Organic Letters
Letter
2
C(sp ) bond under Ni or Ni/photoredox dual catalysis.
However, these reactions only proceed with benzylic-activated
xanthates or thiocarbamates.
TTMSS may be due more facile reaction with trifluoromethyl
radical to produce the active Si-based radical. Switching the
copper complex to 2b decreased the yield, but no product was
formed when complex 2c or 2d was employed (Table 1,
Direct trifluoromethylation of unactivated thiocarbonyl
systems remains an important goal. In a search for a general
and operationally simple methodology, we envisioned that
bpyCu(CF ) (i.e., Grushin’s reagent) could be used for the
trifluoromethylation of O-alkyl xanthates or thiocarbonates.
The homolysis of bpyCu(CF ) could generate CF -based
radical and a highly reactive Cu (CF ) species.
based radical could react with a suitable silane to generate an
Si-based radical for the subsequent reaction with thiocar-
bonates. The coupling reaction between the newly formed
17
entries 5−7). These results suggest that a Cu(I)CF species
3
was not the active CF source for the reaction even under the
3
18
reaction conditions. Further investigation revealed that the Si-
based radical activated the thiocarbonate preferentially to the
3
3
CF radical (Table 1, entry 8). Sodium persulfate (Na S O )
3
2
2
8
3
3
3
II
7a,g,19
was found to significantly increase the reaction yield (Table 1,
entry 9). The persulfate likely serves as a complementary
radical initiator for the generation of silyl radical. Interestingly,
water proved beneficial in the reaction (Table 1, entry 10).
This could be due to the improved solubility of the persulfate
in aqueous solvent, and the potential of lowering the reductive
The CF3-
3
2
II
alkyl radical and Cu (CF ) species finally gives the
3
2
2
0
trifluoromethylated product. At the outset, it was unclear
whether the coupling process would outcompete the direct
reduction of the alkyl radical by silane.
With the above design in mind, we began the investigation
with the trifluoromethylation of unactivated secondary
thiocarbonate 1a. After extensive examination of the reaction
conditions, we identified that visible-light irradiation of
bpyCu(CF ) /1a in the presence of super silane (TTMSS)
and Na S O provided the trifluoromethylation product 3a in
6% yield (Table 1, entry 1). Surprisingly, no desired product
was detected when Bu SnH was used, despite its wide
application in Barton−McCombie-type reactions (Table 1,
entry 2). Triethylsilane and triisopropylsilane were also inferior
to super silane (Table 1, entries 3−4). The greater activity of
7g
elimination energy barrier by aqua complex. The blue light
serves to homolyze 2a to give CF radical and Cu(II) species
3
(
Table 1, entry 11). In addition, the use of 1 equiv
thiocarbonate or excess 2a only gave the desired product in
moderate yield respectively (Table 1, entries 13 and 14).
With the above optimized conditions in hand, we next
evaluated a range of unactivated thiocarbonates (Scheme 2a).
The electron-rich arenes were well tolerated in this protocol,
thus giving the trifluoromethylation products 3a, 3b, and 3f in
moderate-to-high yields. For the substrates with different
amides and phthalimide, the trifluoromethylation also
delivered products 3c−3e in good yields. The reaction was
also compatible with molecules bearing alkyne (1g) or
conjugated and terminal alkenes (1h, 1i), thereby highlighting
the selectivity of the underlying radical reactions. In spite of
numerous reports detailing the reaction of unsaturated C−C
3
3
2
2
8
8
n
3
a
Table 1. Optimization of Reaction Conditions
2
,5
bonds and arenes with CF radical, such functional groups
3
were well tolerated in the reaction. Under these reaction
conditions, the CF radical generated from Grushin’s reagent is
3
quenched rapidly by TTMSS to release Si radical, which avoids
reaction of the CF radical with arenes or other units of
3
unsaturation. In competition experiments with primary and
secondary thiocarbonates (e.g., 1j), the secondary thiocar-
bonate was selectively trifluoromethylated with only a trace
amount of the primary trifluoromethylated product. The
reaction tolerated tosylated (1k) and silylated (1l) substrates,
with selective trifluoromethylation in high yields. Heteroarenes
were well tolerated in the reaction, giving the product 3m in
b
entry
deviation
yield (%)
1
2
3
4
5
6
7
8
9
none
86
4
n
Bu SnH instead of TTMSS
3
Et SiH instead of TTMSS
Pr SiH instead of TTMSS
20
40
74
nd
nd
nd
15
18
nd
10
57
3
i
3
2b instead of 2a
2c instead of 2a
2d instead of 2a
no TTMSS
7
0% yield. Cyclic seven- and six-membered rings were suitable,
which delivered the trifluoromethylation products 3n−3q in
moderate yields. In addition, trifluoromethylation of thymidine
no Na S O
2
2
8
derivative provided CF analogue 3r in 39% yield and excellent
3
10
11
12
13
no H O
no hν
under air
2
diastereoselectivity, which clearly shows the potential of facile
trifluoromethylation of complex molecules. Primary thiocar-
bonates 1s and 1t were subjected to the trifluoromethylation,
producing the products in 33 and 28% yields, respectively. We
attribute the low yields of primary substrates to likely slower
initiation and higher energy carbon-based radicals relative to
secondary substrates.
1 equiv of 1a
c
Next, benzylic thiocarbonates were surveyed in the reaction
Scheme 2b). For substrates derived from primary benzylic
(
alcohols, thiocarbonates with a range of functional groups
provided moderate to good yields of the products. The
tolerance of Bpin (1u), OMs (1v), alcohols (1w, 1x), electron-
deficient (1y, 1z) and -rich arenes (1aa) implies great potential
for this methodology in diverse contexts. In particular, the
tolerance of secondary and tertiary alcohols makes it more
competitive than the trifluoromethylation of alkyl halides, since
8
09
Org. Lett. 2021, 23, 808−813