TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1055–1057
Trifluoroacetophenone as nucleophilic trifluoromethylating
reagent
Lukas Jablonski, Thierry Billard* and Bernard R. Langlois*
Laboratoire SERCOF (UMR CNRS 5622), Universite´ Claude Bernard-Lyon 1, Baˆt. Chevreul, 43 Bd du 11 novembre 1918,
69622 Villeurbanne, France
Received 26 November 2002; revised 28 November 2002; accepted 28 November 2002
Abstract—Trifluoroacetophenone can be used as nucleophilic trifluoromethylating reagent towards non-enolizable ketones by
action of potassium tert-butoxide. © 2003 Elsevier Science Ltd. All rights reserved.
factory results with trifluoroacetamides,6 with tri-
Because of the particular properties of fluorine, the
fluoroacetophenone in the presence of benzophenone
(Table 1).
introduction of such an element on organic substrates
induces dramatic consequences on their physical, chem-
ical and biological properties.1 Among fluorinated com-
pounds, trifluoromethylated ones present unique
biological activities.2 For this reason, a variety of meth-
ods have been developed for their preparation.3 In
recent years, the anionic trifluoromethylation strategy
has emerged as one of the most powerful.4
We can notice, in the case of trifluoroacetamides, that
the use of DMF seems to be essential to reach good
yields. In contrast, the reaction time was shorter (20
min instead of 24 h). Nevertheless, 2 equiv. of tri-
fluoroacetophenone and tert-butoxide were necessary
to achieve quantitative yields. This could be explained
by the high instability of the tetrahedral intermediate
In our quest for new nucleophilic trifluoromethylating
reagents, we previously reported that hemiaminals of
trifluoroacetaldehyde are efficient trifluoromethylating
agents for non-enolizable carbonyl compounds.5 More
recently, we also demonstrated that trifluoroacetic
derivatives (amides and esters) can also constitute pow-
erful trifluoromethylating reagents towards non-enoliz-
able compounds by action of potassium tert-butoxide
(Scheme 1).6
t
arising from the addition of BuOK on 1 which then
released the CF3 anion too fast. Thus the latter partly
collapsed before adding to benzophenone. This hypoth-
esis is in accordance with the shortened reaction timed.
In relation with this concept, we now focus our interest
on an older well-known reaction: the haloform reaction
from trifluoromethylketones (Scheme 2).7 Indeed, in
this reaction, carboxylic acids are obtained by releasing
a CF3 anion but, to our knowledge, nobody tried to
trap it with an electrophile.
In order to use this reaction to achieve nucleophilic
trifluoromethylation, we decided to react potassium
tert-butoxide (solution 1 M in THF), which gave satis-
Scheme 1. Trifluoromethylation with trifluoroacetic acid
derivatives.
Keywords: trifluoroacetophenone; nucleophilic trifluoromethylation;
fluorinated compounds; trifluoromethylcarbinol.
Scheme 2. Haloform reaction with trifluoromethylketones.
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