SCHEME 3. Possible Mechanism for the Formation of
Products from the â-bromostyrene Reaction
SO4. After removal of diethyl ether under vacuum, the residue was
chromatographed on silica gel (pentane/CH2Cl2 ) 1:1) to give ethyl
R,R-difluoro-4-phenyl-3-butenoates 1a and 1b (1.12 g, 66%) in an
1
88:12 ratio as determined by H NMR spectroscopy.
Reaction of Ethyl Chlorodifluoroacetate with Z-â-Bromosty-
rene (3a). The same procedure applied to Z-â-bromostyrene 3a
(0.1 g, 0.55 mmol) in the presence of ethyl chlorodifluoroacetate
(0.115 g, 0.81 mmol), Na2S2O4 (0.069 g, 0.82 mmol), NaHCO3
(0.143 g, 0.82 mmol), and DMSO (5 mL) afforded ethyl R,R-
difluoro-4-phenyl-3-butenoate 1b (68.4 mg, 55%).
Reaction of Ethyl Chlorodifluoroacetate with E-â-Bromosty-
rene (3b). The same procedure applied to â-bromostyrene 3b (1
g, 3a/3b ) 15:85, 5.5 mmol) in the presence of ethyl chloro-
difluoroacetate (1.15 g, 8.13 mmol), Na2S2O4 (0.688 g, 8.19 mmol),
NaHCO3 (1.426 g, 8.19 mmol), and DMSO (25 mL) afforded ethyl
R,R-difluoro-4-phenyl-3-butenoate 1b (745 mg, 60%).
Ethyl 4-Phenyl-2,2-difluoro-3(Z)-butenoate (1a). Colorless oil.
1H NMR: δ 1.07 (t, J ) 7.2 Hz, 3H); 4.01 (q, J ) 7.2 Hz, 2H);
5.90 (dt, JH-H and JH-F )13.0 Hz, 1H); 6.95 (dt, JH-H ) 13.0 Hz
and JH-F ) 1.6 Hz, 1H); 7.35 (s, 5H). 13C NMR: δ 163.8 (t, JC-F
34 Hz); 139.1 (t, JC-F 8.9 Hz); 134.7; 129.3 (t, JC-F 2.7 Hz); 129.1;
128.6; 122.3 (t, JC-F 27.9 Hz); 115.9; 112.7; 109.4; 63.3; 14.0. 19
NMR: δ -94.38.
F
Ethyl 4-Phenyl-2,2-difluoro-3(E)-butenoate (1b). Colorless oil.
1H NMR: δ 1.35 (t, J ) 7.2 Hz, 3H); 4.33 (q, J ) 7.2 Hz, 2H);
6.30 (dt, JH-H ) 16.2 Hz and JH-F ) 11.4 Hz, 1H); 7.08 (dt, JH-H
) 16.2 Hz and JH-F ) 2.6 Hz, 1H); 7.35 (m, 3H); 7.44 (m, 2H).
13C NMR: δ 164.3 (t, JC-F 35 Hz); 137.2 (t, JC-F 9.4 Hz); 134.5;
130.0; 129.2; 127.8; 119.3 (t, JC-F 24.5 Hz); 116.4; 113.1; 109.9;
63.5; 14.3. 19F NMR: δ -103.68.
Typical Procedure for the Saponification of Ethyl 4-Phenyl-
2,2-difluoro-3-butenoates (1a,b). Ethyl 4-phenyl-2,2-difluoro-3-
butenoate 1a or 1b (0.55 g, 2.43 mmol) and LiOH-H2O (0.857 g,
20.4 mmol) were stirred in a THF/H2O (47:20) mixture for 4 h.
The mixture was then acidified to pH 1 with a 35% HCl solution
and extracted with diethyl ether (3 × 30 mL), and the organic layer
was dried over Na2SO4. After diethyl ether was removed under
vacuum, the crude product was crystallized in toluene.
(3a/3b ) 15:85) leads to a mixture of adducts in which the
E-isomer 1b is the main product (Scheme 3). As revealed by
1H NMR spectroscopy, less than 3% of Z-isomer 1a is formed
during the reaction (Figure 1b). In the same manner, pure Z-â-
bromostyrene 3a, prepared in one step by the Wittig reaction
of benzaldehyde and chloromethyltrimethylphosphonium bro-
mide,7 afforded the E-isomer 1b as the main adduct. Ester 1b
was then transformed into the corresponding acid 2b by reaction
with LiOH in THF/H2O. Crystallization in toluene afforded
suitable crystal for X-ray analysis. The structure confirmed the
E configuration for the product 2b (see the Abstract graphic).
In conclusion, in this report we first present results that correct
unambiguously the wrong stereochemical structure attribution
of ethyl Z-R,R-difluoro-4-phenyl-3-butenoate 1a resulting from
addition of the ethyl difluoroacetate radical to phenylacetylene.
Second, inspired from the studies of Long and Chen,2 we
developed a novel and efficient method for the stereoselective
preparation of pure ethyl E-R,R-difluoro-4-phenyl-3-butenoate
1b.
4-Phenyl-2,2-difluoro-3(Z)-butenoic Acid (2a). Yield: 92%.
Colorless crystals. 1H NMR: δ 5.80 (t, JH-H and JH-F ) 13.5 Hz,
1H); 7.00 (dt, JH-H )13.5 Hz and JH-F ) 1.6 Hz, 1H); 7.33 (s,
5H). 19F NMR: δ -95.68. Anal. Calcd for C10H8F2O2 (198.16):
C, 60.61; H, 4.07. Found: C, 60.58; H, 4.05.
4-Phenyl-2,2-difluoro-3(E)-butenoic Acid (2b). Yield: 87%.
Colorless crystals. 1H NMR: δ 6.30 (dt, JH-H ) 16.1 Hz and JH-F
) 11.4 Hz, 1H); 7. 13 (dt, JH-H ) 16.2 Hz and JH-F ) 2.4 Hz,
1H); 7.38 (m, 3H); 7.468 (m, 2H). 19F NMR: δ -104.48. Anal.
Calcd for C10H8F2O2 (198.16): C, 60.61; H, 4.07. Found: C, 60.55;
H, 4.09.
X-ray Structure Analysis. Crystal data for 2a and 2b together
with details of the X-ray diffraction experiment are reported in the
Supporting Information. Suitable colorless crystals of 0.5 × 0.5 ×
0.1 mm3 and 0.4 × 0.3 × 0.1 mm3 for 2a and 2b, respectively,
were mounted on a Bruker-Nonius KappaCCD diffractometer.8 180°
φ scan measurements (through 2° steps of 60 s) were performed at
room temperature using the Mo KR wavelength. The cell parameters
were refined and the data integrated using Denzo-Scalepack.9
Experimental Section
Reaction of Ethyl Chlorodifluoroacetate with Phenylacety-
lene. Under an argon atmosphere, phenylacetylene (0.765 g, 7.5
mmol), ethyl chlorodifluoroacetate (0.792 g, 5 mmol), Na2S2O4
(0.630 g, 7.5 mmol), NaHCO3 (1.38 g, 7.5 mmol), and DMSO (25
mL) were introduced into a 50 mL double-necked round-bottomed
flask equipped with magnetic stirrer, thermometer, and condenser.
The mixture was then heated to 75 °C for 15 h. After cooling, the
mixture was poured into 30 mL of ice-water. The aqueous layer
was extracted with diethyl ether (3 × 30 mL), and the combined
extracts were washed with brine (3 × 20 mL) and dried over Na2-
(7) Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1980, 21, 4021-4024.
(8) Bruker-Nonius 1998. Kappa CCD Reference Manual. Nonius B.V.,
P.O. Box 811, 2600 Av, Delft, The Netherlands.
(9) Otwinowski, Z. and Minor, W. “rocessing of X-ray Diffraction Data
Collected in Oscillation Mode. In Methods in Enzymology, Volume 276:
Macromolecular Crystallography; Carter, C. W., Jr., Sweet, R. M., Eds.;
Academic Press: New York, 1997; Part A, pp 307-326 .
8620 J. Org. Chem., Vol. 71, No. 22, 2006