Transition-metal- and phosphorus-free electrophilic trifluoromethylthiolation of indoles with sodium trifluoromethanesulfinates in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2021.153015

An acid-promoted protocol has been developed to achieve the transition-metal- and phosphorus-free electrophilic trifluoromethylthiolation of indoles using sodium trifluoromethanesulfinates in an imidazolium-based ionic liquid ([Hmim]Br). [Hmim]Br not only acts as a recyclable solvent, but also as the reductant in this transformation. The advantages of this chemistry include simple operation, use of a recyclable solvent, avoidance of transition-metal and phosphorus, and gram-scale synthesis.

Full text of DOI:10.1016/j.tetlet.2021.153015

Tetrahedron Letters 70 (2021) 153015
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition-metal- and phosphorus-free electrophilic
trifluoromethylthiolation of indoles with sodium
trifluoromethanesulfinates in ionic liquids
⇑
Fei Wang, Guo-Ping Lu, Yamei Lin
School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An acid-promoted protocol has been developed to achieve the transition-metal- and phosphorus-free
electrophilic trifluoromethylthiolation of indoles using sodium trifluoromethanesulfinates in an imida-
zolium-based ionic liquid ([Hmim]Br). [Hmim]Br not only acts as a recyclable solvent, but also as the
reductant in this transformation. The advantages of this chemistry include simple operation, use of a
recyclable solvent, avoidance of transition-metal and phosphorus, and gram-scale synthesis.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 2 February 2021
Revised 11 March 2021
Accepted 16 March 2021
Available online 23 March 2021
Keywords:
Electrophilic trifluoromethylthiolation
Indole
Sodium trifluoromethanesulfinates
Imidazolium-based ionic liquid
Introduction
catalyst is necessary. Therefore, further exploration of reaction
conditions for direct trifluoromethylthiolation using SO2CF3-based
Trifluoromethyl sulfides (CF3SR) are widespread in various
pharmaceuticals, agrochemicals, and functional materials due to
their electron-withdrawing effects and extremely high lipophilic-
reagents is still of great importance.
On the other hand, imidazolium-based ionic liquids (ILs) exhibit
several notable properties, such as hydrogen bonding [8], self-
assembly [9] and significant solvation potential [10], which may
help promote transformations when used as solvents or catalysts
[11]. Although imidazolium-based ILs may cause potential envi-
ronmental issues [12], they represent greener alternatives to
organic solvents due to their negligible vapour pressure, non-
flammability and recyclability [13].
Recently, our group has developed a novel acid-induced proto-
col for the chemoselective arylthiolation of electron-rich arenes
using sodium arylsulfinates, in which imidazolium-based ILs play
a dual role (solvent and reducer) [14]. Along this line, we reasoned
that CF3SO2Na could be used as an analog of sodium arylsulfinate
in ILs to achieve the transition-metal- and phosphorus-free elec-
trophilic trifluoromethylthiolation of indole derivatives.
ity (p = 1.44) [1]. Thus, various strategies have been reported for
the trifluoromethylthiolation of organic compounds, especially
aromatic derivatives [2]. Among them, the direct trifluo-
romethylthiolation using SO2CF3-based reagents has become one
of the most efficient methods, since most SO2CF3-based reagents
are stable and easy-to-handle [3]. In 2015, our group first reported
the application of CF3SO2Na for direct introduction of the -SCF3
group into indoles [4a]. Since then, increased attention has been
paid to the direct trifluoromethylthiolation of organic compounds
using SO2CF3-based reagents [3,4]. However, these approaches typ-
ically require stoichiometric amounts of toxic phosphorous
reagents (Scheme 1a) [4,5]. Tf2O was employed to initiate the
disproportionation of CF3SO2Na, generating the ‘‘CF3S+” species
in situ for the direct trifluoromethylthiolation in the absence of
phosphorous reagents (Scheme 1b) [6]. Based on this work, a
new SO2CF3-based reagent, TfNHNHBoc, was developed for direct
trifluoromethylthiolation, which can form trifluoromethylthiola-
tion species via a self-redox process (Scheme 1c) [7]. Nevertheless,
TfNHNHBoc requires pre-preparation, and the use of a copper
Results and discussion
Initially, we examined the model reaction of indole 1a and
CF3SO2Na 2 under various conditions (Table 1). As expected, the
desired product 3a was obtained in [Hmim]Br under acidic condi-
tions (Entry 2), and no reaction took place without the acid (Entry
1). After screening different acids, HCl emerged as the best option
(Entries 2–8). Other organic solvents were also used (Entries 9–16),
⇑
Corresponding author.
E-mail address: linyamei1992@126.com (Y. Lin).
https://doi.org/10.1016/j.tetlet.2021.153015
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

F. Wang, Guo-Ping Lu and Y. Lin
Tetrahedron Letters 70 (2021) 153015
With the optimized reaction conditions in hand, a series of
indole derivatives were examined to establish the scope and gen-
erality of this protocol (Table 2). The trifluoromethylthiolation
reaction selectively occurred at 3-position of indole derivatives
containing methyl (3b-f), methoxy (3g), halogen (3i-l), nitro
(3m) and benzyloxy (3h) groups. It can be observed that elec-
tron-donating and electron-withdrawing substituents did not sig-
nificantly affect the trifluoromethylthiolation of indoles (3b-m).
It was also found that the position of the substituents did not sig-
nificantly affect the yields (3c-f), except in the case of 3b, which is
due to the increased steric hindrance. Furthermore, N-substituted
indoles with alkyl groups gave moderate yields (3n and 3o).
Other substrates such as 2-naphthol and acetophenone were
also employed (Scheme 2). Only the brominated product was
observed in the case of 2-naphthol (eq. 1), while both brominated
and trifluoromethylthiolated products were obtained using ace-
tophenone (eq. 2). These results were evidence for the generation
of bromine during the reaction [14]. The yield did not decrease
when two equivalents of the radical inhibitor TEMPO was added
to the reaction (eq. 3), suggesting that the transformation does
not involve a radical process [16].
According to these experiments and previous reports [4,14], a
tentative mechanism was proposed (Scheme 3). Firstly, trifluoro-
sulfinic acid derived from 2 under acidic conditions is further
reduced by the acid and bromide anion to give 11 (path A)
[4a,14]. Intermediate 11 can undergo electrophilic substitution
with indoles to form 3-trifluoromethylthioindoles as the major
pathway. Enhancement of the [Hmim]Br cation may be attributed
to the formation of hydrogen bonds between the C-2 hydrogen and
X (Br, OSO2CF3), and the charge-charge interaction of the quater-
nary nitrogen atom and X, resulting in electrophilic activation of
the S-X bond [11,17]. Moreover, arylsulfinic acid can also afford
electrophilic sulfur intermediate 13 through dehydrative
Scheme 1. Selected methods for the trifluoromethylthiolation of indoles or arenes.
but the results were unsatisfactory, which verified the necessity of
[Hmim]Br. Different anions of the IL had an obvious influence on
the reaction. No product was afforded in case of [Hmim]Cl due to
the poor reducing capacity of ClÀ (Entry 17). A much lower yield
was observed in [Hmim]I (Entry 18). Although IÀ has stronger
reducing capacity than BrÀ, the in situ generated ‘‘CF3SI” may be
too reactive to form the desired products [15].
Table 1
Optimization of the reaction conditions.a
Entry
Acid
Solvent
Temp
Time
Yield 3a (%)b
1
2
3
4
5
6
7
8
–
HCl
[Hmim]Br
[Hmim]Br
[Hmim]Br
[Hmim]Br
[Hmim]Br
[Hmim]Br
[Hmim]Br
[Hmim]Br
Toluene
THF
DMSO
DMF
Dioxane
DCE
EtOH
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
5 h
0
93 (88)c
HCOOH
TsOHÁH2O
HOAc
H2C2O4Á2H2O
H2SO4
CH3SO3H
HCl
HCl
HCl
HCl
HCl
0
76
0
88
85
69
41
0
46
0
0
3
0
9
10
11
12
14
15
16
17
18
HCl
HCl
HCl
HCl
[Hmim]Cl
[Hmim]I
0
35
a
b
c
Reagents and conditions: 1a (0.25 mmol), 2 (0.30 mmol), solvent (0.5 mL), acid (2 equiv.).
Yields were determined by GC analysis using anisole as the internal standard.
Isolated yield.
2

F. Wang, Guo-Ping Lu and Y. Lin
Tetrahedron Letters 70 (2021) 153015
Table 2
Trifluoromethylthiolation of indoles in [Hmim]Br. Reagents and conditions: 1 (0.25 mmol), 2 (0.30 mmol), [Hmim]Br (0.5 mL), HCl (2 equiv.), 60 °C, 5 h. Isolated yields.
Scheme 2. Control experiments for the mechanistic study.
condensation and tautomerism (path B) [18], which can also react
with indoles to form the desired product as the minor pathway.
This result may explain why the reaction still occurs in the absence
of BrÀ with poor yields (Table 1, entries 9 and 11).
Finally, in order to examine the scalability of this protocol, the
reaction of indole 1a and CF3SO2Na 2 was conducted on a 10 mmol
scale, affording the desired product 3a in 85% yield. Meanwhile,
investigations were also conducted to test the recyclability of
[Hmim]Br. After reaction completion, an in-flask extraction using
minimum amounts of MTBE was conducted to obtain the desired
product. The ionic liquid recovered by extraction (after separation
of the MTBE phase, the residual is the ionic liquid) was reused in
3

F. Wang, Guo-Ping Lu and Y. Lin
Tetrahedron Letters 70 (2021) 153015
Scheme 3. Tentative pathway for the trifluoromethylthiolation of indoles in [Hmim]Br.
iolation of indole derivatives using CF3SO2Na in [Hmim]Br. [Hmim]
Br acts as reducing agent under acidic conditions to reduce CF3SO2-
Na to the ‘‘CF3S+” species. The advantages of this chemistry are sim-
ple operation, gram-scale synthesis and recyclable solvents.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgement
This work was supported by the National Natural Science Foun-
dation of China (grant number: 32001266).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153015.
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