.
Angewandte
Communications
DOI: 10.1002/anie.201300782
Trifluoromethylation
Copper-Catalyzed Trifluoromethylation of N,N-Dialkylhydrazones
Etienne Pair, Nuno Monteiro, Didier Bouyssi,* and Olivier Baudoin*
Trifluoromethylated molecules have been drawing increasing
attention from the pharmaceutical and agrochemical indus-
tries in recent years. This is mainly due to the fact that the
trifluoromethyl (CF3) group often improves the metabolic
stability and lipophilicity of biologically active compounds.[1]
On this basis, the need for efficient methods for the
incorporation of this group into target molecules has spurred
research to discover new, practical CF3-transfer reagents.[2] In
this line, Togni and co-workers have reported new hyper-
valent iodine(III) CF3 compounds as mild electrophilic
reagents for trifluoromethylation.[3] Recent applications of
these reagents have highlighted the benefit of Lewis acid
activation in terms of increasing their electrophilic reactiv-
ity.[4] For instance, the relatively cheap copper salts were
found to be highly efficient CF3-transfer catalysts.[5]
N,N-Dialkylhydrazones are important and versatile
reagents in organic chemistry. Mainly used as synthetic
equivalents of carbonyl compounds, they can also participate
in free radical, pericyclic, and organometallic reactions. As
well as having other interesting features, they are valuable
intermediates for organic-functional-group transformations,
notably as precursors to substituted hydrazines or primary
The first studies to determine the capability of Togniꢀs
reagent (2) to transfer a CF3 group to the azomethine carbon
of hydrazones were conducted on p-nitrobenzaldehyde N,N-
dimethylhydrazone (1a) as a model substrate (Table 1).
Table 1: Selected optimization experiments for the trifluoromethylation
of N,N-dimethylhydrazone 1a with 2.[a]
Entry
Solvent
Cat. (mol%)
t [h]
Yield [%][b]
1
2
3
4
5
6
7
MeOH
MeOH
MeCN
CH2Cl2
CHCl3
CHCl3
CHCl3
CuI (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (5)
none
5
2
2
0.75
0.5
1
59
60
75
92
97 (96)[c]
72
0
20
[a] Reaction conditions: 1a (0.20 mmol), 2 (0.24 mmol), catalyst, solvent
(1.5 mL). [b] Determined by 19F NMR spectroscopy using trifluoro-
toluene as an internal standard. [c] Yield of the isolated product.
ꢀ
amines upon reductive cleavage of the N N bond, and as
chiral auxiliaries in asymmetric synthesis.[6] Efficient proto-
cols for the substitution of aldehyde N,N-dialkylhydrazones at
the azomethine carbon have been developed; these protocols
rely on direct reactions with active electrophiles.[7] However,
to the best of our knowledge, there is no precedent for the
direct incorporation of a CF3 group into these compounds.[8]
Herein we report an efficient, mild procedure for the
trifluoromethylation of (hetero)aromatic aldehyde hydra-
zones based on the use of a hypervalent iodine reagent under
copper catalysis (Scheme 1).
Initially, the reaction in the presence of 10 mol% of CuI at
room temperature with MeOH as solvent, was evaluated.
Gratifyingly, the desired trifluoromethylated hydrazone 3a
was obtained as the sole reaction product in a very promising
59% yield as determined by 19F NMR spectroscopy (Table 1,
entry 1). Other combinations of solvents and copper salts
were then examined. The solvent and catalyst of choice for
this transformation are CHCl3 and CuCl, respectively. Under
these reaction conditions, clean and full conversion of the
starting material was achieved within a few minutes to give 3a
in nearly quantitative yield upon isolation (Table 1, entry 5).
Notably, no reaction occurred in the absence of catalyst under
otherwise identical reaction conditions (Table 1, entry 7).
With the optimized conditions established, we next
investigated the effect of varying the nature of the dialkyl-
amino group of p-nitrobenzaldehyde hydrazones (Table 2).
Other acyclic amino groups were first examined and com-
pared to N,N-dimethylhydrazone 1a. The reaction of N,N-
dibenzylhydrazone 1b still furnished the expected trifluor-
omethylated product in acceptable yield, although a longer
reaction time was required (Table 2, entry 1), whereas the
reaction of hydrazone 1c, having a much less electron-
donating diphenylamino group, resulted in poor conversion
and lower yield (Table 2, entry 2). Importantly, the reaction
did not tolerate secondary amino groups as illustrated by the
reaction of N-methylhydrazone 1d. In this case, an intractable
mixture of several trifluoromethylated products was
Scheme 1. CuI-catalyzed trifluoromethylation of N,N-dialkylhydrazones.
Alk=alkyl.
[*] E. Pair, Dr. N. Monteiro, Dr. D. Bouyssi, Prof. Dr. O. Baudoin
Universitꢀ Claude Bernard Lyon 1, CNRS UMR 5246
Institut de Chimie et Biochimie Molꢀculaires et Supramolꢀculaires
CPE Lyon, 43 Boulevard du 11 Novembre 1918
69622 Villeurbanne (France)
E-mail: didier.bouyssi@univ-lyon1.fr
Supporting information for this article is available on the WWW
5346
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 5346 –5349