StereoselectiVe Synthesis of R-Fluoroacrylates
hydes. The fluoro Julia olefination9 reaction has been applied
to develop a stereoselective synthesis of R-fluoroacrylates from
a fluorobenzothiazolyl sulfone (prepared in two steps) and an
aldehyde or ketone. Depending on the base and the additive
used to perform the reaction, (Z)- or (E)-R-fluoroacrylate could
be obtained as the major isomer. Most of these procedures
generally suffer from major drawbacks such as lack of selectiv-
ity, mutistep synthesis, expensive starting materials or the
necessity to prepare the fluorinated precusor. To the best of our
knowledge, there are only two examples of one-pot stereose-
lective synthesis of (Z)-R-fluoroacrylates. The first one reported
by Kitazume,10 involved a domino reaction between the sodium
salt of dimethyl fluoromalonate and Michael acceptors. The
second, developed by Mioskowski and Falck,11 is based on the
reaction of ethyl trifluoroacetate with aldehydes using a Cr(II)-
mediated olefination sequence. Our group recently developed
an efficient synthesis of R-fluoroacrylates via a diethylzinc-
promoted Wittig reaction.12 Our interest was to develop new
approaches to stereoselective, atom-economical syntheses of
such compounds. Thus, we report a one-pot stereoselective
synthesis of R-fluoroacrylates from aldehydes and ketones using
diethylzinc as an organometallic mediator.
TABLE 1. Optimization of (Z)-Olefination Process with
p-Anisaldehyde
ratioi
entrya
solvent
yieldh (%)
(Z)-1a/2a
Z/E-1a
anti/syn-2a
1b
2c
3c
4c
5c
THFd
THFe
THFe
THFf
96
51
49
40
84
0/100
51/49
56/44
100/0
63/37
45/55
24/76
25/75
>99/1
96/4
>99/1
>99/1
DCMg,j
<1/99
a All the reactions were carried out with [p-MeOPhCHO] ) 0.1 mol
L-1 except entry 3: [p-MeOPhCHO] ) 0.6 mol L-1 b 2 equiv of Et2Zn
.
was used. c 4 equiv of Et2Zn was used. d 2 h. e 3 days. f reflux (3 h). g rt,
3 h. h Global isolated yield. i Determined by 19F NMR spectroscopy on
the crude mixture. j When the same reaction was carried out in refluxing
DCM, we observed the decomposition of syn-2a.
Results and Discussion
Changing the solvent from THF to DCM improved the yield to
an excellent 84% (entry 5). Moreover, in that case, we obtained
the expected R-fluoroacrylate 1a in almost pure Z form (Z/E
ratio >99/1) and the diastereoisomerically pure syn-R-bromo-
R-fluoro-ꢀ-hydroxy ester 2a.
To examine the scope of this one pot stereoselective synthesis
of (Z)-R-fluoroacrylate 1 and syn-R-bromo-R-fluoro-ꢀ-hydroxy
esters 2, this methodology was applied to various aldehydes
employing the above optimal conditions (Table 2).
When a THF solution of p-anisaldehyde (1 equiv) and ethyl
dibromofluoroacetate (2 equiv) was treated at room temperature
with 2 equiv of diethylzinc (Table 1, entry 1),13 we first observed
the formation of syn- and anti-R-bromo-R-fluoro-ꢀ-hydroxy
esters 2a (55/45 ratio) in nearly quantitative yield.
Next, when 4 equiv of diethylzinc (entry 2) were added to
the initial solution, we observed the formation of R-fluoroacry-
late (Z)-1a and esters 2a (syn/anti ratio: 75/25) after 3 days of
reaction. When the concentration of the reaction mixture was
raised, no improvement was noticed (entry 3). In refluxing THF
(entry 4), the addition of diethylzinc to the same mixture
afforded only (Z)-1a but in moderate yield (40%). No trace of
syn- and anti-R-bromo-R-fluoro-ꢀ-hydroxy esters 2a was ob-
served. This last observation could be explained by the
degradation of 2a which occurs under refluxing conditions.
Under these conditions, (Z)-R-fluoroacrylates 1 and syn-R-
bromo-R-fluoro-ꢀ-hydroxy esters 2 were obtained in good to
excellent overall yields. Even nonaromatic aldehydes could be
converted efficiently into the expected products. With yields
always between 43 and 96%, the reaction is general and tolerates
various functional groups such as ester, nitrile, or protected
alcohol. Moreover, in all cases, R-fluoroacrylate 1 is always
obtained in Z pure form. Concerning R-bromo-R-fluoro-ꢀ-
hydroxy esters 2, the syn isomer was obtained selectively in
most cases except for entries 5, 6, 10, and 12 (Table 2). For the
mechanism of this conversion, we suggest the following
sequence (Scheme 1) can be explained by a Zimmerman-Traxler
transition-state model for aldol addition. Thus, enolization of
ethyl dibromofluoroacetate by diethylzinc gives rise to a mixture
of E- and Z-enolates. Each enolate adds to aldehyde through
the intervention of a chairlike transition state resulting in the
formation of zinc aldolate B-1 and zinc aldolate A (Scheme 1).
Aldolate A is prone to E2 elimination due to antiperiplanar
arrangement of bromine atom and leaving group and as a
consequence direct attack by diethylzinc affords fluoroacrylate
(Z)-1. Zinc aldolate B-1 is not properly placed for E2 elimination
to occur as bromine atom and leaving group are not in
antiperiplanar arrangement. So, for the E2 elimination to occur,
a conformation change from conformation B-1 to B must be
developed. Conformation B could go into E2 elimination as
bromine and leaving group are placed in antiperiplanar relation-
ship and should afford (E)-1. However, this compound is not
isolated because conformational movement from B-1 to B is
precluded by nonbonding destabilizing 1,3-diaxial interactions
between R and OEt groups, so that zinc aldolate B-1 remains
(7) (a) Bergmann, E. D.; Shahak, I.; Appelbaum, J. Isr. J. Chem. 1968, 6,
73. (b) Grison, C.; Gene`ve, S.; Halbin, E.; Coutrot, P. Tetrahedron 2001, 57,
4903, and references cited therein. (c) Sano, S.; Yokoyama, M.; Shiro, Y.; Nagao,
Y. Chem. Pharm. Bull. 2002, 50, 706. (d) Sano, S.; Ando, T.; Yokoyama, M.;
Nagao, Y. Chem. Commun. 1997, 559. (e) Sano, S.; Ando, T.; Yokoyama, M.;
Nagao, Y. Synlett 1998, 777. (f) Sano, S.; Teranishi, R.; Nagao, Y. Tetrahedron
Lett. 2002, 43, 9183. (g) Sano, S.; Saito, K.; Nagao, Y. Tetrahedron Lett. 2003,
44, 3987.
(8) (a) Welsh, J. T. J. Org. Chem. 1990, 65, 4782. (b) Lin, J.; Welsh, J. T.
Tetrahedron Lett. 1998, 39, 9613.
(9) (a) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457. (b) Pfund, E.; Lebargy,
C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2007, 72, 7871. (c) Alonso, D. A.;
Fuensanta, M.; Gomez-Bengoa, E.; Najera, AdV. Synth. Catal. 2008, 350, 1823.
(10) (a) Kawasaki, T.; Ichige, T.; Kitazume, T. J. Org. Chem. 1998, 63, 7525.
(b) Kitazume, T.; Tanaka, G. J. Fluorine Chem. 2000, 106, 211.
(11) (a) Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski, C.; Falck, J. R.
J. Am. Chem. Soc. 2003, 125, 3218. (b) Barma, D. K.; Lu, B.; Baati, R.;
Mioskowski, C.; Falck, J. R. Tetrahedron Lett. 2008, 49, 4359. (c) Falck, J. R.;
Bejot, R.; Barma, D. K.; Bandyopadhyay, A.; Joseph, S.; Mioskowski, C. J.
Org. Chem. 2006, 71, 8178. (d) Falck, J. R.; He, A.; Bejot, R.; Mioskowski, C.
Synlett 2006, 16, 2652. (e) Baati, R.; Mioskowski, C.; Kashinath, D.; Kodepelly,
S.; Lu, B.; Falck, J. R. Tetrahedron Lett. 2009, 50, 402.
(12) (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, 7931.
(13) Identification by 19F NMR of syn- and anti-R-bromo-R-fluoro-ꢀ-hydroxy
esters 2 was carried out according to the following publications: (a) Iseki, K.;
Kuroki, Y.; Kobayashi, Y. Tetrahedron 1999, 55, 2225. (b) Iseki, K.; Kuroki,
Y.; Kobayashi, Y. Synlett 1998, 437. (c) Ishihara, T.; Matsuda, T.; Imura, K.;
Matsui, H.; Yamanaka, H. Chem. Lett. 1994, 2167.
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