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Table 2: Copper-catalyzed trifluoromethylthiolation of indoles.
thiolation product 4a in 32% yield (entry 2). Electrophilic
trifluoromethylthiolation of CF3SSCF3 generates 1 equivalent
of CF3SÀ, which could be oxidized back to CF3SSCF3 with
agents such DMSO.[21]
We then performed reactions by adding either DMSO,
TMSO, or I2 to the reaction system (Table 1, entries 4–6). The
reaction with DMSO afforded a trace amount of 4a. Metal
salts are able to catalyze trifluoromethylthiolation with 2b,[15]
while I2 is able to promote sulfenylation of sodium sulfi-
nates.[19] After testing copper and silver salts, as well as I2 for
the CF3SO2Na reactions (entries 7–13), we found that the
reaction with CuCl (0.5 equiv) together with DMSO afforded
a good amount of 4a (55%; entry 13). Optimization of the
reaction conditions (entries 10–17) revealed that using
(EtO)2P(O)H (2.0 equiv), DMSO (3.0 equiv), and CuCl
(1.0 equiv) in toluene at 1108C for 12 hours could increase
the product yield to 94% (entry 14).
Reactions of a series of substituted indoles under the
optimized reaction conditions were conducted. Trifluorome-
thylthiolation took place selectively at the 3-position of
indoles to form products bearing methyl (4b), methoxy (4c),
halogens (4d–f), nitro (4g), esters (4h, 4o), and hydroxy (4n)
groups at the 4-, 5-, 6-, and 7-positions in 42–93% yields
(Table 2). It was found that indoles with an electron-donating
group gave better results than those with an electron-with-
drawing group, for example, 4n and 4o. The bulky substituent
in 4o and 4r affected the yields. N-substituted indoles with
either Me, Et, or Ph groups afforded the products 4s–v in 77,
71, and 63% yield, respectively. The structure of 4h was
confirmed by single-crystal X-ray analysis (see the Supporting
Information).
Similar to indoles, pyrroles are important nitrogen-
containing heterocyclic rings existing in many natural prod-
ucts, biologically active molecules, and dyes for solar cells.[22]
We were able to do direct trifluoromethylthiolation reaction
of pyrroles (Scheme 1). Under the same reaction conditions
for indoles, the reaction of pyrroles afforded 5a–c in good
yields. Enamines, an important building block for a variety of
biologically and synthetically interested nitrogen-containing
heterocycles,[23] were also used for the synthesis of 6a–b.
It was found in the study of glycosidase inhibitors that the
introduction of CF3S and RfS with a fluorous chain could
stabilize the parent molecules and change their amphiphilic
properties.[24] The RfS groups were introduced by the reaction
of a thiophenol or sulfide with perfluoroalkyl iodides.[25] We
have successfully extended the direct trifluoromethylthiola-
tion for perfluoroalkylthiolation. Sodium perfluoroalkanesul-
finates (RfSO2Na), with a different Rf group, were prepared
following the procedure reported by Hu and DesMarteau.[26]
These compounds were used for the perfluoroalkylthiolation
reactions with indole. The products 7a–d, bearing C2F5S,
C4F9S, C6F13S, and C8F17S groups, respectiey, were obtained in
good yields (Scheme 2).
Reaction conditions: 3 (0.2 mmol), 2b (0.4 mmol), (EtO)2P(O)H
(0.4 mmol), DMSO (0.6 mmol), CuCl (0.2 mmol) in PhMe (1 mL) under
N2 at 1108C for 12 h. Yields are those for the isolated products.
Scheme 1. Trifluoromethylthiolation of pyrroles and enamines. Reac-
tion conditions: pyrroles or enamines (0.2 mmol), 2b (0.4 mmol),
(EtO)2P(O)H (0.4 mmol), DMSO (0.6 mmol), CuCl (0.2 mmol) in
PhMe (1 mL) under N2 at 1108C for 12 h. [a] Yield of isolated product.
[b] Yield determined by GC-MS.
intermediates (8 at d = À78.58 ppm, 9 at d = À62.14 ppm, and
10 at d = À45.48 ppm), and product 4a (d = À44.50 ppm)
were observed (Figure 2). The CF3SO2Na peak disappeared
after 2 hours. The amount of 4a increased steadily during the
reaction process. The structure of 10 was confirmed to be
CF3SSCF3 by its 19F NMR data.[15b,c] To gain more information
for the intermediates, we performed four control reactions in
To understand the mechanism of CF3SO2Na-based direct
trifluoromethylthiolation, a reaction of indole under the
optimized reaction conditions was closely monitored by
19F NMR spectroscopy using PhCF3 as an internal standard.
During the 12 hour reaction process, five fluorine peaks,
including those for the reagent 2b (d = À84.46 ppm), three
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Angew. Chem. Int. Ed. 2015, 54, 14965 –14969