Oxidative trifluoromethylthiolation of terminal alkynes with AgSCF 3: A convenient approach to alkynyl trifluoromethyl sulfides

Article abstract of DOI:10.1002/ejoc.201402533

A new method for the efficient synthesis of alkynyl trifluoromethyl sulfides was developed. By combining AgSCF₃ and NCS in N,N-dimethylacetamide, an electrophilic active intermediate was produced, which was then treated with a variety of terminal alkynes to afford the corresponding trifluoromethanesulfenylated products in moderate to excellent yields. A new oxidative trifluoromethylthiolation system, AgSCF₃/NCS, is developed and applied in the efficient synthesis of alkynyl trifluoromethyl sulfides. Various desired compounds are obtained under mild conditions in moderate to excellent yields. Copyright

Full text of DOI:10.1002/ejoc.201402533

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402533
Oxidative Trifluoromethylthiolation of Terminal Alkynes with AgSCF3:
A Convenient Approach to Alkynyl Trifluoromethyl Sulfides
Sheng-Qing Zhu,[a] Xiu-Hua Xu,*[a] and Feng-Ling Qing*[a,b]
Keywords: Synthetic methods / Alkynes / Sulfur / Silver / Oxidation
A new method for the efficient synthesis of alkynyl trifluoro-
methyl sulfides was developed. By combining AgSCF3 and
NCS in N,N-dimethylacetamide, an electrophilic active in-
termediate was produced, which was then treated with a
variety of terminal alkynes to afford the corresponding tri-
fluoromethanesulfenylated products in moderate to excellent
yields.
of terminal alkynes by the combination of commercially
available TMSCF3 and S8 [Scheme 1, Equation (c)].[10e] This
method represented a straightforward approach to a broad
range of alkynyl trifluoromethyl sulfides. However, an ex-
cess amount of expensive TMSCF3 was required. Consider-
ing the fact that alkynes are of paramount importance in
organic chemistry,[12] alkynyl trifluoromethyl sulfides
should become a type of useful building block that can po-
tentially be used in medicinal and material chemistry.[13]
Thus, it is highly desirable to develop other more conve-
nient and efficient methods for the preparation of alkynyl
trifluoromethyl sulfides. In continuation of our recent re-
search interest in oxidative trifluoromethylation[14] and tri-
fluoromethylthiolation reactions,[10b,10e] we herein report
another type of oxidative trifluoromethylthiolation[15] with
AgSCF3 for the preparation of alkynyl trifluoromethyl sulf-
ides [Scheme 1, Equation (d)]. Compared to previous meth-
ods, the current one avoids the use of pre-prepared electro-
philic reagents and an excess amount of TMSCF3.[16]
Introduction
The trifluoromethanesulfenyl group (SCF3) is one of the
most important fluorine-containing groups. Its unique
properties, such as its strong electron-withdrawing effects
and extremely high lipophilicity,[1] have received increasing
attention from the pharmaceutical and agrochemical indus-
tries.[2] Thus, numerous methods have been reported for the
preparation of trifluoromethylated compounds.[3] Especially
over the past several years, significant progress has been
made in SCF3 chemistry. A lot of effort has been devoted
to the direct trifluoromethylation of different substrates.
Typical examples involve the development of new trifluoro-
methylthiolating reagents[4–9] and transition-metal-medi-
ated/catalyzed trifluoromethylthiolation reactions.[10,11] De-
spite the fact that great achievements have been made in the
direct formation of C–SCF3 bonds, the construction of
Csp–SCF3 bonds has been rarely described. Lu and Shen
developed a copper-catalyzed trifluoromethylthiolation of
terminal alkynes by using a novel thioperoxy reagent devel-
oped by their group [Scheme 1, Equation (a)].[5a] Billard re-
ported
a
base-catalyzed trifluoromethylthiolation of
terminal alkynes by using a trifluoromethanesulfenamide
reagent [Scheme 1, Equation (b)].[4e] Although both of these
methods supplied alkynyl trifluoromethyl sulfides in good
to excellent yields, they suffered from the pre-preparation
of electrophilic trifluoromethylthiolation reagents. In 2012,
our group described the oxidative trifluoromethylthiolation
[a] Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Science,
345 Lingling Lu, Shanghai 200032, China
E-mail: xuxiuhua@mail.sioc.ac.cn
flq@mail.sioc.ac.cn
http://www.fluorinelab.ac.cn
[b] College of Chemistry, Chemical Engineering and
Biotechnology, Donghua University
2999 North Renmin Road, Shanghai 201620, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402533.
Scheme 1. Different strategies to alkynyl trifluoromethyl sulfides;
bpy = 2,2Ј-bipyridyl, LiHMDS = lithium hexamethyldisilazane.
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S.-Q. Zhu, X.-H. Xu, F.-L. Qing
SHORT COMMUNICATION
entries 8 and 9). K3PO4 was selected from the several potas-
sium salts, and the yield slightly improved to 67% (Table 1,
entry 11). The solvent was crucial to the reaction yield. If
the reaction was performed in DMA, the yield sharply im-
proved to 88% (Table 1, entry 14). In contrast, only a trace
amount of 2a was obtained in CH3CN (Table 1, entry 15).
The reaction yield was further improved by increasing the
amount of base, AgSCF3, and oxidant, and it finally
reached as high as 98% (Table 1, entries 16 and 17). No-
tably, 2a was obtained in 35% yield if PhICl2 was used as
the oxidant under the optimal reaction conditions (Table 1,
entry 18). Upon using CuSCF3 as the trifluoromethylthio
source, 2a was obtained in only 7% yield (Table 1, en-
try 19).
The substrate scope of the oxidative trifluoromethylthiol-
ation reaction was then investigated with various terminal
alkynes under the optimal reaction conditions (Table 2). A
series of electron-rich and electron-deficient terminal alk-
ynes were transformed into their corresponding alkynyl tri-
fluoromethyl sulfides in moderate to excellent yields. Dif-
ferent functional groups, including F and Br, were compati-
ble with the reaction conditions. Thiophene derivative 1k
was trifluoromethylthiolated under the standard conditions
to give 2k in 65% yield. Aliphatic alkynes also reacted un-
der these conditions to afford desired products 2l and 2m
in moderate to good yields.
Results and Discussion
Shen’s electrophilic trifluoromethylthiolation reagent
[Scheme 1, Equation (a)] was prepared from AgSCF3 and a
hypervalent iodine compound.[5a,5c] Inspired by this excel-
lent work, we wondered if the electrophilic trifluoromethyl-
thiolation reagent could be generated in situ from a nucleo-
philic trifluoromethylthiolation reagent and an oxidant and
then treated with different nucleophiles. Initially, phenyl-
acetylene (1a) was chosen as the test substrate by using
AgSCF3 as the trifluoromethylthio (CF3S–) source to opti-
mize the reaction conditions (Table 1). To our disappoint-
ment, only a trace amount of desired product 2a was ob-
tained if PhI(OAc)2 was added to the reaction mixture
(Table 1, entry 1). Neither PhICl2 nor (NH4)2S2O8 gave bet-
ter results (Table 1, entries 2 and 3). The important break-
through happened upon using NBS and its derivatives as
oxidants (Table 1, entries 4–7).[11c,17] Among them, NCS
was the best one; it gave 2a in 52% yield (Table 1, entry 5).
Then, the reaction conditions were screened with different
bases (Table 1, entries 8–13). A lower yield of 2a was ob-
tained if NaOAc was used, whereas a trace amount of 2a
was obtained if the organic base NEt3 was used (Table 1,
Table 1. Optimization of the reaction conditions.[a]
Table 2. Oxidative trifluoromethylthiolation of terminal alkynes
under the optimal reaction conditions.
Entry Oxidant
Base
Solvent
Yield[b] [%]
1
2
3
4
PhI(OAc)2
PhICl2
(NH4)2S2O8
NBS
NCS
NIS
TCCA
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
PhICl2
NCS
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
NaOAc
NEt3
K2CO3
K3PO4
K2HPO4
KOtBu
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
CH3CN
DMA
DMA
DMA
DMA
trace
3
0
46
52
20
24
36
trace
58
67
53
39
88
trace
94
98
35
7
5
6
7[c]
8
9
10
11
12
13
14
15
16[d]
17[e]
18[e]
19[f]
[a] Reaction conditions: 1a (0.5 mmol), AgSCF3 (0.6 mmol,
1.2 equiv.), oxidant (0.6 mmol, 1.2 equiv.), base (0.75 mmol,
1.5 equiv.), solvent (10.0 mL), r.t., overnight, under an atmosphere
of N2. DMF = N,N-dimethylformamide, DMA = N,N-dimethyl-
acetamide, NBS = N-bromosuccinimide, NCS = N-chlorosuc-
cinimide, NIS = N-iodosuccinimide, TCCA = trichloroisocyanuric
acid. [b] Yields were determined by 19F NMR spectroscopy by
using trifluoromethoxybenzene as an internal standard. [c] TCCA
(0.2 mmol, 0.4 equiv.). [d] K3PO4 (1.2 mmol, 2.4 equiv.).
[e] AgSCF3 (0.75 mmol, 1.5 equiv.), oxidant (0.75 mmol,
1.5 equiv.), K3PO4 (1.2 mmol, 2.4 equiv.). [f] CuSCF3 (0.75 mmol,
1.5 equiv.), NCS (0.75 mmol, 1.5 equiv.), K3PO4 (1.2 mmol,
2.4 equiv.).
2
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Oxidative Trifluoromethylthiolation of Terminal Alkynes
To understand the reaction mechanism, 19F NMR spec-
troscopy was used to track the reaction (Table 3). It was
found that after 10 min AgSCF3 was completely converted
into a new intermediate, which was consistent with known
electrophilic trifluoromethylthiolation reagent 3 (resonance
at δ = –48.1 ppm, see the Supporting Information).[11c,17]
As time went on, resonances attributable to desired product
2a gradually increased, whereas those for intermediate 3 de-
creased. Thus, it is concluded that intermediate 3 is the
active species in our reaction system.
Conclusions
We demonstrated the novel oxidative trifluoromethyl-
thiolation of terminal alkynes by mixing AgSCF3 and NCS
in DMA. Electrophilic intermediate 3 is believed to be
formed in situ and involved in the silver-mediated trifluoro-
methylthiolation reaction. This protocol provides a conve-
nient and efficient method for the synthesis of various
alkynyl trifluoromethyl sulfides in high yields. Further in-
vestigation of this reaction system and its potential applica-
tions are in progress.
Table 3. Monitoring the reaction by 19F NMR spectroscopy.[a]
Experimental Section
General Procedure for the Oxidative Trifluoromethylthiolation of
Terminal Alkynes 1: Terminal alkyne 1 (0.50 mmol) was added to a
stirred solution of AgSCF3 (156.7 mg, 0.75 mmol), NCS (100.1 mg,
0.75 mmol), and K3PO4 (254.8 mg, 1.20 mmol) in anhydrous DMA
(10.0 mL) under a nitrogen atmosphere at room temperature. The
reaction mixture was stirred at room temperature overnight, then
diluted with H2O and extracted with Et2O. The combined organic
layer was washed with brine, dried with Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel to give alkynyl trifluoromethyl sulfide 2.
SCF3 source
Yield[b] [%]
10 min
1 h
4 h
24 h
AgSCF3
AgSCF3 + NCS
2a
0
149
2
0
98
28
0
47
62
0
4
92
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, and characteriza-
tion data for all compounds.
[a] Reaction conditions: 1a (0.5 mmol), AgSCF3 (0.75 mmol), NCS
(0.75 mmol), K3PO4 (1.2 mmol), DMA (10.0 mL), r.t., under an
atmosphere of N2. [b] Yields were determined by 19F NMR spec-
troscopy by using trifluoromethoxybenzene as an internal stan-
dard.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 21072028, 20832008) and the
National Basic Research Program of China (grant number
2012CB21600) for funding this work.
Several experiments were performed to obtain more de-
tails of the reaction process (Scheme 2). The reaction of
phenylacetylene (1a) with reagent 3 under basic conditions
did not give desired product 2a [Scheme 2, Equation (a)].
The addition of a sliver salt was necessary for the formation
of 2a [Scheme 2, Equations (b) and (c)]. Although the exact
reaction mechanism is still unclear, the above results show
that the formation of the Csp–SCF3 bond does not pass
through a typical SN2-type reaction, but rather a silver-me-
diated electrophilic reaction.
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system has some advantages over the normal electrophilic
trifluoromethylthiolation reactions.
Eur. J. Org. Chem. 0000, 0–0
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SHORT COMMUNICATION
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Received: May 3, 2014
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Oxidative Trifluoromethylthiolation of Terminal Alkynes
Trifluoromethylthiolation
S.-Q. Zhu, X.-H. Xu,*
F.-L. Qing* ....................................... 1–5
Oxidative Trifluoromethylthiolation of Ter-
A new oxidative trifluoromethylthiolation
system, AgSCF3/NCS, is developed and
applied in the efficient synthesis of alkynyl
trifluoromethyl sulfides. Various desired
compounds are obtained under mild con-
ditions in moderate to excellent yields.
DMA = N,N-dimethylacetamide.
minal Alkynes with AgSCF3:
venient Approach to Alkynyl Trifluoro-
methyl Sulfides
A Con-
Keywords: Synthetic methods / Alkynes /
Sulfur / Silver / Oxidation
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