Stereospecific preparation of (Z)- and (E)-2,3-difluoro-3-stannylacrylic ester synthons and a new, efficient stereospecific route to (Z)- and (E)-2,3-difluoroacrylic esters

Article abstract of DOI:10.1021/jo0517949

The (Z)-2,3-difluoro-3-stannylacrylic ester is readily prepared from (Z)-1,2-difluorovinyltriethylsilane via stereospecific stannyl/silyl exchange with KF/(Bu₃Sn)₂O or Bu₃SnCl in DMF at 70 °C. The corresponding (E)-2,3-difluoro-3-stannylacrylate is prepared by stereospecific carbonylation of (E)-1,2-difluorovinyl iodide followed by low temperature/in situ stannylation of the resultant (Z)-2,3-difluoroacrylic ester. With Cu(I) iodide and Pd(PPh₃)₄ catalysis, the (Z)- and (E)-stannylacrylate esters readily couple with aryl iodides and vinyl bromides, as well as 2-iodothiophene, at room temperature to stereospecifically produce the respective (E)- and (Z)-2,3-difluoro-3-aryl substituted acrylic esters or conjugated dienes in high yields.

Full text of DOI:10.1021/jo0517949

Stereospecific Preparation of (Z)- and
(E)-2,3-Difluoro-3-stannylacrylic Ester Synthons and a New,
Efficient Stereospecific Route to (Z)- and (E)-2,3-Difluoroacrylic
Esters1
Yi Wang, Long Lu, and Donald J. Burton*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
Received August 25, 2005
The (Z)-2,3-difluoro-3-stannylacrylic ester is readily prepared from (Z)-1,2-difluorovinyltriethylsilane
via stereospecific stannyl/silyl exchange with KF/(Bu3Sn)2O or Bu3SnCl in DMF at 70 °C. The
corresponding (E)-2,3-difluoro-3-stannylacrylate is prepared by stereospecific carbonylation of (E)-
1,2-difluorovinyl iodide followed by low temperature/in situ stannylation of the resultant (Z)-2,3-
difluoroacrylic ester. With Cu(I) iodide and Pd(PPh3)4 catalysis, the (Z)- and (E)-stannylacrylate
esters readily couple with aryl iodides and vinyl bromides, as well as 2-iodothiophene, at room
temperature to stereospecifically produce the respective (E)- and (Z)-2,3-difluoro-3-aryl substituted
acrylic esters or conjugated dienes in high yields.
Introduction
been investigated by Normant and us,7 the preparation
of cis-1,2-functionalized difluoroethenyl units still re-
mains a challenging problem.8 One functional derivative
of high interest to synthetic chemists is the preparation
of isomerically pure (Z)- and (E)-2,3-difluoroacrylic esters,
and we address this unsolved problem in this article.
A few methods have been reported for the stereoselec-
tive synthesis of (E)-2,3-difluoroacrylic esters. Normant
and co-workers reported the palladium catalyzed cross-
coupling reaction of (Z)-RCFdCFZnCl with ethyl chlo-
roformate;9 however, in our hands this approach has been
problematic.10,11 Lu and Zhang3a partially circumvented
The unique properties of organic compounds that
contain one or more fluorine atoms at strategic positions
in the molecule continue to attract the interest of polymer
chemists, pharmaceutical chemists, and agrochemists.2
2,3-Difluoroacrylic esters are especially interesting in-
termediates in organic chemistry due to their prolific
chemistry3 and potential for further elaboration into
fluorinated analogues of natural products,4 application
in polymers,5 and in liquid crystal composition for liquid
crystal display (LCD).6 Although methodology for the
introduction of the trans-1,2-difluoroethenyl unit has
(1) Presented in part at the 227th ACS National Meeting, Anaheim,
CA, March 28-April 1, 2004; FLUO-004.
(5) (a) Poss, A.; Nalewajek, D.; Demmin, T. R.; Nair, H. K. PCT Int.
Appl. WO 2003073169, 2003; Chem. Abstr. 2003, 139, 237695. (b)
Hetakeyama, J.; Watanabe, J.; Harada, Y. U.S. Patent Appl. Publ.
2001010890, 2001. (c) Groh, W.; Herbrechtsmeier, P.; Heumueller, R.;
Theis, J.; Wieners, G. Ger. Offen. 19901018, 1990.
(6) Selected references: (a) Heckmeier, M.; Goetz, A.; Czanta, M.
Ger. Offen. DE 200410241301, 2004; Chem. Abstr. 2004, 140, 278503.
(b) Heckmeier, M.; Goetz, A. PCT Int. Appl. WO 2002093244, 2002;
Chem. Abstr. 2002, 137, 391146. (c) Kirsch, P.; Krause, J.; Heckmeier,
M. Ger. Offen. DE10151492, 2002; Chem. Abstr. 2002, 136, 361922.
(7) (a) Normant, J. F. J. Organomet. Chem. 1990, 400, 19-34. (b)
Liu, Q.; Burton, D. J. Tetrahedron Lett. 2000, 41, 8045-8048. (c) Liu,
Q.; Burton, D. J. Org. Lett. 2002, 4, 1483-1485.
(8) (a) Leroy, J. J. Org. Chem. 1981, 46, 206-209. (b) Dubuffet, T.;
Bidon, C.; Martinet, P.; Sauvetre, R.; Normant, J. F. J. Organomet.
Chem. 1990, 393, 161-172. (c) Spawn, T.; Heinze, P.; Bailey, A.; Shin-
Ya, S.; Burton, D. J. J. Fluorine Chem. 1988, 38, 131-134. (d) Davis,
C. R.; Burton, D. J. J. Org. Chem. 1997, 62, 9217-9222. (e) Fontana,
S. A.; Davis, C. R.; He, Y.; Burton, D. J. Tetrahedron 1996, 52, 37-44.
(2) (a) Biochemical Aspects of Fluorine Chemistry; Filler, R., Koba-
yashi, Y., Eds.; Elsevier Biomedical Press and Kodansha Ltd: Am-
sterdam, Tokyo, Japan, 1982. (b) Fluorine in Bioorganic Chemistry;
Welch, J. T., Eswarakrishnan, S., Eds.; Wiley & Sons: New York, 1991.
(c) Welch, J. T. Tetrahedron 1987, 43, 3123. (d) Organofluorine
Compounds: Chemistry and Application; Hiyama, T., Ed.; Springer:
New York, 2000. (e) Organofluorine Chemistry: Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;
Plenum: New York, 1994.
(3) (a) Zhang, Q.; Lu, L. Tetrahedron Lett. 2000, 41, 8545-8548.
(b) Hudlicky, M. J. Fluorine Chem. 1988, 40, 99-108. (c) Knunyants
I. L.; Postovoi, S. A.; Delyagina, N. I.; Zeifman, Yu. V. Izv. Akad. Nauk,
Ser. Khim. 1987, 10, 2256-2261. (d) Linhart, I.; Trska, P.; Dedek, V.
Collect. Czech. Chem. Commun. 1985, 50, 1727-1736.
(4) (a) Asato, A. E.; Liu, R. S. H. Tetrahedron Lett. 1986, 27, 3337-
3340. (b) Colmenares, L. U.; Zou, X.; Liu, J.; Asato, A. E.; Liu, R. S. H.
J. Am. Chem. Soc. 1999, 121, 5803-5804.
10.1021/jo0517949 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/30/2005
J. Org. Chem. 2005, 70, 10743-10746
10743

Wang et al.
SCHEME 1. Lu and Zhang’s Preparation of
(E)-2,3-Difluoropropenoates
SCHEME 3. Preparation of
(Z)-1,2-Difluoro-2-triethylsilylethene
SCHEME 4. Stereospecific Preparation of 3
SCHEME 2. Wesolowski and Burton’s
Stereospecific Carboalkoxylation of Vinyl Iodides
this difficulty via a modified Normant/Hiyama route
outlined in Scheme 1.
Results and Discussion
Our initial target molecule for the preparation of a
general trans synthon to acrylic esters was (Z)-1,2-
difluoro-2-triethylsilylethene, 1, which can be readily
prepared on a molar scale from commercial precursors,
such as CF2dCFCl or CF2dCFBr8e (Scheme 3).
However, this route is applicable only to simple alkyl
groups and aryl groups that contain functionality com-
patible with RLi reagents and thus of limited use with
functionalized derivatives. Czech workers utilized an
addition-elimination reaction between potassium cya-
nide and methyl trifluoropropenoate to prepare a precur-
sor to the acrylic ester.12 However, this approach yielded
a mixture of (E)- and (Z)-MeO2CCFdCFCN. Liu and co-
workers reported the Wohl-Ziegler bromination of an
isomeric mixture of ethyl 2,3-difluoro-2-butenoate to
stereospecifically afford (Z)-4-bromo-2,3-difluoro-2-buten-
oate, which was subsequently utilized in the preparation
of difluororetinal analogues.4b Although this report pro-
vided an interesting example of a cis-1,2-difluoroethenyl
unit, this work is not a general entry to (Z)- and (E)-2,3-
difluoroacrylic esters. The only stereospecific preparation
of (Z)- and (E)-2,3-difluoroacrylic esters reported in the
literature is that of Wesolowski and Burton,10,11 who
synthesized this class of esters via the palladium-
catalyzed stereospecific carboalkoxylation of 1,2-difluoro-
1-iodoalkenes and R,â-difluoro-â-iodostyrenes (Scheme 2).
Treatment of 1 with n-BuLi at -90 °C, followed by
addition of ethyl chloroformate, however, gave the desired
ester, ethyl (Z)-2,3-difluoro-3-(triethylsilyl)acrylate, 2,
only as minor product. Similarly, treatment of 1 with
n-BuLi, followed by ZnI2, followed by ethyl chloroformate,
gave only a complicated mixture of products. Since 1 gave
a stable lithium reagent at low temperatures, (Z)-Et3-
SiCFdCFLi was generated at -90 °C via reaction of 1
with t-BuLi, followed by treatment of the resultant
lithium reagent with CO2 (g), maintaining the internal
temperature of the reaction mixture below -85 °C (ca.
0.5 h), to give a stable lithium carboxylate, which on
acidification with an aqueous HCl solution afforded the
corresponding acid. Without further purification, esteri-
fication of the crude acid in the presence of PTSA, using
a Dean-Stark trap, gave 2 in 70-75% isolated yield
(Scheme 4).
Although this route stereospecifically provides the (E)-
and (Z)-acrylic esters, it has two major limitations. For
the aryl derivatives the requisite number of steps for the
preparation of the vinyl iodide is high, and second and
more importantly, each vinyl iodide must be prepared
independently.8d A common synthon for the introduction
of the aryl group in the final step of the synthetic
sequence would be more advantageous and efficient.
Thus, our goal in this work has been to design the (E)-
and (Z)-synthons that allow introduction of the aryl group
in the last step and would not be limited by the types of
substituent on a functionalized aryl ring.14
Under these conditions, the unstable (E)-Et3SiCFd
CFLi decomposes, and 2 is isolated isomerically pure as
exclusively the (Z)-isomer. Treatment of 2 with bis(tri-
n-butyltin) oxide and a catalytic amount of KF in DMF
at 70-80 °C stereospecifically gives ethyl (Z)-2,3-difluoro-
3-(tributylstannyl)acrylate, 3, in 70% isolated yield15
(Scheme 4). Thus, 3 is readily prepared in four steps from
CF2dCFCl in about 40% overall yield via readily scalable
processes. 3 is colorless oil and can be stored in a
refrigerator for an extended period without detectable
decomposition or isomerization.
(13) Z)-tBuCFdCFI was prepared in three steps from CF2dCFCl.
(E)-tBuCFdCFI can be prepared in five steps from CF2dCFCl or CF2d
CFBr.
(14) The alkyl derivatives in Wesolowski’s report are based on a
cheap, commercial precursor (CF2dCFCl) and commercially available
RLi reagents. Thus, the number of steps in the overall reaction
sequence is of less importance than with the aryl analogues.
(15) (a) Xue, L.; Lu, L.; Pederson, S.; Liu, Q.; Narske, R.; Burton,
D. J. Tetrahedron Lett. 1996, 37, 1921-1924. (b) Xue, L.; Lu, L.;
Pederson, S.; Liu, Q.; Narske, R.; Burton, D. J. J. Org. Chem. 1997,
62, 1064-1071.
(9) (a) Gillet, J. P.; Sauvetre, R.; Normant, J. F. Tetrahedron Lett.
1985, 26, 3999-4002. (b) Gillet, J. P.; Sauvetre, R.; Normant, J. F.
Synthesis 1986, 538-543.
(10) Wesolowski, C. A. Ph.D. Thesis, University of Iowa, Iowa City,
IA, 2000; pp 17-31.
(11) Wesolowski, C. A.; Burton, D. J. Tetrahedron Lett. 1999, 40,
2243-2246.
(12) Svoboda, J.; Paleta, O.; Dedek, V. Collect. Czech. Chem.
Commun. 1981, 46, 1495-1503.
10744 J. Org. Chem., Vol. 70, No. 26, 2005

New Route to (Z)- and (E)-2,3-Difluoroacrylic Esters
TABLE 1. Reactions of 3 with Organic Halides
entry
ArI
product
isolated yield (%)a,b
1
2
4-iodotoluene
(E)-4-CH3C6H4CFdCFCO2Et (4)
(E)-C6H5CFdCFCO2Et (5)
84
87
90
83
74
83
94
89
88
81
iodobenzene
3
4-iodobenzonitrile
3-iodobenzotrifluoride
1-iodonaphthalene
2-iodothiophene
1-bromo-4-iodobenzene
1-iodo-4-nitrobenzene
1-fluoro-4-iodobenzene
(E)-CHBrdCHCO2Et
(E)-4-NCC6H4CFdCFCO2Et (6)
(E)-3-F3CC6H4CFdCFCO2Et (7)
(E)-C10H7CFdCFCO2Et (8)
4
5
6
(E)-C4H3SCFdCFCO2Et (9)
7
(E)-4-BrC6H4CFdCFCO2Et (10)
(E)-4-O2NC6H4CFdCFCO2Et (11)
(E)-4-FC6H4CFdCFCO2Et (12)
(2E,4E)-EtO2CCHdCHCFdCFCO2Et (13)
8
9
10
a Isolated yields based on 3. b Configuration assigned on the basis of JF,F trans ) 100-140 Hz.18,19
TABLE 2. Reactions of 16 with Organic Halides
entry
ArI
product
isolated yield (%)a,b
1
2
3
4
5
6
7
8
9
iodobenzene
(Z)-C6H5CFdCFCO2Et (17)
75
83
78
86
73
74
69
94
86
4-iodoanisole
(Z)-4-CH3OC6H4CFdCFCO2Et (18)
(Z)-4-O2NC6H4CFdCFCO2Et (19)
(Z)-3-O2NC6H4CFdCFCO2Et (20)
(Z)-C4H3SCFdCFCO2Et (21)
1-iodo-4-nitrobenzene
1-iodo-3-nitrobenzene
2-iodothiophene
3-iodoanisole
(Z)-3-CH3OC6H4CFdCFCO2Et (22)
(Z)-4-BrC6H4CFdCFCO2Et (23)
(2Z,4E)-EtO2CCHdCHCFdCFCO2Et (24)
(2Z,4Z)-EtO2CCHdCHCFdCFCO2Et (25)
1-bromo-4-iodobenzene
(E)-CHBrdCHCO2Et
(Z)-CHBrdCHCO2Et
a Isolated yields based on 16. b Configuration assigned on the basis of JF,F cis ) 0-22 Hz.18,19
SCHEME 5. Stereospecific Preparation of 16
Although Stille reported that Pd(PPh3)4 catalyzed the
coupling reaction of vinylstannanes with organic ha-
lides,16 the use of Pd(PPh3)4 alone was ineffective for the
coupling of 3 with iodobenzene (24 h/rt). Cu(I) iodide did
not catalyze the coupling reaction with 3 either. However,
the combination of Pd(PPh3)4 (5 mol %)/CuI (50 mol %)
(Liebeskind conditions17) effectively catalyzed the cross-
coupling reactions of 3 with aryl iodides and vinyl
bromides, as well as 2-iodothiophene. These results are
summarized in Table 1.
Both electron-withdrawing and electron-releasing sub-
stituents worked well (entries 1-5, 7-9); the heterocyclic
iodide also worked well (entry 6), and the use of a vinyl
halide (entry 10) demonstrated that the methodology
could also be utilized as a stereospecific route to conju-
gated dienes.19 Moreover, a common synthon precursor
was employed to prepare the various derivatives.
The procedure outlined above for the preparation of 2,
however, could not be utilized for the synthesis of the
analogous synthon, (E)-Et3SiCFdCFCO2Et, due to the
instability of the precursor, (E)-Et3SiCCFdCFLi. We
attempted to react (E)-CHFdCFSiMe3 and ethyl chloro-
formate in the presence of KF to prepare (Z)-CHFd
CFCO2Et (Lu and Zhang’s approach3a) without success.
We were able, however, to modify the chemistry of
Wesolowski and Burton11 to ultimately prepare the
appropriate precursor (Z)-CHFdCFCO2Et. Thus, iso-
merically pure (E)-CHFdCFI, 14, was prepared by the
methodology reported by Wesolowski.20 Carboalkoxyla-
tion of (E)-CHFdCFI stereospecifically gave (Z)-CHFd
CFCO2Et (15), which reacted in situ with Bu3SnCl and
LDA at -90 to -100 °C and provided the ethyl (E)-2,3-
difluoroacrylic ester21 (Scheme 5).
(16) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-
524. (b) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771-1780. (c) Espinet,
P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 4704-4734.
(17) (a) Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind,
L. S. J. Org. Chem. 1994, 59, 5905-5911 and references therein. (b)
Farina, V. Pure Appl. Chem. 1996, 68, 73-78. (c) Casado, A. L.;
Espinet, P. Organometallics 2003, 22, 1305-1309. (d) Lu, L.; Burton,
D. J. Tetrahedron Lett. 1997, 38, 7673-7676.
(18) (a) Martin, S.; Sauvetre, R.; Normant, J. F. Tetrahedron Lett.
1982, 23, 4329-4332. (b) Martin, S.; Sauvetre, R.; Normant, J. F.
Tetrahedron Lett. 1983, 24, 5615-5618.
(19) Zhang, X.; Lu, L.; Burton, D. J. Collect. Czech. Chem. Commun.
2002, 67, 1247-1261.
Under Liebeskind conditions, 16 readily couples with
aryl iodides (entries 1, 4, 6, and 7), 2-iodothiophene (entry
5), and vinyl bromides (entries 8 and 9) to stereospecifi-
(20) Wesolowski, C. A. Ph.D. Thesis, University of Iowa, Iowa City,
IA, 2000; pp 104-119.
(21) See ref 8e for similar in situ capture of an unstable vinyllithium.
J. Org. Chem, Vol. 70, No. 26, 2005 10745

Wang et al.
of hexane and ethyl acetate (30:1) afforded 0.19 g of the cross
cally give the isomerically pure (Z)-acrylic esters or
conjugated dienes. These results are summarized in
Table 2.
coupling product as an oil. 19F NMR (CDCl3) δ -134.8 (d, J )
1
127.8 Hz, 1 F), -162.8 (d, J ) 127.8 Hz, 1 F) ppm; H NMR
(CDCl3) δ 7.53 (d, J ) 8.1 Hz, 2 H), 7.14 (d, J ) 8.1 Hz, 2 H),
4.27 (qd, J ) 7.1, 0.6 Hz, 2 H), 1.27 (td, J ) 7.1, 0.9 Hz, 3 H)
ppm; 13C NMR (CDCl3) δ 160.1 (dd, J ) 29.9, 6.1 Hz), 155.8
(dd, J ) 58.7, 19.1 Hz), 141.7 (d, J ) 2.4 Hz), 139.2 (dd, J )
243.0, 44.0 Hz), 129.3 (d, J ) 2.5 Hz), 126.9 (dd, J ) 9.8, 8.6
Hz), 125.4 (dd, J ) 23.2, 6.1 Hz), 61.5, 12.3, 14.0 ppm; GC-
MS m/z (relative intensity): 226 (M+, 87), 197 (26), 181 (28),
154 (100); HRMS calcd 226.0805 for C12H12F2O2, found 226.0813.
Ethyl (Z)-2,3-Difluoro-2-propenoate (15). (E)-1,2-Di-
fluoro-1-iodoethylene (16.20 g, 85 mmol), triethylamine (12.0
mL, 86 mmol), PdCl2(PPh3)2 (0.72 g, 1 mmol), and EtOH (30
mL) were added to a 120-mL Hastelloy Parr pressure reactor
with a stirring bar (caution: the reaction should be carried
out behind a safety shield in a well-ventilated hood).The
pressure reactor was pressurized to 160 psi of CO, and the
pressure was released. This process was repeated 4 times to
rid the system of air. Finally, the reactor was pressurized to
160 psi of CO and was stirred vigorously at room temperature.
After 5 h, when the reaction was completed, the pressure was
carefully released. The mixture was transferred to a separatory
funnel containing 100 mL of ether. The organic layer was
washed with water (20 mL), 10% aqueous HCl (10 mL),
saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The
organic layer was dried over anhydrous Na2SO4 and concen-
trated by rotary evaporation. The crude product was purified
by fractional distillation (7.28 g colorless oil, yield: 63%, bp:
88-90 °C/760 mm). 19F NMR (CDCl3) δ -145.2 (dd, J ) 70.5,
6.8 Hz, 1 F), -151.6 (dd, J ) 14.1, 6.8 Hz, 1 F) ppm; 1H NMR
(CDCl3) δ 7.34 (dd, J ) 70.6, 14.1 Hz, 1 H), 4.32 (q, J ) 7.1
Hz, 2 H), 1.34 (t, J ) 7.1 Hz, 3 H) ppm; 13C NMR (CDCl3) δ
160.2 (dd, J ) 28.6, 8.5 Hz), 144.0 (dd, J ) 274.5, 10.4 Hz),
139.5 (dd, J ) 255.5, 9.1 Hz), 61.9, 14.1 ppm; HRMS for
C5H6F2O2 calcd 136.0336, found 136.0333.
Aryl iodides substituted with either electron-donating
or electron-withdrawing groups reacted smoothly with 16
under the coupling conditions to give the (Z)-acrylic esters
in good to excellent yields. With 1-bromo-4-iodobenzene
(entry 7) only the iodide site coupled. The (E)- and (Z)-
vinyl bromides readily coupled to stereospecifically give
the conjugated dienes.
The configuration of both the (Z)- and (E)-2,3-difluoro-
3-stannylacrylic esters, as well as the configuration of
the aryl acrylic esters and dienes, was unambiguously
1
assigned on the basis of 19F and H coupling constants.
All products exhibited vicinal couplings (3JF,F ) 0-22 Hz)
consistent with the cis-CFdCF- configuration versus the
vicinal coupling (3JF,F ) 100-140 Hz) for the trans-CFd
CF- configuration.18 Vicinal coupling of 3JH,H ) 6-12 Hz
for cis and 3JH,H ) 12-18 Hz for trans was used to assign
the configuration of the -CHdCH- unit in the dienes.22
Conclusions
We have developed a useful methodology for the
preparation of both (Z)- and (E)-2,3-difluoro-3-stannyl-
acrylic esters. These new synthons readily undergo cross-
coupling reactions under Liebeskind conditions [(Pd-
(PPh3)4/CuI)] with aryl iodides and vinyl bromides, as
well as 2-iodothiophene, to stereospecifically provide the
corresponding 2,3-difluoro-3-arylacrylate esters and con-
jugated dienes from a common synthon precursor, thus
providing a new, efficient entry to this important class
of compounds.
Ethyl
(E)-2,3-Difluoro-3-(tri-n-butyl)stannyl-2-pro-
Experimental Section
penoate (16). To a two-necked round-bottomed flask with a
stirring bar was added ethyl (Z)-2,3-difluoropropenoate (0.68
g, 5 mmol) and 1.68 mL of Bu3SnCl (6.2 mmol) in a mixture of
5 mL of dry THF and 5 mL of dry ether. The solution was
cooled to -100 °C in a hexane/liquid nitrogen bath. A solution
of LDA (6.2 mmol) (prepared by reaction of iPr2NH and n-BuLi)
was added dropwise, carefully maintaining the internal tem-
perature at -90 to -100 °C throughout the addition. After
the addition was completed, the reaction mixture was stirred
at -100 °C for 1 h and slowly warmed to room temperature.
Water (2 mL) was added to quench any unreacted base. The
mixture was transferred to a 125-mL separatory funnel
containing 50 mL of ether. The organic layer was washed with
20 mL of water and 5 mL of brine, dried over anhydrous Na2-
SO4, and concentrated by rotary evaporation. The crude
stannane was purified by silica gel chromatography (hexane/
ethyl acetate ) 30:1) to yield 1.61 g of colorless oil. 19F NMR
(CDCl3) δ -116.6 (s, 1 F), -138.6 (s, 1 F) ppm; 1H NMR (CDCl3)
δ 4.29 (q, J ) 7.1 Hz, 2 H), 1.62-1.44 (m, 6 H), 1.37-1.27 (m,
6 H), 1.10 (t, J ) 8.1 Hz, 3 H), 0.90 (t, J ) 7.3 Hz, 9 H) ppm;
13C NMR (CDCl3) δ 171.3 (dd, J ) 333.5, 7.7 Hz), 162.5 (dd, J
) 29.0, 12.3 Hz), 145.7 (dd, J ) 279.2, 10.7 Hz), 61.6, 28.7,
27.1, 14.2, 13.6, 11.2 ppm; HRMS calcd for C17H31F2O2120Sn-
C4H9 369.0688, found 369.0680.
The preparation of (Z)-2,3-difluoro-3-(tri-n-butyl)stannyl-
acrylate 3 has been described in a previous report.19 Compound
14 was prepared according to the reported procedure.8d
General Procedure for the Stille-Liebeskind Cross-
Coupling Reactions of Ethyl (Z)- or (E)-2,3-Difluoro-3-
(tri-n-butyl)stannylpropenoate with Aromatic Iodides
and Vinyl Bromides. A round-bottomed flask was charged
with a stirring bar and nitrogen tee, CuI (0.05 g, 0.26 mmol),
Pd(PPh3)4 (0.03 g, 0.026 mmol), and 3 mL of dry DMF. Ethyl
(Z)- or (E)-2,3-difluoro-3-(tri-n-butyl)stannylpropenoate (0.21
g, 0.5 mmol) and 0.55 mmol of aromatic iodide or vinyl bromide
were added sequentially. After the reaction was completed (the
reaction progress was monitored by TLC), the reaction mixture
was diluted with ether (100 mL) and washed with aqueous
KF solution (15%, 50 mL). The organic layer was dried over
Na2SO4 and concentrated. The crude product was purified by
silica gel column chromatography. An alternative procedure
of workup is to use Co(OAc)2‚4H2O23 instead of aqueous KF
solution. Therefore, after the reaction was completed, Co-
(OAc)2‚4H2O (0.25 g, 1 mmol) was added to the reaction
mixture, and the mixture was stirred for 10 min at room
temperature. Then the mixture was poured directly onto silica
gel and purified by column chromatography.
Ethyl (E)-2,3-Difluoro-3-(4-methylphenyl)-2-propenoate
(4). The reaction mixture of (Z)-2,3-difluoro-3-(tri-n-butyl)-
stannylpropenoate (0.50 g, 1.17 mmol) with 4-iodotoluene (0.22
g, 1.01 mmol) in the presence of Pd(PPh3)4 (0.05 g, 0.043 mmol),
CuI (0.10 g, 0.52 mmol) in DMF (5 mL) was stirred at room
temperature for 10 h. Column chromatography with a mixture
Acknowledgment. We greatly acknowledge the
National Science Foundation for their financial support
of this work.
Supporting Information Available: Experimental pro-
cedure for the synthesis of 5-13 and 17-25 and their
1
characterization by H, 19F, 13C NMR, GC-MS, and HRMS.
1
Copies of H, 19F, and 13C NMR of compounds 4-13 and 15-
(22) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds, 5th ed.; Wiley & Sons: New
York, 1991; p 221.
(23) Blumenthal, E. J. Ph.D. Thesis, University of Iowa, Iowa City,
IA, 2000; pp 122-144.
25. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0517949
10746 J. Org. Chem., Vol. 70, No. 26, 2005