Highly stereoselective synthesis of (E)- and (Z)-α-fluoro-α, β-unsaturated esters and (E)- and (Z)-α-fluoro-α,β- unsaturated amides from 1-bromo-1-fluoroalkenes via palladium-catalyzed carbonylation reactions

Article abstract of DOI:10.1021/jo050314a

The highly stereoselective synthesis of (E)- and (Z)-α-fluoro- α,β-unsaturated esters and (E)- and (Z)-α-fluoro-α, β-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z ≈ 1:1), which are readily available starting materials, have been found to i

Full text of DOI:10.1021/jo050314a

Highly Stereoselective Synthesis of (E)- and
(Z)-r-Fluoro-r,â-unsaturated Esters and (E)- and
(Z)-r-Fluoro-r,â-unsaturated Amides from 1-Bromo-1-fluoroalkenes
via Palladium-Catalyzed Carbonylation Reactions
Jianjun Xu and Donald J. Burton*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
Received February 18, 2005
The highly stereoselective synthesis of (E)- and (Z)-R-fluoro-R,â-unsaturated esters and (E)- and
(Z)-R-fluoro-R,â-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z ≈ 1:1), which are
readily available starting materials, have been found to isomerize to high E/Z ratios after storage
at -20 °C for 1 week or by photolysis at 254 nm. Since the (E)-isomers have been found to react
faster than the corresponding (Z)-isomers at room temperature in Pd(0)-catalyzed reactions, the
palladium-catalyzed carboalkoxylation of high E/Z 1-bromo-1-fluoroalkenes lead to a high Z/E (Z/E
g 98:2) ratio of the R-fluoro-R,â-unsaturated esters. When 1-bromo-1-fluoroalkenes (E/Z ≈ 1:1) were
reacted with HCOOH/NBu3/Pd(II)/DMF, the (E)-isomer was selectively reduced, and the remaining
(Z)-1-bromo-1-fluoroalkenes were recovered in essentially pure isomeric form. The resulting mixture
of (Z)-1-bromo-1-fluoroalkenes and the reduced products underwent similar palladium-catalyzed
carboalkoxylation reactions at 70 °C, and the (E)-R-fluoro-R,â-unsaturated esters were stereospe-
cifically obtained. This methodology was also successfully applied for the stereospecific synthesis
of (Z)- and (E)-R-fluoro-R,â-unsaturated amides: the palladium-catalyzed carboamidation reaction
of high E/Z and (Z)-1-bromo-1-fluoroalkenes lead to pure (Z)- and (E)-R-fluoro-R,â-unsaturated
amides, respectively.
Introduction
ated esters has also been converted into high ee 2-fluo-
roalkanoic acids via asymmetric hydrogenation;6 there-
fore, the preparation of isomerically pure (E)- and
(Z)-R-fluoro-R,â-unsaturated esters has become a key
challenge for synthetic chemists.
R,â-Unsaturated amides can serve as Michael accep-
tors to afford an important method of carbon-carbon
bond formation.7 The Michael addition reactions of cu-
prate reagents8 or Grignard reagents9 to R,â-unsaturated
amides have been reported. Some compounds that con-
R-Fluoro-R,â-unsaturated esters have attracted in-
creased interest since they can serve as useful intermedi-
ates in the synthesis of a variety of biologically active
compounds.1,2 Substitution of a fluorine atom adjacent
to the ester functionality usually increases the biological
activity of these compounds significantly, as exemplified
in vitamin A and pheromone chemistry.2 Therefore,
R-fluoro-R,â-unsaturated esters have been widely em-
ployed as precursors in the preparation of monofluori-
nated retinoids,3 fluorinated analogues of insect sex
pheromones,4 and pyrethroids.5 This class of R,â-unsatur-
(4) Camps, F.; Coll, J.; Fabrias, G.; Guerrero, A. Tetrahedron 1984,
40, 2871-2878.
(5) Arlt, D.; Jautelat, M.; Lantzsch, R. Angew. Chem., Int. Ed. Engl.
1981, 20, 703-818.
(1) Shen, Y.; Zhou, Y. J. Fluorine Chem. 1993, 61, 247-251.
(2) Fieler, R.; Kobayashi, Y. Biomedical Aspects of Fluorine Chem-
istry; Elsevier: Amsterdam, 1982.
(3) Liu, R. S. H.; Matsumoto, H.; Asato, A. E.; Denny, M.; Schichida,
Y.; Yoshizawa, T.; Dahlquist, F. W. J. Am. Chem. Soc. 1981, 103, 7195-
7201.
(6) Saburi, M.; Shao, L.; Sakurai, T.; Uchida, Y. Tetrahedron Lett.
1992, 33, 7877-7880.
(7) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Tetrahedron Organic Chemistry Series Vol. 9; Pergamon
Press: Oxford, 1992.
10.1021/jo050314a CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/21/2005
4346
J. Org. Chem. 2005, 70, 4346-4353

Synthesis of (E)- and (Z)-R-Fluoro-R,â-unsaturated Esters
tain R,â-unsaturated amide moieties have been shown
to be irreversible inhibitors of guinea pig liver trans-
glutaminase (TGase)10 or potential ACE (angiotensin
converting enzyme) inhibitors.11 Due to the introduction
of fluorine neighboring the amide structure unit, R-fluoro-
R,â-unsaturated amides have shown very important
applications in medicinal chemistry: for example, R-fluoro-
R,â-unsaturated amide derivatives have been studied as
potential anticonvulsants,12 glucagon antagonists,13 CCR5
receptor modulators,14 IMPDH enzyme inhibitors,15 and
retinoid metabolism inhibitors.16 However, to the best of
our knowledge, no systematic synthetic method for
R-fluoro-R,â-unsaturated amides has been reported, al-
though there are some methods describing the synthesis
of nonfluorinated R,â-unsaturated amides.17,18 The lack
of a reliable, convenient, and stereospecific synthetic
method of R-fluoro-R,â-unsaturated amides has inhibited
further medicinal chemistry studies of this category of
compounds.
A variety of synthetic methods have been reported on
the stereoselective synthesis of (Z)-R-fluoro-R,â-unsatur-
ated esters. Some examples include Cr(II)-mediated
olefination of aldehydes with trifluoroacetates,19 Pom-
melet’s method by Durst reaction from 3-hydroxy-2-
fluoro-2-sulfinyl esters,20 the tandem reduction-olefina-
tion of R-fluoro-R-acylphosphonoesters,21 the Wittig
reaction between aldehydes and trifluorinated ylides,22
the heteropoly acid-medicated ethanolysis of R-substi-
tuted â,γ,γ-trifluoroallyl alcohols,23 dehydroxylation of
R-fluoro-â-hydroxy esters,24 thermal elimination reaction
from R-fluorosulfoxide,25 the condensation reaction be-
tween 2-fluoro-3-oxo-succinnates and aldehydes,26 mul-
tistep preparation from trifluorovinyl compounds,27 the
reaction between R-azoesters and phenylselenenyl fluo-
ride equivalent, followed by oxidation by H2O2,28 Peterson
olefination,29 one-pot reaction between aldehydes or
ketones and diethyl chloromalonate in the “spray-dried”
KF-sulfolane system,30 reductive coupling-elimination
reaction between methyl dichlorofluoroacetate and car-
bonyl compounds in the presence of zinc(0)-copper(I)
chloride,31 and reaction between â,â′-dihydroxy carboxylic
acid esters and vanadium(V) trichloride oxide.32
Fewer methods have been documented for the stereo-
selective synthesis of (E)-R-fluoro-R,â-unsaturated esters.
The Wadsworth-Horner-Emmons reaction between flu-
orocarboalkoxy-substituted dialkylphosphonate anion and
carbonyl compounds has been the most popular choice.33
Preparation from R-halo-â-mesyloxy sulfoxides has also
been reported.34
Although many of these methods provide a convenient
route to prepare either the (E)- or (Z)-R-fluoro-R,â-
unsaturated esters stereoselectively, there is no general
method that can offer a straightforward route to both (E)-
and (Z)-isomers. Therefore, we explored our methodology
for the stereoselective synthesis of (E)- and (Z)-R-fluoro-
R,â-unsaturated esters and amides from high E/Z and
(Z)-1-bromo-1-fluoroalkenes via palladium-catalyzed car-
boalkoxylation/carboamidation reactions. A portion of this
work has been reported as a preliminary communica-
tion.35
Results and Discussion
(8) Nicolas, E.; Russell, K. C.; Hruby, V. J. J. Org. Chem. 1993, 58,
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K. Tetrahedron Lett. 1986, 27, 369-372.
1-Bromo-1-fluoroalkenes (E/Z ≈ 1:1) 1, which can be
readily prepared from CFBr3, PPh3, and RCHO,36 are
potential synthons for the preparation of (Z)- and (E)-R-
fluoro-R,â-unsaturated esters. However, the (E)- and (Z)-
isomers are difficult to separate by either simple distil-
lation or column chromatography.
McCarthy and co-workers have separated (E)- and (Z)-
1-bromo-1-fluoro-2-phenylethylene by gas chromatogra-
phy (the (E)-isomer has an E/Z ratio of 92:8).37 As most
of the reactions were carried out on a millimolar scale,
it is unlikely to be of practical use for large-scale
(9) Mukaiyama, T.; Iwasawa, N. Chem. Lett. 1981, 913-916.
(10) Marrano, C.; de Macedo, P.; Keillor, J. W. Bioorg. Med. Chem.
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(11) Choo, H. Y. P.; Peak, K. H.; Park, J.; Kim, D. H.; Chung, H. S.
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2000/007 993, 2000.
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A.; Shi, S.; Naerum, L.; Madsen, P.; Sams, C.; Lau, J.; Plewe, M. B.;
Feng, J.; Teng, M.; Johnson, M. D.; Teston, K. A.; Sidelmann, U. G.;
Knudsen, L. B. US Patent 107 400, 2003. (b) Gonzales, J.; Sams, C.;
Teng, M.; Ling, A.; Gregor, V.; Hong, Y.; Kiel, D.; Kuki, A.; Shi, S.;
Naerum, L.; Madsen, P.; Lau, J.; Plewe, M. B.; Feng, J.; Johnson, M.
D.; Teston, K. A.; Sidelmann, U. G.; Knudsen, L. B. WO PCT 99/01
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2000.
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99/29 674, 1999.
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4038. (b) Clemenceau, D.; Cousseau, J. Tetrahedron Lett. 1993, 34,
6903-6906.
(27) Park, H. M.; Uegaki, T.; Konno, T.; Ishihara, T.; Yamanaka,
H. Tetrahedron Lett. 1999, 40, 2985-2988.
(28) Usuki, Y.; Iwaoka, M.; Tomoda, S. J. Chem. Soc., Chem.
Commun. 1992, 1148-1150.
(29) Lin, J.; Welch, J. T. Tetrahedron Lett. 1998, 39, 9613-9616.
(30) Kitazume, T.; Ishikawa, N. Chem. Lett. 1981, 1259-1260.
(31) Ishihara, T.; Kuroboshi, M. Chem. Lett. 1987, 1145-1148.
(32) Ishihara, T.; Shintani, A.; Yamanaka, H.; Tetrahedron Lett.
1998, 39, 4865-4868.
(17) Choi, T. L.; Chatterjee, A. K.; Grubbs, R. H. Abstracts of Papers,
222nd American Chemical Society National Meeting, Chicago, IL, Aug
26-30, 2001; American Chemical Society: Washington, DC, 2001; 303-
ORGN, Part 2.
(18) Kojima, S.; Inai, H.; Hidaka, T.; Ohkata, K. Chem. Commun.
2000, 1795-1796.
(33) (a) Thenappan, A.; Burton, D. J. J. Org. Chem. 1990, 55, 4639-
4642. (b) Machleidt, H.; Wessendorf, R. Liebig Ann. Chem. 1964, 674,
1-10. (c) Daubresse, N.; Chupeau, Y.; Francesch, C.; Lapierre, C.;
Pollet, B.; Rolando, C. Chem. Comm. 1997, 1489-1490. (d) Sano, S.;
Ando, T.; Yokoyama, K.; Nagao, Y. Synlett 1998, 7, 777-779.
(34) Satoh, T.; Itoh, N.; Onda, K.-i.; Kitoh, Y.; Yamakawa, K.
Tetrahedron Lett. 1992, 33, 1483-1484.
(35) Xu, J.; Burton, D. J. Org. Lett. 2002, 4, 831-833.
(36) (a) Vanderhaar, R. W.; Burton, D. J.; Naae, D. G. J. Fluorine
Chem. 1971/72, 1, 381-383. (b) Burton, D. J.; Yang, Z.-Y.; Qiu, W.
Chem. Rev. 1996, 96, 1641-1715. (c) Burton, D. J. J. Fluorine Chem.
1983, 23, 339-357.
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Lett. 1999, 40, 827-830.
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1, 1539-1541. (b) Jouen, C.; Lemaitre, S.; Lequeux, T.; Pommelet J.
C. Tetrahedron 1998, 54, 10801-10810.
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J. Org. Chem, Vol. 70, No. 11, 2005 4347

Xu and Burton
SCHEME 1. Preparation and Isomerization of
1-Bromo-1-fluoroalkenes
SCHEME 2. Preparation of (E)- and
(Z)-r-Fluorovinyl Phosphonates by Kinetic
Separation Methodology
preparative purposes. It has been reported that a few (Z)-
1-bromo-1-fluoroalkenes could be prepared by bromina-
tion of (E)-2-fluoro-3-phenylacrylic acid followed by de-
bromocarboxylation,38 although this route takes several
steps.24,39 Rolando and co-workers also reported the
isomerization of (Z)-1-bromo-1-fluoroalkenes to high E/Z
ratios catalyzed by Pd(OAc)2 at 110 °C; however, this
route was not thoroughly studied and was only partially
successful.38 Recently, McCarthy and co-workers noted
the isomerization of (Z)-1-bromo-1-fluoro-2-phenylethyl-
ene to an E/Z ratio of 92:8.37 In our hands, the addition
of Br2 to 1-bromo-1-fluoro-2-phenylethylene was only
partially successful, and the saturated addition product
dominated. Only low yields (<20%) of high E/Z ratio
1-bromo-1-fluoro-2-phenylethylene could be obtained by
this procedure.
Recently, we found that 1-bromo-1-fluoroalkenes (1:1)
1 isomerize to high E/Z ratio (E/Z g 75:25) 2 when they
are stored at -20 °C (Scheme 1).40 Presumably, this
isomerization is caused by a trace amount of bromine in
the products.35,40 For 1-bromo-1-fluoroalkenes (R ) phen-
yl or substituted phenyl groups), the isomerization
proceeded smoothly; for others (R ) 1-naphthyl or alkyl
groups), no obvious isomerization was observed. Alter-
natively, a similar isomerization was found to occur by
photolysis of the E/Z mixture at 254 nm.40 For example,
an E/Z mixture of o-ClC6H4CHdCFBr (E/Z ) 63:37)
isomerized to an E/Z mixture of 78:22 cleanly after
photolysis at 254 nm for 1 h.
SCHEME 3. Preparation of
(Z)-r-Fluoro-r,â-unsaturated Esters
(PPh3)2 (4 mol %), NBu3, n-BuOH, and CO (160 psi) at
room temperature, the (E)-isomers, which dominated in
2, reacted faster than the corresponding (Z)-isomers at
room temperature, and high Z/E ratios were obtained for
the corresponding R-fluoro-R,â-unsaturated esters in the
reaction mixture. The products (Z)-R-fluoro-R,â-unsatur-
ated esters Z-6 could be separated pure or obtained in
very high Z/E ratios (Table 1). For example, after the
reaction of the 1-bromo-1-fluoro-2-(4-chlorophenyl)alk-
enes (E/Z ) 87:13) with n-BuOH, NBu3, Cl2Pd(PPh3)2,
and CO (160 psi) for 144 h at room temperature, 19F NMR
analysis of the reaction mixture showed that the result-
ing product, (Z)-n-butyl 3-(4-chlorophenyl)-2-fluoropro-
penoate (Z-6d), had a Z/E ratio of 99:1. After workup and
purification by column chromatography, pure Z-6d was
obtained in 78% yield. The conversion, which was calcu-
lated on the basis of the amount of (E)-isomer in the
starting 1-bromo-1-fluoroalkenes, was 89%.
These high E/Z ratio 1-bromo-1-fluoroalkenes are
utilized in the preparation of (Z)-R-fluoro-R,â-unsaturated
esters. Recently, we reported that the (E)-isomer in 1
reacts faster than the corresponding (Z)-isomer at room
temperature.41 For example, when 1 was reacted with
Pd(PPh3)4, (EtO)2P(O)H, and NEt3 at 35 °C, high E/Z
ratio (E/Z ) 95:5) R-fluorovinyl phosphonates were
formed and pure (E)-R-fluorovinyl phosphonate was
isolated. At the same time, most of the (Z)-1-bromo-1-
fluoroalkene 4 could be recovered. Similar coupling
reaction of recovered 4 at 70 °C led to (Z)-R-fluorovinyl
phosphonates 5 stereospecifically (Scheme 2).41a
A stereospecific palladium-catalyzed carboalkoxylation
of 2-substituted-1,2-difluorovinyl iodides has been devel-
oped in this research group.42 Therefore, we tested similar
palladium-catalyzed carboalkoxylation of 2 at room tem-
perature (Scheme 3). When 2 was reacted with Cl2Pd-
A new kinetic separation methodology was developed
for the separation of (Z)-1-bromo-1-fluoroalkene from its
E/Z mixture. Presumably, similar palladium-catalyzed
carboalkoxylation of (Z)-1-bromo-1-fluoroalkenes at higher
temperature could lead to (E)-R-fluoro-R,â-unsaturated
esters stereospecifically. The separation of 4 from an E/Z
mixture 1 is the key problem. Therefore, we decided to
selectively reduce the (E)-isomers by a palladium-
catalyzed reaction, so that the (Z)-1-bromo-1-fluoro-
alkenes 4 could be recovered. For that purpose, the
reducing system of HCOOH/NBu3/Pd(II)/DMF was ex-
amined. This system has been used in the reduction of
vinyl triflate43 and aryl halides.44 Similar reduction using
HCOONa/Pd(II)/DMF has also been reported.45
The reduction of 1 was successful; all of the (E)-isomer
(as well as a small amount of (Z)-isomer) was reduced,
and most of the (Z)-1-bromo-1-fluoroalkenes 4 remained
unreacted. This reaction could be used to recover 4 from
1 (Scheme 4). For example, the reaction of 1-bromo-1-
fluoro-2-phenylethylene 1a (E/Z ) 44:56) with formic
acid, tributylamine, and Cl2Pd(PPh3)2 in DMF at 35 °C
(38) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Bull. Soc.
Chim. Fr. 1997, 134, 741-755.
(39) (a) Elkik, E.; Francesch, C. Bull. Soc. Chim. Fr. 1973, 1277-
1280; 1281-1285. (b) Etemad-Moghadam, G.; Seyden-Penne, J. Bull.
Soc. Chim. Fr. 1985, 448-454.
(40) Xu, J.; Burton, D. J. Tetrahedron Lett. 2002, 43, 2877-2879.
(41) (a) Zhang, X.; Burton, D. J. J. Fluorine Chem. 2001, 112, 47-
54. (b) Zhang, X.; Burton, D. J. J. Fluorine Chem. 2001, 112, 317-
324.
(42) Wesolowski, C. A.; Burton, D. J. Tetrahedron Lett. 1999, 40,
2243-2246.
(43) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821-4824.
(44) Cortese, N. A.; Heck, R. F. J. Org. Chem. 1977, 42, 3491-3498.
(45) Leung, S. H.; Edington, D. G.; Griffith, T. E.; James, J. J.
Tetrahedron Lett. 1999, 40, 7189-7191.
4348 J. Org. Chem., Vol. 70, No. 11, 2005

Synthesis of (E)- and (Z)-R-Fluoro-R,â-unsaturated Esters
TABLE 1. Preparation of (Z)-r-Fluoro-r,â-unsaturated Esters from High E/Z 1-Bromo-1-fluoroalkenes (Scheme 3)
entry
R
E/Z of 2
T (°C)
time (h)
Z/E of isolated Z-6a
Z/E in the mixtureb
yield (%) (conversion, %)c
1
2
3
4
5
6
7
Ph (2a)
88:12
82:18
81:19
88:12
87:13
81:19
83:17
rt
rt
rt
rt
rt
rt
45
57
96
99:1 Z-6a
99:1 Z-6b
100:0 Z-6c
100:0 Z-6d
100:0 Z-6e
100:0 Z-6f
98:2 Z-6 g
99:1
99:1
98:2
99:1
96:4
97:3
98:2
72 (82)
78 (95)
73 (91)
78 (89)
75 (86)
67 (83)
56 (67)
o-ClC6H4 (2b)
p-OMeC6H4 (2c)
p-ClC6H4 (2d)
p-FC6H4 (2e)
258
134
144
96
m-NO2C6H4 (2f)
PhC(CH3)H (2g)
115
a
All products gave satisfactory 19F, 1H, and 13C NMR and GC-MS, HRMS (or elemental analysis) data. b Z/E ratios were determined
by 19F NMR analysis of the reaction mixtures when the reactions were completed. c Conversion was calculated on the basis of the amount
of (E)-1-bromo-1-fluoroalkenes in 2.
SCHEME 4
SCHEME 5
ratios of 4 and 7 in the mixture can be easily determined
by 19F NMR analysis, which was utilized to calculate the
weight percentage of 4 in a mixture of 4 and 7. This
kinetic separation method successfully led to several
1-bromo-1-fluoroalkenes (E/Z ) 0:100) 4 and 7 (Table 2).
The methodology to prepare (E)-R-fluoro-R,â-unsatur-
ated esters E-6 from 4 was tested. First, 4a (E/Z ) 2:98)
was used as the starting material. It was reacted with
n-BuOH, NBu3, Cl2Pd(PPh3)2, and CO (160 psi) at 70 °C
(Scheme 5). After 81 h, 19F NMR analysis of the reaction
mixture showed that the reaction was completed and that
the products had a Z/E ratio of 98:2. The reaction was
presumably stereospecific since the starting E/Z ratio was
2:98. After workup and purification by silica gel column
chromatography, the corresponding n-butyl 2-fluoro-3-
phenylpropenoate (Z/E ) 98:2) was obtained in 81% yield
(Table 3).
TABLE 2. Kinetic Separation of
(Z)-1-Bromo-1-fluoroalkenes from E/Z Mixtures (Scheme
4)
yield
(recovery)
E/Z of 4
21 (38)b 2:98 4a
time
entry
R
(h) E/Z of 1 of 4a (%)
1
2
3
4
5
6
7
8
9
Ph (1a)
Ph (1a)
o-ClC6H4 (1b)
o-ClC6H4 (1b)
p-MeOC6H4 (1c) 135
p-MeOC6H4 (1c) 110
PhC(Me)H (1g)
1-naphthyl (1h) 129
n-C7H5 (1i) 121
75
143
141
171
44:56
43:57
48:52
26:74
51:49
51:49
36:64
48:52
43:57
(83)
(81)
(57)
0:100 4a
0:100 4b
0:100 4b
22 (45)b 0.5:99.5 4c
(75)
(82)
(77)
(37)
0:100 4c
0:100 4g
0:100 4h
0:100 4i
156
a Recovery (number in the parentheses) was calculated on the
basis of the amount of 4 obtained and the amount of the (Z)-isomer
in the starting E/Z mixture 1. b 4 was separated from 7 by
distillation using a Vigreux column.
Therefore, we directly utilized the mixtures of 4 and 7
as the starting materials in the carboalkoxylation reac-
tion. Their reactions with n-BuOH, NBu3, Cl2Pd(PPh3)2,
and CO (160 psi) at 70 °C were also successful (Table 3).
When these reactions were completed, 19F NMR analysis
showed that the products had a Z/E ratio of 100:0. Again,
this palladium-catalyzed carboalkoxylation reaction was
shown to be stereospecific, since the starting 1-bromo-1-
fluoroalkenes had E/Z ratios of 0:100. The products E-6
could be obtained pure; some products, however, were
shown to partially isomerize in the process of isolation.
For example, the mixture of 4c (E/Z ) 0:100) and 7 gave
a Z/E ratio of 100:0 by 19F NMR analysis of the reaction
mixture when the reaction was completed. After workup
and purification by silica gel column chromatography,
n-butyl 2-fluoro-3-(4-methoxyphenyl)propenoate E-6c (Z/E
) 98:2) was obtained; 2% of the product had isomerized
in the process of purification.
The carboalkoxylation reaction of (Z)-1-bromo-1-fluo-
roalkenes is stereospecific; this is similar to the car-
boalkoxylation reactions of 2-substituted-1,2-difluoro-1-
iodoalkenes and R,â-difluoro-â-iodostyrenes.42 However,
it has been reported by Heck and co-workers that
nonfluorinated vinyl halides can suffer from isomeriza-
tion problems in similar carboalkoxylation reactions.46
For example, (Z) n-BuCHdCHI leads to (Z) n-BuCHd
CHCOOBu-n and (E) n-BuCHdCHCOOBu-n in 79% and
6% yield, respectively.46
for 75 h gave 21% (Z)-1-bromo-1-fluoro-2-phenylethylene
(E/Z ) 2:98, recovery 38%) as well as the reduced
products (Table 2, entry 1).
Problems arose when we applied this method to the
preparation of 4 in larger quantities (>100 mmol). The
reactions went smoothly; however, when we tried to
separate pure 4 from the mixture by silica gel column
chromatography, it proved to be difficult for most sub-
strates. A repeated distillation of the E/Z mixture of
1-bromo-1-fluoroalkenes using a Vigreux column under
full vacuum led to pure (Z)-1-bromo-1-fluoroalkenes;
however, we noticed the formation of 1% or 2% of the
(E)-isomer, formed by isomerization of the (Z)-isomer in
the process of distillation (Table 2, entries 1 and 5). The
isolation of (Z)-1-bromo-1-fluoroalkenes was time-con-
suming, and the yields were lowered accordingly.
An effective solution to this problem was not to
separate 4 from 7 at this stage. Instead, we directly used
the mixture of 4 and 7 in the palladium-catalyzed
reactions and separated the product from 7 at that time.
This decision was based on the following considerations:
the reduced products 7 generally do not participate in
further palladium-catalyzed reactions (such as carboalkox-
ylation); the products of the reaction (for example, (E)-
R-fluoro-R,â-unsaturated esters) can easily be separated
from 7 by column chromatography; and the relative molar
J. Org. Chem, Vol. 70, No. 11, 2005 4349

Xu and Burton
yieldb (%)
TABLE 3. Preparation of (E)-r-Fluoro-r,â-unsaturated Esters (Scheme 5)
entry
R
E/Z of 4
T (°C)
time (h)
Z/E of E-6a
1
2
3
4
5
6
7
Ph (4a)
Ph (4a)
o-ClC6H4 (4b)
p-OMeC6H4 (4c)
PhC(CH3)H (4g)
1-naphthyl (4h)
n-C7H15 (4i)
2:98c
0:100
0:100
0:100
0:100
0:100
0:100
70
70
70
70
70
70
70
81
180
125
155
161
160
160
2:98 E-6a
81
0:100 E-6a
0:100 E-6b
2:98d E-6c
0:100 E-6g
7:93d E-6h
inseparable
90
94
79
92
81
inseparable
a All products gave satisfactory 19F, 1H, and 13C NMR and GC-MS, HRMS data. b Isolated yield. c The starting material did not contain
reduced products. d Z/E ratio was 100:0 when the reaction was completed; isomerization happened to the product in the process of separation.
TABLE 4. Preparation of (Z)-r-Fluoro-r,â-unsaturated Amides (Scheme 6)
entry
R
E/Z of 2
T (°C)
time (h)
Z/E of Z-8a
Z/E in mixtureb
yield (%) (conversion, %)c
1
2
3
4
5
6
7
Ph (2a)
85:15
82:18
81:19
88:12
87:13
81:19
83:17
rt
rt
rt
rt
rt
rt
50
90d
148
336
94
140
110
117
100:0 Z-8a
100:0 Z-8b
100:0 Z-8c
100:0 Z-8d
100:0 Z-8e
100:0 Z-8f
100:0 Z-8g
94:6
89:11
96:4
95:5
95:5
98:2
97:3
46 (54)
74 (90)
70 (87)
44 (50)
77 (89)
46 (57)
55 (64)
o-ClC6H4 (2b)
p-MeOC6H4 (2c)
p-ClC6H4 (2d)
p-FC6H4 (2e)
m-NO2C6H4 (2f)
PhC(CH3)H (2g)
a All products gave satisfactory 19F, 1H, and 13C NMR and GC-MS, HRMS data. b Z/E was obtained by 19F NMR analysis of the reaction
mixture when the reaction was completed. c The conversion was calculated on the basis of the amount of (E)-1-bromo-1-fluoroalkenes in
the starting materials. d NEt3 was used instead of NBu3.
TABLE 5. Preparation of (E)-r-Fluoro-r,â-unsaturated Amides (Scheme 7)
entry
E/Z of 4
T (°C)
time (h)
Z/E of E-8a
yield (%)
1
2
3
4
5
6
Ph (4a)
0:100
0:100
0:100
0:100
0:100
0:100
70
70
70
70
70
70
182
140
139
109
175
122
0:100 E-8a
0:100 E-8b
inseparable
0:100 E-8g
0:100 E-8h
inseparable
25
o-ClC6H4 (4b)
p-MeOC6H4 (4c)
PhC(CH3)H (4g)
1-naphthyl (4h)
n-C7H15 (4i)
27
inseparable
74
42
inseparable
a All products gave satisfactory 19F, 1H, and 13C NMR and GC-MS and HRMS data.
SCHEME 6
SCHEME 7
High E/Z ratios and (Z)-1-bromo-1-fluoroalkenes were
also used as the starting material in the preparation of
(Z)-and (E)-R-fluoro-R,â-unsaturated amides. Following
the success with the highly stereoselective preparation
of (Z)- and (E)-R-fluoro-R,â-unsaturated esters, we begun
to explore the preparation of (Z)- and (E)-R-fluoro-R,â-
unsaturated amides by similar methodology. Therefore,
aniline replaced the n-BuOH in above palladium-cata-
lyzed reactions of high E/Z and (Z)-1-bromo-1-fluoro-
alkenes.
The reactions between 2 and aniline, NBu3, Cl2Pd-
(PPh3)2, and CO (160 psi) at room temperature (except
50 °C for 2g) were carried out smoothly, and high Z/E
ratios were detected for the corresponding amide products
by 19F NMR analysis of the reaction mixture (Scheme 6).
After separation by silica gel column chromatography
followed by recrystallization, pure (Z)-R-fluoro-R,â-
unsaturated amide Z-8 was obtained (Table 4).
70 °C gave (E)-R-fluoro-R,â-unsaturated amides E-8
(Scheme 7). When the reactions were completed, 19F NMR
analysis of the mixture showed that Z/E ratios of the
products were 0:100. Most products were successfully
separated pure in moderate yields (Table 5). However,
in certain cases, an unknown impurity in the mixture
made it difficult to separate the desired products (R )
p-MeOC6H4-, n-C7H15-). When R ) o-ClC6H4-, the yield
of the desired product was very low. A side product, which
had very close chemical shift and the same coupling
patterns with the desired product, was observed by 19F
NMR. Attempts to separate this side product failed. This
side product could be (E) RCHdCFC(O)C(O)NHPh which
was formed at high temperature.47
Most Z-8 and E-8 showed a doublet of doublet (dd)
pattern in their 19F NMR spectra in CDCl3. The second
doublet (with typical coupling constants of 3-6 Hz) is
presumably due to the intramolecular coupling between
F and HN. To test this hypothesis, (Z)-2-fluoro-3,N-
Starting from the mixtures of 4 and 7, similar reactions
with aniline, NBu3, Cl2Pd(PPh3)2, and CO (160 psi) at
(46) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974,
39, 3318-3326.
(47) Uozumi, Y.; Arii, T.; Watanabe, T. J. Org. Chem. 2001, 66,
5272-5274.
4350 J. Org. Chem., Vol. 70, No. 11, 2005

Synthesis of (E)- and (Z)-R-Fluoro-R,â-unsaturated Esters
SCHEME 8. Proposed Mechanism for the Carboalkoxylation and Carboamidation Reaction
1
preliminary communication;35 their H and 13C NMR spectra
diphenylacrylamide was used as a representative of these
amides. 19F NMR of this amide in CDCl3 showed a
doublet of doublet pattern; when one drop of D2O was
added to the NMR solution, 19F NMR analysis of this
mixture gave a sharp doublet. Most probably, NH had
underwent a fast exchange with D2O so that the in-
tramolecular coupling between F and HN was no longer
detectable.
The carboalkoxylation and carboamidation reactions
presumably follow the mechanism proposed by Heck and
co-workers (Scheme 8):46 Cl2PdL2 (L ) PPh3) is first
reduced to PdL2; CO is added to PdL2 and Pd(CO)L is
formed; oxidative addition of vinyl halide (RX) to Pd-
(CO)L leads to the formation of the complex RPdX(CO)L;
CO is inserted to the R-Pd bond and RC(O)PdXL2 is
formed; R′OH (R′ ) n-Bu) or PhNH2 attacks the carbonyl
group, and the product RCOOR′ (or RCONHPh) leaves;
reductive elimination of HPdXL2 by NBu3 recovers the
active catalyst PdL2. Again, as shown in our previous
report,41 (Z)-1-bromo-1-fluoroalkene only participates in
the oxidative addition step at higher temperature (70 °C).
are included in the Supporting Information.
General Procedures for the Preparation of (Z)-r-
Fluoro-r,â-unsaturated Esters Z-6. An oven-dried 120 mL
Hastelloy Parr pressure reactor equipped with a stirring bar
was charged with 0.07 g (0.10 mmol) of Cl2Pd(PPh3)2, 5 mL of
n-butanol, and 0.59 g (3.2 mmol) of tri-n-butylamine. 1-Bromo-
1-fluoroalkene (3.0 mmol, high E/Z ratio) was added, and the
pressure reactor was closed. (Caution: All reactions should
be carried out behind a safety shield in a well-ventilated hood.)
The pressure reactor was pressurized to 160 psi with carbon
monoxide, and the pressure was released. This process was
repeated four times to rid the system of air. Finally, the
pressure reactor was pressurized to 160 psi and was allowed
to stir at room temperature (for 1-bromo-1-fluoroalkenes, R )
aryl) or in an oil bath at 45 °C (for 1-bromo-1-fluoroalkenes, R
) alkyl). The consumption of carbon monoxide could be roughly
determined by the reading on the gauge. When the reaction
was completed, the reactor was allowed to cool to room
temperature (if necessary) and the pressure was carefully
released. The reaction mixture was transferred to a separatory
funnel containing 100 mL of ethyl acetate. The organic layer
was washed with aqueous 10% hydrochloric acid (3 × 15 mL),
saturated sodium bicarbonate (2 × 15 mL), and brine (2 × 10
mL). The combined organic layers were dried over anhydrous
MgSO4 and concentrated by rotary evaporation, and the crude
product was further purified by silica gel column chromatog-
raphy.
(Z)-n-Butyl 3-(4-Chlorophenyl)-2-fluoropropenoate (Z-
6d). Similarly, a mixture of 1-bromo-1-fluoro-2-(4-chloro-
phenyl)ethylene (0.24 g, 1.0 mmol, E/Z ) 88:12), NBu3 (0.78
g, 1.14 mmol), and Cl2Pd(PPh3)2 (0.03 g, 0.04 mmol) in
n-butanol (6 mL) was reacted with CO at room temperature
for 134 h. When the reaction was completed, 19F NMR analysis
of the mixture showed that the Z/E ratio of the crude product
was 99:1. Silica gel column chromatography (ethyl acetate/
hexanes ) 5:95, Rf ) 0.35) followed by recrystallization from
hexanes gave white crystals: mp 63-65 °C; 0.20 g, yield 78%
(conversion 89% based on the consumed (E)-1-bromo-1-fluoro-
2-(4-chlorophenyl)ethylene), Z/E ) 100:0; 19F NMR (CDCl3) δ
Conclusion
1-Bromo-1-fluoroalkenes were successfully employed to
prepare (E)- and (Z)-R-fluoro-R,â-unsaturated esters and
(E)- and (Z)-R-fluoro-R,â-unsaturated amides in high
stereoselectivity. 1-Bromo-1-fluoroalkenes were found to
isomerize to high E/Z ratios when stored at -20 °C or
by photolysis at 254 nm. Kinetic separation strategy was
successfully utilized to prepare (Z)-1-bromo-1-fluoroalk-
enes (E/Z ) 0:100).
Room-temperature palladium-catalyzed carboalkox-
ylation of high E/Z 1-bromo-1-fluoroalkenes led to (Z)-R-
fluoro-R,â-unsaturated esters in high Z/E ratios; similar
carboalkoxylation of (Z)-1-bromo-1-fluoroalkenes led to
(E)-R-fluoro-R,â-unsaturated esters stereospecifically.
Starting from high E/Z and (Z)-1-bromo-1-fluoroalkenes,
(Z)- and (E)-R-fluoro-R,â-unsaturated amides were ste-
reospecifically prepared, respectively.
3
1
-124.6 (d, JFH(trans) ) 33.8 Hz, 1 F) ppm; H NMR (CDCl3) δ
7.58 (dm, J ) 8.5 Hz, 2 H), 7.37 (dm, J ) 8.6 Hz, 2 H), 6.86 (d,
3J HF(trans) ) 34.7 Hz, 1 H), 4.29 (t, J ) 6.6 Hz, 2 H), 1.73 (pentet,
J ) 7.1 Hz, 2 H), 1.45 (sextet, J ) 7.4 Hz, 2 H), 0.98 (t, J )
7.3 Hz, 3 H) ppm; 13C NMR (CDCl3) δ 161.0 (d, J ) 34.2 Hz),
147.2 (d, J ) 268.0 Hz), 135.4 (d, J ) 3.6 Hz), 131.3 (d, J )
Experimental Section
The preparation and characterization of Z-6a, Z-6b, Z-6c,
Z-6g, E-6a, E-6b, E-6c, and E-6g were described in the
(48) King, A. O.; Negishi, E.-i.; Villani, F. J., Jr.; Silveira, A., Jr. J.
Org. Chem. 1978, 43, 358-360.
J. Org. Chem, Vol. 70, No. 11, 2005 4351

Xu and Burton
8.8 Hz), 129.5 (d, J ) 5.8 Hz), 128.9, 116.0 (d, J ) 4.2 Hz),
65.6, 30.4, 19.0, 13.5 ppm; GC-MS m/z (relative intensity):
258 (M+ + 2, 11), 257 (4), 256 (M+, 33), 236 (2), 202 (45), 200
(100), 183 (29), 180 (55), 165 (9), 163 (10), 154 (16), 152 (16),
136 (7), 135 (10), 120 (80), 99 (23); HRMS calcd 256.0666 for
C13H14O235ClF, obsd 256.0656.
General Procedures for the Preparation of the Mix-
ture of 4 and 7 from 1. A 100 mL dry flask equipped with a
stirring bar and N2 tee was charged with 0.074 g (0.106 mmol)
of Cl2Pd(PPh3)2 and 8 mL of dry DMF. Then 6.00 mmol of
1-bromo-1-fluoroalkene (E/Z ≈ 1:1, includes (E)-isomer 3.0
mmol) was added, and the solution was stirred at room
temperature for 15 min. After the addition of 1.67 g (9.00
mmol, 3.0 equiv) of NBu3, the reaction mixture was allowed
to stir for 5 min and 0.23 g (5.1 mmol, 1.7 equiv) of HCOOH
was added. The mixture was stirred at 35 °C. The reaction
progress was monitored by 19F NMR analysis of the mixture.
When the reaction was completed, the reaction mixture was
added directly to a silica gel column and a mixture of 4 and 7
was obtained.
General Procedures for the Preparation of (E)-r-
Fluoro-r,â-unsaturated Esters E-6. An oven-dried 120 mL
Hastelloy Parr pressure reactor equipped with a stirring bar
was charged with 0.07 g (0.10 mmol) of Cl2Pd(PPh3)2, 5 mL of
n-butanol, and tri-n-butylamine (0.48 g, 2.6 mmol). A mixture
of (Z)-1-bromo-1-fluoroalkene (2.0 mmol) and the reduced
olefins was added, and the pressure reactor was closed.
(Caution: All reactions should be carried out behind a safety
shield in a well-ventilated hood.) The pressure reactor was
pressurized to 160 psi with carbon monoxide, and the pressure
was released. This process was repeated four times to rid the
system of air. Finally, this pressure reactor was pressurized
to 160 psi and was allowed to stir in an oil bath at 70 °C. The
consumption of carbon monoxide could be roughly determined
by the reading on the gauge. When the reaction was completed,
the reactor was allowed to cool to room temperature and the
pressure was carefully released. The reaction mixture was
transferred to a separatory funnel containing 100 mL of ethyl
acetate. The organic layer was washed with aqueous 10%
hydrochloric acid (3 × 15 mL), saturated sodium bicarbonate
(2 × 15 mL), and brine (2 × 10 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated by
rotary evaporation, and the crude product was further purified
by silica gel column chromatography.
was charged with 0.07 g (0.10 mmol) of Cl2Pd(PPh3)2, 0.36 g
(3.8 mmol) of freshly distilled aniline, and 4.0 mL of tri-n-
butylamine. A 3.0 mmol portion of high E/Z ratio 1-bromo-1-
fluoroalkene was added, and the pressure reactor was closed.
(Caution: All reactions should be carried out behind a safety
shield in a well-ventilated hood.) The pressure reactor was
pressurized to 160 psi with carbon monoxide, and the pressure
was released. This process was repeated four times to rid the
system of air. Finally, this pressure reactor was pressurized
to 160 psi and was allowed to stir at room temperature (for
1-bromo-1-fluoroalkenes, R) aryl) or in an oil bath at 50 °C
(for 1-bromo-1-fluoroalkenes, R) alkyl). The consumption of
carbon monoxide could be roughly determined by the reading
on the gauge. When the reaction was completed, the reactor
was allowed to cool to room temperature (if necessary) and
the pressure was carefully released. The reaction mixture was
transferred to a separatory funnel containing 100 mL of ethyl
acetate. The organic layer was washed with aqueous 10%
hydrochloric acid (3 × 15 mL), saturated sodium bicarbonate
(2 × 15 mL), and brine (2 × 10 mL). The combined organic
layers were dried over anhydrous MgSO4 and concentrated by
rotary evaporation, and the crude product was further purified
by silica gel column chromatography. Recrystallization from
hexanes gave 100% pure (Z)-R-fluoro-R,â-unsaturated amides.
(Z)-2-Fluoro-3,N-diphenylacrylamide (Z-8a). Similarly,
a mixture of 1-bromo-1-fluoro-2-phenylethylene (0.60 g, 3.0
mmol, E/Z ) 85:15), aniline (0.36 g, 3.8 mmol), and Cl2Pd-
(PPh3)2 (0.07 g, 0.10 mmol) in triethylamine (3.5 mL) was
reacted with CO at room temperature for 90 h. 19F NMR
analysis of the mixture showed that the Z/E ratio of the crude
product was 94:6. Silica gel column chromatography (ethyl
acetate/hexanes ) 15:85, Rf ) 0.33) gave white crystals: mp
166-167 °C; 0.33 g, 46% yield (54% conversion based on the
consumed (E)-1-bromo-1-fluoro-2-phenylethylene), Z/E
)
3
100:0; 19F NMR (CDCl3) δ -129.9 (dd, JFH ) 39.6 Hz, JF‚‚‚HN
1
) 5.1 Hz) ppm; H NMR (CDCl3) δ 8.01 (broad s, 1 H), 7.63-
7.68 (m, 4 H), 7.35-7.46 (m, 5 H), 7.18 (tt, J ) 7.5 Hz, J ) 1.0
3
Hz, 1 H), 7.08 (d, JHF(trans) ) 39.5 Hz, 1 H) ppm; 13C NMR
1
(CDCl3) δ 158.2 (d, J ) 26.1 Hz), 149.8 (d, JCF ) 275.6 Hz),
136.8, 131.2 (d, J ) 3.2 Hz), 130.2 (d, J ) 8.2 Hz), 129.5 (d, J
2
) 2.7 Hz), 129.2, 128.8, 125.1, 120.2, 114.6 (d, JCF ) 4.9 Hz)
ppm; GC-MS m/z (relative intensity) 241 (M+, 73), 240 (31),
149 (100), 129(13), 121 (48), 120 (12), 101 (98), 93 (17), 77 (12),
75 (18), 65 (17), 51 (16); HRMS calcd 241.0903 for C15H12FON,
obsd 241.0898.
(E)-n-Butyl 2-Fluoro-3-(1-naphthyl)propenoate (E-6h).
Similarly, a mixture of (Z)-1-bromo-1-fluoro-2-(1-naphthyl)-
ethylene (contains 1-bromo-1-fluoro-2-(1-naphthyl)ethylene
0.25 g, 1.0 mmol, E/Z ) 0:100) and the reduced olefins, tri-n-
butylamine (0.24 g, 1.3 mmol), and Cl2Pd(PPh3)2 (0.03 g, 0.04
mmol) in n-butanol (4 mL) was reacted with CO at 70 °C for
160 h. 19F NMR analysis of the reaction mixture showed that
the Z/E ratio of the product was 0:100. A colorless liquid was
obtained after silica gel column chromatography (ethyl acetate/
General Procedure for the Preparation of (E)-r-Fluoro-
r,â-unsaturated Amides E-8. An oven-dried 120 mL Has-
telloy Parr pressure reactor equipped with a stirring bar was
charged with 0.03 g (0.04 mmol) of Cl2Pd(PPh3)2, 0.14 g (1.5
mmol) of freshly distilled aniline, and 4.0 mL of tri-n-
butylamine. A mixture of (Z)-1-bromo-1-fluoroalkene (1.0
mmol) and the reduced products was added, and the pressure
reactor was closed. (Caution: All reactions should be carried
out behind a safety shield in a well-ventilated hood.) The
pressure reactor was pressurized to 160 psi with carbon
monoxide, and the pressure was released. This process was
repeated four times to rid the system of air. Finally, the
pressure reactor was pressurized to 160 psi and was allowed
to stir in an oil bath at 70 °C. The consumption of carbon
monoxide could be roughly determined by the reading on the
gauge. When the reaction was completed, the reactor was
allowed to cool to room temperature and the pressure was
carefully released. The reaction mixture was transferred to a
separatory funnel containing 100 mL of ethyl acetate. The
organic layer was washed with aqueous 10% hydrochloric acid
(3 × 15 mL), saturated sodium bicarbonate (2 × 15 mL), and
brine (2 × 10 mL). The combined organic layers were dried
over anhydrous MgSO4 and concentrated by rotary evapora-
tion, and the crude product was further purified by silica gel
column chromatography. Recrystallization from hexanes gave
100% pure (E)-R-fluoro-R,â-unsaturated amides.
hexanes ) 5:95, Rf ) 0.31): 0.22 g, 81% yield, Z/E ) 7:93; 19
F
3
NMR (CDCl3) δ -116.0 (d, JFH(cis) ) 19.2 Hz, 1 F) ppm; 1H
NMR (CDCl3) δ 7.81-7.88 (m, 3 H), 7.48-7.51 (m, 2 H), 7.42-
7.44 (m, 2 H), 7.33 (d, 3JHF(cis) ) 19.3 Hz, 1 H), 3.95 (t, J ) 6.4
Hz, 2 H), 1.17 (m, 2 H), 0.86 (sextet, J ) 7.4 Hz, 2 H), 0.66 (t,
J ) 7.1 Hz, 3 H) ppm; 13C NMR (CDCl3) δ 160.2 (d, J ) 37.1
1
Hz), 148.1 (d, JCF ) 254.7 Hz), 133.0, 131.1 (d, J ) 3.0 Hz),
128.6 (d, J ) 9.1 Hz), 128.4, 128l.1, 126.8 (d, J ) 1.9 Hz), 126.1,
125.7, 124.7, 124.2, 118.5 (d, 2JCF ) 23.9 Hz), 104.0, 65.1, 29.6,
18.4, 13.1 ppm; GC-MS, product isomerized on GC column,
m/z (relative intensity) of one isomer 273 (M+ + 1, 10), 272
(M+, 61), 224 (2), 216 (5), 199 (16), 196 (78), 179 (43), 172 (21),
171 (39), 170 (100), 168 (18), 152 (28), 151 (51); the other
isomer 272 (M+ + 1, 9), 272 (M+, 57), 216 (4), 199 (13), 196
(73), 179 (30), 171 (100), 170 (75), 168 (12), 152 (21), 151 (35);
HRMS calcd 272.1213 for C17H17FO2, obsd 272.1216.
General Procedures for the Preparation of (Z)-r-
Fluoro-r,â-unsaturated Amides Z-8. An oven-dried 120 mL
Hastelloy Parr pressure reactor equipped with a stirring bar
4352 J. Org. Chem., Vol. 70, No. 11, 2005

Synthesis of (E)- and (Z)-R-Fluoro-R,â-unsaturated Esters
(E)-2-Fluoro-3,N-diphenylacrylamide (E-8a). Similarly,
a mixture of (Z)-1-bromo-1-fluoro-2-phenylethylene (contains
(Z)-1-bromo-1-fluoro-2-phenylethylene 0.09 g, 0.4 mmol, E/Z
) 0:100) and the reduced products, aniline (0.06 g, 0.6 mmol),
and Cl2Pd(PPh3)2 (0.01 g, 0.02 mmol) in tributylamine (4 mL)
was reacted with CO at 70 °C for 182 h. Silica gel column
chromatography (ethyl acetate/hexanes ) 10:90, Rf ) 0.31)
followed by recrystallization from hexanes gave white crys-
tals: mp 135-137 °C; 0.03 g, 25% yield, Z/E ) 0:100; 19F NMR
(CDCl3) δ -117.7 (dd, 3JFH(cis) ) 26.7 Hz, JF...HN ) 5.5 Hz, 1 F)
ppm; 1H NMR (CDCl3) δ 7.88 (broad s, 1 H), 7.67 (dm, J ) 7.3
Hz, 2 H), 7.53 (dm, J ) 8.3 Hz, 2 H), 7.31-7.40 (m, 5 H), 7.15
77 (25), 75 (35), 65 (46), 63 (17), 51 (38); HRMS calcd 241.0903
for C15H12FON, observed 241.0901.
Acknowledgment. We greatly acknowledge the
National Science Foundation for their financial support
of this work.
Supporting Information Available: Experimental pro-
cedures for the synthesis of Z-6e, Z-6f, Z-8(b-g), E-8b, E-8g,
and E-8h and their characterization by 19F, 1H, and 13C NMR,
GC-MS, and HRMS; copies of 1H and 13C NMR spectra of
compounds Z-6(a-g), E-6a, E-6b, E-6c, E-6g, E-6h, Z-8(a-
g), E-8a, E-8b, E-8g, and E-8h; NMR experiments on the
existence of intramolecular F‚‚‚HN coupling in (Z)- and (E)-
R-fluoro-R,â-unsaturated amides. This material is available
free of charge via the Internet at http://pubs.acs.org.
3
(tt, J ) 7.4 Hz, J ) 1.1 Hz, 1 H)), 6.87 (d, JHF(cis) ) 26.7 Hz,
1 H) ppm; 13C NMR (CDCl3) δ 157.5 (d, J ) 30.8 Hz), 148.7 (d,
1JCF ) 259.2 Hz), 136.7, 130.6 (d, J ) 11.6 Hz), 130.2 (d, J )
2.5 Hz), 129.1, 129.0, 128.2, 125.1, 120.3, 120.1 (d, 2JCF ) 27.6
Hz) ppm; GC-MS m/z (relative intensity) 243 (M+ + 2, 1),
242 (9), 241 (M+, 58), 240 (35), 221 (15), 220 (9), 193 (5), 164
(13), 149 (76), 129 (23), 121 (41), 120 (18), 101 (100), 93 (20),
JO050314A
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