Generation of trifluoromethyl thiolsulphonate through one-pot reaction of sulfonyl chloride and trifluoromethanesulfanylamides

Article abstract of DOI:10.1016/j.tetlet.2017.01.018

A novel and efficient tandem reaction of sulfonyl chloride and trifluoromethylsulfanylamide is described here for the synthesis of various trifluoromethyl thiolsulphonates with a broad functional group tolerance. In the process, it is believed that sulfinate generated from sulfonyl chloride is a critical intermediate and the additive 4-methylbenzenesulfonic acid (p-TsOH) facilitates the formation of “CF₃S⁺”. Electrophilic trifluoromethylthiolation of in situ generated sulfinate and “CF₃S⁺” provides the final products.

Full text of DOI:10.1016/j.tetlet.2017.01.018

Accepted Manuscript
Generation of Trifluoromethyl Thiolsulphonate Through One-pot Reaction of
Sulfonyl Chloride and Trifluoromethanesulfonanylamides
Yuewen Li, Guanyinsheng Qiu, Hailong Wang, Jie Sheng
PII:
S0040-4039(17)30030-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.018
TETL 48521
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
31 December 2016
6 January 2017
Please cite this article as: Li, Y., Qiu, G., Wang, H., Sheng, J., Generation of Trifluoromethyl Thiolsulphonate
Through One-pot Reaction of Sulfonyl Chloride and Trifluoromethanesulfonanylamides, Tetrahedron Letters
(2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.018
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Generation of Trifluoromethyl
thiolsulphonates Through One-pot Reaction
of Sulfonyl Chloride and
Leave this area blank for abstract info.
Trifluoromethanesulfanylamide
Yuewen Li, Guanyinsheng Qiu*, Hailong Wang, and Jie Sheng*

1
Tetrahedron Letters
Generation of Trifluoromethyl Thiolsulphonate Through One-pot Reaction of
Sulfonyl Chloride and Trifluoromethanesulfonanylamides
Yuewen Li,a Guanyinsheng Qiu,a  Hailong Wang,a and Jie Sheng,b
a College of Biological, Chemical Science and Engineering, Jiaxing University, 118 Jiahang Road, Jiaxing 314001, China.
b College of Food Sciencee and Technology, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and efficient tandem reaction of sulfonyl chloride and trifluoromethylsulfanylamide is
described here for the synthesis of various trifluoromethyl thiolsulphonates with a broad
functional group tolerance. In the process, it is believed that sulfinate generated from sulfonyl
chloride is a critical intermediate and the additive 4-methylbenzenesulfonic acid (p-TsOH)
facilitates the formation of "CF3S+". Electrophilic trifluoromethylthiolation of in situ generated
sulfinate and "CF3S+" provides the final products.
Available online
Keywords:
Sulfinate
2009 Elsevier Ltd. All rights reserved.
Electrophilic trifluoromethylthiolation
Trifluoromethanesulfanylamide
Trifluoromethyl thiolsulphonate
Tandem reaction
It was generally accepted that organic fluorine chemistry was
one of the hottest fields in organic chemistry.1-5 Consequently,
tremendous efforts were made on introducing fluoro-containing
building blocks into final products, and an unprecedented
progress on fluorine chemistry (especially, synthetic fluorine
chemistry) has been achieved so far.2 Among these established
achievements, it's well-known that trifluoromethylthiolation
could be reached through three major pathways, which were
generally concluded as electrophilic trifluoromethylthiolation,3
resorted to the use of moisture-sensitive zinc sulfinate and toxic
"CF3S" reagents (such as CF3SCl).6b Its generality and
application on synthetic chemistry was thus restricted, perhaps
because the availability of sulfinates was commercially
inadequate and the nature of trifluoromethylthiolating reagent
was toxic. To date, it remained rare that the synthesis of
trifluoromethyl thiolsulphonate was realized from simple
substrates under mild conditions. Considering its great
application potential, it's highly desirable to develop a mild
procedure for the synthesis of trifluoromethyl thiolsulphonate
with high efficiency.
nucleophilic
trifluoromethylthiolation,4
and
radical
trifluoromethylthiolation,5 respectively. Interestingly, a particular
emphasis was put on incorporating "CF3S" motif into organic
molecules by electrophilic trifluoromethylthiolation, probably
attributing
to
its
abundant
accessibility
of
trifluoromethylthiolating reagents (Figure 1).
As a privileged core, trifluoromethyl thiolsulphonate was a
kind of important compounds in medicinal chemistry due to its
potential bioactivity against fungal infections.6 According to the
findings from Weidner and co-workers, trifluoromethyl
thiolsulphonate showed much higher antifungal activity than that
of alkyl, aryl, and trichloromethyl thiolsulphonates,
respectively.6a Traditionally, synthesis of this useful architecture
Figure 1 Electrophilic trifluoromethylthiolating reagents
 G. Qiu, Tel.: +86-0573-83642057; fax: +86-0573-83642057; e-mail: 11110220028@fudan.edu.cn
 J. Sheng, Tel.: +86-021-88120380; fax: +86-021-88120380; e-mail: jsheng@shou.edu.cn

2
Tetrahedron Letters
To verify possibility of this tandem process, the reaction of
phenyl sulfonyl chloride 1a and N-phenyl-S-(trifluoromethyl)
thiohydroxylamine 2a was selected as model reaction. To the
best of our knowledge, sulfinate salt could be derived from
o
sulfonyl chloride and sodium sulfite (Na2SO3) in water at 80 C
with extremely high efficiency. As a result, herein in situ
generation of sulfinate was not optimized. After evaporation of
the solvent H2O, the in situ generated sulfinate was directly
employed into the sequential step without further purification.
During the reaction optimization, we were pleased to find that the
reaction of in situ generated sulfinate and 2a gave rise to a
desired product 3a in 48% isolated yield when the reaction was
treated with an additive bismuth chloride (BiCl3, 2.5 equiv) at 80
oC in acetonitrile (entry 1, table 1). Change of the additive to
FeCl3 and BF3.Et2O was not favorable for the formation of 3a
(entries 2-3, table 1). According to the previous findings from
Shen's group, it seemed that protonic acid could promote
electrophilic trifluoromethylthiolation of sulfinate. Consequently,
acetic acid and 4-methylbenzenesulfonic acid (p-TsOH) were
used as the additive. To our delight, the use of p-TsOH greatly
improved the reaction efficiency, leading to the final product 3a
in 70% yield (entry 5, table 1). A control experiment without the
additive implied that the additive was pivotal for the formation of
the final product 3a (entry 1, table 1). We then explored the
solvent effect. Pleasingly, the use of 1, 2-dichloroethane
improved the yield to 79% (entry 7, table 1). Other solvents such
as toluene, N, N-dimethylamide, tetrahydrofuran, and dimethyl
sulfoxide did not provide better results (entries 8-11, table 1).
Decrease of reaction temperature facilitated the reaction. For
example, the reaction afforded the final product 3a in 85% yield
Scheme 1 Proposed route for the synthesis of trifluoromethyl
thiolsulphonates via electrophilic trifluoromethylthiolation
Starting from aniline, an elegant protocol was highlighted by
our group for the preparation of trifluoromethyl thiolsulphonate
(Scheme 1a).7 Distinctively, sulfonyl group in trifluoromethyl
thiolsulphonate was installed through reductive insertion of
sulfur dioxide. In the process, a tandem pathway involving
diazotization of aniline, radical sulfur dioxide fixation, and
electrophilic trifluoromethylthiolation contributed to providing
trifluoromethyl thiolsulphonate. Based on the results from control
experiments, sulfinate was postulated as a critical intermediate.
Unfortunately, our methodology mentioned above always
suffered from relatively low reaction efficiency, thus producing
trifluoromethyl thiolsulphonate in moderate yields. Besides,
heteroaryl-connected trifluoromethyl thiolsulphonate was not
achieved by this strategy. As a consequence, to modify this
protocol is highly desirable for improving reaction efficiency and
widening reaction scope (especially for heteroaryl-substituted
substrate). As a part of our program on constructing a library of
potential bioactive molecules with privileged structural core
through tandem reaction8 and in light of rich commercial
availability of sulfonyl chloride, we would like to explore
preparation of trifluoromethyl thiolsulphonate from sulfonyl
chloride by a tandem reaction strategy.
From our previous result and Shen's work, it's well-known that
the sulfinate-based electrophilic trifluoromethylthiolation can
produce trifluoromethyl thiolsulphonate with high efficiency.
Acceptably, sulfonyl chloride could offer sulfinate by means of a
Na2SO3-based reduction.9 Therefore, it seemed rationally reliable
that in situ generation of sulfinate from sulfonyl chloride and
electrophilic trifluoromethylthiolation could be combined in an one-
pot fashion for the synthesis of trifluoromethyl thiolsulphonate
(Scheme 1b). Compared to our previous findings described in
Scheme 1a, this projected protocol avoided the use of Lewis acid
(bismuth chloride) and reaction operation was relatively practical.
More importantly, this tandem process was herein performed
with an aim to address the two unsettled issues (reaction
efficiency and reaction scope) mentioned in Scheme 1a for the
synthesis of trifluoromethyl thiolsulphonate. Considering our
continuous interests in smuggling "CF3S" group in the final
product using N-SCF3 reagent,7,10 we employed N-phenyl-S-
(trifluoromethyl) thiohydroxylamine 2a as the electrophilic
trifluoromethylthiolating reagent in this paper.
o
when the reaction proceeded at 50 C (entry 12, table 1). Further
reduction of temperature to room temperature offered the desired
product 3a in 90% yield (entry 13, table 1). The reactions were
retarded when loading of either p-TsOH or PhNHSCF3 was
decreased (entries 14-15, table 1).
To the best of our knowledge, Shen's group employed Shen's
trifluoromethylthiolating reagent (a stable and easy-to- handle O-
Table 1 Initial studies for electrophilic trifluoromethylthiolation
of sodium sulfinate 1a with trifluoromethanesulfanylamide 2a a
Entry
1
2
Additive
BiCl3
Solvent
MeCN
MeCN
Temp. (oC) Yield (%) b
80
80
48
32
FeCl3
.
3
4
80
80
80
80
80
80
80
80
42
56
BF3 Et2O
MeCN
MeCN
MeCN
MeCN
DCE
HOAc
p-TsOH
-
5
6
70
N.R.
79
7
8
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
p-TsOH
72
Toluene
DMF
9
36
10
11
12
61
THF
DMSO
DCE
DCE
DCE
80
50
rt
rt
49
85
90
79
87
13
14c
15d
rt
DCE
a
Reaction conditions: 1a (0.2 mmol ), 2a (1.5 equiv),
b
additive (2.5 equiv), 8 hrs.
Isolated yield based on
sulfinate 1a. c 1.5 equiv p-TsOH. d 1.3 equiv PhNHSCF3. p-
TsOH: 4-methylbenzenesulfonic acid; DCE
dichlorethane; N. R. = no reaction
=
1,2-

3
SCF3 reagent) to prepare trifluoromethyl thiolsulphonate as
well.11a Different from the traditional protocol,6 Shen's
methodology avoided the use of gaseous and toxic CF3SCl as a
trifluoromethylthiolating reagent, and employed bench-stable
sodium sulfinate as a reaction partner.
Our method described here served as a supplementary of
Shen's work and our previous result, and relatively simple
reaction operation and easy substrate's accessibility of our
method were impressive.
70% yield. This result is probably attributed to the effect of
steric hindrance in the substrate. To support this conclusion, the
reaction of 2, 4, 6-trimethylbenzenesulfonyl chloride was carried
out under standard conditions. As expected, the reaction yield
was decreased to 50%. Additionally, the substrates with
naphthalene and heterocycles were also tested accordingly. To
our delight, the corresponding products 3o and 3p were achieved
in good yields. The reaction using N-methyl-N-phenyl-S-
(trifluoromethyl)thiohydroxylamine was conducted as well, and
3a was observed in a similar yield.
In conclusion, we have developed an alternative route for the
generation of trifluoromethyl thiolsulphonate from sulfonyl
chloride. The reaction proceeded smoothly under mild reaction
conditions and an array of trifluoromethyl thiolsulphonate was
achieved with high efficiency and excellent functional group
tolerance. A tandem process comprised by in situ generation of
sulfinate and electrophilic trifluoromethylthiolation was involved
in the reaction.
With the above conditions in hand, we then examined the
scope. The results were illustrated in Table 2. A series of
Table 2 Synthesis of trifluoromethyl thiolsulphonate through
electrophilic trifluoromethylthiolation of sodium sulfinate 1
with trifluoromethanesulfanylamide 2a a
Acknowledgments
Financial supports from the Natural Science Foundation of
China (No: 21502069), the Natural Science Foundation of
Zhejiang Province (No: LQ15B020006) and the Ph.D.
Scientific Research Starting Foundation of Jiaxing
University (No: 70515015) and Shanghai Ocean University
(No. A2-0203-00-100338) are gratefully acknowledged.
Generous support of human resources from Prof. Jie Wu
(Fudan University, China) is very gratefully acknowledged.
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a Isolated yield based on sulfinate 1.
trifluoromethyl thiolsulphonate 3 were constructed as expected.
For example, the substrates with methyl, methoxyl, fluoro, chloro,
bromo, cyano, and trifluoromethyl were compatible for the
reactions,
producing
corresponding
trifluoromethyl
thiolsulphonate 3 in 70-96% yields. The ester group was also
tolerated, and the corresponding thiolsulphonate 3d was obtained
in 81% yield, while that of 4-nitro-connected substrate produced
the desired product 3e in 65% yield. Interestingly, the reaction of
4-toluenesulfonyl chloride afforded the desired sulphonate 3j in
93% yield, while the reaction of 2-toluenesulfonyl chloride was
greatly suppressed, leading to the corresponding product 3k in
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4
Tetrahedron Letters
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Supplementary material that may be helpful in the review
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5
Highlights
Research Highlights:

A
tandem reaction of sulfonyl chloride and
trifluoromethylsulfanylamide is described here for
the synthesis of various trifluoromethyl
thiolsulphonates.
This tandem reaction includes in situ reduction of
sulfonyl chloride and electrophilic
trifluoromethylation.



Sulfinate was postulated as a key intermediate.
This tandem process worked efficiently with a broad
functional tolerance.