Copper-catalyzed synthesis of aryl and alkyl trifluoromethyl sulfides using CF3SiMe3and Na2S2O3as -SCF3source

Article abstract of DOI:10.1016/j.tetlet.2014.07.039

A universal and efficient Cu(I)-catalyzed synthesis of aryl and alkyl trifluoromethyl sulfides has been developed. In this catalytic system, S-aryl or S-alkyl sulfothioate (I or II) proved to be the key intermediate. Substrates bearing groups of I, Br, Cl, OTs, and OMs on the aryl carbon and no matter electron-withdrawing and electron-donating substitutions on the aromatic ring could afford good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.07.039

Tetrahedron Letters 55 (2014) 4909–4911
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Tetrahedron Letters
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Copper-catalyzed synthesis of aryl and alkyl trifluoromethyl sulfides
using CF3SiMe3 and Na2S2O3 as –SCF3 source
a
Wei Zhong a,b, , Xiaoming Liu
⇑
a College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing 314001, Zhejiang, China
b State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, Jiangsu, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A universal and efficient Cu(I)-catalyzed synthesis of aryl and alkyl trifluoromethyl sulfides has been
developed. In this catalytic system, S-aryl or S-alkyl sulfothioate (I or II) proved to be the key intermedi-
ate. Substrates bearing groups of I, Br, Cl, OTs, and OMs on the aryl carbon and no matter electron-
withdrawing and electron-donating substitutions on the aromatic ring could afford good to excellent
yields.
Received 1 May 2014
Revised 6 July 2014
Accepted 10 July 2014
Available online 15 July 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylthiolation
Copper catalysis
Trifluoromethylthio group
One-pot reaction
Developing novel synthetic approaches for fluorinated deriva-
tives is of long-standing interest to chemists in a variety of fields.1
As an important member in this family, the trifluoromethylthio
group (–SCF3) has attracted increasing attention in the past dec-
ades because of the biological potentials of the compounds con-
taining this group2 and its strong electron-withdrawing effect
S
S
8 + FSO2CF2CO2Me (Ref. 12)
8 + CF3SiMe3 (Ref. 13)
MSCF3
M = Cu, Ag, Hg
(Ref. 4)
Indirect
'SCF3'
Direct
'SCF3'
S
8 + CF3CO2Na
(Ref. 14)
Ar SCF3
Alk SCF3
+
N2
-
NaSCN +
R
BF4
(Ref. 15)
RnXSCF3
X = C, O, N, S, Cl, I
(with large Hansch lipophilicity parameter, p
R = 1.44).3
Na2S2O3 + CF3SiMe3
(this paper)
(Ref. 5~11)
Over the past few decades, two general strategies for introduc-
ing the –SCF3 group into organic molecules have been developed,
direct and indirect insertions (Scheme 1). In the direct strategy,
both metal complexes MSCF3 (M = Cu, Ag, Hg)4 and organic species
(R1R2NSCF3,5 ROSCF3,6 [R4N]+[SCF3]À,7 RSO2CF3,8 ROCOSCF3,9
Scheme 1. Strategies for the preparation of trifluoromethyl sulfides.
terminal alkynes,13b and arylamine.15 Thus, developing a universal
and efficient method to introduce the –SCF3 group into various
substrates is highly desirable.
Inspired by Reeves’ and Jiang’s recent work, which used Na2S2O3
as sulfurating reagent to construct a C–S bond,16 we attempted
to employ the same sulfurating reagent to achieve trifluoromethyl-
thiolation. Herein, we report an efficient Cu(I)-catalyzed synthesis
of aryl and alkyl trifluoromethyl sulfides using CF3SiMe3 and
Na2S2O3 as the indirect –SCF3 source.
We began our investigation by reacting bromobenzene 1a1 with
Na2S2O3 and CF3SiMe3 in the presence of different copper salts,
bases, and solvents to optimize the reaction conditions. To our
delight, when the reaction was conducted with CuCl (0.05 equiv)
and 1,10-phenanthroline (Phen; 0.05 equiv) in the presence of
K2CO3 as the base in DMSO at 80 °C, 2a was formed in 42% yield
(Table 1, entry 1). Our investigation turned out that a base plays
a crucial role in the reaction and no product was detected without
10
F3CSSCF3, F3CSCl11) have been used as –SCF3 sources. The short-
comings of these –SCF3 sources are either expensive or highly toxic
and/or instable, which limit their further applications. In the indi-
rect one, the first example was reported by Chen and coworkers
using sulfur and FSO2CF2CO2Me as –SCF3 source.12 Very recently,
elemental sulfur and CF3SiMe3 were successfully used to introduce
the –SCF3 group by Qing’s group,13 While Li and co-workers used
sodium trifluoroacetate and elemental sulfur to achieve the triflu-
oromethylthiolation process.14 The latest way reported by Goossen
and co-workers employed arenediazonium salts and sodium
thiocyanate to prepare the corresponding aryl trifluoromethyl
thioethers.15 But these approaches were applied only to limited
starting substrates, such as aryl iodide,12 aryl boronic acids,13a,14
⇑
Corresponding author. Tel.: +86 573 83640303; fax: +86 573 83643937.
E-mail address: weizhong@mail.zjxu.edu.cn (W. Zhong).
http://dx.doi.org/10.1016/j.tetlet.2014.07.039
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

4910
W. Zhong, X. Liu / Tetrahedron Letters 55 (2014) 4909–4911
Table 1
substrates (Scheme 2). Substrates bearing groups of I, Br, Cl, OTs,
and OMs on the aryl carbon could afford good yields (2a, Scheme 2).
Both the electronic nature and position of a substituent on the aro-
matic ring affect the reaction. An electron-withdrawing group can
lower the reaction yield. But a decent yield was still obtained even
when a strong electron-withdrawing group like the –NO2 group
was present. As shown in Scheme 2, an ortho-substituent exercises
more profound effect on the reaction compared to a meta- and
para-substituent. This is certainly due to steric reason. When a
tbutyl is present at the ortho position, the reaction did not occur
(2l, Scheme 2) at all due to the steric hindrance caused by its
bulkiness. The universal applications of this approach are further
supported by the success in both heterocyclic and aliphatic iodides
(2r–2w, Scheme 2).
To gain some insight of the reaction mechanism and understand
the roles of each component in the transformation, control
experiments were performed (Scheme 3, SI-3). Reacting 1a2 with
Na2S2O3 in DMSO catalyzed by CuCl and 1,10-phenanthroline
(Phen) under air, the intermediate I16b was isolated in 75% yield.
Further reaction of this isolated intermediate I with CF3SiMe3 led
to the desired product 2a in 88% yield under the optimized reaction
conditions. Again, no 2a was detected without the base in the reaction
system. Furthermore, when two normal radical-trapping reagents,
TEMPO and 1,1-diphenylethene, were employed under standard
conditions, desired 2a was afforded in 81% and 85%, respectively.
These results suggested that K3PO4 takes its action in the process,
in which it may be to cleave off the C–Si bond in CF3SiMe3 but not
to form CF3 radical assembling into the final product.17 Finally,
iodocyclohexane 1t showed more activity than 1a2, affording
excellent yield of II16b in the absence of catalyst.
On the basis of our preliminary results and previous related
studies,4–15 it is clear that the installation of the –SCF3 group takes
place stepwise. In the first step, the intermediate I or II was formed
via nucleophilic attack on the cationic carbon of substrate 1 by
thiosulfate.16b When the carbocation can be well stabilized, the
reaction may not need the catalyst at all, for example, in the case
of iodocyclohexane (1t, Scheme 3). In the second step, the conjunc-
tion of leaving of the SO23À group and cleavage of the C–Si bond in
CF3SiMe3 affords the desired product 2 catalyzed by CuCl/Phen in
the presence of K3PO4.17
In summary, we have developed an approach for trifluorometh-
ylthiolation of aryl or alkyl iodide using readily available reagents
Na2S2O3 (as sulfur source) and CF3SiMe3 in one-pot reaction under
the catalysis of Cu(I)/Phen system. The reaction proceeds in two
steps and the S-aryl or S-alkyl sulfothioate (I or II) is the key inter-
mediate. The approach exhibits excellent suitability to a wide
range of substrates with decent yield and may have great potential
in both pharmaceutical and agrochemical industries.
Optimization of Cu(I)-catalyzed synthesis of trifluoromethyl sulfides
Br
SCF3
[Cu], Phen
Na2S2O3
CF3SiMe3
Base, DMSO
1a1
2a
Entrya
Cat: [Cu]
Base
Yieldc
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl2
CuBr
CuOAc
CuOTf
—
K2CO3
Na2CO3
KOAc
K3PO4
KOH
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
—
42%
26%
51%
83%
<5%
58%
75%
63%
69%
0
9
10
11
12b
CuCl
CuCl
0
81%
K3PO4
a
Reaction conditions: 1a1 (0.2 mmol), Na2S2O3 (0.21 mmol), CF3SiMe3
(0.4 mmol), base (0.3 mmol), catalyst/ligand (5 mol %), DMSO (2 mL), 24 h, 80 °C in
air.
b
Standard reaction stirring under inert Ar atmosphere.
Isolated yield.
c
the presence of a base (Table 1, entry 11). Among the examined
bases, K3PO4 shows the best performance, which increases the
reaction yield to 83% (Table 1, entries 2–4). When KOH was used,
the reaction proceeds hardly (<5%, entry 5). Contrary to the influ-
ence of the base, the copper salts possess almost no affection on
the reaction (entries 6–9). The use of other solvents and ligands,
increasing the amount of loading catalyst, changes in reaction tem-
perature (Supporting information, SI-Tables 1 and 2), or carrying
out the standard reaction under inert Ar atmosphere (Table 1,
entry 12), led no significant improvement on the yield.
The approach exhibits its applicability to various substrates.
Under the optimized reaction conditions (Table 1, entry 4), the –
SCF3 group was successfully introduced into a wide range of
CuCl, Phen
Ar
X
X
Ar SCF3
Alk SCF3
Na2S2O3
CF3SiMe3
Alk
K3PO4, DMSO
1
2
SCF3
SCF3
SCF3
H3CO
SCF3
Ph
2d
2a
Cl, OTs, OMs
2b, X = I, 88%
2c
, X = I, 92%
, X = I, 72%
X = Br, I,
83%, 91%, 74%, 71%, 68%
SCF3
SCF3
SCF3
SCF3
O2N
2f, X = I, 58% 2g, X = I, 65%
H3COC
NC
2e, X = I, 63%
OCH3
, X = I, 78%
2h
O
SCF3
SCF3
SCF3
SCF3
I
S
S
ONa
CuCl, Phen,DMSO
Cat, Necessary!
Na2S2O3
O
COOCH3
NO2
Ph
tBu
, X = I, 0%
2i, X = I, 68%
2j
2k
2l
, X = I, 74%
, X = I, 55%
I
1a2
SCF3
SCF3
SCF3
SCF3
CuCl, Phen
DMSO
CuCl, Phen
CF SiMe
I +
I + CF3SiMe3
2a, 88%
3
3
Base, DMSO
CONH2
CN
OCH3
2n
2o
2p, X = I, 84%
2m, X = I, 68%
, X = I, 49%
, X = I, 86%
I
S
Cl
SCF3
CF3SiMe3, CuCl
SCF3
SCF3
DMSO
SO3Na
+
Na2S2O3
2t
SCF3
S
N
do not need
Cu-Cat
Phen, Base, DMSO
Cl
II
1t
2r
2s, X = I, 65%
, X = I, 79%
2t, X = I, 93%
2q, X = I, 53%
SCF3
2u, X = I, 88%
SCF3
SCF3
TEMPO
1,1-diphenylethene
standard conditions
NC(H2C)3H2C
2w, X = I, 75%
Ph
H3C(H2C)9H2C
2v, X = I, 81%
2a, 81%
1a1 Na S O
3 + CF3SiMe3
2
2a
, 85%
+
2
standard conditions
Scheme 2. Scope of the aryl or alkyl substrates.
Scheme 3. Control experiments.

W. Zhong, X. Liu / Tetrahedron Letters 55 (2014) 4909–4911
4911
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Acknowledgments
We thank the National Natural Science Foundation of China
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Zhejiang Province (LQ13B010002), and the Government of
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