)3Cl2
fac-Ir(ppy)3
Eosin B
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMSO
Toluene
CH2Cl2
EtOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
47
35
13
11
77
18
Trace
68
85
Eosin Y
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
—
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
Rose bengal
9
10
11
12c
13d
14e
15f
16g
17h
50
n.d.
n.d.
78
n.d.
n.d.
n.d.
72
a
Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), catalyst (1
mol%), solvent (2.0 mL), open to air under a 5 W 415 nm lamp at
b
room temperature for 12 h. GC yields based on 1a with n-dodecane
c
as an internal standard. Reaction condition was added 1 eq. K2CO3.
d
f
e
under 10 W 415 nm lamp promoted. under nitrogen atmosphere.
Scheme 2 Substrate scope of thiophenols. aAll reactions were per-
formed with 1a (0.10 mmol), 2 (0.12 mmol), and rose bengal (1 mol%) in
2.0 mL of CH2Cl2, open to air under a 5 W 415 nm lamp at room
temperature for 12 h. bIsolated yields (based on 1a).
g
h
in a vacuum. in the dark. The reaction was performed with 1a (10
mmol), 2a (12 mmol), rose bengal (1 mol%), in 5 mL CH2Cl2, open to
air under a 5 W 415 nm lamp at room temperature for 12 h.
37740 | RSC Adv., 2017, 7, 37739–37742
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Scheme 4 Mechanistic studies.
Scheme 3 Substrate scope of indoles. aUnless otherwise noted, all
reactions were performed with 1 (0.10 mmol), 2a (0.12 mmol), and rose
bengal (1 mol%) in 2.0 mL of CH3CN, open to air under a 5 W 415 nm
lamp at room temperature for 12 h. bIsolated yields (based on 1a).
(3) in good yields (Scheme 3). Either electron-withdrawing
group or electron-donating group at C-4, C-5, C-6, C-7 position
of indoles were reacted with 2a smoothly to give the corre-
sponding products in moderate to good yields 3ba–3ha.
However, 4-nitro-1H-indole (1i) failed to react with 2a and no
desired product was detected. 5-Bromo-1-methyl-1H-indole (1j)
with 2a was examined, providing 3ja in 22% yield. Satisfactorily,
1,2-dimethyl-1H-indole (1k) and 1-methyl-2-phenyl-1H-indole
(1l) were also underwent the reaction with 2a to afford the
desired products 3ka and 3la in 71% and 52% yields.
Scheme 5 Proposed mechanism.
which affords the product 3 via deprotonation. Aerobic oxygen
probably plays a crucial role to complete the photoredox cycle by
oxidation of the RB radical anion to the ground state (Table 1,
entries 14 and 15).18
Several control experiments were conducted to gain more
insight into the mechanism of this unique reaction and the
results are presented in Scheme 4. When 3 equivalents of
2,2,6,6-tetramethylpiperidyl-1-oxyl (TEMPO) or 1,1-diphenyl-
ethylene (DPE), a radical scavenger, were added to the reaction,
no desired product 3aa obtained, however, we detected 1-
methyl-3-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)-1H-indole (4),
2,2,6,6-tetramethyl-1-((p-tolylthio)oxy)piperidine (5) and (2,2-
diphenylethyl)(4-methylphenyl)sulfane (6) by GC-MS (Scheme
4a and b). Moreover, when 1-methyl-1H-indole reacted with
disuldes (7) under standard conditions, the corresponding
product 3aa was obtained in 30% yields (Scheme 4c).
On the basis of above results, a possible mechanism is
proposed in Scheme 5.9b,c First, rose bengal (RB) is excited under
light irradiation to produce its excited state species RB*, which
interacts with O2 to generate 1O2 via the energy transfer. In this
process, the excited state RB* returns to its ground state (RB).18
Subsequently, the generated 1O2 abstracts a hydrogen atom
from thiophenol 1 to afford the thioyl radical A. Next, the
resulting thioyl radical A interacts with 2 to produce the radical
intermediate C. Finally, C is oxidized to the intermediate D,
Conclusions
In conclusion, we have successfully accomplished attractive
strategy for direct assembly of 3-sulfenylindoles via photo-
catalytic direct C-3 sulfenylation of indoles with thiophenols at
mild conditions. A variety of indoles and thiophenols have been
efficiently transformed to structurally diverse products at
room temperature. The reaction uses an inexpensive and
readily available organic dye, rose bengal as the photocatalyst
and air as the terminal oxidant. Moreover, no heavy-metal waste
was generated during the process. It is a practical and
environmentally-benign protocol that could prove useful to the
chemical and pharmaceutical industries.
Experimental
General information
Melting points were measured using a melting point instru-
ment and are uncorrected. 1H and 13C NMR spectra were
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 37739–37742 | 37741

View Article Online
RSC Advances
Paper
recorded on a 400 MHz NMR spectrometer. IR spectra were
obtained with an infrared spectrometer on either potassium
bromide pellets or liquid lms between two potassium bromide
pellets. GC-MS data were obtained using electron ionization.
HRMS was conducted on a high-resolution mass spectrometer.
TLC was performed using commercially available 100–400 mesh
silica gel plates (GF254). The photoreaction instrument (WP-
TEC-1020L) was purchased from WATTCAS, China. Unless
otherwise noted, purchased chemicals were used without
further purication.
5 J. Li, C. Li, S. Yang, Y. An, W. Wu and H. Jiang, J. Org. Chem.,
2016, 81, 2875–2887.
´
6 P. Hamel and P. Preville, J. Org. Chem., 1996, 61, 1573–1577.
7 For reviews, see: (a) Q. Wu, D. Zhao, X. Qin, J. Lan and J. You,
Chem. Commun., 2011, 47, 9188–9190; (b) M. Chen,
Z.-T. Huang and Q.-Y. Zheng, Chem. Commun., 2012, 48,
11686–11688; (c) G. Kumaraswamy, R. Raju and
V. Narayanarao, RSC Adv., 2015, 5, 22718–22723.
8 X. Li, Y. Xu, W. Wu, C. Jiang, C. Qi and H. Jiang, Chem.–Eur.
J., 2014, 20, 7911–7915.
9 For reviews, see: (a) C. C. Browder, M. O. Mitchell,
R. L. Smith and G. el-Sylayman, Tetrahedron Lett., 1993, 34,
6245–6246; (b) W. Ge and Y. Wei, Green Chem., 2012, 14,
2066–2070; (c) P. Sang, Z. Chen, J. Zou and Y. Zhang, Green
Chem., 2013, 15, 2096–2100; (d) X. Zhou and X. Li, RSC
Adv., 2014, 4, 1241–1245.
10 T. Hostier, V. Ferey, G. Ricci, D. G. Pardo and J. Cossy, Chem.
Commun., 2015, 51, 13898–13901.
11 M. Matsugi, K. Gotanda, K. Murata and Y. Kita, Chem.
Commun., 1997, 15, 1387–1388.
12 H. Rao, P. Wang, J. Wang, Z. Li, X. Sun and S. Cao, RSC Adv.,
2014, 4, 49165–49169.
13 C.-R. Liu and L.-H. Ding, Org. Biomol. Chem., 2015, 13, 2251–
2254.
14 H. Qi, T. Zhang, K. Wan and M. Luo, J. Org. Chem., 2016, 81,
4262–4268.
General procedure for the synthesis of 3-sulfenylindoles
derivatives
A mixture of indoles (0.10 mmol), benzenethiols (0.12 mmol),
and rose bengal (1 mol%) was stirred in CH2Cl2 (2.0 mL) under
a 5 W 415 nm lamp in the photoreaction instrument at room
temperature for 12 h. Aer completion of the reaction (moni-
tored by TLC), water (10 mL) was added to the reaction mixture,
and the resulting mixture was extracted with ethyl acetate. The
combined organic layers were then dried over MgSO4, ltered,
and then concentrated in vacuum. The residue was puried by
ash chromatography on silica gel to give the desired product
(using the mixture of petroleum ether and ethyl acetate as
eluents).
15 X. Liu, H. Cui, D. Yang, S. Dai, G. Zhang, W. Wei and
H. Wang, Catal. Lett., 2016, 146, 1743–1748.
Acknowledgements
16 For reviews, see: (a) Y. Maeda, M. Koyabu, T. Nishimura and
S. Uemura, J. Org. Chem., 2004, 69, 7688–7693; (b) Y. Liu,
Y. Zhang, C. Hu, J.-P. Wan and C. Wen, RSC Adv., 2014, 4,
35528–35530; (c) X. Zhang, X. Zhou, H. Xiao and X. Li, RSC
Adv., 2013, 3, 22280–22284; (d) K. M. Schlosser,
A. P. Krasutsky, H. W. Hamilton, J. E. Reed and K. Sexton,
Org. Lett., 2004, 5, 819–821.
We are grateful to the National Natural Science Foundation of
China (21602031 and 21662002), the Advanced Innovation
Research Teams Project of Jiangxi Province (20133BCB24011),
and the Jiangxi Natural Science Foundation (20171BAB203010,
20141BBG70070 and 20151BAB203011).
17 For reviews, see: (a) J.-R. Chen, X.-Q. Hu, L.-Q. Lu and
W.-J. Xiao, Chem. Soc. Rev., 2016, 45, 2044–2056; (b)
J.-R. Chen, X.-Q. Hu, L.-Q. Lu and W.-J. Xiao, Acc. Chem.
Res., 2016, 49, 1911–1923; (c) J. C. Tellis, C. B. Kelly,
D. N. Primer, M. Jouffroy, N. R. Patel and G. A. Molander,
Acc. Chem. Res., 2016, 49, 1429–1439; (d) I. Ghosh,
Notes and references
1 For reviews, see: (a) C. D. Funk, Nat. Rev. Drug Discovery,
2005, 4, 664–672; (b) R. Ragno, A. Coluccia, G. La Regina,
G. De Martino, F. Piscitelli, A. Lavecchia, E. Novellino,
A. Bergamini, C. Ciaprini, A. Sinistro, G. Maga, E. Crespan,
M. Artico and R. Silvestri, J. Med. Chem., 2006, 49, 3172–
3184; (c) G. La Regina, M. C. Edler, A. Brancale, S. Kandil,
A. Coluccia, F. Piscitelli, E. Hamel, G. De Martino,
R. Matesanz, J. F. Diaz, A. I. Scovassi, E. Prosperi,
A. Lavecchia, E. Novellino, M. Artico and R. Silvestri, J.
Med. Chem., 2007, 50, 2865–2874.
2 S. S. Khandekar, D. R. Gentry, G. S. Van Aler, P. Warren,
H. Xiang, C. Silverman, M. L. Doyle, P. A. Chambers,
A. K. Konstantinidis, M. Brandt, R. A. Daines and
J. T. Lonsdale, J. Biol. Chem., 2001, 276, 30024–30030.
3 P. C. Unangst, D. T. Connor, S. R. Stabler, R. J. Weikert,
M. E. Carethers, J. A. Kennedy, D. O. Thueson,
J. C. Chestnut, R. L. Adolphson and M. C. Conroy, J. Med.
Chem., 1989, 32, 1360–1366.
¨
L. Marzo, R. Shaikh and B. Konig, Acc. Chem. Res., 2016,
49, 1566–1577; (e) K. Nakajima, Y. Miyake and
Y. Nishibayashi, Acc. Chem. Res., 2016, 49, 1946–1956; (f)
S. A. Morris, J. Wang and N. Zheng, Acc. Chem. Res., 2016,
49, 1957–1968; (g) T. Koike and M. Akita, Acc. Chem. Res.,
2016, 49, 1937–1945; (h) K. A. Margrey and D. A. Nicewicz,
Acc. Chem. Res., 2016, 49, 1997–2006; (i) Y.-Y. Liu, X.-Y. Yu,
J.-R. Chen, M.-M. Qiao, X. Qi, D.-Q. Shi and W.-J. Xiao,
Angew. Chem., Int. Ed., 2017, 56, 9527–9531; (j)
¨
¨
U. K. Sharma, H. P. L. Gemoets, F. Schroder, T. Noel and
E. V. van der Eycken, ACS Catal., 2017, 7, 3818–3823; (k)
W.-J. Xiao, J.-R. Chen, D.-M. Yan and Q. Wei,
ChemPhotoChem, 2017, 1, 148–158.
18 (a) Q. Shi, P. Li, Y. Zhang and L. Wang, Org. Chem. Front.,
2017, 4, 1322–1330; (b) W. Fan, Q. Yang, F. Xu and P. Li, J.
Org. Chem., 2014, 79, 10588–10592.
4 J. Li, C. Li, S. Yang, Y. An, W. Wu and H. Jiang, J. Org. Chem.,
2016, 81, 7771–7783.
37742 | RSC Adv., 2017, 7, 37739–37742
This journal is © The Royal Society of Chemistry 2017