Palladium(0)/copper(I)-cocatalyzed cross-coupling of the zinc reagent of ethyl 3-bromo-3,3-difluoropropionate with aryl (alkenyl) halides: An efficient stereoselective synthesis of β-fluoro-α,β-unsaturated esters

Article abstract of DOI:10.1021/jo991276w

Ethyl 3-bromo-3, 3-difluoropropionate was prepared in an overall yield of 75% from the radical addition of dibromodifluoromethane to ethyl vinyl ether under Na₂S₂O₄ initiation, followed by oxidation of the acetal with Caro acid. The treatment of 1 with active zinc dust in anhydrous DMF at room temperature produced the zinc reagent ZnBrCF₂CH₂CO₂C₂H₅ (2). The cross coupling of the zinc reagent 2 with aryl (alkenyl) halides (R-X) in DMF using Pd(0)-Cu(I) as cocatalyst stereoselectively provided the β-fluoro-α,β- unsaturated esters (RCF=CHCO₂C₂H₅ 4) directly and in moderate yields. An E/Z ratio ranging from 3:2 to 1:0 was observed. This is the first example that Cu(I) can improve the selectivity of the cross-coupling reaction. Mechanistic studies revealed that zinc reagent 2 underwent stereoselective elimination to produce (Z)-1-fluoro-2-(ethoxycarbonyl)ethenylzinc reagent 6, and then the cross-coupling of 6 with aryl(alkenyl) halides under palladium(O) catalysis afforded the β-fluoro-α,β-unsaturated esters 4.

Full text of DOI:10.1021/jo991276w

694
J . Org. Chem. 2000, 65, 694-700
P a lla d iu m (0)/Cop p er (I)-Coca ta lyzed Cr oss-Cou p lin g of th e Zin c
Rea gen t of Eth yl 3-Br om o-3,3-d iflu or op r op ion a te w ith Ar yl
(Alk en yl) Ha lid es: An Efficien t Ster eoselective Syn th esis of
â-F lu or o-r,â-u n sa tu r a ted Ester s
Sheng Peng, Feng-Ling Qing,* Yi-Qun Li, and Chang-Ming Hu
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received August 11, 1999
Ethyl 3-bromo-3, 3-difluoropropionate (1) was prepared in an overall yield of 75% from the radical
addition of dibromodifluoromethane to ethyl vinyl ether under Na2S2O4 initiation, followed by
oxidation of the acetal with Caro acid. The treatment of 1 with active zinc dust in anhydrous DMF
at room temperature produced the zinc reagent ZnBrCF2CH2CO2C2H5 (2). The cross coupling of
the zinc reagent 2 with aryl (alkenyl) halides (R-X) in DMF using Pd(0)-Cu(I) as cocatalyst
stereoselectively provided the â-fluoro-R,â-unsaturated esters (RCFdCHCO2C2H5 4) directly and
in moderate yields. An E/Z ratio ranging from 3:2 to 1:0 was observed. This is the first example
that Cu(I) can improve the selectivity of the cross-coupling reaction. Mechanistic studies revealed
that zinc reagent 2 underwent stereoselective elimination to produce (Z)-1-fluoro-2-(ethoxycarbonyl)-
ethenylzinc reagent 6, and then the cross-coupling of 6 with aryl(alkenyl) halides under palladium-
(0) catalysis afforded the â-fluoro-R,â-unsaturated esters 4.
In tr od u ction
were introduced late in the synthesis by â-elimina-
tion reactions. R-Fluoro-R,â-unsaturated esters (RCHd
CFCO2C2H5), mainly prepared by the reaction of lithium
triethylphosphonofluoroacetate with aldehydes,5 have
been used as building blocks for the preparation of the
monofluorinated compounds of biological interest.6 How-
ever, the synthetic application of â-fluoro-R,â-unsaturated
esters (RCFdCHCO2C2H5) is far less developed, because
few reports have been published on the general and
practical methods for the preparation of â-fluoro-R,â-
unsaturated esters.7 In this article, we document a novel,
Monofluorine-containing organic molecules have been
received considerable attention due to the high electron
negativity and small atomic size that fluorine may confer
to biologically active molecules, and great effort has been
made to explore practical and effective methods for the
synthesis of selective monofluorinated organic com-
pounds.1 Various fluorinating agents have been used to
for the incorporation fluorine into a molecule;2 however,
most of these reagents are not only expensive and
difficult to prepare, but there are also limitation to
functional groups compatible with the reactive reagents.
Another approach is to synthesize fluorine-containing
intermediates and to use them as synthons. This is
becoming the main trend for the construction of fluori-
nated compounds. Among these, monofluorinated acrylic
esters, in particular, are interesting synthons due to their
chemical versatility and potential for further elaboration
into fluorinated analogues of natural products. Mono-
fluoroacrylic esters of the type CFHdCHCO2R3 and
CH2dCFCO2R4 have been prepared by multistep se-
quences in which the R,â-unsaturated double bonds
(4) (a) Tolman, V.; Spronglova, P. Collect. Czech. Chem. Commun.
1983, 48, 319. (b) Boguslavskaya, L. S.; Chuvatkin, N. N. J . Fluorine
Chem. 1991, 54, 138. (c) Molines, H.; Nguyen, T.; Wakselman, C.
Synthesis 1985, 755. (d) Nguyen, T.; Molines, H.; Wakselman, C. Synth.
Commun. 1985, 15, 925. (e) Gassen, K. R.; Bielefeldt, D.; Marhold, A.;
Andres, P. J . Fluorine Chem. 1991, 55, 149. (f) Dapperheld, S.;
Heumuller, R.; Ulmschneider, D. J . Fluorine Chem. 1991, 54, 74.
(5) (a) Pawson, B. A.; Chan, K. K.; Denoble, J .; Han, R. L.;
Piermattie, V.; Specian, A. C.; Srisethnil, S. J . Med. Chem. 1979, 22,
1059. (b) Etemad-Moghadam, G.; Deyden-Penne, J . Bull. Soc. Chim.
Fr. 1985, 448. (c) Elkik, E.; Francesch, C. Bull. Soc. Chim. Fr. 1986,
423.
(6) (a) 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. (b) Camps, F.; Coll, J .; Fabrias, G.; Guerrero, A. Tetrahedron
1984, 40, 2871. (c) Patrick, T. B.; Lanahan, M. V.; Yang, C.; Walker,
J . K.; Hutchinson, C. L.; Neal. B. E. J . Org. Chem. 1994, 59, 1210. (d)
Patrick, T. B.; Neal, B. E. Synlett. 1996, 1227. (e) Kim, B. T.; Min, Y.
K.; Asami, T.; Park, N. K.; Kwon, O. Y.; Cho, K. Y.; Yoshida, S.
Tetrahedron Lett. 1997, 38, 1797. (f) Robustell, B. J .; Abe, I.; Prestwich,
G. D. Tetrahedron Lett. 1998, 39, 9385.
(7) To our knowledge, only ethyl 3-phenyl-3-fluoro-2-propenoate was
prepared by three different procedures, but the yield or the E/Z ratio
of the product is not high. (a) Fluoriantion of alkenylstannanes with
silver triflate and xenon difluoride: Tius, M. A.; Kawakami, J . K.
Synlett 1993, 207. (b) Monohydrofluorination of electrophilic alkynes
with HF: Gorgues, A.; Stephan, D.; Cousseau, J . J . Chem. Soc., Chem.
Commun. 1989, 1493. (c) Carboxylation of 2,2-difluorovinyllithium:
Gillet, J . P.; Sauvetre, R.; Normant, J . F. Synthesis 1982, 297. (d) When
our manuscript was examined, the stereoselective synthesis of (E)-â-
fluoro-R,â-unsaturated esters by carbonylation of (E)-2-fluoro-1-iodo-
1-alkenyliodonium salts had been reported: Hara, S.; Yamamoto, K.;
Yoshida, M.; Fukuhara, T.; Yoneda, N. Tetrahedron Lett. 1999, 40,
7815.
* To whom correspondence should be addressed. Tel: 86-21-
64163300. Fax: 86-21-64166128. E-mail: FLQ@pub.sioc.ac.cn.
(1) (a) Welch, J . T.; Eswarakrishnan, S. Fluorine Bioorganic Chem-
istry; J ohn Wiley & Sons: New York, 1991. (b) Filler, R., Kobayashi.
Y., Yagupolski, L. M., Eds. Organofluorine Compounds in Medicinal
Chemistry and Biomedical Applications; Elsevier: Amsterdam, 1993.
(c) Hudlicky, M., Pavlath, A. E., Eds. Chemistry of Organic Fluorine
Compounds II. A Critical Review; American Chemical Society: Wash-
ington, D. C., 1995. (d) Welch, J . T. Tetrahedron 1987, 43, 3123.
(2) (a) German, L., Zemskov, S., Eds. New Fluorinating Agents in
Organic Chemistry; Springer-Verlag: Heidelberg, New York, 1989. (b)
Lal, G. S.; Pez, G. P.; Syvret, R. G. Chem. Rev. 1996, 96, 1737. (c)
Okonya, J . F.; J ohnson, M. C.; Hoffman, R. V. J . Org. Chem. 1998, 63,
6409. (d) Lal, G. S.; Pez, G. P.; Pesaresi, R. J .; Prozonic, F. M. Chem.
Commun. 1999, 215.
(3) (a) Molines, H.; Wakselman, C. J . Fluorine Chem. 1984, 25, 447.
(b) Molines, H.; Wakselman, C. J . Fluorine Chem. 1989, 45, 155. (c)
Nguyen, T.; Leroy, J .; Wakselman, C. J . Org. Chem. 1993, 58, 3772.
(d) Krishnan, G.; Sampson, P. Tetrahedron Lett. 1990, 31, 5609.
10.1021/jo991276w CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/20/2000

Synthesis of â-Fluoro-R,â-unsaturated Esters
J . Org. Chem., Vol. 65, No. 3, 2000 695
Sch em e 1
Sch em e 2
that it would be necessary to find a solvent which can
improve the stability of the zinc reagent 2. Fortunately,
when anhydrous DMF was used instead of THF as the
solvent, an exothermic reaction occurred spontaneously
at room temperature. 19F NMR monitoring of the reaction
mixture revealed that compound 1 had disappeared, and
only a new triplet appeared at +16.5 ppm (J ) 24.0 Hz)12
corresponding to the zinc reagent 2. Furthermore, the
zinc reagent 2 in DMF is thermally stable in the range
general route to â-fluoro-R,â-unsaturated esters based on
palladium(0)/copper(I)-cocatalyzed cross-coupling of the
zinc reagent of ethyl 3-bromo-3,3-difluoropropionate with
aryl (alkenyl) halides.
Resu lts a n d Discu ssion
o
Syn t h esis of E t h yl 3-Br om o-3,3-d iflu or op r op i-
on a te 1. Wakselman had reported8 the preparation of
ethyl 3-bromo-3,3-difluoropropionate 1 through the con-
densation of dibromodifluoromethane and ethyl vinyl
ether under ultraviolet irradiation, subsequent treatment
with ethanol, and then oxidation using Caro acid or
m-chloroperoxybenzoic acid. However, the overall yield
(three steps) is only 49%, and the first step is not
convenient due to the difficulty in handling reactive and
volatile substrates (the boiling points of dibromodifluo-
romethane and ethyl vinyl ether are 22 °C and 23 °C,
respectively). We developed a convenient and practical
synthesis of 1 in 75% overall yield (two steps) from the
radical addition of dibromodifluoromethane to ethyl vinyl
ether under Na2S2O4 initiation9 in ethanol, followed by
oxidation of the acetal with Caro acid (Scheme 1). The
radical addition is initiated by radical anion of sulfur
dioxide (SO2•-) produced by decomposition of Na2S2O4.
of room temperature to 80 C, and in the absence of air
or moisture showing no sign of decomposition.
P r ep a r a tion of â-F lu or o-r,â-u n sa tu r a ted ester s 4.
With the zinc reagent 2 in hand, we were interested in
exploring the feasibility of using 2 in cross-coupling
reactions. Although the palladium- or nickel-catalyzed
cross-coupling between alkyl organozinc reagent and aryl
halides is well-known,13 the application of perfluorinated
or fluorinated alkylzinc reagent as partner in cross-
coupling reactions has rarely appeared.14 When aryl
(alkenyl) halides (1.0 equiv) were treated with zinc
reagent 2 (1.5-2.0 equiv) in DMF under argon at 70 °C
using Pd(PPh3)4 (5 mol %) and CuI (20 mol %) as
cocatalyst, the cross-coupling reaction occurred smoothly,
affording not the expected product 3, but the â-fluoro-
R,â-unsaturated esters 4 directly in moderate yields
(Scheme 3 and Table 1). Compounds (E)-4 and (Z)-4 can
be separated by flash chromatography. The configuration
of double bond in 4 was assigned with the coupling
•-
The transfer of a single electron to CF2Br2 from SO2
gave BrCF2 and Br-, and then BrCF2 added to ethyl
vinyl ether to form intermediate BrCF2CH2CH•OC2H5,
which abstracted a bromine from CF2Br2 to produce
BrCF2CH2CHBrOC2H5. The reaction of BrCF2CH2-
CHBrOC2H5 with ethanol produced acetal.
•
•
constant of the vinyl proton and fluorine ((E)-4 J H-F
)
16.0-25.0 Hz; (Z)-4 J H-F ) 33.0-35.0 Hz).15
The following points derived from the cross-coupling
reaction are noteworthy: (1) No appreciable reactions
observed in the presence of CuI alone without Pd(PPh3)4.
(2) Although the reaction could proceed using 5 mol %
Pd(PPh3)4 alone as the catalyst, the E/Z selectivity is
poor, only a 1:1 E/Z ratio was obtained. When 20 mol %
CuI was added, the E/Z selectivity of product was greatly
improved. For example, when iodobenzene was used as
the reaction partner, the E/Z ratio of product 4 was
changed from 1:1 (only 5 mol % Pd(PPh3)4 as catalyst) to
5:1 (5 mol % Pd(PPh3)4 and 20 mol % CuI as cocatalyst).
For some halides, only E isomers were formed (entries
2, 4, 8, 12, 13, and 19). Use of 1.0 equiv of CuI offered no
advantage over 20 mol % CuI. CuBr and CuCl both
possessed similar effects on improving the E/Z selectivity
of this reaction. Usually, addition of Cu(I) halide acceler-
ates the rate of cross-coupling16 but does not effect the
E/Z selectivity. To the best of our knowledge, this is the
first example that CuI can improve the selectivity of a
P r epar ation of th e Zin c Reagen t of Eth yl 3-Br om o-
3,3-d iflu or op r op ion a te 2. Only one example of the
synthetic application of 1 has been reported, in which
the product of dehydrobromination of 1 acted as a
dienophile in a Diels-Alder reaction to afford monoflu-
orinated cyclohexadienol.8 As a very useful fluorine-
containing intermediate, further utilization of 1 would
be a worthwhile undertaking. Since organozinc deriva-
tives have been found to be increasingly useful reagents
for carrying out organic transformations10 and many
fluorinated organozinc reagents provide a useful method
for the introduction of fluorine to organic molecules,11 we
attempted to prepare the zinc reagent of 1. Initially, the
treatment of 1 with active zinc dust in anhydrous THF
was performed. Though the exothermic reaction occurred
at room temperature, 19F NMR analysis of the reaction
mixture revealed that the starting material 1 had disap-
peared; however, new peaks mainly included a small
amount of zinc reagent 2 and much HCF2CH2CO2C2H5
(Scheme 2). As such, it can be concluded first that zinc
reagent 2 had formed, but it was not stable in THF, and
(12) 19F NMR spectra (56.4 Hz) were recorded on Varian EM-360L
instrument using CF3CO2H as an external standard, upfield positive.
(13) (a) Giovannini, R.; Knochel, P. J . Am. Chem. Soc. 1998, 120,
11186. (b) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. (c)
Erdik, E. Tetrahedron 1992, 48, 9577.
(14) The cross-coupling of perfluoroalkylzinc iodides with alkenyl
bromides: Kitazume, T.; Ishikawa, N. J . Am. Chem. Soc. 1985, 107,
5186.
(15) (a) Xiang, J .; J iang, W. l.; Gong, J . C.; Fuchs, P. L. J . Am. Chem.
Soc. 1997, 119, 4123. (b) Fields, R. J . Fluorine Chem. 1986, 33, 288.
(16) (a) Piers, E.; Romero, M. A. J . Am. Chem. Soc. 1996, 118, 1215.
(b) Allred, G. D.; Liebeskind, L. S. J . Am. Chem. Soc. 1996, 118, 2748.
(c) Han, X.; Stoltz, B. M.; Corey, E. J . J . Am. Chem. Soc. 1999, 121,
7600 and references therein.
(8) Leroy, J .; Molines, H.; Wakselman, C. J . Org. Chem. 1987, 52,
290
(9) Huang, W. Y.; Lu, L.: Zhang, Y. F. Chinese J . Chem. 1990, 3,
281.
(10) Charette, A. B.; Beauchemin, A.; Marcoux, J . F.J . Am. Chem.
Soc. 1998, 120, 5114 and references therein.
(11) (a) Burton, D. J .; Yang, Z.-Y.; Morken, D. A. Tetrahedron 1994,
50, 2993. (b) Burton, D. J .; Yang, Z.-Y. Tetrahedron 1992, 48, 189.

696 J . Org. Chem., Vol. 65, No. 3, 2000
Peng et al.
Sch em e 3
cross-coupling reaction. (3) Both aryl bromides and aryl
iodides can be effectively used for the coupling reaction;
however, for aryl bromides, the reaction was somewhat
sluggish and required a higher temperature and longer
time. This difference of reactivity has made the chemose-
lective coupling possible with 4-bromoiodobenzene (entry
2). In addition, aryl triflates (entry 15) are also suitable
substrates for the synthesis of â-fluoro-R,â-unsaturated
esters. (4) The coupling reactions of vinyl halides (entries
16, 17) with zinc reagent 2 afforded the corresponding
monofluorinated 1,3-dienes in good yields and high
selectivities. Because conjugated dienes are important
intermediates in organic synthesis due to a variety of
aliphatic natural products containing the 1,3-diene unit,17
these monofluorinated dienes should be very valuable in
the synthesis of fluorinated analogues of natural prod-
ucts. (5) Because oligomers with 5-(3-aminopropyn-1-yl)-
deoxyuridine were considered as potential antisense
molecules,18 and 5-(3-aminopropenyl)deoxyuridine triph-
osphate was suitable for the enzymatic synthesis of
combinatorial DNA libraries,19 5-(2-(ethoxycarbonyl)-1-
fluoro-1-ethenyl)deoxyuridine, prepared from the cou-
pling reaction of iodo-nucleoside with zinc reagent (entry
19), should be useful in the preparation of fluorinated
anticancer and antiviral agents.
Mech a n ism for th e F or m a tion of â-F lu or o-r,â-
u n sa tu r a ted Ester s in th e P r esen ce of P d (P P h 3)4
w ith ou t Cu I. To explain the formation of unexpected
compound 4 in the reaction of zinc reagent 2 with aryl
(alkenyl) halides, the investigation of reaction mechanism
was undertaken. A mixture of zinc reagent 2 (2.0 equiv,
previously prepared clear solution in DMF), iodobenzene
(1.0 equiv), and Pd(PPh3)4 (5 mol %) was heated at 70 °C
in an NMR tube. 19F NMR monitoring of the reaction
mixture every 10 min revealed that the formation of 4
(E/Z: 1:1) was accompanied by the appearance of HCF2-
CH2CO2C2H5; the amount of 4 and HCF2CH2CO2C2H5
was equivalent, and 19F NMR spectrum displayed a new
triplet near the peak of zinc reagent corresponding
possibly to C6H5CF2CH2CO2C2H5. As the reaction time
was prolonged, the new triplet disappeared quickly.
Based upon these experimental results, the proposed
mechanism for the formation of â-fluoro-R,â-unsaturated
esters in the presence of Pd(PPh3)4 without CuI is
outlined in Scheme 4. The cross-coupling of zinc reagent
2 with aryl (alkenyl) halides under palladium(0) catalysis
formed compound RCF2CH2CO2C2H5, which underwent
elimination simultaneously to afford the â-fluoro-R,â-
unsaturated esters 4. Zinc reagent 2 acted as base and
was converted to HCF2CH2CO2C2H5 in the elimination
reaction. Thus, zinc reagent 2 was used as both cross-
coupling partner and base in the formation of â-fluoro-
R,â-unsaturated esters 4.
Mech a n ism for t h e Select ive F or m a t ion of (E)-
â-F lu or o-r,â-u n sa tu r a ted Ester s in th e P r esen ce of
Both P d (P P h 3)4 a n d Cu I. Pd(PPh3)4 was necessary for
the formation of â-fluoro-R,â-unsaturated esters, and
addition of CuI to the reaction mixture improved the E/Z
selectivity. Initially experiments were performed to de-
termine if CuI was operative in the double bond isomer-
ization of â-fluoro-R,â-unsaturated esters. In fact, when
CuI was added to the solution of the mixture of 1:1 E/Z
â-fluoro-R,â-unsaturated esters in DMF and stirred at
80 °C for 4 h, the E/Z ratio did not change anymore. This
result implied that CuI with Pd(PPh3)4 together took part
in the selective formation of â-fluoro-R,â-unsaturated
esters; a number of reactions were done to explain how
this affects the selectivity. A mixture of zinc reagent 2
(1.5 equiv, previously prepared clear solution in DMF),
iodobenzene (1.0 equiv), Pd(PPh3)4 (5 mol %), and CuI
(20 mol %) was heated at 70 °C in NMR tube. 19F NMR
monitoring of the reaction mixture every 10 min revealed
that the zinc reagent 2 disappeared in 1 h and 4 (E/Z:
5:1) was formed. Furthermore, the 19F NMR spectrum
displayed a new doublet of doublets at +36.3 ppm (J )
80.0, 16.0 Hz) corresponding to compound 5. The appear-
ance of 5 prompted the study of the mechanism of
selective formation of (E)-â-fluoro-R,â-unsaturated esters.
Thus, the following experiments were performed to probe
the path of the formation of 5 and to assign the structure
of compound 5. Treatment of zinc reagent 2 with either
5 mol % of Pd(PPh3)4 or 1.0 equiv of iodobenzene at 70
°C for 2 h did not produce compound 5, and zinc reagent
2 was unchanged as determined by 19F NMR. However,
when a mixture of zinc reagent 2 and 20 mol % of CuI
was stirred at 70 °C for only 10 min, the 19F NMR
spectrum showed that zinc reagent 2 was totally con-
verted to compound 5. Then the reaction mixture was
analyzed by GC-MS and GC-IR. The infrared spectra
of compound 5 showed carbonyl stretching at 1750 cm-1
and strong absorption at 1666 cm-1, characteristic of a
double bond. The MS of compound 5 showed the molec-
ular ion peak at m/z 118. Based on these data and the
chemical shift and coupling constants in the 19F NMR
spectrum (+36.3 ppm, dd, J ) 80.0, 16.0 Hz), the
structure of compound 5 was assigned to ethyl (E)-3-
fluoro-2-propenoate. This structure was further proven
by comparison with the chemical shift and coupling
(17) (a) Trost, B. M.; Lautens, M.; Peterson, B. Tetrahedron Lett.
1983, 24, 4525. (b) Sakai, T.; Seko, T.; Tsuji, A.; Vtaka, M.; Takeda,
A. J . Org. Chem. 1982, 47, 1101. (c) Cha, J . K.; Oh, T. Curr. Org. Chem.
1998, 2, 217. (d) Smith, A. B., III.; Ott, G. R. J . Am. Chem. Soc. 1998,
120, 3935.
(18) Heystek, L. E.; Zhou, H. Q.; Dande, P.; Gold, B. J . Am. Chem.
Soc. 1998, 120, 12165.
(19) Sakthivel, K.; Barbas, C. F., III. Angew. Chem., Int. Ed. 1998,
37, 2872.

Synthesis of â-Fluoro-R,â-unsaturated Esters
J . Org. Chem., Vol. 65, No. 3, 2000 697
Ta ble 1. P a lla d iu m /Cop p er -Coca ta lyzed Cr oss-Cou p lin g of 2 w ith Ha lid es
a
b
Total yield of two isolated isomers based on organic halides. Determined by 19F NMR.

698 J . Org. Chem., Vol. 65, No. 3, 2000
Peng et al.
Sch em e 4
reasoned that the Lewis base should produce similar
effects in this coupling reaction. Indeed, treatment of zinc
reagent 2 (2.0 equiv, previously prepared clear solution
in DMF) with iodobenzene (1.0 equiv), Pd(PPh3)4 (5 mol
%), and triethylamine (20 mol %) at 70 °C for 8 h
produced the (E)-4 exclusively. However, triethylamine
was used instead of CuI as a base for other aryl halides
(p-HOC6H5I and p-MeCOC6H5I were tested), and for
these, the coupling reaction was unsuccessful.
Su m m a r y
In conclusion, this paper describes an efficient general
route to ethyl 3-bromo-3, 3-difluoropropionate (1). We
have demonstrated that the palladium(0)/copper(I)-co-
catalyzed cross-coupling of the zinc reagent of ethyl
3-bromo-3,3-difluoropropionate with aryl(alkenyl) halides
allows preparation of â-fluoro-R,â-unsaturated esters (4).
Studies on synthetic applications to produce mono-
fluorinated compounds of biological interest is currently
underway.
Sch em e 5
Exp er im en ta l Section
The preparation of â-fluoro-R,â-unsaturated esters was
performed under an argon atmosphere in flame-dried glass-
ware. DMF was freshly distilled from CaH2. CuI was purified
by a literature procedure.20 Commercial zinc powder was
activated by a standard method.21
P r ep a r a tion of Eth yl 3-Br om o-3,3-d iflu or op r op ion a te
(1). A 250 mL, three-necked, round-bottomed flask was
equipped with an efficient magnetic stirring bar, a thermom-
eter, and a dry ice-acetone condenser. To this flask were
added dibromodifluoromethane (31.5 g, 150 mmol), ethyl vinyl
ether (7.2 g, 100 mmol), Na2S2O4 (26.1 g, 150 mmol), NaHCO3
(25.2 g, 300 mmol), and ethanol (40 mL). After the mixture
was stirred at 60 °C for 2 h, the reaction mixture was poured
into water (30 mL) and extracted with diethyl ether (3 × 20
mL). After evaporation of the solvent, the residue was distilled
under reduced pressure gave 20 g of acetal (81% yield) as a
colorless liquid (bp 64 °C/4 mmHg). The caro acid, prepared
from 85% sulfuric acid (144 g) and ammonium persulfate
(114 g), was added at 5-10 °C for 30 min to a vigorously stirred
solution of the above prepared acetal (24.7 g, 100 mmol) in
ethanol (200 mL). The reaction mixture was stirred for 24 h
at room temperature. The reaction mixture was poured
into ice water (600 mL), and extracted with diethyl ether (3 ×
250 mL). After evaporation of the solvent, the residue was
distilled under reduced pressure gave 20 g of 1 (91% yield)
as a colorless liquid (bp 58-60 °C/20 mmHg). 1H NMR (CDCl3)
δ 4.20(2H, q, J ) 7.0 Hz), 3.42 (2H, t, J ) 16.0 Hz), 1.28 (3H,
t, J ) 7.0 Hz); 19F NMR (CDCl3) δ -34 (s); IR (cm-1) 1750,
1220.
Gen er a l P r oced u r e for th e P r ep a r a tion of â-F lu or o-
r,â-u n sa tu r a ted Ester s 4. Freshly activated zinc powder (104
mg, 1.6 mmol) was added to the stirred solution of 1 (325 mg,
1.5 mmol) in DMF (10 mL) at room temperature. After the
heat evolution had ceased, iodobenzene (200 mg, 1.0 mmol),
Pd(PPh3)4 (58 mg, 0.05 mmol), and purified CuI (22 mg, 0.2
mmol) were added to the zinc reagent solution. The reaction
mixture was heated to 70 °C and stirred for 2 h, and then ethyl
acetate (10 mL) was added to the reaction mixture. The
mixture was washed with brine, dried over anhydrous Na2-
SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel, eluting with a solution
of hexanes-ethyl acetate (100:1) to give the separated E/Z
isomers of ethyl 3-phenyl-3-fluoro-2-propenoate (97 mg, 50%
yield). The E-isomer was less polar.
constants of isopropyl (E)-3-fluoro-2-propenoate in the 19
F
NMR spectrum (+35.0 ppm, dd, J ) 80.0, 15.0 Hz).3 The
formation of compound 5 indicated zinc reagent 2 was
dehydrofluorinated stereoselectively to produce (Z)-1-
fluoro-2-(ethoxycarbonyl)ethenylzinc reagent 6 in the
presence of CuI, though 6 was not detected by 19F NMR
monitoring. There remains the question of what is the
hydrogen source that converts 6 to 5? When zinc reagent
2 in d7-DMF (d7-DMF was used instead of DMF as the
solvent for the preparation of 2) was treated with 20 mol
% of CuI at 70 °C for 10 min, zinc reagent 2 was also
totally converted to compound 5. This suggests that 6
reacted with HF rather than abstracting a hydrogen from
the solvent to form 5. From the above experimental
results, the proposed mechanism for the selective forma-
tion of (E)-â-fluoro-R,â-unsaturated esters in the presence
of both Pd(PPh3)4 and CuI is outlined in Scheme 5.
Oxidative addition of the Pd(0)L2 complex to the aryl
(alkenyl) halide afforded 7. Substitution of the halide
with 6 afforded 8. Reductive elimination of 8 gave (E)-
â-fluoro-R,â-unsaturated ester 4 with regeneration of the
active catalyst. The formation of 6 plays role in the
stereoselective synthesis of (E)-â-fluoro-R,â-unsaturated
ester.
The following points derived from the reaction mech-
anism for the cross-coupling reaction in the presence of
both Pd(PPh3)4 and CuI are noteworthy: (1) some aryl
(alkenyl) halides proceed by both pathways shown in
Scheme 5 and Scheme 4, which afforded the mixture of
E/Z (E/Z: from 3:2 to 8:1) compound 4. The others
underwent the sole pathway outlined in Scheme 5, which
produced compound (E)-4 exclusively. (2) At present, the
mechanistic pathway of totally selective conversion of 2
using 20 mol % of CuI to the vinyl zinc reagent 6 remains
obscure. (3) As outlined in Scheme 5, CuI was used as
base for the dehydrofluorination of 2 to give 6; thus, we
(20) Kauffman, G. B.; Fang, L. Y. Inorg. Synth. 1983, 22, 101.
(21) Tsuda, K.; Ohki, E.; Nozoe, S. J . Org. Chem. 1963, 28, 783.

Synthesis of â-Fluoro-R,â-unsaturated Esters
J . Org. Chem., Vol. 65, No. 3, 2000 699
Eth yl 3-P h en yl-3-flu or o-2-p r op en oa te (4a ). (E)-Isom er :
1H NMR (CD3COCD3) δ 7.78-7.49 (5H, m), 5.93 (1H, d, J )
7.83 (2H, d, J ) 8.4 Hz), 6.02 (1H, d, J ) 20.4 Hz), 4.14 (2H,
q, J ) 7.1 Hz), 2.63 (3H, s), 1.17 (3H, t, J ) 7.1 Hz); 19F NMR
(CCl4) δ 3.6 (d, J ) 20.4 Hz); MS (m/z) 236 (M+, 34.97), 221
20.8 Hz), 4.12 (2H, q, J ) 7.0 Hz), 1.18 (3H, t, J ) 7.0 Hz); 19
F
NMR (CCl4) δ 0.3 (d, J ) 20.8 Hz); MS (m/z) 194 (M+, 18.21),
(100.00); IR (cm-1) 1725, 1690, 1661. Anal. Calcd for C13H13
-
149 (100.00); IR (cm-1) 1726, 1659. Anal. Calcd for C11H11
-
FO3: C, 66.10; H, 5.51. Found: C, 65.95; H, 5.70. (Z)-
Isom er : 1H NMR (CD3COCD3) δ 8.09 (2H, d, J ) 8.4 Hz),
7.92 (2H, d, J ) 8.4 Hz), 6.26 (1H, d, J ) 34.3 Hz), 4.20 (2H,
q, J ) 7.1 Hz), 2.63 (3H, S), 1.27 (3H, t, J ) 7.2 Hz); 19F NMR
(CCl4) δ 21.6 (d, J ) 34.3 Hz); MS (m/z) 236 (M+, 28.78), 221
(100.00).
FO2: C, 68.04; H, 5.67; F, 9.79. Found: C, 68.33; H, 5.83; F,
9.80. (Z)-Isom er : 1H NMR (CD3COCD3) δ 7.81-7.78 (2H, m),
7.58-7.53 (3H, m), 6.12 (1H, d, J ) 34.4 Hz), 4.21 (2H, q, J )
7.0 Hz), 1.29 (3H, t, J ) 7.0 Hz); 19F NMR (CCl4) δ 17.6 (d, J
) 34.4 Hz); MS (m/z) 194 (M+, 20.24), 149 (100.00).
(E)-Eth yl 3-(4-br om oph en yl)-3-flu or o-2-pr open oate (4b):
1H NMR (CD3COCD3) δ 7.70 (4H, s), 5.99 (1H, d, J ) 20.8
Hz), 4.11 (2H, q, J ) 7.0 Hz), 1.18 (3H, t, J ) 7.0 Hz); 19F
NMR (CCl4) δ 1.3 (d, J ) 20.8 Hz); MS (m/z) 273 (M+, 4.86),
Eth yl 3-(4-Hyd r oxyp h en yl)-3-flu or o-2-p r op en oa te (4j).
(E)-Isom er : 1H NMR (CD3COCD3) δ 7.65 (2H, d, J ) 9.5 Hz),
6.90 (2H, d, J ) 9.5 Hz), 5.73 (1H, d, J ) 22.1 Hz), 4.10 (2H,
q, J ) 7.1 Hz), 1.19 (3H, t, J ) 7.1 Hz); 19F NMR (CCl4) δ 3.0
(d, J ) 22.1 Hz); MS (m/z) 211 (M+ + 1, 24.15), 210 ((M+,
43.48), 165 (100.00); IR (cm-1) 3388, 1699, 1652. Anal. Calcd
for C11H11FO3: C, 62.86; H, 5.24; F, 9.05. Found: C, 62.77; H,
5.49; F, 8.86. (Z)-Isom er : 1H NMR (CD3COCD3) δ 7.63 (2H,
d, J ) 8.8 Hz), 6.98 (2H, d, J ) 8.8 Hz), 5.89 (1H, d, J ) 34.8
Hz), 4.15 (2H, q, J ) 7.1 Hz), 1.24 (3H, t, J ) 7.1 Hz); 19F
NMR (CCl4) δ 17.0 (d, J ) 34.8 Hz); MS (m/z) 210 ((M+, 40.89),
165 (100.00).
227 (100.00); IR (cm-1) 1728, 1656; HRMS calcd for C11H10
Br79FO2: 271.9849, found: 271.9847.
-
Eth yl 3-(4-Nitr oph en yl)-3-flu or o-2-pr open oate (4c). (E)-
Isom er : 1H NMR (CD3COCD3) δ 8.34 (2H, d, J ) 8.3 Hz), 8.00
(2H, d, J ) 8.4 Hz), 6.12 (1H, d, J ) 20.2 Hz), 4.12 (2H, q, J
) 7.0 Hz), 1.17 (3H, t, J ) 7.0 Hz); 19F NMR (CCl4) δ 1.6 (d, J
) 20.2 Hz); MS (m/z) 240 (M++1, 0.68), 239 (M+, 2.92), 194
(100.00); IR (cm-1) 1724, 1664. Anal. Calcd for C11H10FNO4:
C, 55.23; H, 4.18; N, 5.86. Found: C, 55.44; H, 4.24; N, 5.80.
(Z)-Isom er : 1H NMR (CCl4) δ 8.27 (2H, d, J ) 8.0 Hz), 7.84
(2H, d, J ) 8.0 Hz), 5.93 (1H, d, J ) 33.0 Hz), 4.23 (2H, q, J
) 7.0 Hz), 1.37 (3H, t, J ) 7.0 Hz); 19F NMR (CCl4) δ 19.0 (d,
J ) 33.0 Hz); MS (m/z) 240 (M+ + 1, 7.03), 239 (M+, 36.10),
194 (100.00).
Eth yl 3-(4-Ch or op h en yl)-3-flu or o-2-p r op en oa te (4k ):
1H NMR (CD3COCD3) δ 7.78 (2H, d, J ) 8.5 Hz), 7.54 (2H, d,
J ) 8.7 Hz), 5.97 (1H, d, J ) 20.7 Hz), 4.12 (2H, q, J ) 7.1
Hz), 1.19 (3H, t, J ) 7.1 Hz); 19F NMR (CCl4) δ 3.67 (d, J )
20.7 Hz); MS (m/z) 228 (M+, 36.43), 183 (100.00); IR (cm-1
)
1726, 1659; HRMS calcd for C11H10FCl35O2: 228.0354, found:
228.0336.
(E)-E t h yl
3-(3-n it r op h en yl)-3-flu or o-2-p r op en oa t e
(4d ): 1H NMR (CD3COCD3) δ 8.62 (1H, s), 8.43-8.40 (1H, m),
8.17-8.14 (1H, m), 7.83 (1H, t, J ) 8.4 Hz), 6.11 (1H, d, J )
(E)-Eth yl 3-(2-n a p h th yl)-3-flu or o-2-p r op en oa te (4l): 1H
NMR (CD3COCD3) δ 8.11-7.92 (3H, m,), 7.69-7.56 (4H, m),
6.22 (1H, d, J ) 17.1 Hz), 3.90 (2H, q, J ) 7.1 Hz), 0.92 (3H,
t, J ) 7.1 Hz); 19F NMR (CCl4) δ -7.7 (d, J ) 17.1 Hz); MS
(m/z) 244 (M+, 55.81), 171 (100.00); IR (cm-1) 1728, 1667. Anal.
Calcd for C15H13FO2: C, 73.77; H, 5.33. Found: C, 73.78; H,
5.43.
20.3 Hz), 4.13 (2H, q, J ) 7.0 Hz), 1.18 (3H, t, J ) 7.0 Hz); 19
F
NMR (CCl4) δ 2.3 (d, J ) 20.3 Hz); MS (m/z) 239 (M+, 2.85),
194 (100.00); IR (cm-1) 1724, 1662. Anal. Calcd for C11H10
-
FNO4: C, 55.23; H, 4.18; N, 5.86. Found: C, 55.02; H, 4.21;
N, 5.84.
Eth yl 3-(4-Meth oxyp h en yl)-3-flu or o-2-p r op en oa te (4e).
(E)-Isom er : 1H NMR (CCl4) δ 7.80 (2H, d, J ) 9.0 Hz), 6.90
(2H, d, J ) 9.0 Hz), 5.73 (1H, d, J ) 21.0 Hz), 4.13 (2H, q, J
) 7.0 Hz), 3.86 (3H, s), 1.30 (3H, t, J ) 7.0 Hz); 19F NMR (CCl4)
δ 0.7 (d, J ) 21.0 Hz); MS (m/z) 224 (M+, 62.01), 179 (100.00);
IR (cm-1) 1723, 1630. Anal. Calcd for C12H13FO3: C, 64.29; H,
5.80. Found: C, 64.40; H, 5.79. (Z)-Isom er : 1H NMR (CCl4)
δ 7.5 (2H, d, J ) 9.0 Hz), 6.8 (2H, d, J ) 9.0 Hz), 5.62 (1H, d,
J ) 33.0 Hz), 4.1 (2H, q, J ) 7.0 Hz), 3.8 (3H, s), 1.3 (3H, t, J
) 7.0 Hz); 19F NMR (CCl4) δ 17.6 (d, J ) 33.0 Hz).
(E)-Eth yl 3-(2-m eth oxyp h en yl)-3-flu or o-2-p r op en oa te
(4f): 1H NMR (CD3COCD3) δ 7.51-7.45 (1H, m), 7.38-7.34
(1H, m), 7.10 (1H, d, J ) 8.5 Hz), 7.04-6.98 (1H, m), 5.90 (1H,
d, J ) 17.0 Hz), 4.00 (2H, q, J ) 7.1 Hz), 3.85 (3H, s), 1.07
(3H, t, J ) 7.1 Hz); 19F NMR (CCl4) δ -3.7 (d, J ) 17.0 Hz);
MS (m/z) 224 (M+, 24.61), 193 (100.00); IR (cm-1) 1729, 1670.
Anal. Calcd for C12H13FO3: C, 64.29; H, 5.80. Found: C, 63.90;
H, 5.90.
(E)-E t h yl
3-(2-t h iop h en e-yl)-3-flu or o-2-p r op en oa t e
(4m ): 1H NMR (CD3COCD3) δ 8.09 (1H, d, J ) 3.8 Hz), 7.90-
7.88 (1H, m), 7.25-7.21 (1H, m), 5.83 (1H, d, J ) 24.2 Hz),
4.20 (2H, q, J ) 7.1 Hz), 1.26 (3H, t, J ) 7.2 Hz); 19F NMR
(CCl4) δ 3.3 (d, J ) 24.2 Hz); MS (m/z) 201 (M+, 9.19), 200
(M+-1, 55.33), 155 (100.00); IR (cm-1) 1716, 1634. Anal. Calcd
for C9H10FSO2: C, 53.73; H, 4.98. Found: C, 54.00; H, 4.62.
Eth yl 3-Flu or o-5-(tr im eth ylsilyl)pen ta-2,4-dien oate (4n ).
(2E)-Isom er : 1H NMR (CD3COCD3) δ 7.57 (1H, d-d, J ) 27.2,
19.2 Hz), 6.77 (1H, d, J ) 18.7 Hz), 5.63 (1H, d, J ) 19.2 Hz),
4.17 (2H, q, J ) 7.1 Hz), 1.25 (3H, t, J ) 7.1 Hz), 0.0 (9H,s);
19F NMR (CCl4) δ 23.0 (d-d, J ) 27.2, 18.7 Hz); MS (m/z) 217
(M+ + 1, 20.30), 77 (100.00); IR (cm-1) 1720, 1645. Anal. Calcd
for C10H17FO5Si: C, 55.56; H, 7.87. Found: C, 55.55; H, 8.06.
(2Z)-Isom er : 1H NMR (CD3COCD3) δ 6.72 (1H, d, J ) 18.9
Hz), 6.53 (1H, d-d, J ) 22.4, 18.9 Hz), 5.58 (1H, d, J ) 32.8
Hz), 4.14 (2H, q, J ) 7.1 Hz), 1.27 (3H, t, J ) 7.1 Hz), 0.0 (9H,
s); 19F NMR (CCl4) δ 24.0 (ddd, J ) 32.8, 22.4, 3.5 Hz); MS
(m/z) 217 (M+ + 1, 10.68), 77 (100.00).
(2E)-Dieth yl 3-flu or oh exa-2,4-dien edioate (4o): 1H NMR
(CD3COCD3) δ 8.18 (1H, dd, J ) 29.1, 15.9 Hz), 6.47 (1H, d-d,
J ) 15.9, 0.5 Hz), 5.97 (1H, d-d, J ) 18.0, 0.4 Hz), 4.26 (2H,
q, J ) 6.8 Hz), 4.19 (2H, q, J ) 7.1 Hz), 1.30 (3H, t, J ) 7.2
Hz), 1.27 (3H, t, J ) 6.8 Hz); 19F NMR (CCl4) δ 25.6 (d-d, J )
29.0, 18.0 Hz); MS (m/z) 217 (M++1, 10.40), 143 (100.00); IR
(cm-1) 1724, 1657. Anal. Calcd for C10H13FO4: C, 55.56; H,
6.02. Found: C, 55.80; H, 6.22.
Meth yl 4-(2-(Eth oxyca r bon yl)-1-flu or o-1-eth en yl)ben -
zoa te (4g). (E)-Isom er : 1H NMR (CD3COCD3) δ 8.09 (2H, d,
J ) 8.3 Hz), 7.84 (2H, d, J ) 8.3 Hz), 6.03 (1H, d, J ) 20.6
Hz), 4.12 (2H, q, J ) 7.1 Hz), 3.91 (3H, s), 1.17 (3H, t, J ) 7.1
Hz); 19F NMR (CCl4) δ 0.6 (d, J ) 20.6 Hz); MS (m/z) 252 (M+,
24.44), 207 (100); IR (cm-1) 1728, 1649. Anal. Calcd for C13H13
-
FO4: C, 61.90; H, 5.16. Found: C, 61.76; H, 5.28. (Z)-
Isom er : 1H NMR (CCl4) δ 7.90 (2H, d, J ) 9.0 Hz), 7.60 (2H,
d, J ) 9.0 Hz), 5.80 (1H, d, J ) 33.0 Hz), 4.16 (2H, q, J ) 7.0
Hz), 3.86 (3H, S), 1.26 (3H, t, J ) 7.0 Hz); 19F NMR (CCl4) δ
18.3 (d, J ) 33.0 Hz); MS (m/z) 252 (M+, 21.27), 207 (100.00).
(E)-Meth yl 2-(2-(eth oxyca r bon yl)-1-flu or o-1-eth en yl)-
ben zoa te (4h ): 1H NMR (CD3COCD3) δ 8.05-8.03 (1H, m),
771-7.65 (2H, m), 7.57-7.54 (1H, m), 5.91 (1H, d, J ) 17.2
Hz), 3.95 (2H, q, J ) 7.1 Hz), 3.85 (3H, s), 1.03 (3H, t, J ) 7.2
Hz); 19F NMR (CCl4) δ -10.0 (d, J ) 17.2 Hz); MS (m/z) 252
(M+, 1.13), 179 (100.00); IR (cm-1) 1730, 1674. Anal. Calcd for
(E)-Eth yl 3-(1,3-d im eth yl-2,4-d ioxo-1,2,3,4-tetr a h yd r o-
p yr im id in -5-yl)-3-flu or o-2-p r op en oa te (4p ): 1H NMR (CD3-
COCD3) δ 8.07 (1H, s), 5.86 (1H, d, J ) 16.4 Hz), 4.09 (2H, q,
J ) 7.1 Hz), 3.50 (3H, s), 3.27 (3H, s), 1.19 (3H, t, J ) 7.1 Hz);
19F NMR (CCl4) δ 2.0 (d, J ) 16.4 Hz); MS (m/z) 256 (M+,
15.92), 184 (100.00); IR (cm-1) 1716, 1674; HRMS calcd for
C11H13FN2O4: 256.0860, found: 256.0848.
C
13H13FO4: C, 61.90; H, 5.16. Found: C, 61.69; H, 5.28.
Eth yl 3-(4-Acetylp h en yl)-3-flu or o-2-p r op en oa te (4i).
(E)-3,5-Di-O-b en zoyl-5-[1-flu or o-2-(et h oxyca r b on yl)-
eth en yl]-2-d eoxyu r id in e (4q): R20D -69.3° (c ) 0.9, CHCl3);
1H NMR (CDCl3) δ 8.08-7.97 (5H, m), 7.66-7.42 (6H, m),
(E)-Isom er : 1H NMR (CD3COCD3) δ 8.06 (2H, d, J ) 8.4 Hz),

700 J . Org. Chem., Vol. 65, No. 3, 2000
Peng et al.
6.48-6.37(1H, m), 5.67-5.64 (2H, m), 4.77-4.65 (2H, m),
4.62-4.60 (1H, m), 4.08 (2H, g, J ) 7.1 Hz), 2.88-2.77 (1H,
m), 2.46-2.35 (1H, m), 1.23 (3H, t, J ) 7.1 Hz); 19F NMR (CCl4)
δ 3.3 (d, J ) 17.0 Hz); MS (FAB, m/z) 553 (M+ + 1, 29.00), 154
(100.0); IR (cm-1) 3199, 1721, 1601; HRMS (FAB) calcd for
Ack n ow led gm en t. We thank the National Natural
Science Foundation of China for financial support, Dr.
J oseph W. Epstein (Wyeth-Ayest Research, Pearl River,
New York) for helpful discussions and improving the
English of the manuscript, and Dr. Andre Asselin
(Wyeth-Ayest Research, Pearl River, New York) for
providing the references for preparation of â-fluoro-R,â-
unsaturated esters. This paper was dedicated to Profes-
sor Qing-Yun Chen on the occasion of his 70th birthday.
C
28H26FN2O9: 553.1622, found: 553.1593.
(E)-Eth yl 3-F lu or o-2-p r op en oa te (5). A mixture of zinc
reagent 2 and 20 mmol % of CuI was stirred at 70 °C for 10
min. Then the reaction was analyzed by 19F NMR, GC-IR and
GC-MS. 19F NMR (DMF) δ 33.6 (dd, J ) 80.0, 16.0 Hz). MS
(m/z) 119 (M+ + 1, 8.0), 118 (M+, 10.5), 43 (100.0). IR (cm-1
1750, 1666.
)
J O991276W