Facile syntheses of 3-trifluoromethylthio substituted thioflavones and benzothiophenes via the radical cyclization

Article abstract of DOI:10.1016/j.cclet.2020.02.040

3-CF₃S substituted thioflavones and benzothiophenes were achieved via the reactions of AgSCF₃ with methylthiolated alkynones and alkynylthioanisoles, respectively, promoted by persulfate. This protocol possesses good functional group tolerance and high yields. Mechanistic studies suggested that a classic two-step radical process was involved, which includes addition of CF₃S radical to triple bond and cyclization with SMe moiety.

Full text of DOI:10.1016/j.cclet.2020.02.040

Journal Pre-proof
Facile syntheses of 3-trifluoromethylthio substituted thioflavones and
benzothiophenes via the radical cyclization
Lu Wang, Huaiyu Wang, Weidong Meng, Xiu-Hua Xu, Yangen
Huang
PII:
S1001-8417(20)30100-5
https://doi.org/10.1016/j.cclet.2020.02.040
CCLET 5481
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Chinese Chemical Letters
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Revised Date:
Accepted Date:
19 January 2020
6 February 2020
20 February 2020
Please cite this article as: Wang L, Wang H, Meng W, Xu X-Hua, Huang Y, Facile syntheses
of 3-trifluoromethylthio substituted thioflavones and benzothiophenes via the radical
cyclization, Chinese Chemical Letters (2020), doi: https://doi.org/10.1016/j.cclet.2020.02.040
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Chinese Chemical Letters
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Communication
Facile syntheses of 3-trifluoromethylthio substituted thioflavones and
benzothiophenes via the radical cyclization
Lu Wanga, Huaiyu Wanga, Weidong Menga, Xiu-Hua Xub, Yangen Huanga, 
a Key Laboratory of Science and Technology of Eco-Textiles, Ministry of Education, College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, Shanghai 201620, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Graphical Abstract
An efficient and practical protocol for preparation of 3-CF3S substituted thioflavones and benzothiophenes was developed. This
protocol possesses good functional group tolerance and high yields. Mechanistic studies suggested that a classic two-step radical
addition and cyclization process was involved.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
3-CF3S substituted thioflavones and benzothiophenes were achieved via the reactions of
AgSCF3 with methylthiolated alkynones and alkynylthioanisoles, respectively, promoted by
persulfate. This protocol possesses good functional group tolerance and high yields.
Mechanistic studies suggested that a classic two-step radical process was involved, which
includes addition of CF3S radical to triple bond and cyclization with SMe moiety.
Available online
Keywords:
Trifluoromethylthiolation
Radical cyclization
Thioflavone
Benzothiophene
Methylthiolated alkynone
Alkynylthioanisole
Organosulfur heterocycles are important compounds due to
their unique physical properties and versatile biological activity.
Thioflavones and benzothiophenes are two class of representative
pharmaceuticals,
functional
materials,
and
synthetic
intermediates [1-7]. Studies have shown that thioflavones are
easy to pass through the cell membrane of fungi, changing the
ultrastructure of fungal cells, thereby exhibit antibacterial [8] and
o—rg—ano—sulfur heterocycles, and have been widely used as
 Corresponding author.
E-mail address: hyg@dhu.edu.cn

antiviral activities [9]. So the development of efficient synthetic
methods for construction of thioflavone and benzothiophene
skeletons has retained the interest of organic researchers along
decades of historical development of chemistry [10,11]. For
instance, Schneller's group reported the synthesis of thioflavones
by reacting thiophenols and keto esters in 1975 [12]. In 2014,
Seijiro’s group developed a nickel-catalyzed decarbonylative
cyclo-addition reaction of thioisatins and alkynes to form
thioflavones [13,14]. In 2009, Takimiya's group reported a one-
pot procedure for the synthesis of benzothiophene derivatives
from readily available o-halo-ethynylbenzene precursors [15].
Nowadays, radical cascade reactions have become one of the
most efficient synthetic strategy for the construction of
organosulfur heterocycles. Thereinto, thioanisole derivatives
have been widely used in the radical cyclization process with the
release of a methyl group for the construction of thioflavone and
benzothiophene skeletons. Most recently, Song and co-workers
reported a radical-promoted cyclization of methylthiolated
alkynones with diverse radical precursors, and allows an efficient
synthesis of a variety of phosphoryl-, sulfenyl-, EtOOCCF2-, and
acyl-containing thioflavone derivatives under mild conditions
(Scheme 1) [16]. Methylthiolated alkynones can also be
transferred into 3-aryl [17] and 3-phosphorylated [18]
thioflavones by visible-light induced radical reactions with
arenediazonium salts and phosphine oxides, respectively. On the
other hand, 2-alkynylthioanisoles as versatile building blocks
have been widely used in the synthesis of 3-substituted
benzothiophenes [19-28].
target molecules have attracted much attentions in the field of
organic chemistry [31-33]. To date, through the efforts of
chemists, direct trifluoromethylthiolation to construct C-SCF3 has
achieved rapid development [34-36]. According to the source of
trifluoromethylthio group, the direct trifluoromethylthiolation is
classified into nucleophilic, electrophilic and free radical
pathways [37-54]. In 2014, Wu and co-workers synthesized
several 3-trifluoromethylthiobenzothiophenes through the
reactions
of
trifluoromethanesulfanylamide
with
2-
alkynylthioanisoles promoted by BiCl3 [52]. As part of our
ongoing interest in development of synthetic methods for
fluorinated compounds, we envisioned that 3-trifluoromethylthio
substituted thioflavones and benzothiophenes can be constructed
by a radical addition of trifluoromethylthio radical (CF3S·)
generated from AgSCF3 to methylthiolated alkynones and 2-
alkynylthioanisoles, respectively, followed by an intramolecular
radical cyclization reaction (Scheme 1).
Initially, tert-butyl hydroperoxide (TBHP) or benzoyl peroxide
(BPO) was chosen as the oxidant, and the reaction of 1-(2-
(methylthio)phenyl)-3-phenylprop-2-yn-1-one (1a) with AgSCF3
(2) was conducted in the presence of AgNO3 in CH3CN. But no
desired 3-CF3S substituted thioflavone 3a was detected (Table 1,
entries 1 and 2). When K2S2O8 was chosen as an oxidant, 3a was
formed in 60% yield in the presence of AgNO3 (Table 1, entry 3).
However, the yield of 3a was slightly increased in the absence of
AgNO3, which indicated that extra transition metal catalyst was
not necessary for this reaction (Table 1, entry 4).
Table 1
For example, Wu and co-workers disclosed a radical relay
Optimization of the reaction conditions.a
strategy
for
the
preparation
of
3-
(methylsulfonyl)benzothiophenes through
a
reaction of 2-
alkynylthioanisoles with sodium metabisulfite (Scheme 1) in the
presence of a photocatalyst under visible light irradiation [29].
Gao and co-workers developed a direct synthetic method for 3-
phosphinoylbenzothiophenes through an Ag-mediated radical
addition−cyclization of 2-alkynylthioanisoles with secondary
phosphine oxides [20].
Entry Ag salt
Oxidant
Temp
(oC)
80
80
80
80
80
80
80
80
90
70
80
80
80
Solvent
Yield
(%)b
0
1
2
3
AgNO3
AgNO3
AgNO3
—
TBHP
BPO
K2S2O8
K2S2O8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
CH3CN/H2O
DMSO/H2O
0
60
67
65
75
67
57
63
46
54
18
25
4
5
—
Na2S2O8
6
—
—
—
—
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
7c
8 d
9
10
11
12 e
—
—
—
—
13 f
a
Unless otherwise specified, the reactions were carried out in the
presence of 1a (0.2 mmol), 2 (0.4 mmol), oxidant (0.3 mmol),
solvents (2.0 mL), N2, 80 °C, 12 h.
b
Yields were determined by 19F NMR spectroscopy using
trifluoromethylbenzene as an internal standard.
c oxidant (0.2 mmol).
d oxidant (0.4 mmol).
e CH3CN/H2O = (1 mL/1 mL).
f DMSO/H2O = (1 mL/1 mL).
Scheme 1. Syntheses of 3-substituted thioflavones and
benzothiophenes.
Other persulfate as an oxidant was then screened (Table 1,
entries 5 and 6), and the results indicated that (NH4)2S2O8 was the
best choice affording the desired product 3a in 75% yield (Table
1, entry 6). The amount of (NH4)2S2O8 was then adjusted, and the
results revealed that 1.5 equiv. of oxidant was optimal (Table 1,
entries 7 and 8). The yield of product 3a was decreased when the
At the meantime, the special properties of trifluoromethylthio
group have led to the widespread use of trifluoromethylthio-
containing compounds in many fields, particularly in
pharmaceutical and pesticide chemistry [30]. The development of
efficient methods for introducing trifluoromethylthio groups into

o
o
reaction temperature was increased to 90 C or reduced to 70 C
(Table 1, entries 9 and 10). Subsequently, different solvents were
investigated, and no better yield was observed when the reaction
was carried out in different solvents other than CH3CN (Table 1,
entries 11-13).
substituents, such as cyano, trifluoromethyl and nitro groups,
were also compatible with the reaction, affording the desired
products 3l-3o in yields of 60%-75%. Notably, formyl group as
an electron-withdrawing substituent suppressed the radical
cyclization significantly due to its high reactivity to radicals [55],
the desired product 3p was obtained only in yield of 30%.
Substituent such as bromine group at the R2 position were also
amenable for this reaction, affording 3q in 65% yield.
Additionally, the thiophenyl group could be tolerated as well
under the reaction conditions, and the corresponding products 3r
and 3s were obtained in 61% and 57% yields, respectively. The
structure of thioflavone 3i was further unambiguously established
by X-ray diffraction studies. The supplementary crystallographic
data can be obtained free of charge from The Cambridge
Cryatallographic Data Center (CCDC No. 1968769).
With the optimized reaction conditions in hand (Table1, entry
6), the efficiency and generality of this reaction was explored,
and the results were presented in Scheme 2. The R1 group on the
benzene ring of alkynones was first investigated and most of the
functional groups were tolerated under the optimized conditions.
With electron-donating substituents at the R1 position, such as
methyl, methoxy, tert-butyl, and phenyl groups, products 3b-3f
were obtained in yields of 55%-67%. Halogen atoms such as
fluorine, chlorine, and bromine have little influences under the
optimized reaction conditions to afford the corresponding
products 3g-3k in moderate yields. Electron-withdrawing
Scheme 2. Synthesis of 3-CF3S substituted thioflavones. Reaction conditions:
CH3CN (5 mL), 80 , N2, 12 h. Isolated yields.
1 (0.5 mmol), 2 (1.0 mmol), (NH4)2S2O8 (0.75 mmol),
℃
With the above investigation in hand, we assumed that the 2-
alkynylthioanisoles would also be suitable for this transformation
to afford 3-CF3S substituted benzothiophenes. Thus, the
exploration of the reaction of 2-alkynylphenylmethylsulfides 4
and AgSCF3 (2) was conducted. The optimal reaction conditions
were slightly adjusted with K2S2O8 instead of (NH4)2S2O8 as the
oxidant and CH3CN/H2O as a mixed solvent (Supporting
information). As shown in Scheme 3, the reactions of 2-
alkynylphenylmethylsulfides with an electron-donating group at
R3 position proceeded smoothly to provide the corresponding
products 5a-5e in moderate to good yields. Several sensitive
functional groups such as fluoro, chloro, bromo, trifluoromethyl,
ester, nitro, cyano, and formyl groups were all compatible. For
example, the formyl-containing product 5m was produced in
47% yield. Additionally, methyl substituent at the meta-position
of the right benzene ring also presented good reactivity, and the
corresponding product 5n was obtained in 80% yield. Then,
different substituents on the benzene ring of 2-methylthio-
arylalkyne were studied. To our delight, the electronic effects of
substituents including methyl, methoxy, trifluoromethoxy, chloro
and bromo have no significant influence on the yields of the
products, and the expected benzothiophenes 5o-5u were
generated in 50%-86% yields. Furthermore, the thiophenyl group
could be tolerated as well under the reaction conditions, and the
corresponding products 5v and 5w were generated in 65% and
67% yield, respectively. Compared to Wu’s protocol reported in
2014 [52], the CF3S source was different and wider substrate
scope was investigated in this methodology.

Scheme 5. Proposed mechanism.
In summary, we have developed an efficient method for
synthesis of 3-trifluoromethylthioflavones through a radical
addition and cyclization of methylthio substituted arylalkynyl
ketones with AgSCF3. Besides, a facile and general route to 3-
trifluoromethylthiobenzothiophenes via
a
reaction of 2-
alkynylphenylmethylsulfides and AgSCF3 was described. These
protocols featured simple operation, mild conditions, good
functional group tolerance and high yields.
Declaration of interests
Scheme 3. Synthesis of 3-CF3S substituted benzothiophenes.
Reaction conditions: 4 (0.5 mmol), 2 (1.0 mmol), K2S2O8 (0.75
The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
mmol), CH3CN/H2O (v/v = 3:3, 6 mL), 70
℃ , 12 h. Isolated yields.
With a radical process hypothesized, control experiments
were carried out to gain the detailed reaction mechanism. As
demonstrated in Scheme 4, the formation of 3a or 5a was
completely suppressed after adding 2,2,6,6-tetramethylpiperidine
oxide (TEMPO) as a free radical scavenger, and a large amount
of starting material 1a or 4a was recovered from the reaction
system (Scheme 4, a and b). This result indicated that a radical
process might be involved in this reaction. In order to verify
whether CF3S radical participated in the reaction, F3CSSCF3 was
prepared from AgSCF3 and then reacted with 1a. The formation
of product 3a was detected in a yield of 60%, which confirmed
that CF3S radical was participated in the reaction (Scheme 4, c).
Acknowledgment
We thank the National Natural Science Foundation of China
(Nos. 21991123, 21677094) for financial support.
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