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

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 Care 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(O)-Cu(I) as cocatalyst stereoselectively provided the beta-fluoro-alpha,beta-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(0) catalysis afforded the beta-fluoro-alpha,beta-unsaturated esters 4.