A facile and general route to 3-((trifluoromethyl)thio)benzofurans and 3-((trifluoromethyl)thio)benzothiophenes

Article abstract of DOI:10.1039/c4cc01904k

A facile and general route to 3-((trifluoromethyl)thio)benzofurans and 3-((trifluoromethyl)thio)benzothiophenes is reported. The reactions of trifluoromethanesulfanylamide with 1-methoxy-2-alkynylbenzenes or methyl(2-alkynylphenyl)sulfanes promoted by BiCl₃ proceed smoothly with broad functional group tolerance. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01904k

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A facile and general route to
3-((trifluoromethyl)thio)benzofurans and
3-((trifluoromethyl)thio)benzothiophenes†
Jie Sheng,‡a Congbin Fan‡a and Jie Wu*ab
Cite this: Chem. Commun., 2014,
50, 5494
Received 14th March 2014,
Accepted 3rd April 2014
DOI: 10.1039/c4cc01904k
www.rsc.org/chemcomm
A facile and general route to 3-((trifluoromethyl)thio)benzofurans introduced as well. For example, trifluoromethanesulfanylamide as
and 3-((trifluoromethyl)thio)benzothiophenes is reported. The an equivalent of the trifluoromethanesulfanyl cation (CF3S+) showed
reactions of trifluoromethanesulfanylamide with 1-methoxy-2- good reactivity for the formation of the C–SCF3 bond.8a
alkynylbenzenes or methyl(2-alkynylphenyl)sulfanes promoted by
BiCl3 proceed smoothly with broad functional group tolerance.
Recently, we developed an efficient method for the preparation
of 3-((trifluoromethyl)thio)indoles via a reaction of 2-alkynylaniline
with trifluoromethanesulfanylamide.9a The transformation might
Natural product-like compounds with privileged structures attract proceed through an indole intermediate via electrophilic substitu-
growing interest in the field of chemical genetics as well as the tion. Due to the structural similarity and our interest in the
process of drug discovery.1 Methodologies development and com- generation of fluorinated molecules, we envisioned that 3-((trifluoro-
binatorial chemistry provide an efficient pathway for gaining access methyl)thio)benzofurans and 3-((trifluoromethyl)thio)benzothio-
to natural product-like compounds. Among the scaffolds, benzo- phenes would be formed as well through a same strategy. However,
furan and benzothiophene are ubiquitous structural motifs found the initial studies for the reaction of 2-alkynylphenol A with
in a large number of biologically important natural products and trifluoromethanesulfanylamide 2 could not afford positive results
pharmaceutics. Molecules with the core structures usually have a (Scheme 1). Only 2-phenylbenzofuran B was obtained instead of the
broad range of biological activities.2 Therefore, continuous efforts desired 3-((trifluoromethyl)thio)benzofuran 3a (Scheme 1, eqn (1)).
have been directed towards the development of efficient construc-
tion of benzofurans and benzothiophenes in organic synthesis and
medicinal chemistry.3
Recently, much attention has been paid to the fluorinated
molecules, and various approaches have been developed for the
introduction of the fluoro atom into small molecules, with the aim
of improving the corresponding biological activities.4,5 Among the
fragments, increasing interest is focused on the (trifluoromethyl)thio
moiety (SCF3) due to its high hydrophobicity.6 So far, some methods
have been developed for the incorporation of the (trifluoromethyl)thio
moiety into small molecules, including nucleophilic trifluoro-
methylthiolation and electrophilic trifluoromethylthiolation.7–9
Several efficient reagents for trifluoromethylthiolation have been
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: +86 21 6510 2412
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032,
China
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H and 13C NMR spectra of compounds 3. See DOI:
Scheme 1 Initial studies on the synthesis of 3-((trifluoromethyl)-
10.1039/c4cc01904k
thio)benzofuran.
‡ J. Sheng and C. Fan contributed equally.
5494 | Chem. Commun., 2014, 50, 5494--5496
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Table
2
Synthesis
of
3-((trifluoromethyl)thio)benzofurans
and
Further exploration revealed that the trifluoromethylthiolation
would not occur through an electrophilic substitution of 2-phenyl-
benzofuran B with trifluoromethanesulfanylamide 2 (Scheme 1,
eqn (2)).
3-((trifluoromethyl)thio)benzothiophenesa
With the above investigation in hand, we considered that the
nucleophilicity of 2-alkynylphenol A would not be suitable for this
transformation. Thus, we began our exploration with the reaction of
1-methoxy-2-alkynylbenzene 1a with trifluoromethanesulfanylamide
2. We expected that the employment of 1-methoxy-2-alkynylbenzene
would facilitate the electrophilic trifluoromethylthiolation first, with
the formation of the benzofuran ring system (Scheme 1). The
preliminary screening results are presented in Table 1. At the outset,
the reaction occurred in the presence of 1.0 equiv. of iron(III)
chloride in DCE at 100 1C (Table 1, entry 1). However, no desired
product was detected. The same result was observed when the Lewis
acid was changed to InCl3, CuCl2, or AgOTf (Table 1, entries 2–4).
Gratifyingly, the desired 3-((trifluoromethyl)thio)benzofuran 3a was
isolated in 34% yield when the reaction was performed with TsOH
as an acid promoter (Table 1, entry 5). The corresponding product
could be obtained as well (25% yield) when BiCl3 was used as a
replacement (Table 1, entry 6). The yield was increased to 54% when
2.0 equiv. of TsOH was employed in the reaction (Table 1, entry 7).
No desired product was formed when the reaction was performed in
DMF or DMA (Table 1, entries 8 and 9). A lower yield was obtained
when the solvent was changed to toluene or MeCN (Table 1, entries
10 and 11). A trace amount of product was detected when THF was
employed as the solvent (Table 1, entry 12). The results were inferior
a
Isolated yield based on 2-alkynylbenzene 1.
when the reaction temperature decreased (Table 1, entries 13 and However, the yield was lowered to 54% when 1.5 equiv. of BiCl3
14). We also examined the reaction in the presence of 2.0 equiv. of was employed (Table 1, entry 18). It is undoubtedly that trifluoro-
BiCl3 at 100 1C (Table 1, entry 15). To our delight, the expected methanesulfanylamide 2 would be activated by bismuth(III) chloride
product 3a was furnished in 87% yield. A similar result was to release the trifluoromethanesulfanyl cation. We reasoned that the
obtained when the reaction occurred at 85 1C (Table 1, entry 16). presence of the heteroatom in the reaction system would deactivate
the role of bismuth(III) chloride. Thus, 2.0 equiv. of bismuth(III)
chloride was essential for this transformation. It is interesting that
Table 1 Initial studies on the reaction of 1-methoxy-2-alkynylbenzene 1a
the reaction could occur under an air atmosphere without the loss
of efficiency.
with trifluoromethanesulfanylamide 2
After obtaining the above optimized reaction conditions
(2.0 equiv. of BiCl3, DCE, 85 1C, air), we next explored the generality
of the trifluoromethylthiolation reaction of 1-methoxy-2-alkynyl-
benzenes 1 with trifluoromethanesulfanylamide 2. The results are
summarized in Table 2. For most cases, all reactions worked well,
giving rise to the expected 3-((trifluoromethyl)thio)benzofurans in
good yields. For example, the reactions proceeded efficiently when
various 1-methoxy-2-alkynylbenzenes 1 with aryl or alkyl substituents
attached on the triple bond reacted with trifluoromethanesul-
fanylamide 2. However, the reaction failed when ((2-methoxy-
phenyl)ethynyl)trimethylsilane was employed as a substrate in the
transformation. Reactions of 1-methoxy-2-alkynylbenzenes 1 with
different substituents (chloro, nitro, and methoxy) on the aromatic
ring were explored in the meantime. It was noteworthy that the nitro-
substituted 1-methoxy-2-alkynylbenzene was a suitable reactant as
well under the standard conditions, leading to the desired product 3j
in 80% yield. We further applied this method for the synthesis of
3-((trifluoromethyl)thio)benzothiophenes under the same conditions
through a reaction of trifluoromethanesulfanylamide with methyl-
(2-alkynylphenyl)sulfanes. Again, the conditions were demonstrated
Entry
Acid
Solvent
T (1C)
Yielda (%)
1
2
3
4
5
6
7
8
FeCl3 (1.0 equiv.)
InCl3 (1.0 equiv.)
CuCl2 (1.0 equiv.)
AgOTf (1.0 equiv.)
TsOHÁH2O (1.0 equiv.)
BiCl3 (1.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
TsOHÁH2O (2.0 equiv.)
BiCl3 (2.0 equiv.)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
DMA
Toluene
MeCN
THF
DCE
DCE
DCE
DCE
DCE
DCE
100
100
100
100
100
100
100
100
100
100
100
100
85
0
0
0
0
34
25
54
nd
nd
43
25
Trace
31
Trace
87
88
72
54
9
10
11
12
13
14
15
16
17
18
50
100
85
80
85
BiCl3 (2.0 equiv.)
BiCl3 (2.0 equiv.)
BiCl3 (1.5 equiv.)
a
Isolated yield based on 1-methoxy-2-(2-phenylethynyl)benzene 1a.
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In conclusion, we have described a facile and general route
to 3-((trifluoromethyl)thio)benzofurans and 3-((trifluoromethyl)-
thio)benzothiophenes via a reaction of trifluoromethanesulfanyl-
amide with 1-methoxy-2-alkynylbenzenes or methyl(2-alkynyl-
phenyl)sulfanes. The reaction proceeds smoothly promoted by
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