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major product, but the double bond was isomerized in this reaction. A mixture of Z- and E-isomers of
compound 1c and 1d was formed from the Z-isomer of compound 3c and 3d, respectively, (entries 3 and
4). When a mixture of Z- and E-isomers of compound 3 was used for the trifluoromethylation, the Z:E
ratio of compound 1 decreased (entries 1, 2, 5 and 6); (3) in the case of compound 3d (entry 4), the yield
was low (42% isolated yield) because fluoro-containing by-products were produced and detected by 19
NMR of the reaction mixture.
F
The preparation of α-trifluoromethyl-α,β-unsaturated esters is illustrated by the synthesis of 1c: A
solution of FSO2CF2CO2CH3 (1.80 ml, 14.15 mmol) in DMF (3.6 ml) was added dropwise over a
period of 2 h to a mixture of Z-3c (1.00 g, 3.34 mmol), CuI (1.60 g, 8.39 mmol) and HMPA (1.5 ml)
in DMF (9.0 ml) at 75°C. The reaction mixture was stirred at 75°C for 10 h before being cooled to
room temperature. Saturated aq. NH4Cl (10 ml) was added and the mixture was extracted with Et2O
(3×15 ml). The organic layer was washed with water, brine and dried over Na2SO4. The solvent was
removed in vacuo. Purification of the residue by column chromatography on silica gel and elution with
15:1 hexanes:ethyl acetate to afford Z-1c (0.74 g, 77% isolated yield) as a white solid and E-1c (96 mg,
10% isolated yield) also as a white solid.10
In summary, a new method for the synthesis of α-trifluoromethyl-α,β-unsaturated esters was develo-
ped. We are currently trying to apply these developed procedures to the synthesis of nucleosides bearing
trifluoromethyl groups.
Acknowledgements
We thank the National Natural Science Foundation of China for funding this work.
References
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10. Compound Z-1c: 19F NMR (CDCl3, 376 MHz, CF3CO2H as an external standard, upfield positive) δ −19.0 (s); 1H NMR
(CDCl3, 400 MHz) δ 1.39 (t, J=7.0 Hz, 3H), 4.26 (q, J=7.0 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 8.11 (s, 1H), 8.27 (d, J=9.0
Hz, 2H); m/z (EI): 290 (M++1, 12), 289 (M+, 26), 244 (100); IR (KBr): γmax: 1772, 1639, 1603, 1521 cm−1. Anal. calcd for
C12H10F3NO4: C, 49.83; H, 3.49; N, 4.84. Found: C, 49.80; H, 3.59; N, 4.84. Compound E-1c: 19F NMR (CDCl3, 376 Hz,
CF3CO2H as an external standard, upfield positive) δ −12.6 (s); 1H NMR (CDCl3, 400 MHz) δ 1.39 (t, J=7.0 Hz, 3H), 4.39
(q, J=7.0 Hz, 2H), 7.51 (s, 1H), 7.53 (d, J=9.0 Hz, 2H), 8.27 (d, J=9.0 Hz, 2H); m/z (EI): 289 (M+, 27), 244 (100); IR (KBr):
γ
max: 1727, 1656, 1600, 1519 cm−1. Anal. calcd for C12H10F3NO4: C, 49.83; H, 3.49; N, 4.84. Found: C, 49.86; H, 3.65; N,
4.78.