Communication
Scheme 3. Trifluoromethylthiolation of different N-heteroarenes. Reaction
conditions: Heteroarene (0.5 mmol), reagent 5 (1.1 equiv), sodium chloride
(
10 mol%), DMF (2.5 mL), 908C, 14 h. Yields of isolated product are given.
thylthiolation of imidazo[1,2a]pyridine, which represents an im-
[20]
portant class of drugs acting as GABAA receptor agonists.
giving product 12.
To elucidate the mechanistic aspects of the transformation,
we first carried out the trifluoromethylthiolation of indole in
the presence of radical inhibitors (Scheme 4). In the case of hy-
droquinone and 2,6-di-tert-butyl-4-methylphenol (BHT), no in-
Scheme 2. Trifluoromethylthiolation of indole derivatives. Reaction condi-
tions (unless otherwise stated): Indole (0.5 mmol), reagent 5 (1.1 equiv),
sodium chloride (10 mol%), DMF (2.5 mL), 908C, 24 h. Yields of isolated
2
product are given. [a] reaction time=14 h. [b] PdCl (5 mol%) as catalyst.
(
Scheme 2). Again, no protecting group was required and both
Scheme 4. Trifluoromethylthiolation of indole in the presence of radical in-
hibitors. Reaction conditions: indole (0.1 mmol), reagent 5 (1.1 equiv),
electron-withdrawing (Scheme 2, 9c–h) and electron-donating
substituents (Scheme 2, 9i) were well tolerated. Notably, substi-
tution of the benzo moiety, in any position, did not negatively
influence the reaction (Scheme 2, 9c–i). However, whereas a 2-
substituted indole was smoothly converted to the desired
product (Scheme 2, 9b), no product was observed in the case
of 3-substituted indole derivatives. Since the latter represent
an important structural motif in pharmaceuticals and natural
sodium chloride (10 mol%), radical inhibitor (0.5 equiv), DMF (0.5 mL), 908C,
19
1
4 h. Yields were determined by F NMR spectroscopy with (trifluorome-
thoxy)benzene as internal standard.
fluence on the yield of the reaction was observed, whereas
free radicals, namely 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and galvinoxyl, led to diminished yields. However, no
radical coupling products were observed. These results, com-
bined with the observed C3-selective functionalization of in-
doles, indicate an electrophilic substitution mechanism rather
than a radical pathway.
[
1b–e]
products,
we conducted a brief screening of chloride sour-
ces with other metal cations for the additional activation of
the indole core. To our delight, palladium(II) chloride and
gold(III) chloride both displayed high catalytic activities. Thus,
employing palladium(II) chloride as the catalyst, under other-
wise identical conditions, 3-methylindole (Scheme 2, 8k) and
ethyl-3-indole-acetate (Scheme 2, 8l) were converted to the
desired trifluoromethylthiolated compounds. The latter repre-
sents a derivative of indole-3-acetic acid (IAA), a naturally oc-
curring phytohormone that, along with its derivatives, is used
[17a,21]
In light of previous reports,
we propose that catalytic
amounts of chloride acting as a Lewis base lead to the in situ
formation of highly reactive trifluoromethylsulfenyl chloride
(CF SCl). The latter subsequently undergoes an electrophilic ar-
3
omatic substitution reaction with the N-heteroarene, yielding
[10a]
the desired trifluoromethylthiolated product (Scheme 5).
Monitoring the trifluoromethylthiolation of 2-phenylpyrrole
[
18]
in the agrochemical field.
19
Finally, we turned our attention to the trifluoromethylthiola-
tion of more challenging N-heteroarenes (Scheme 3). To our
delight, 7-azaindole and an indolizine derivative provided the
desired products (10, 11) in excellent yields. Both heteroarenes
constitute important classes of bioactive compounds. Fur-
thermore, we successfully performed the selective trifluorome-
by F NMR spectroscopy (470 MHz, [D ]DMSO), we observed
6
the continuous decrease of the signal from reagent 5 (d=
À48.4 ppm), whereas the signal from the product (d=
À44.6 ppm) increased. However, neither CF SCl nor any related
3
[19]
intermediate were detected, which may be attributed to its
high reactivity. Repeating the reaction in the absence of 2-phe-
Chem. Eur. J. 2015, 21, 1 – 6
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