Although a series of electrophilic trifluoromethylating
reagents have been extensively designed and synthesized,
they are still limited to electrophilic and radical reactions.[9,11]
In our previous study, we reported that fluoroalkyl radicals
are formed when (S)-(fluoroalkyl)diphenylsulfonium salts
react with nucleophiles at low temperature.[12] It seems that a
redox process cannot be excluded in the generation of these
radicals. Based on this result, we have continued to investigate
the reaction of sulfonium salts with metals. Owing to the
straightforward one-pot process discovered by Magnier and
co-workers, the preparation of (S)-(trifluoromethyl)diphe-
nylsulfonium salts is most convenient.[13] For this reason, (S)-
(trifluoromethyl)diphenylsulfonium triflate was employed as
the prototype.
intermediate CuCF3 still remained in the reaction, as deter-
mined by 19F NMR spectroscopy (see the Supporting Infor-
mation), according to the literature (d = À35.5 ppm).[14]
Therefore, sufficient reaction time should be provided to
ensure the complete transformation of CuCF3 into the
trifluoromethylated product. Increasing the reaction time to
more than 9 hours, however, always gave yields of 2a that
were less than 50%, if the sulfonium salt was used as the
standard. It appears that only one half of the salt was effective
in the trifluoromethylation step. Moreover, the amount of
copper added was shown to have an important influence on
the reaction yield. When the amount of copper was reduced
from two to one equivalents of [Ph2SCF3]+[OTf]À, a yield of
only 10% of 2a was obtained (Table 1, entry 8), and no 2a at
all was obtained when half an equivalent of copper was used
(Table 1, entry 9). Finally, thermal energy was necessary to
initiate the reaction. Treating [Ph2SCF3]+[OTf]À with 1a and
Cu at room temperature did not yield any of the product 2a
(Table 1, entry 10).
As shown in Table 1, (S)-(trifluoromethyl)diphenylsulfo-
nium triflate can be successfully reduced by metals. For
example, after the treatment of [Ph2SCF3]+[OTf]À with
iodobenzene 1a in the presence of Fe at 1108C for 10 hours,
It is well known that the synthesis of trifluoromethylated
heteroaromatic compounds under mild conditions is chal-
lenging. Encouraged by the results described above, we
turned our attention to the copper-mediated trifluoromethy-
lation of iodo-substituted heteroaromatic compounds. As
shown in Table 2, 4-iodopyridine 1b (1 equiv) was treated
with [Ph2SCF3]+[OTf]À (2 equiv) in the presence of Cu
(3 equiv) and gave 4-(trifluoromethyl)pyridine 2b in 91%
yield (Table 2, entry 1). Under the same reaction conditions,
the iodopyridazine 1c was converted into the corresponding
trifluoromethylpyridazine 2c in almost quantitative yield
(Table 2, entry 2). These yields are much higher than those
obtained using the previously reported reagent mixtures
TMSCF3/CuI/KF or ClCF2CO2CH3/KF/CuI.[14a,15a,b] Similar
results were found when 1d, 1e, and 1 f were treated with
[Ph2SCF3]+[OTf]À (Table 2, entries 3–5).
Table 1: Trifluoromethylation of iodobenzene 1a by [Ph2SCF3]+[OTf]À in
the presence of metals.
Entry
M
1a/[Ph2SCF3]+[OTf]À/ T [8C] t [h] 2a/[Ph2SCF3]+/
M[a]
[OTf]À[b]
(conv. [%][c])
1
2
3
4
5
6
Fe
1:1:1.5
110
110
60
60
60
10 0:0.17:1 (83)
10 0:0.3:1 (70)
[Pd(PPh3)4] 1:1:1.5
Zn
Ag
CuI
Cu
1:1:2
1:1:2
1:1:2
1:1:2
9
9
9
9
0:0:1 (quant.)
0:0.92:1 (8)
0:0.85:1 (15)
0.5:0:1
60
(quant.)
The steric hindrance around the iodo-substituent in the
substrates had a marked impact on the trifluoromethylation
reaction. When iodine is flanked by two methyl groups on a
pyrazole ring, higher reaction temperatures were needed to
ensure complete trifluoromethylation (compare Table 2,
entries 3 and 4). The 2-iodoimidazoles 1g and 1i were also
trifluoromethylated in high yield (Table 2, entries 6 and 8).
Changing the N-phenyl group to the much more bulky trityl
group, however, yielded none of the desired product, even
when the reaction was run at 808C for 11 hours (compare
Table 2, entries 6 and 7). Trifluoromethylation of 1j by
[Ph2SCF3]+[OTf]À in the presence of Cu gave 2j in a 92%
yield (Table 2, entry 9), which is much higher than the 65%
yield previously reported for the same transformation using
TMSCF3/CuI/KF as the reagent mixture.[15c] 6-Trifluoro-
methyl-2-phenylimidazo[1,2-a]pyridine (2k) could also be
prepared under our reaction conditions when 1k was
employed as the substrate (Table 2, entry 10). Upon Treat-
ment of 1l with [Ph2SCF3]+[OTf]À/Cu, 2l was successfully
generated, without loss of the N-tert-butoxycarbonyl group
(Table 2, entry 11). Moreover, our method was suitable for
the trifluoromethylation of 3-iodo-1H-indole (1m) and pro-
duced 2m (Table 2, entry 12). This result is particularly
significant because reactions previously employed to prepare
7
Cu
1:1:2
60
4
0.34:0:1
(quant.)
0.1:0:1 (quant.)
0:0.3:1 (70)
0:1:1 (0)
8
9
10
Cu
Cu
Cu
1:1:1
1:1:0.5
1:1:2
60
60
RT
9
9
9
[a] Molar ratio. [b] Molar ratio, determined by 19F NMR spectroscopy.
[c] Conversion of [Ph2SCF3]+[OTf]À determined by 19F NMR spectroscopy.
DMF=N,N-dimethylformamide, Tf=triflate.
only 17% of [Ph2SCF3]+ remained (Table 1, entry 1). Upon
replacement of Fe by [Pd(PPh3)4], 70% of the cation was
converted under the same conditions (Table 1, entry 2). Zinc
was a good reductant for the reaction compared to Ag, Fe,
and CuI (Table 1, entries 1, 3–5) and, with this metal, the
[Ph2SCF3]+ cation was completely transformed even when the
reaction was conducted at 608C for 9 hours (Table 1, entry 3).
Although zinc was effective in reducing the sulfonium salt,
serious defluorination of the CF3 synthon invariably took
place, and none of the desired trifluoromethylbenzene 2a was
formed. Using Cu instead of Zn, however, we found that
defluorination was somewhat alleviated and 2a was detected
(Table 1, entry 6). When the reaction time was shortened, 2a
was obtained in a lower yield (Table 1, entry 7). The
[Ph2SCF3]+[OTf]À was completely reduced but the active
Angew. Chem. Int. Ed. 2011, 50, 1896 –1900
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