Communication
ample, acetyl or tert-butyloxycarbonyl, did not lead to the
product formation, even at elevated temperatures. Modifying
the substitution pattern of the benzene ring did not affect the
generality of our method. Halides (3e–h) as well as an ether
[
a]
Table 1. Optimization of reaction conditions.
(
3i), as functional groups that represent a possible handle for
further diversification of the structural motif, were tolerated
well. Strongly electron-deficient substituents required elevated
temperatures for the product formation. Indoles containing
ester, nitro, and cyano substituents were isolated in good
yields (3j–m). Finally, substituting either the 2- or 3-position of
indole provided the desired trichloromethylthiolated products
[
b]
Entry
Solvent
Reagent
Yield [%]
1
2
3
4
5
6
7
DCE
toluene
DMF
DMSO
1,4-dioxane
MeCN
MeCN
1b
1b
1b
1b
1b
1b
1a
45
82
0
0
27
99 (88)
0
(
3n and 3o) in good to excellent yields that should allow for
the trichloromethylthiolation of various naturally abundant
[
3e]
indole alkaloids.
The obtained regioselectivity was un-
[
a] Reactions were performed on a 0.1 mmol scale with TMSCl (1.5 equiv)
equivocally validated by single-crystal X-ray analysis of 3b
19
and reagent (1.5 equiv). [b] Yields determined by F NMR spectroscopic
analysis with 1-fluoronaphthalene as internal standard. Isolated yields in
parentheses.
[
13]
(
Figure 2).
To further demonstrate the generality, we performed the tri-
chloromethylthiolation of more sensitive pyrroles under the
optimized reaction conditions (Table 3). In all cases,
the reaction exclusively provided the single regioiso-
mer shown. Pleasingly, alkyl and aryl substituents on
the nitrogen were tolerated in moderate to good
yields (5a–c) that is of high importance because N-
substituted pyrroles are core structures for various
[
a]
Table 2. Trichloromethylthiolation of indoles.
[
3c]
bioactive compounds. Additionally, several substi-
tution patterns at the pyrrole core provided the de-
sired products; ketone-, ester-, and aryl-substituted
pyrroles could be isolated in moderate to good
yields (5d–f). Substituting the reactive 2- and 5-posi-
tion of the pyrrole core did not inhibit the reaction,
with the trichloromethylthiolation at the 3-position
occurred in moderate yield (5g).
With the trichloromethylthiolated products in
hand, we wanted to explore possible diversifications
of the SCCl3 group (Scheme 2). Subjecting product
3
c to meta-chloroperbenzoic acid (mCPBA) afforded
sulfonyl 6a in a moderate yield, giving access to pre-
viously inaccessible trichloromethylsulfonyl-substitut-
ed indole derivatives. Additionally, we were able to
selectively perform the chlorine/fluorine exchange
employing triethylamine trihydrofluoride as fluoride
source in good yield and perfect selectivity. The tri-
chloromethylthiolated products could, therefore, act
18
as precursors for F-radiolabelled compounds, which
cannot be synthesized from the corresponding tri-
fluoromethylthiolated compounds. Furthermore, di-
chlorofluoromethylthiolated indoles possess biologi-
[
14]
cal activity against acarids and insects.
[
a] Reactions were performed on a 0.5mmol scale. Isolated yields of products are re-
ported. [b] Reaction was performed on a 2.5mmol scale. [c] Reaction was run at
008C.
After determining the scope of the reaction, we
wanted to explore the robustness of our developed
method. Therefore, we decided to also apply an addi-
tive-based robustness screen to our reaction
1
[
15]
(
Table 4). Using this screen, it is possible to identify
reaction conditions, impressively with complete C3-regioselec-
tivity. In addition to the unprotected indole, various substitu-
ents on the nitrogen were tolerated in good to excellent yields
which functional groups are tolerated under the reaction con-
ditions and by the reaction. To our delight, a broad range of
different additives bearing a variety of functional groups were
tolerated under the reaction conditions. In addition to halides
(
3a–d). Electron-deficient substituents on the nitrogen, for ex-
4401
Chem. Eur. J. 2016, 22, 4400 – 4404
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