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 Na 2 S 2 O 4 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 ZnBrCF 2 CH 2 CO 2 C 2 H 5 ( 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 CHCO 2 C 2 H 5 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 β-fluoro-α,β-unsaturated esters 4 .