Copper-catalyzed trifluoromethyl thiolation-mild and efficient synthesis of trifluoromethyl thioethers

Article abstract of DOI:10.1002/chem.201302692

The perfluoroalkyl groups act as lipophilic electron-withdrawing groups, introducing additional unique properties in the molecules when compared to their non-fluorinated analogues. These properties are closely related to those of trifluoromethoxy (OCF

Full text of DOI:10.1002/chem.201302692

COMMUNICATION
DOI: 10.1002/chem.201302692
Copper-Catalyzed Trifluormethyl Thiolation—Mild and Efficient Synthesis of
Trifluormethyl Thioethers
[
a]
Magnus Rueping,* Nikita Tolstoluzhsky, and Pavlo Nikolaienko
The development of new, superior synthetic approaches
for the preparation of perfluoroalkyl thioethers is of particu-
report for their reaction with vinyl halides. It is known that
vinyl iodides and bromides can react with S nucleophiles.
Initial search for conditions that could promote nucleophilic
substitution showed, however, that bromides are completely
inert and do not react under any conditions in which iodides
showed reactivity (Table 1). Due to the reduced nucleophi-
[10]
[1]
lar interest for both industry and academia. Perfluoroalkyl
thio groups (e.g., CF S, C F S, C F S) constitute interesting
3
2
5
3 7
moieties found in numerous molecules that are relevant for
[2]
medicinal and agrochemical industries. The perfluoroalkyl
groups act as lipophilic electron-withdrawing groups, intro-
ducing additional unique properties in the molecules when
licity of the SCF anion, the coupling is considerably more
3
difficult relative to non-fluorinated thiolate.
[3]
compared to their non-fluorinated analogues. These prop-
erties are closely related to those of trifluoromethoxy
[4]
(
OCF ) and trifluoromethyl (CF ) groups. For example,
3
3
Table 1. Optimization of reaction conditions for the trifluoromethyl thio-
the pyridine derivative depicted in Figure 1 was described to
possess herbicidal properties whilst carrying a vinyl trifluor-
[a]
lation of vinyl iodides.
[5]
omethyl thioether group.
Entry
Solvent
t
[
T
[8C]
CuSCF
[equiv]
3
Yield
[%]
[
b]
h]
A
H
U
G
R
N
U
G
1
2
3
4
5
6
7
8
9
10
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMF
DMF
DMA
24
24
24
24
24
24
24
48
48
48
48
10
RT
40
40
1.2
1.2
1.2
2
2
1.2
2
2
2
2
2
25
50
50
25
25
40
85
90
91
10
93
[
[
c]
Figure 1. Known herbicide that contains a vinyl trifluoromethyl thioether
group.
70
d]
100
RT
70
70
70
70
70
110
However, to date, the direct synthesis of such significant
compounds is unfortunately limited due to lack of safe, effi-
cient, and general synthetic methods. There are few methods
reported for the synthesis of vinyl trifluoromethyl thioeth-
acetone
pyridine
pyridine
1
1
1
2
[
e]
2
94
[
6,7]
[a] Unless otherwise noted, the reactions were carried in 0.3 mL solvent
and at the temperature indicated. [b] NMR yield; the E product was iso-
lated along with its Z isomer with retention of the E/Z isomer ratio as it
ers
with limited scope and moderate yields, the most
recent one involving multistep procedures for the prepara-
tion of starting vinyl boronic acids and making use of expen-
1
was in the starting iodide 1a as determined by H NMR analysis.
[7b]
sive reagents in stoichiometric quantities. Hence, our at-
tention was drawn to the development of alternative, safe,
and powerful methods for the synthesis of vinyl trifluoro-
methyl thioethers.
[c] 10 mol% of Pd
ditive. [e] Yield after column chromatography.
2 3
ACHTUNGTRENN(UG OAc) was used as additive. [d] 20 mol% of PPh ad-
Despite few publications that describe MSCF (M=Cu,
Moderate conversions were observed when DMSO was
used as solvent under different conditions and in all cases
the starting vinyl iodide 1a was still present in the reaction
3
Ag) and [R N]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[SCF ] as effective reagents for the direct in-
4
3
2
troduction of SCF groups on sp -aromatic carbon atoms by
3
[1,8,9]
the reaction with aromatic halides,
there is no general
mixture. Prolonged reaction time and use of Pd ACHTUNREGTNNUNG( OAc) and
2
PPh as additives did not have any positive effect (Table 1,
3
entries 3 and 5). Good results were obtained in DMF and
DMA as reaction media (Table 1, entries 8 and 9). Acetone
showed low compatibility for our reaction (Table 1,
entry 10). Application of pyridine as solvent proved to be
the most effective and, at higher temperature, the desired
product 2a was obtained in 94% yield (Table 1, entry 12).
[
a] Prof. Dr. M. Rueping, N. Tolstoluzhsky, P. Nikolaienko
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: Magnus.Rueping@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302692.
Chem. Eur. J. 2013, 00, 0 – 0
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With the optimized conditions in hand, the scope of the
reaction with respect to the structure and substitution pat-
tern of the vinyl iodides was investigated and the results are
summarized in Table 2. Notably, various alkyl and aryl di-,
tri- and tetrasubstituted vinyl iodides were applied in the re-
action and the corresponding products were isolated with
Tri- and tetrasubstituted substrates 1k–n provided the cor-
responding products 2k–n with up to 98% yield. In summa-
ry; we demonstrate that different alkyl and aryl di-, tri-; and
tetrasubstituted vinyl iodides can be readily applied in this
new trifluoromethyl thiolation and that the corresponding
thioethers can be obtained with good to excellent yields.
After the successful application of CuSCF , we turned our
3
attention to [Bu N] ACHTUNGTERNNGN[U SCF ] which has proven to be an effec-
3
4
Table 2. Substrate scope for the trifluoromethyl thiolation reaction of
vinyl iodides.
[
a,b]
tive reagent for the nucleophilic introduction of SCF group-
3
[8a,b]
s.
The use of CuI as a catalyst was required in order to
achieve high yields and reaction times comparable to the re-
action with CuSCF (Table 3). With one equivalent of CuI,
3
the product 2n was obtained in 91% yield (Table 3,
entry 2). The amount of CuI can also be reduced to
[
a]
Table 3. Evaluation
of
[Bu
4
N]
A
H
U
G
R
N
U
G
3
]
as
SCF
3
source.
[
b]
[c]
Entry
Salt
t [h]
CuI [equiv]
Yield [%]
1
2
3
4
5
6
CuSCF
3
10
24
36
60
60
60
–
1
0.1
0.05
0.01
–
95
91
92
85
80
65
Bu
Bu
Bu
Bu
Bu
4
4
4
4
4
NSCF
NSCF
NSCF
NSCF
NSCF
3
3
3
3
3
[
[
d]
d]
[
a] The reactions were carried in 0.3 mL of pyridine at 1108C. [b] Two
equivalents of SCF source salt. [c] Yield after chromatography. [d] NMR
conversion; no full conversion even after 60 h.
3
0
.01 equivalents, although in this case longer reaction time is
required to obtain a satisfactory yield (Table 3, entry 5).
Nevertheless, with 0.1 equivalents of CuI the product 2n
was isolated in 92% yield after 36 h (Table 3, entry 3).
Under these conditions various substrates were tested and
the corresponding products were obtained with very good
yields ranging from 86 to 93% (Table 4).
Finally, we could show that the vinyl trifluoromethyl thio-
ethers such as 2a can be readily converted into the corre-
sponding vinyl sulfone 3a by oxidation with hydrogen per-
oxide (Scheme 1).
[
3
a] The reactions were carried out with 2 equiv of CuSCF in 0.3 mL of
pyridine at 1108C for 10–48 h. [b] Yield after column chromatography;
the E product was isolated along with its Z isomer with retention of the
1
The proposed mechanism for the Cu-catalyzed reaction
E/Z isomer ratio as it was in starting iodide as determined by H and
1
9
F NMR analysis. [c] The E/Z isomer ratio was determined from the
F NMR analysis. [d] Reaction was carried out at RT for 3 h.
(Table 4) is depicted in Scheme 2. Initially a [CuI
complex A will be formed from CuI and pyridine solvent
molecules. Reaction of complex A with [NBu4][SCF ] results
in the formation of [CuSCF (pyridine) ] complex B, which
ACHTUNGTNERNUNG( pyridine) ]
n
1
9
AHCTUNGTRENNUNG
3
AHCTUNGTRENNUNG
3
n
excellent yields. Aryl-substituted vinyl iodides 1a–g bearing
aromatic groups with electron-withdrawing and electron-do-
nating groups all undergo reaction under the optimized con-
ditions to give the vinyl trifluoromethyl thioethers 2a–g in
high to excellent yields (86–97%) without affecting the ini-
tial E/Z isomer ratio. Furthermore; heteroaryl-substituted
vinyl iodides 1i–j are also suitable substrates for this reac-
tion. Alkyl-substituted vinyl iodides 1h and 1o perform also
well to give 2h and 2o in 91 and 90% yield; respectively.
reacts with the vinyl iodide through oxidative insertion to
Scheme 1. Oxidation of vinyl trifluoromethyl thioether into the corre-
sponding vinyl sulfone.
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Copper-Catalyzed Trifluormethyl Thiolation
COMMUNICATION
Table 4. Substrate scope for the trifluoromethyl thiolation reaction of
vinyl iodides with [Bu N] ACHTUNRTGENNUNG[ SCF ].
4 3
yields. In contrast to previous methods the protocols devel-
oped show broad scope, use safe and non-toxic metals and
reagents, and can be carried out under mild reaction condi-
tions, making them useful for organic synthesis.
[
a,b]
Keywords: copper · CÀS bond formation · thioethers ·
trifluoromethyl thiolation · vinyl iodide
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lents of Bu NSCF and 0.1 equivalents CuI in 0.3 mL pyridine at 1108C;
the E/Z isomer ratio was determined by H or F NMR analysis.
b] Yield after chromatography. [c] Reaction was performed at RT for
4 h.
4
3
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dides with [Bu N][SCF ].
4
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
3
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product 2 and regenerates complex A.
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2
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3
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4
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A
C
H
T
U
N
G
T
R
E
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N
U
N
G
[SCF ] salt and provides the trifluormethyl thioether in good
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Chem. Eur. J. 2013, 00, 0 – 0
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2
Received: July 10, 2013
Published online: && &&, 0000
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Copper-Catalyzed Trifluormethyl Thiolation
COMMUNICATION
CÀS bond formation
M. Rueping,* N. Tolstoluzhsky,
Mild-mannered sulfur: A general
method for the synthesis of vinyl tri-
fluoromethyl thioethers starting from
readily available di-, tri- and tetrasub-
stituted vinyl iodides was developed
with CuSCF to give the corresponding
P. Nikolaienko ................ &&&& — &&&&
3
products in high yields, within short
reaction times, with retention of the
initial E/Z isomer ratio. In addition, a
copper-catalyzed trifluoromethyl thio-
ether protocol has been also devel-
oped.
Copper-Catalyzed Trifluormethyl
Thiolation—Mild and Efficient
Synthesis of Trifluormethyl Thioethers
(
see scheme). A wide variety of sub-
strates were applied in the reaction
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