ORGANIC
LETTERS
2006
Vol. 8, No. 5
843-845
Novel Synthesis of (Z)-Difluoroacrylates
via a Highly Stereoselective
Addition−Elimination Reaction
Shigeyuki Yamada, Mayumi Noma, Tsutomu Konno, Takashi Ishihara,* and
Hiroki Yamanaka
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Received November 30, 2005
ABSTRACT
On treating readily prepared benzyl 2,3,3-trifluoroacrylate with various Grignard reagents, e.g., aryl-, alkyl-, or alkenylmagnesium halide, in the
presence of a catalytic amount of copper(I) salt in THF at
yields with high Z-selectivity.
−78 °C for 1 h, the corresponding r,â-difluoroacrylates were obtained in 54−98%
R,â-Unsaturated carbonyl compounds occupy a central
position in organic synthesis owing to their wide utility as
potent synthetic blocks, particularly as Michael acceptors for
conjugate addition reactions1 or dienophiles and dipolaro-
philes for cycloaddition reactions.2-4 Fluorinated acrylates
and their derivatives are likewise of great synthetic value as
building blocks for constructing various sorts of fluorine-
containing compounds,5 which attract much attention in
biological and materials chemistry.6
Therefore, it is a very significant subject to develop a
convenient and effective route to such fluorinated acrylates
and related compounds.7 Out of such compounds, R,â-
difluoro-R,â-unsaturated esters8 have been recognized to be
very useful synthetic intermediates. Several examples of the
E-selective synthesis9 of such Vic-difluorinated carbonyl
compounds has appeared in the literature, while the Z-
selective synthesis of them has not been realized at all. We
wish to disclose the highly Z-selective synthesis of R,â-
difluoroacrylates 2 based on the addition-elimination reac-
tion of 2,3,3-trifluoroacrylate (1) with organocopper reagents.
The starting ester, benzyl 2,3,3-trifluoroacrylate (1), was
readily prepared in two steps as shown in Scheme 1.10
On treating 2-bromo-2,3,3,3-tetrafluoropropanoyl chloride
with benzyl alcohol in the presence of Et3N in Et2O at room
temperature for 20 h, the corresponding benzyl ester was
obtained in 94% yield. Subsequent reductive dehalogena-
(1) For selected reviews on the conjugate addition reactions, see: (a)
Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13-21. (b) Jagnou, K.; Lautens,
M. Chem. ReV. 2003, 103, 169-196. (c) Alexakis, A.; Benhaim, C. Eur. J.
Org. Chem. 2002, 3221-3236. (d) Nakamura, E.; Mori, S. Angew. Chem.,
Int. Ed. 2000, 39, 3751-3771. (e) Sibi, M. P.; Manyem, S. Tetrahedron
2000, 56, 8033-8061.
(5) (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214-
231. (b) Qiu, X.; Meng, W.; Qing, F. Tetrahedron 2004, 60, 6711-6745.
(c) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1-16. (d)
Ichikawa, J.; Wada, Y.; Fujiwara, M. Sakoda, K. Synthesis 2002, 1917-
1936. (e) Soloshonok, V. A. Enantiocontrolled Synthesis of Fluoro-organic
Compounds; Wiley: New York, 1999. (f) Kitazume, T.; Yamazaki, T.
Experimental Methods in Organic Fluorine Chemistry; Kodansha: Tokyo,
1998.
(2) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Per-
gamon Press: Oxford, 1990.
(3) For selected reviews on the Diels-Alder reactions, see: (a) Corey,
E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667. (b) Francesco, F.; Priana,
P.; Ferdinando, P.; Luigi, V. Eur. J. Org. Chem. 2001, 439-455.
(4) For reviews on the 1,3-dipolar cycloaddition reactions, see: (a)
Kanemasa, S. Synlett 2002, 1371-1387. (b) Gothelf, K. V.; Jorgensen, K.
A. Chem. Commun. 2000, 1449-1458. (c) Kanemasa, S. Nippon Kagaku
Kaishi 2000, 155-165.
(6) (a) O’Hagen, D.; Rzepa, H. S. Chem. Commun. 1997, 645-652. (b)
Biomedical Frontiers of Fluorine Chemistry; Ojima, I., McCarthy, J. R.,
Welch, J. T., Eds.; American Chemical Society: Washington, DC, 1996;
Vol. 639. (c) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedical
Aspects of Fluorine Chemistry; Elsevier: Amsterdam, 1993. (d) Welch, J.
T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley-Inter-
science: New York, 1991.
10.1021/ol052897g CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/09/2006