Preparation and addition-elimination reactions of benzyl α,β,β-trifluoroacrylate. A new stereoselective approach to (Z)-β-substituted α,β-difluoroacrylates

Article abstract of DOI:10.1021/jo701975y

(Chemical Equation Presented) Benzyl α,β,β- trifluoroacrylate (1) was prepared in good yield via the reductive Br-F elimination of benzyl 2-bromo-2,3,3,3-tetrafluoropropanoate or the palladium-catalyzed cross-coupling reaction of 1,2,2-trifluorovinylstannane with benzyl chloroformate. On treating 1 with various Grignard reagents or dialkylzinc reagents in the presence of copper(I) salt, the corresponding β-substituted α,β-difluoroacrylates were obtained in high yields with high Z-selectivity. Additionally, trialkylaluminum reagents were also found to be good nucleophiles, the corresponding addition-elimination products being afforded in good yields but with low stereoselectivity.

Full text of DOI:10.1021/jo701975y

Preparation and Addition-Elimination Reactions of Benzyl
r,â,â-Trifluoroacrylate. A New Stereoselective Approach to
(Z)-â-Substituted r,â-Difluoroacrylates
Shigeyuki Yamada, Mayumi Noma, Kazunori Hondo, Tsutomu Konno, and
Takashi Ishihara*
Department of Chemistry and Materials Technology, Kyoto Institute of Technology,
Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
ishihara@kit.ac.jp
ReceiVed September 7, 2007
Benzyl R,â,â-trifluoroacrylate (1) was prepared in good yield via the reductive Br-F elimination of
benzyl 2-bromo-2,3,3,3-tetrafluoropropanoate or the palladium-catalyzed cross-coupling reaction of 1,2,2-
trifluorovinylstannane with benzyl chloroformate. On treating 1 with various Grignard reagents or
dialkylzinc reagents in the presence of copper(I) salt, the corresponding â-substituted R,â-difluoroacrylates
were obtained in high yields with high Z-selectivity. Additionally, trialkylaluminum reagents were also
found to be good nucleophiles, the corresponding addition-elimination products being afforded in good
yields but with low stereoselectivity.
Introduction
R,â-Unsaturated carbonyl compounds occupy a central posi-
tion in organic synthesis owing to their wide utility as potent
synthetic blocks, particularly as Michael acceptors for conjugate
addition reactions1 or dienophiles and dipolarophiles for cy-
cloaddition reactions.2-4 Fluorinated acrylates such as R,â,â-
trifluoroacrylates 1 and â-substituted R,â-difluoroacrylates 2
(Figure 1) are likewise of great synthetic value as building
blocks for constructing various sorts of fluorine-containing
FIGURE 1. Fluorinated acrylates.
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
(1) For selected reviews on 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) For selected reports on transformation using fluorinated R,â-
unsaturated carbonyl compounds as building blocks, see. (a) Wang, Y.;
Burton, D. J. J. Org. Chem. 2006, 71, 3859-3862. (b) Wang, Y.; Burton,
D. J. Org. Lett. 2006, 8, 1109-1111. (c) Wang, Y.; Lu, L.; Burton, D. J.
J. Org. Chem. 2005, 70, 10743-10746. (d) Crowley, P. J.; Fawcett, J.;
Kariuki, B. M.; Moralee, A. C.; Percy, J. M.; Salafia, V. Org. Lett. 2002,
4, 4125-4128. (e) Essers, M.; Mu¨ck-Lichtenfeld, C.; Haufe, G. J. Org.
Chem. 2002, 67, 4715-4721. (f) Ichikawa, J.; Wada, Y.; Fujiwara, M.
Sakoda, K. Synthesis 2002, 1917-1936. (g) Chanteau, F.; Essers, M.;
Plantler-Royon, R.; Haufe, G.; Portella, R. Tetrahedron Lett. 2002, 43,
1677-1680. (h) Colmenares, L. U.; Zou, X.; Liu, J.; Asato, A. E.; Liu, R.
S. H. J. Am. Chem. Soc. 1999, 121, 5803-5804. (i) Ichikawa, J.; Kobayashi,
M.; Noda, Y.; Yokota, N.; Amano, K.; Minami, T. J. Org. Chem. 1996,
61, 2763-2769.
(2) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Per-
gamon Press: Oxford, 1990.
(3) For selected reviews on 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 1,3-dipolar cycloaddition reactions, see: (a) Kane-
masa, 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.
10.1021/jo701975y CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/21/2007
522
J. Org. Chem. 2008, 73, 522-528

StereoselectiVe Approach to (Z)-â-Substituted R,â-Difluoroacrylates
SCHEME 1. Reported Preparations of
r,â-Difluoroacrylates 2
Although the preparation of R,â,â-trifluoroacrylates 1 has
already been achieved by several groups, most of the methods
for the preparation suffer from the defects that multiple steps
are required and/or the chemical yield of 1 is poor.8 For instance,
Wakselman et al. reported the preparation of 1 in five steps
from 2,2,3,3-tetrafluoropropanol,8c which involved the bromi-
nation of 2,3,3-trifluoroallyl alcohol, prepared from 2,2,3,3-
tetrafluoropropanol and methyllithium, followed by oxidation,
esterification with MeOH, and reductive elimination, leading
to methyl R,â,â-trifluoroacrylate (1) in 15% overall yield. Paleta
et al. prepared 1-adamantyl R,â,â-trifluoroacrylate (1) from 1,2-
dichlorodifluoroethene in four steps (29% overall yield).8a
On the other hand, there have been found only a few examples
for the preparation of â-substituted R,â-difluoroacrylates 2 in
the literature.9 Asato and Liu prepared 2 from â-keto esters using
diethylaminosulfur trifluoride (DAST), the isomer ratios (E/Z)
of 2 being almost 50:50.9i Lu and Zhang also reported that (E)-2
was prepared by the coupling reaction of (E)-2-alkyl-1,2-
difluorovinylsilane with ethyl chloroformate in the presence of
KF.9e Recently, Burton et al. achieved the preparation of (Z)-
â-stannyl-R,â-difluoroacrylates and subsequent palladium-
catalyzed cross-coupling reaction with aryl iodides, which led
to (Z)-â-aryl-R,â-difluoroacrylates 2.9a-c This method, to our
knowledge, is only one example for the Z-selective preparation
of â-substituted R,â-difluoroacrylates (Scheme 1).
SCHEME 2. Synthetic Apparoaches to 1 and
Addition-Elimination Reaction with Organocopper
Reagents
Herein are described convenient synthetic approaches to 1
via the reductive Br-F elimination of 2-bromo-2,3,3,3-tet-
rafluoropropanoate (3) (path A) or via the palladium-catalyzed
cross-coupling reaction of 1,2,2-trifluorovinylstannane (4) with
chloroformate (path B). In addition, are disclosed the stereo-
selective addition-elimination reactions of 1 with organocopper
reagents derived from Grignard,10 dialkylzinc, or trialkylalu-
(6) For selected reports on applications of organofluorine compounds,
see: (a) Be´gue´, J. -P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127,
992-1012. (b) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303-
319. (c) Morimoto, K.; Irie, M. Chem. Commun. 2005, 3895-3905. (d)
Miethchen, R. J. Fluorine Chem. 2004, 125, 895-901. (e) Poss, A.;
Nalowajok, D.; Demmin, T. R.; Nair, H. K. PCT Int. Appl. WO
2003073169, 2003. (f) Hatakeyama, J.; Watanabe, J.; Harada, Y. U.S. Patent
Appl. Publ. 2001010890, 2001. (g) Hatakeyama, J.; Watanabe, A.; Harada,
Y. Japanese Patent JP2001-226432A, 2001.
(7) (a) Essers, M.; Muck-Lichtenfeld, C.; Haufe, G. J. Org. Chem. 2002,
67, 4715-4721. (b) Jiang, B.; Zhang, X.; Shi, G. Tetrahedron Lett. 2002,
43, 6819-6821. (c) Huang, X. H.; He, P. Y.; Shi, G. Q. J. Org. Chem.
2000, 65, 627-629. (d) Wakselman, C.; Molines, H.; Tordeux, M. J.
Fluorine Chem. 2000, 102, 211-213. (e) Ito, H.; Saito, A.; Kakuuchi, A.;
Taguchi, T. Tetrahedron 1999, 55, 12741-12750. (f) Ichikawa, J.; Yokota,
N.; Kobayashi, M.; Minami, T. Synlett 1993, 186-188. (g) Bumgardner,
C. L.; Burgess, J. P.; Everett, T. S.; Purrington, S. T. J. Fluorine Chem.
1992, 56, 189-193. (h) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990,
55, 4639-4642. (i) Krishnan, G.; Sampson, P. Tetrahedron Lett. 1990, 31,
5609-5612. (j) Archibald, T. G.; Baum, K. J. Org. Chem. 1990, 55, 3562-
3565.
(8) (a) Paleta, O.; Stepan, L J. Fluorine Chem. 1990, 47, 435-440. (b)
Peter, B.; Klaus, H.; Werner, S.; Dieter, U. US Patent US 4835305, 1989.
(c) Wakselman, C.; Nguyen, T.; Molines, H. PCT Int. Appl. WO 8911470,
1989. (d) Molines, H.; Wakselman, C. J. Fluorine Chem. 1984, 25, 447-
451.
minum reagents, leading to (Z)-â-substituted R,â-difluoroacry-
lates 2 (Scheme 2).
Results and Discussion
Preparation of 1 via Path A. As a route to the desired
trifluoroacrylate 1, the reductive Br-F elimination of benzyl
2-bromo-2,3,3,3-tetrafluoropropanoate (3) was initially studied,
which could easily be prepared from the corresponding com-
mercially available acid chloride. The results are summarized
in Table 1. Thus, treatment of 3 with 1.1 equiv of zinc dust in
Et2O at room temperature for 0.5 h did not provide the desired
â-elimination product 1 at all (entry 1). However, the addition
of Et2AlCl (1.3 equiv) as Lewis acid allowed the expected
â-elimination reaction to proceed efficiently, producing the
desired product 1 in 72% yield (entry 2). Various solvents, such
as DME (1,2-dimethoxyethane), THF, C6H6, and DMF, were
examined. The reaction in DME proceeded effectively to give
1 in 72% yield together with the R-reduction product 3-H in
(9) (a) Wang, Y.; Burton, D. J. J. Org. Chem. 2006, 71, 3859-3862.
(b) Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 1109-1111. (c) Wang, Y.;
Lu, L.; Burton, D. J. J. Org. Chem. 2005, 70, 10743-10746. (d) Zhang,
X.; Lu, L.; Burton, D. J. Collect. Czech. Chem. Commun. 2002, 67, 1247-
1261. (e) Zhang, Q.; Lu, L. Tetrahedron Lett. 2000, 41, 8545-8548. (f)
McElroy, K. T.; Purrington, S. T.; Bumgerdner, C. L.; Burgess, J. P. J.
Fluorine Chem. 1999, 95, 117-120. (g) Shi, G.; Cao, Z. J. Chem. Soc.,
Chem. Commun. 1995, 1969-1972. (h) Archibald, T. G.; Baum, K. J. Org.
Chem. 1990, 55, 3562-3565. (i) Asato, A. E.; Liu, R. S. H. Tetrahedron
Lett. 1986, 27, 3337-3340.
(10) Yamada, S.; Noma, M.; Konno, T.; Ishihara, T.; Yamanaka, H. Org.
Lett. 2006, 8, 843-845.
J. Org. Chem, Vol. 73, No. 2, 2008 523

Yamada et al.
TABLE 1. Br-F Elimination of Benzyl Ester 3 with Zinc Dust
TABLE 2. Cross-Coupling Reaction of 4 with Benzyl
Chloroformate
yielda
mol % equiv of
yielda
recoverya
Lewis
acid
T
(°C)
time yielda
(%)
(h) (%) of 1 of 3-H (%) of 3
recoverya
entry
catalyst
of Pd
CuCN T (°C) (%) of 1 (%) of 4
entry solvent
1
2
3
4
5
6
7
Cl2Pd(PPh3)2
Cl2Pd(PPh3)2
Cl2Pd(PPh3)2
Cl2Pd(PPh3)2
Cl2Pd(PPh3)2
Cl2Pd(PPh3)2
Cl2Pd(PPh3)2
5
5
5
5
5
10
1
5
5
5
1.1
1.1
1.1
0.5
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
rt
0
19
43
52
65 (51)
42
20
83
36
0
0
0
0
30
0
0
0
1
2
3
4
5
6
7
8
9
Et2O
Et2O
DME
THF
C6H6
DMF
Et2O
Et2O
Et2O
none
rt
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0
72
72
47
0
31
8
57
0
trace
0
19
0
0
0
59
0
0
0
50
80
80
80
80
80
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et3Al
Et2Zn
BF3‚OEt2 rt
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
Et2AlCl
rt
rt
rt
rt
rt
rt
rt
17
42
46
97
28
3
35
16
15
18
16
4
0
8b Cl2Pd(PPh3)2
9c Cl2Pd(PPh3)2
10d Cl2Pd(PPh3)2
11e Cl2Pd(PPh3)2
12
13
14
reflux 17
70
63
0
48
56
72
70
72
80
80
80
80
80
80
0
22
14
0
0
16
10 Et2O
11 Et2O
12 Et2O
13 Et2O
14b Et2O
-20
5
5
5
5
21
42
40
0
0
Pd(OAc)2
Cl2Pd(PhCN)2
Pd(PPh3)4
reflux 0.5
rt
rt
1.0
0.5
0
0
a Determined by 19F NMR. Value in parentheses is of the isolated yield.
b THF was employed as the solvent. c DMF was employed as the solvent.
d CuBr was used instead of CuCN. e CuI was used instead of CuCN.
a Determined by 19F NMR. b The amount of Et2AlCl was 0.1 equiv.
SCHEME 3. Possible Reaction Mechanism for the
Et2AlCl-Catalyzed Br-F Elimination of 3
rovinylstannane (4)12 with benzyl chloroformate for the prepara-
tion of 1.13 The results are collected in Table 2. Thus, the
reaction of 4 with 2.2 equiv of benzyl chloroformate in the
presence of 5 mol % of Cl2Pd(PPh3)2 and 1.1 equiv of CuCN
in toluene at room temperature for 2 h did not occur at all, the
vinylstannane 4 being recovered in 83% yield (entry 1). As
shown in entries 2-7, it was observed that the reaction
temperature, the amount of copper(I) salt, and the palladium
catalyst significantly affected the chemical yield of 1. The best
yield (51% isolated) was given when the reaction was performed
in the presence of 5 mol % of Cl2Pd(PPh3)2 and 0.1 equiv of
CuCN in toluene at 80 °C for 2 h (entry 5). The reaction in
THF at reflux temperature or in DMF at 80 °C was reluctant,
the acrylate 1 being obtained in very low yield or not obtained
at all (entries 8 and 9). Other copper(I) salts (CuBr and CuI) or
palladium catalysts (Pd(OAc)2, Cl2Pd(PhCN)2, and Pd(PPh3)4)
were found to be ineffective for the coupling reaction (entries
10-14).
17% yield, while the use of THF did not give a satisfactory
result (entries 3 and 4). In the case of C6H6 or DMF, the
â-elimination reaction did not take place at all, the R-reduction
product 3-H being afforded in 46% or 97% yields, respectively
(entries 5 and 6). It was found, moreover, that triethylaluminum
and diethylzinc were effective as Lewis acid but BF3‚OEt2 was
not at all (entries 7-9). The reaction at room temperature or at
reflux temperature gave a higher yield of 1 than did the reaction
at 0 or -20 °C (entries 10 and 11). Eventually, treatment of 3
with 1.1 equiv of zinc dust in the presence of 0.1 equiv of Et2-
AlCl as Lewis acid in Et2O at room temperature for 0.5 h led
to the best result, the acrylate 1 being obtained in 72% yield
(entry 14).
A possible reaction mechanism for the Et2AlCl-catalyzed
Br-F elimination of the benzyl ester 3 is outlined in Scheme
3. Thus, 2-bromo-2,3,3,3-tetrafluoropropanoate 3 reacts with
zinc dust to form an intermediary 3-Int. This intermediate may
undergo the Br-F elimination assisted with Et2AlCl through a
six-membered transition state, which would be facilitated by
an interaction between Al and F.11 Then, the elimination of
ZnBrCl and Et2AlF takes place simultaneously to lead to the
desired product, benzyl R,â,â-trifluoroacrylate (1). The resulting
Et2AlF may act as Lewis acid catalyst.
Reaction of 1 with Organocopper Reagents: Reaction of
1 with Organocopper Reagents Derived from Organolithium
or Grignard Reagents.10 We investigated the reaction of 1 with
various organometallic reagents, particularly organocopper
(11) For related reports on the interaction between metal and fluorine
atom, see: (a) Yamazaki, T. J. Synth. Org. Chem. Jpn. 2004, 62, 911-
918. (b) Ishihara, T. J. Synth. Org. Chem. Jpn. 1999, 57, 313-322. (c)
Ooi, T.; Furuta, K.; Maruoka, K. Chem. Lett. 1998, 817-818. (d) Ooi, T.;
Kagoshima, N.; Uraguchi, D.; Maruoka, K. Tetrahedron Lett. 1998, 39,
7105-7108. (e) Ooi, T.; Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc.
1997, 119, 5754-5755. (f) Ooi, T.; Uraguchi, D.; Kagoshima, N.; Maruoka,
K. Tetrahedron Lett. 1997, 38, 5679-5682. (g) Yamazaki, T.; Kitazume,
T. J. Synth. Org. Chem. Jpn. 1996, 54, 665-674. (h) Yamazaki, T.;
Shinohara, N.; Kitazume, T.; Sato, S. J. Org. Chem. 1995, 60, 8140-8141.
(i) Hanamoto, T.; Fuchikami, T. J. Org. Chem. 1990, 55, 4969-4971.
(12) (a) Banger, K. K.; Brisdon, A. K.; Gupta, A. Chem. Commun. 1997,
139-140. (b) Burdon, J.; Coe, P. L.; Haslock, I. B.; Powell, R. L. J. Fluorine
Chem. 1999, 99, 127-131.
(13) For related reports on the cross-coupling reaction of fluorinated
vinylstannane with chloroformates, see: (a) Arany, A.; Crowley, P. J.;
Fawcett, J.; Hursthouse, M. B.; Kariuki, B. M.; Light, M. E.; Moralee, A.
C.; Percy, J. M.; Salafia, V. Org. Biomol. Chem. 2004, 2, 455-465. (b)
Jeong, I. H.; Park, Y. S.; Kim, M. S.; Song, Y. S. J. Fluorine Chem. 2003,
120, 195-209.
Preparation of 1 via Path B. We next examined the
palladium-catalyzed cross-coupling reaction of 1,2,2-trifluo-
524 J. Org. Chem., Vol. 73, No. 2, 2008

StereoselectiVe Approach to (Z)-â-Substituted R,â-Difluoroacrylates
TABLE 3. Reaction of 1 with PhLi or PhMgBr in the Absence or
Presence of CuBr
SCHEME 4. Reaction of 1 with Allylmagnesium Chloride
(5p) in the Presence of a Catalytic Amount of CuBr
entry
Met
Li
Li
Li
CuBr (equiv)
yielda (%) of 2a
E/Za
1
none
1.30
0.65
0.13
none
1.30
0.65
0.13
complex mixture
0
0
complex mixture
5
60
62
2b
3c
4
high Z-selectivity (entries 15, 20, and 21). The reaction with
benzyl- (5k) or 4-pentenylmagnesium bromide (5l) resulted in
a significant decrease of the Z-selectivity or chemical yield
(entries 16 and 18). Additionally, the reaction with an alkenyl
Grignard reagent, such as â-styrylmagnesium bromide (5o), gave
the corresponding â-vinylated product 2o in only 22% yield,
together with a large recovery of the starting acrylate 1 (entry
22).
Li
5
6
7
8
MgBr
MgBr
MgBr
MgBr
43:57
9:91
12:88
14:86
94 (90)
a Determined by 19F NMR. Value in parentheses is of isolated yield.
b The starting acrylate 1 was recovered in 55% yield. c The starting acrylate
1 was recovered in 42% yield.
Further attempts were made to improve the chemical yield
for the less efficient Grignard reagents 5c,e-h,k,l,o. On
conducting these reactions by use of 5.0 equiv of Grignard
reagent in the presence of 0.25 equiv of CuBr in THF at -78
°C for 1 h, the corresponding products were given in 56-98%
(55-90% isolated) yields with high Z-selectivity (entries 4, 7,
9, 11, 13, 17, 19, and 23).
When allylmagnesium chloride (5p) was employed as Grig-
nard reagent, the 1,2-adduct 6p and the 1,2:1,4-bis-adduct 7p
were obtained in 74% and 22% yields, respectively (Scheme
4).
reagents, in detail. The results are summarized in Table 3. Thus,
the reaction of 1 with 1.3 equiv of phenyllithium in THF at
-78 °C for 1 h led to a complex mixture (entry 1). Even addition
of CuBr (1.3-0.13 equiv) did not improve the reaction at all
(entries 2-4). In entries 5-8, the reactions with phenylmag-
nesium bromide in the absence or presence of CuBr were
conducted. Although the reaction without copper(I) salt did not
give a satisfactory result (entry 5), the reaction in the presence
of 1.3 equiv of CuBr proceeded smoothly to give the â-sub-
stituted R,â-difluoroacrylate 2a in 60% yield (entry 6).14 Of
much significance is that high Z-selectivity was observed in
the reaction. Changing the amount of CuBr from 1.3 to 0.65
equiv did not affect the yield as well as the stereoselectivity
(entry 7). However, the use of 0.13 equiv of CuBr led to a
dramatic improvement in the reaction, 2a being afforded in
94% (90% isolated) as an isolated yield with good Z-selectivity
(entry 8).
Subsequently, we carried out addition-elimination reactions
of 1 with various Grignard reagents (5a-o) in the presence of
0.13 equiv of CuBr. The results are tabulated in Table 4.
4-Methoxyphenylmagnesium bromide (5b) could participate
nicely in the reaction to afford the corresponding â-arylated
R,â-difluoroacrylate 2b in a highly stereoselective manner (entry
2). However, 3-methoxyphenylmagnesium bromide (5c) pro-
vided the product 2c in only 38% yield, and 2-methoxyphe-
nylmagnesium bromide (5d) gave no arylated product 2d
(entries 3 and 5). Tolyl- (5e), 4-vinylphenyl- (5f), and R- and
â-naphthylmagnesium bromide (5g and 5h) were somewhat less
efficient, the corresponding products being produced in 70%
(64% isolated), 51%, 36%, and 46% yields, respectively (entries
6, 8, 10, and 12). The reaction with Grignard reagent bearing
an electron-withdrawing group on the benzene ring, such as
4-(trifluoromethyl)phenylmagnesium bromide (5i), did not give
a satisfactory result (entry 14). In the case of alkyl Grignard
reagents, like n-Bu- (5j), s-Bu- (5m), and c-C6H11MgBr (5n),
the corresponding â-alkylated R,â-difluoroacrylates 2j, 2m, and
2n were obtained in 91-94% (77-87% isolated) yields with
Reaction of 1 with Organocopper Reagents Derived from
Organozinc Reagents. We also examined the reaction of 1 with
organocopper reagents derived from organozinc reagents. The
results are summarized in Table 5.
The reaction of 1 with diethylzinc (8q) in the absence of a
copper(I) salt in THF at -78 °C for 1 h did not proceed at all,
no â-ethylated difluoroacrylate 2q being detected (entry 1).
Although various sorts of copper(I) salts, such as CuCl, CuBr,
CuI, and CuCN, were used together with TMSCl,15 the desired
â-ethylated product 2q was not formed at all (entries 2-5).
However, when 1 was treated with 8q in the presence of CuCN‚
2LiCl, prepared from CuCN and 2.0 equiv of LiCl, and TMSCl
in THF at -78 °C for 1 h, the addition-elimination reaction
took place smoothly to afford the corresponding difluoroacrylate
2q in 80% yield with high Z-selectivity (E/Z ) 6/94) (entry
6).16 A more extended reaction time resulted in a slight increase
in the conversion to 2q (entry 7). As shown in entries 8 and 9,
the reaction at higher temperature (-20 °C) or in the absence
of TMSCl also proceeded smoothly to give the corresponding
product 2q in high yields, though the stereoselectivity slightly
decreased.
Subsequently, the reactions of 1 with other commercially
available dialkyl- or diarylzinc reagents, such as diisopropylzinc
(15) For related reports on Michael addition reactions with organocopper
reagents derived from organozinc reagents in the presence of TMSCl, see:
(a) Nakamura, M.; Nakamura, E. J. Synth. Org. Chem. Jpn. 1998, 56, 632-
644. (b) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390-2392. (c) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.;
Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056-8066. (d) Nakamura,
E.; Kuwajima, I. J. Am. Chem. Soc. 1984, 106, 3368-3370.
(16) For related reports on the preparation of organocopper reagents by
the treatment of organozinc reagents with CuCN‚2LiCl, see: (a) Rozema,
M. J.; AchyuthaRao, S.; Knochel, P. J. Org. Chem. 1992, 57, 1956-1958.
(b) AchyuthaRao, S.; Knochel, P. J. Am. Chem. Soc. 1991, 113, 5735-
5741. (c) Ref. 15b.
(14) For related reports on Michael addition reactions with organocopper
reagents derived from Grignard reagents, see: (a) Yamazaki, T.; Shinohara,
N.; Kitazume, T.; Sato, S. J. Fluorine Chem. 1999, 97, 91-96. (b)
Horiguchi, Y.; Matsuzawa, S.; Nakamura, E.; Kuwajima, I. Tetrahedron
Lett. 1986, 27, 4025-4028. (c) Aguiar, A. M.; Irelan, J. R. S. J. Org. Chem.
1969, 34, 4030-4031. (d) Kharasch, M. S.; Tawney, P. O. J. Am. Chem.
Soc. 1941, 63, 2308-2316.
J. Org. Chem, Vol. 73, No. 2, 2008 525

Yamada et al.
TABLE 4. Reaction of 1 with Various Grignard Reagents (5) in the Presence of a Catalytic Amount of CuBr
yielda (%)
recoverya (%)
yielda (%)
recoverya (%)
entry
R
of 2
E/Za
of 1
entry
R
of 2
E/Za
of 1
1
2
Ph (a)
94 (90)
93 (84)
38
56 (55)
0
70 (64)
97 (87)
51
97 (89)
36
14:86
16:84
11:89
12:88
0
0
36
20
59
0
0
47
0
12
â-naphthyl (h)
â-naphthyl (h)
4-CF3C6H4 (i)
n-Bu (j)
Bn (k)
Bn (k)
4-pentenyl (l)
4-pentenyl (l)
s-Bu (m)
46
98 (90)
6
92 (77)
70
84 (80)
43
82 (81)
94 (87)
91 (83)
22
12:88
8:92
53
0
91
0
0
0
37
0
0
0
41
0
4-MeOC6H4 (b)
3-MeOC6H4 (c)
3-MeOC6H4 (c)
2-MeOC6H4 (d)
4-MeC6H4 (e)
13b
14
3
16:84
14:86
28:72
31:69
14:86
6:94
14:86
9:91
<1:99
4:96
4b
5
15
16c
17b,c
18
6
11:89
14:86
9:91
12:88
8:92
7b
8
4-MeC6H4 (e)
4-(CH2dCH)C6H4 (f)
4-(CH2dCH)C6H4 (f)
R-Naphthyl (g)
R-Naphthyl (g)
19b
20
9b
10
11b
60
16
21
c-Hex (n)
â-Styryl (o)
â-Styryl (o)
74 (70)
5:95
22
23b
85 (45)
a
Determined by 19F NMR. Values in parentheses are of the isolated yield. b A large excess amount of organocopper reagent (RMgBr, 5.0 equiv; CuBr,
0.25 equiv) was used. c Benzylmagnesium chloride (5k) was employed as Grignard reagent.
TABLE 5. Reaction of 1 with Organocopper Reagents Derived from Dialkylzinc (8) and Copper(I) Salt
entry
R
copper(I) salt
additive
T (°C)
yielda (%) of 2
E/Za
recoverya (%) of 1
1
2
3
none
CuCl
CuBr
Cul
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
none
none
none
none
none
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
-78
-78
-78
-78
-78
-78
-78
-20
-78
-78
-78
-78
0
0
0
0
93
70
71
78
quant
15
5
0
11
0
4
5
Et (q)
0
80
89 (63)
80
87
98 (97)
0
0
6b
6:94
8:92
20:80
14:86
2:98
7b,c
8b
9b,d
10b,c
11b,c
12b,c
i-Pr (r)
Me (s)
Ph (a)
89
85
a
Determined by 19F NMR. Values in parentheses are of the isolated yield. b Two equiv of LiCl was employed based on CuCN. c Carried out for 2 h.
d TMSCl was not employed.
(8r), dimethylzinc (8s), and diphenylzinc (8a), were conducted
under the optimized reaction conditions (entry 7 in Table 5).
Diisopropylzinc (8r) participated in the addition-elimination
reaction to afford the corresponding â-isopropylated R,â-
difluoroacrylate 2r in excellent yield with high Z-selectivity
(97% isolated; E/Z ) 2/98) (entry 10). In the case of dimeth-
ylzinc (8s) or diphenylzinc (8a), the expected reaction did not
occur at all, the starting acrylate 1 being recovered in 89% and
85% yields, respectively (entries 11 and 12). It was found that
dialkylzinc reagents prepared in situ by literature methods17 were
not efficient for the reaction.
Reaction of 1 with Organoaluminum Reagents.18 The
reactions of 1 using organoaluminum reagents 9 were also
examined, and the results are shown in Table 6.
As shown in entries 1 and 2, the reaction in THF or Et2O at
-78 °C for 2 h did not provide any trace of the â-ethylated
difluoroacrylate 2q, while the use of dichloromethane, toluene,
and hexane as the solvent resulted in the formation of the
addition-elimination product 2q in 40%, 12%, and 57% yields,
respectively (entries 3-5). In these cases, 2q was obtained as
a mixture of E/Z isomers (ca. 35/65). Raising the reaction
temperature (-20 °C, 0 °C, and rt) was found to be very
effective, giving rise to the corresponding product 2q in 69-
75% yields as a mixture of E/Z isomers (E/Z ) 36/64 to 45/55)
(17) For related reviews on the preparation of organozinc reagents, see:
(a) Nakamura, E. In Organometallics in Synthesis: A Manual; Schlosser,
M., Ed.; John Wiley & Sons: New York, 2002. (b) Knochel, P.; Millet,
N.; Rodriguez, A. L. Org. React. 2001, 58, 417-731. (c) Knochel, P.; Perea,
J. J. A.; Jones, P. Tetrahedron 1998, 54, 8275-8319. (d) Knochel, P.; Jones,
P., Langer, F. In A Practical ApproachsOrganozinc Reagents; Knochel,
P., Jones, P., Eds.; Oxford University Press: New York, 1998. (e) Knochel,
P. Synlett 1995, 393-403. (g) Knochel, P.; Singer, R. D. Chem. ReV. 1993,
93, 2117-2188.
(18) For related reports on Michael addition reactions with organoalu-
minum reagents without copper(I) salt, see: (a) Elzner, S.; Maas, S.; Engel,
S.; Kunz, H. Synthesis 2004, 2153-2164. (b) Carren˜o, M. C.; Gonza´lez,
M. P.; Ribagorda, M.; Houk, K. N. J. Org. Chem. 1998, 63, 3687-3693.
(c) Carren˜o, M. C.; Gonza´lez, M. P.; Ribagorda, M. J. Org. Chem. 1996,
61, 6758-6759. (d) Ru¨ck, K.; Kunz, H. Synthesis 1993, 1018-1028. (e)
Ru¨ck, K.; Kunz, H. Synlett 1992, 343-344. (f) Ashby, E. C.; Noding, S.
A. J. Org. Chem. 1979, 44, 4792-4797.
526 J. Org. Chem., Vol. 73, No. 2, 2008

StereoselectiVe Approach to (Z)-â-Substituted R,â-Difluoroacrylates
TABLE 6. Reaction of 1 with Trialkylaluminum Reagents
SCHEME 5. Possible Reaction Mechanism
yielda
(%)
of 2
Cu(I)
salt
T
recoverya
(%) of 1
entry
R
solvent (°C)
E/Za
1
2
3
4
5
6
7
8
THF
Et2O
-78
-78
0
0
82
79
56
73
39
22
22
18
19
66
57
45
88
28
14
CH2Cl2 -78 40
toluene -78 12
hexane -78 57
hexane -20 75 (51) 43:57
hexane
hexane
35:65
ndb
35:65
none
Et (q)
0
70
41:59
36:64
40:60
33:67
38:62
44:56
rt 69
9c
10d
11d
12d
13
14
15
hexane -20 75
CuBr hexane -78 33
Cul hexane -78 42
CuCN hexane -78 55
Me (s)
i-Bu (t)
none
none
n-Oct (u) none
hexane -20
0
copper species leads to an enolate-like intermediate Int-A, which
will be in a rigid conformation due to a dual interaction of metal
(M) with copper and fluorine atom.11 Then, the elimination of
MF takes place to form Int-B, followed by simultaneous
reductive elimination of RCu, leading to the final product, (Z)-
benzyl R,â-difluoroacrylate 2.
hexane -20 69 (35) 38:62
hexane -20 53 (43) 32:68
a Determined by 19F NMR. Values in parentheses are of the isolated
yields. b Not determined. c The amount of 9q was 4.4 equiv. d The amount
of Cu(I) salt was 1.1 equiv.
(entries 6-8). As shown in entry 9, the reaction with 4.4 equiv
of 9q in hexane at -20 °C for 2 h also proceeded smoothly to
give the â-ethylated product 2q in 75% yield (E/Z ) 40/60). In
entries 10-12, even when a copper(I) salt, like CuBr, CuI, and
CuCN, was employed in the reaction, neither chemical yield
nor E/Z isomer ratio was improved.19
The reactions of 1 with other commercially available trialky-
laluminum reagents, such as trimethyl- (9s), triisobutyl- (9t),
and tri-n-octylaluminum (9u), were carried out under the
optimized reaction conditions (entry 6 in Table 6). The reaction
with trimethylaluminum (9s) gave no â-methylated difluoro-
acrylate 2s (entry 13). Triisobutyl (9t) or tri-n-octylaluminum
reagents (9u) participated smoothly in the addition-elimination
reaction, leading to the corresponding â-alkylated products 2t
and 2u in 69% (35% isolated) and 53% (43% isolated) yields,
respectively (entries 14 and 15).
Conclusions
In conclusion, we have achieved an efficient and facile
preparation of benzyl R,â,â-trifluoroacrylate (1) via Et2AlCl-
catalyzed reductive Br-F elimination of benzyl 2-bromo-
2,3,3,3-tetrafluoropropanoate (3) or via the palladium-catalyzed
cross-coupling reaction of 1,2,2-trifluorovinylstannane (4) with
benzyl chloroformate. The reaction of benzyl R,â,â-trifluoro-
acrylate 1 with various Grignard reagents 5 in the presence of
a catalytic amount of CuBr gave the corresponding â-substituted
benzyl R,â-difluoroacrylates 2 in good to excellent yields with
high Z selectivity. Similarly, the acrylate 1 also reacted with
commercially available dialkylzinc reagents 8 in the presence
of CuCN‚2LiCl, leading to (Z)-â-alkylated acrylates 2 in
excellent yields in a Z-selective manner. Trialkylaluminum
reagents 9 could also participate in the addition-elimination
reaction to afford the corresponding â-alkylated products 2 as
a mixture of the E and Z isomers in good yields.
Possible Reaction Mechanism. Scheme 5 depicts a possible
reaction mechanism for the addition-elimination reaction of 1
with organocopper reagents derived from Grignard reagents or
dialkylzinc reagents and copper(I) salts.
Experimental Section
The in situ generated organocuprate14,16,17g may coordinate
with an olefinic double bond, followed by an interaction between
magnesium or zinc metal (M) and the carbonyl oxygen atom,
to form a π-complex.20 Subsequent oxidative addition of the
Typical Procedure for Reaction of 1 with Phenylmagnesium
Bromide (5a) in the Presence of a Catalytic Amount of CuBr.
A 50 mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a thermometer, a rubber septum, and an inlet
tube for argon was charged with a suspension of CuBr (0.009 g,
0.065 mmol) in THF (0.5 mL). To this suspension was slowly
dropwise added a 0.85 M solution of phenylmagnesium bromide
(5a, 0.76 mL, 0.65 mmol) in THF at -78 °C. To the resulting
solution was slowly added 0.108 g (0.50 mmol) of 1 in THF (1.5
mL) via a syringe at -78 °C. After being stirred for 1 h at -78
°C, the reaction mixture was poured into ice-cooled water (50 mL),
followed by extraction with Et2O (30 mL × 5). The organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. Column chromatography of the residue using hexane/
benzene (2:1) yielded benzyl 2,3-difluoro-3-phenylacrylate (2a,
0.123 g, 90%).
(19) For related reports on Michael addition reactions of organocopper
reagents derived from trialkylaluminum, see: (a) d’Augustin, M.; Palais,
L.; Alexakis, A. Angew. Chem., Int. Ed. 2005, 44, 1376-1378. (b) Alexakis,
A.; Albrow, V.; Biswas, K.; d’Augustin, M.; Prieto, O.; Woodward, S.
Chem. Commun. 2005, 2843-2845. (c) Polet, D.; Alexakis, A. Tetrahedron
Lett. 2005, 46, 1529-1532. (d) Kabbara, J.; Flemming, S.; Nickisch, K.;
Neh, H.; Westermann, J. Tetrahedron 1995, 51, 743-754. (e) Kabbara, J.;
Flemming, S.; Nickisch, K.; Neh, H.; Westermann, J. Synlett 1994, 679-
680. (f) Kabbara, J.; Flemming, S.; Nickisch, K.; Neh, H.; Westermann, J.
Tetrahedron Lett. 1994, 35, 8591-8594. (g) Wipf, P.; Smitrovich, J. H.;
Moon, C.-W. J. Org. Chem. 1992, 57, 3178-3186.
(20) For related reports on π-complex between transition metal and
polyfluorinated alkene, see: (a) Braun, T.; Noveski, D.; Neumann, B.;
Stammler, H.-G. Angew. Chem., Int. Ed. 2002, 41, 2745-2748. (b) Fujiwara,
M.; Ichikawa, J.; Okauchi, T.; Minami, T. Tetrahedron Lett. 1999, 40,
7261-7265. (c) Siedle, A. R.; Newmark, R. A. Organometallics 1989, 8,
1442-1450.
Benzyl 2,3-difluoro-3-phenyl-2-propenoate (2a). (Z)-2a: mp
1
60-61 °C; H NMR (CDCl3) δ 5.17 (s, 2H), 7.17-7.32 (m, 5H),
7.36-7.53 (m, 5H); 13C NMR (CDCl3) δ 67.2, 128.0, 128.5, 129.3
(dd, J ) 3.3, 3.3 Hz), 131.4, 134.5, 135.1, 137.2 (dd, J ) 254.5,
J. Org. Chem, Vol. 73, No. 2, 2008 527

Yamada et al.
21.9 Hz), 156.3 (dd, J ) 267.1, 16.4 Hz), 160.2 (dd, J ) 29.4, 8.0
Hz); 19F NMR (CDCl3, CFCl3) δ -99.88 (d, J ) 6.6 Hz, 1F),
-148.73 (d, J ) 6.6 Hz, 1F). (E)-2a: 1H NMR (CDCl3) δ 5.15 (s,
2H), 7.15-7.32 (m, 5H), 7.34-7.51 (m, 5H); 19F NMR (CDCl3,
CFCl3) δ -133.85 (d, J ) 127.6 Hz, 1F), -162.16 (d, J ) 127.6
Supporting Information Available: General experimental
procedures for the preparation of 1 and the reaction with various
organocopper reagents, characterization data for new compounds
(1, 2a-c,e-h,j-o,q,r,t,u, 3, and 4), and copies of 1H and 13C NMR
spectra for the new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Hz, 1F); IR (KBr) 3040, 1736, 1666, 1447, 1277, 1084, 968 cm-1
;
HRMS (EI) calcd for (M+) C16H12F2O2 274.0805, found 274.0801.
Anal.Calcd for C16H12F2O2: C, 70.07; H, 4.41. Found: C, 69.67;
H, 4.27.
JO701975Y
528 J. Org. Chem., Vol. 73, No. 2, 2008