DOI: 10.1002/anie.201103526
Synthetic Methods
Synthesis of Trifluoroethyl-Substituted Ketones from Aldehydes and
Cyclohexanones**
Bill Morandi and Erick M. Carreira*
The demand for and applications of organofluoride com-
pounds in pharmaceuticals and agrochemicals[1] has kindled
interest in the development of convenient methods for their
preparation. Trifluoromethyl-substituted aldehydes and
ketones at the a-carbon center constitute particularly useful
starting materials for the synthesis of a wide range of
condensed, derived building blocks. The synthetic approaches
to a-carbon trifluoromethyl-substituted carbonyl compounds
rely on the reaction of enolates with intermediates generated
from single electron-transfer processes or electrophilic CF3-
transfer reagents.[2,3] Carbonyl homologation reactions that
employ fluorinated diazoalkanes provide alternative means for
the introduction of CF3 subunits.[4,5] Yet there is a lack of useful
methods that rely on these for the preparation of trifluor-
oethyl-substituted ketones.[6,7] The absence of safe methods for
the generation and handling of fluorinated diazoalkanes, in
particular F3CCHN2, has been a hindrance to the development
of this approach. Herein, we report the homologation of
aldehydes and cyclohexanones employing F3CCHN2 generated
in situ from F3CCH2NH2·HCl.[8,9] The method allows straight-
forward conversion of these substrates into trifluoromethyl-
substituted ketones whose syntheses have not been previously
reported. Key to the success of the process is the identification
of ZrCl4 as a suitable Lewis acid that is compatible with the
conditions for generation of F3CCHN2 in situ.
The chemistry of trifluoromethyl diazomethane has not
been extensively investigated, outside of its use in cyclo-
propanation reactions, because of the hazardous nature of this
reagent. The handful of early reports involving this reagent
prescribe its isolation and purification by distillation prior to
its use, which comes with risk.[10] We have been interested in
examining reactions utilizing trifluoromethyl diazomethane
generated in situ without isolation. These boundary condi-
tions have prompted the identification of catalysts that are
competent in acidic, aqueous media. We have recently
reported reactions that take advantage of F3CCHN2 gener-
ated in situ and its subsequent metal-catalyzed (Fe, Rh, Co)
reactivity in aqueous media to afford trifluoromethyl-sub-
stituted cyclopropane and cyclopropene derivatives.[8] Our
interest in the chemistry of F3CCHN2 has subsequently led us
to examine it in aldehyde homologation processes.
In the initial screening, we were concerned with the ability
to conduct the homologation reaction with F3CCHN2 gen-
erated in situ under operationally simple conditions. The use
of F3CCHN2 in homologation reactions is not without
precedence; however, reports on its reaction with aldehydes
and ketones are rather limited in scope. Moreover the
conditions and/or activating agents render the processes
impractical and untenable. Thus in work limited to only two
cyclohexanones, Mock and Hartman disclosed the use of large
excess of Et3OBF4 as an activating agent.[4g–h] Only few
examples have been reported involving aldehydes. Tordeux
and Wakselman examined three aldehydes (pentanal, cyclo-
hexane carbaldehyde, and benzaldehyde) in the homologa-
tion reaction with stoichiometric amounts of BF3 or SbCl5,
and only pentanal afforded CF3-substituted ketone (52%
yield), and the rest furnished mixtures including oxiranes and
other products.[7a] Activated aldehydes have also been the
subject of limited investigations with a notable lack of success.
Thus the reaction of ethyl glyoxylate proceeds in 41% yield[7b]
after two days. The process employing chloral[7c] or fluoral was
conducted in the dark for six weeks to provide products in
undetermined yield for the former, as an inseparable mixture
with the epoxides, and 5% yield for the latter.
Because of the lack of precedent for homologation
reactions with F3CCHN2 under a more practical set of
conditions, we examined whether the homologation of more
useful set of aldehydes could be executed without recourse to
isolation and handling of the diazoalkane. In this respect we
were concerned about the use of Lewis acids under conditions
for the generation of the diazoalkane from an amine with
NaNO2, because the process typically requires aqueous media
and, significantly, itself leads to water formation
(F3CCH2NH3Cl + NaNO2!F3CCHN2 + 2H2O + NaCl).
We set reaction boundary conditions wherein
F3CCH2NH2·HCl and NaNO2 were stirred for 1 hour at 08C
in CH2Cl2/water (30:1) followed by cooling and addition of
substrate and Lewis acid after 10 minutes. A wide range of
Lewis acids were screened, including BF3·OEt2, SnCl2, ZrCl4,
[*] B. Morandi, Prof. Dr. E. M. Carreira
Laboratorium fꢀr Organische Chemie, ETH Zꢀrich
8093 Zꢀrich (Switzerland)
E-mail: carreira@org.chem.ethz.ch
[**] We are grateful to the Swiss National Foundation and the SSCI for a
fellowship to B.M. Dr. Schweizer is acknowledged for crystallo-
graphic analyses.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 9085 –9088
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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