ORGANIC
LETTERS
2009
Vol. 11, No. 23
5406-5409
Stereocontrolled Access to
Unsymmetrical 1,1-Diaryl-2-fluoroethenes
Gre´gory Landelle, Marc-Olivier Turcotte-Savard, Judikae¨lle Marterer, Pier
Alexandre Champagne, and Jean-Franc¸ois Paquin*
Canada Research Chair in Organic and Medicinal Chemistry, De´partement de chimie,
1045 aVenue de la Me´decine, UniVersite´ LaVal, Que´bec, QC, Canada G1V 0A6
Received September 30, 2009
ABSTRACT
A simple and effective method for stereocontrolled preparation of 1,1-diaryl-2-fluoroethenes is reported. First, 1-aryl-1-bromo-2-fluoroethenes are
generated using an addition/elimination reaction of hydride to silylated ꢀ,ꢀ-difluorostyrene derivatives followed by a bromination/desilicobromination
reaction. Subsequent Suzuki-Miyaura coupling with a variety of boronic acids gives access to the desired 1,1-diaryl-2-fluoroethenes.
1,1-Disubstituted-2-fluoroethenes (1-3 in Figure 1) are of
interest in medicinal chemistry because they can be used,
for example, in the design of mechanism-based enzyme
inhibitors.1 Although a few methods for the stereoselective
preparation of 1 (R1 * R2)2-4 and 25,6 exist, to the best of
our knowledge, no method for the stereoselective preparation
of 3 (R1 * R2) has been reported.7 Regardless of this
synthetic shortcoming, bioactive 1,1-diaryl-2-fluoroethenes
(i.e., 4 and 5 in Figure 1) have been reported (as a E/Z
mixture).8
We have recently reported an addition/elimination reaction
of organolithium reagents to silylated ꢀ,ꢀ-difluorostyrene
derivatives (6 or 7 in Scheme 1) followed by a bromination/
desilicobromination reaction as a simple and effective
synthetic approach to a wide range of bromofluoroalkenes
(Z/E up to >97/3). These were then submitted to a number
of Pd-catalyzed transformations giving access to both tri-
and tetrasubstituted fluoroalkenes.9 On the basis of these
(1) (a) McDonald, I. A.; Lacoste, J. M.; Bey, P.; Wagner, J.; Zreika,
M.; Palfreyman, M. G. J. Am. Chem. Soc. 1984, 106, 3354–3356. (b)
McCarthy, J. R.; Jarvi, E. T.; Matthews, D. P.; Edwards, M. L.; Prakash,
N. J.; Bowlin, T. L.; Mehdi, S.; Sunkara, P. S.; Bey, P. J. Am. Chem. Soc.
1989, 111, 1127–1128. (c) Kirsh, P. Modern Fluororganic Chemistry;
Wiley-VCH: Weinheim, 2004. (d) Berlowitz, D. B.; Karukurichi, K. R.;
de la Salud-Bea, R.; Nelson, D. L.; McCune, C. D. J. Fluorine Chem. 2008,
129, 731–742. (e) Be´gue´, J.-P.; Bonnet-Delphon, D. Bioorganic and
Medicinal Chemistry of Fluorine; Wiley & Sons: Hoboken, 2008.
(2) (a) McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber,
E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S. J. Am. Chem.
Soc. 1991, 113, 7439–7440. (b) McCarthy, J. R.; Huber, E. W.; Le, T.-B.;
(7) For examples of methodology for the preparation of 3 with R1 )
R2, see: (a) Bornstein, J.; Blum, M. S.; Pratt, J. J., Jr. J. Org. Chem. 1957,
22, 1210–1213. (b) Bergmann, E. D.; Moses, P.; Neeman, N.; Cohen, S.;
Kaluszyner, A.; Reuter, S. J. Am. Chem. Soc. 1957, 79, 4174–4178. (c)
Silversmith, E. F.; Smith, D. J. Org. Chem. 1958, 23, 427–430. (d) Beltrame,
P.; Beltrame, P. L.; Cereda, M. L.; Lazzerini, G. J. Chem. Soc. B 1969,
1100–1102. (e) Boys, M. L.; Collington, E. W.; Finch, H.; Swanson, S.;
Whitehead, J. F. Tetrahedron Lett. 1988, 29, 3365–3368. (f) Matthews,
D. P.; Miller, S. C.; Jarvi, E. T.; Sabol, J. S.; McCarthy, J. R. Tetrahedron
Lett. 1993, 34, 3057–3060. (g) Satoh, T.; Takano, K.; Someya, H.; Matsuda,
K. Tetrahedron Lett. 1995, 36, 7097–7100. (h) Asakura, N.; Usuki, Y.;
Iio, H. J. Fluorine Chem. 2003, 124, 81–88.
Laskovics, M.; Matthews, D. P. Tetrahedron 1996, 52, 45–58
(3) For a nonselective method for the preparation of 1 (R1 * R2), see:
Tius, M. A.; Kawakami, J. K. Tetrahedron 1995, 51, 3997–4010
(4) For the preparation of 1 with R1 ) R2, see: Du, Z.; Haglund, M. J.;
Pratt, L. A.; Erickson, K. L. J. Org. Chem. 1998, 63, 8880–8887
(5) (a) Reference 1a. (b) Miura, T.; Ito, Y.; Murakami, M. Chem. Lett.
2008, 37, 1006–1007
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(6) For nonselective or moderately selective methods for the preparation
of 2, see: (a) Burton, D. J.; Greenlimb, P. E. J. Org. Chem. 1975, 40, 2796–
2801. (b) Hayashi, S.-i.; Nakai, T.; Ishikawa, N.; Burton, D. J.; Naae, D. G.;
Kesling, H. S. Chem. Lett. 1979, 983–986. (c) Purrington, S. T.; Pittman,
J. H. Tetrahedron Lett. 1987, 28, 3901–3904. (d) Reference 3. (e) Greedy,
B.; Gouverneur, V. Chem. Commun. 2001, 233–234. (f) Ichikawa, J.; Wada,
(8) (a) Coghlan, M. J.; Green, J. E.; Grese, T. A.; Jadhav, P. K.;
Matthews, D. P.; Steinberg, M. I.; Fales, K. R.; Bell, M. G. WO 2004052847
A2, 2004. (b) Katsuta, Y.; Hirobe, H.; Namite, Y. JP 60209503 A, 1985.
(9) Landelle, G.; Champagne, P. A.; Barbeau, X.; Paquin, J.-F. Org.
Lett. 2009, 11, 681–684.
Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 1917–1936
.
10.1021/ol9022672 CCC: $40.75
Published on Web 11/04/2009
2009 American Chemical Society