Regioselective electrophilic trifluoromethylation of substituted anilines and derivatives in superacid

Article abstract of DOI:10.1016/S0040-4039(03)00124-2

In a one pot procedure, treatment of chloro or methyl substituted acetanilides in HF/SbF₅/CCl₄ followed by addition of HF/pyridine yields trifluoromethyl derivatives with high regioselectivity.

Full text of DOI:10.1016/S0040-4039(03)00124-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1747–1750
Regioselective electrophilic trifluoromethylation of substituted
anilines and derivatives in superacid
Se´bastien Debarge, Bruno Violeau, Nohair Bendaoud, Marie-Paule Jouannetaud* and
Jean-Claude Jacquesy
Laboratoire ‘Synthe`se et Re´activite´ des Substances Naturelles’, UMR 6514, 40, Avenue du Recteur Pineau,
F-86022 Poitiers Cedex, France
Received 18 December 2002; revised 10 January 2003; accepted 14 January 2003
Abstract—In a one pot procedure, treatment of chloro or methyl substituted acetanilides in HF/SbF5/CCl4 followed by addition
of HF/pyridine yields trifluoromethyl derivatives with high regioselectivity. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results
Trifluoromethylated aromatics are of major importance
and have found a large number of uses as pharmaceuti-
cal and agrochemical agents.
In a typical experiment, to a mixture of HF (6 mL) and
antimony pentafluoride SbF5 (3 mL) magnetically
stirred at −20°C in a teflon reactor, was firstly added
the substrate (2 mmol), then carbon tetrachloride (0.58
mL, 3 equiv.). The mixture was maintained at 0°C for
0.5–2 h, according to the substrate (see Tables 1 and 2).
The mixture was then cooled at −78°C and HF/pyridine
70/30 (v/v) (2 mL) was carefully added. The reaction
mixture was then kept at 0°C overnight, then very
carefully poured into a vigorously stirred mixture of
Na2CO3, H2O and ice. After extraction with ethyl ace-
tate (three times) and usual work-up, the reaction mix-
ture was evaporated to dryness.
Trifluoromethylation of aromatics can be carried out
by conversion of a substituted methyl group (-CCl3,
-C(SMe)3, CO2H) to a trifluoromethyl group, by use of
trifluoromethyl radicals or trifluoromethylcopper, or by
trifluoromethyl dibenzothiophenium salts and their
seleno analogues.1 One pot direct trifluoromethylation
can be performed when an aromatic substrate is reacted
with carbon tetrachloride in the presence of HF and a
Lewis acid.2
We have previously reported the electrophilic bromina-
tion or hydroxylation of anilines, and anilides in a
superacid.3–5
The results reported in Table 1 deserve several com-
ments: anilines 1a–d are too deactivated by N-protona-
tion to react.6 This result reflects the poor electrophilic
+
power of ‘CCl3 ’ obtained from CCl4, the same sub-
We would like to report in this paper the electrophilic
trifluoromethylation of these substrates in HF/SbF5 in
the presence of carbon tetrachloride, followed by the
treatment of the resulting mixture with the fluorinating
agent HF/pyridine to complete the halogen exchange
(Scheme 1).
strates yielding the three hydroxyanilines when treated
with HF/SbF5/H2O2.4 On the other hand, with toluidi-
* Corresponding author. Tel.: +33-(0)5-4945-3702; fax: 33-(0)5-4945-
3501; e-mail: marie.paule.jouannetaud@univ-poitiers.fr
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00124-2

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S. Debarge et al. / Tetrahedron Letters 44 (2003) 1747–1750
Table 1. Trifluoromethylation of anilines
nes 2–4, which are activated by a methyl substituent,
trifluoromethylation is observed in ortho and/or para to
the methyl group. Trifluoromethylation of toluidine 4 in
the presence of trifluoromethyl bromide, zinc and SO2
has been reported to yield the trifluoromethyl derivative,
ortho to the amino group in low yield.7
meta-isomer 14 yields a mixture of chloro-derivatives 23
as major products and only traces of the expected
para-substituted isomer 24 which is recovered unchanged
when submitted again to the same reaction conditions.
This implies that chlorination should occur on the
trichloro (or partially fluorinated) intermediate, carbon
tetrachloride acting as a chlorinating agent.10
Table 2 shows that selective para-trifluoromethylation is
observed with acetanilide 9 to yield compound 16 (65%),
the more stabilized O-protonated substrate being more
reactive than the anilinium ion (vide supra). This result
has to be compared to the trifluoromethylation of
acetanilide 9 by a source of trifluoromethyl radical
leading to a mixture of the three trifluoromethyl deriva-
tives.8 Chloroacetanilides 10–12 give trifluoromethyl
derivatives in excellent yields. A chlorine substituent is
directing the substitution, leading for compounds 11 and
12 to a single isomer (19 and 20, respectively), and for
compound 10 to two isomers 17 and 18.8,9 For compound
11, no trifluoromethylation is observed in para of the
chlorine because of steric hindrance and electronic repul-
sion between the electrophile and the O-protonated
function. A similar substitution pattern is observed in the
trifluoromethylation of compounds 13 to 15 activated by
a methyl group. But surprisingly, the reaction of the
Hydrogenolysis by H2/Pd of the mixture of compounds
23 and 24 yields quantitatively compound 24 (global
yield 70%). Similarly, treatment of compounds 19 and 20
gives compounds 16 and 26, respectively, in excellent
yield (Scheme 2).
To conclude, aniline and chloroanilines 1a–d appear to
be too deactivated by protonation to react with the
poorly electrophilic trichloromethyl ion, whereas
hydroxylation of the same substrates was observed with
protonated hydrogen peroxide in similar conditions. On
the other hand, all the acetanilides studied yield tri-
fluomethylderivatives with high regioselectivity and good
yields. Whereas acetanilide yields directly the para-

S. Debarge et al. / Tetrahedron Letters 44 (2003) 1747–1750
1749
Table 2. Trifluoromethylation of acetanilides
trifluoromethyl analog, meta-trifluoromethylation of
para-chloroacetanilide followed by hydrogenolysis
leads selectively to a meta-trifluoroacetanilide, the chlo-
rine atom acting as an efficient auxiliary group. The
selective synthesis of these trifluoro derivatives appears
to be superior to those previously reported.

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S. Debarge et al. / Tetrahedron Letters 44 (2003) 1747–1750
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Scheme 2.
6. The poor reactivity of the aromatic ring in aminophenols
was also observed by Feiring, trifluoromethylation occur-
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J. Org. Chem. 1979, 44, 2907–2910.
7. Wakselman, C.; Tordeux, M. J. Chem. Soc., Chem. Com-
mun. 1987, 1701–1703.
Acknowledgements
We thank CNRS for financial support and Re´gion
Poitou-Charentes for grant to Se´bastien Debarge.
8. (a) Umemoto, T.; Ando, A. Bull. Chem. Soc. Jpn. 1986,
59, 447–452; (b) Langlois, B. R.; Laurent, E.; Roidot, N.
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