ORGANIC
LETTERS
2010
Vol. 12, No. 4
844-846
First Efficient Synthesis of Fluorinated
Glycidic Esters from Ketones
Ge´rald Lemonnier, Ludivine Zoute, Jean-Charles Quirion, and Philippe Jubault*
INSA de Rouen et UniVersite´ de Rouen, CNRS UMR 6014 COBRA & FR 3038,
IRCOF, 1 rue Tesnie`re, 76821 Mont-Saint-Aignan Cedex, France
Received December 17, 2009
ABSTRACT
Treatment of various ketones with ethyl dibromofluoroacetate in the presence of diethylzinc and dimethylaminoethanol or triphenylphosphine
provides rapid access to corresponding fluorinated glycidic esters. Simplified workup allowed first characterization of these compounds.
Because of their unique properties, organofluorine com-
pounds have a large range of applications, especially for drug
development purposes and crop protection.1 Indeed, a large
number of new pharmaceuticals incorporate one or more
fluorine atoms.2 In this context, our group is interested in
developing new efficient synthesis methodologies of monof-
luorinated building blocks from commercially available
products. We recently reported the use of ethyl dibromof-
luoroacetate associated with diethylzinc to achieve the
synthesis of R-fluoro-R,ꢀ-unsaturated esters.3
O-cyclization of R-halogeno-R-fluorohydrines,4 fluoroalkene
epoxidation,5 Darzens reaction,6 and tandem fluorination-
cyclization of R,ꢀ-unsaturated ketones.7 To our knowledge,
only one method allowing preparation of fluorinated glycidic
esters has been described, highlighting the particular instabil-
ity of such compounds.5a
During the study of the reactivity of ethyl dibromofluo-
roacetate associated with diethylzinc toward ketones, we
found out that the use of triphenylphosphine as additive
allowed the formation of fluorinated epoxides (Table 1).
Indeed, when 4 equiv of diethylzinc was added to a THF
solution of benzophenone (1 equiv), triphenylphosphine (4
equiv), and ethyl dibromo fluoroacetate (2 equiv), we
observed the complete conversion of the carbonyl compound
and the subsequent formation of the corresponding fluori-
nated glycidic ester by 19F NMR spectroscopy. However,
Epoxides are useful intermediates in organic synthesis
since C-C or C-heteroatom bonds can be created by simple
nucleophilic addition. However, only a few methods of
synthesis of monofluorinated epoxides have been reported:
(1) For reviews on fluorine-containing compounds, see: (a) Hiyama, T.
Organofluorine Compounds: Chemistry Applications; Springer: Berlin, 2000.
(b) Iseki, K. Tetrahedron 1998, 54, 13887. (c) Kirsch, P. Modern
Fluoorganic Chemistry; Wiley-VCH: Weinheim, 2004. (d) Adejare, A.;
Ojima, I.; McCarthy, J. R.; Welch, J. T. J. Med. Chem. 1997, 40, 2967.
(2) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
ReV. 2008, 107, 320. (b) Begue´, J.-P.; Bonnet-Delpon, D. Chimie bioor-
ganique et me´dicinale du fluor; CNRS Editions: Paris, 2005. (c) Mikami,
K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1. (d) Thomas, C. J.
Curr. Top. Med. Chem. 2006, 6, 1529. (e) Kirk, K. L. J. Fluorine Chem.
2006, 127, 1013.
(4) (a) Atlani, M.; Leroy, J. C. R. Acad. Sci. Ser. C 1969, 349. (b)
Cantacuze`ne, J.; Normant, J.-M. Acad. Sc. Ser. C 1970, 748. (c) Duhamel,
P.; Leblond, B.; Poirier, J.-M. J. Chem. Soc., Chem. Commun. 1993, 476.
(d) Duhamel, P.; Leblond, B.; Bidois-Se´ry, L.; Poirier, J.-M. J. Chem. Soc.,
Perkin Trans. I 1994, 2265.
(5) (a) Elkik, E.; LeBlanc, M. Bull. Soc. Chim. Fr. 1971, 870. (b) Michel,
D.; Schlosser, M. Tetrahedron 1996, 52, 2429. (c) Tranel, F.; Haufe, G. J.
Fluorine Chem. 2004, 125, 1593. (d) Bortoloni, O.; Fogagnolo, M.; Fantin,
G.; Maietti, S.; Medici, A. Tetrahedron: Asymmetry 2001, 12, 1113.
(6) (a) Shimizu, M.; Hata, T.; Hiyama, T. Tetrahedron Lett. 1997, 38,
4591. (b) Sa¨ıkia, A. K.; Tsubo¨ı, S. J. Org. Chem. 2001, 66, 643.
(7) Tamura, M.; Matsukawa, Y.; Quan, H.; Mizukado, J.; Sekiya, A. J.
Fluorine Chem. 2004, 125, 705.
(3) (a) Zoute, L.; Dutheuil, G.; Quirion, J.-C.; Jubault, P.; Pannecoucke,
X. Synthesis 2006, 3409. (b) Zoute, L.; Lacombe, C.; Quirion, J. C.; Charette,
A. B.; Jubault, P. Tetrahedron Lett. 2006, 47, 7931. (c) Lemonnier, G.;
Zoute, L.; Dupas, G.; Quirion, J.-C.; Jubault, P. J. Org. Chem. 2009, 74,
4124.
10.1021/ol902903v 2010 American Chemical Society
Published on Web 01/22/2010