Highly Stereoselective Synthesis of (E)- and (Z)-α-Fluoro-α,β-unsaturated Esters and (E)- and (Z)-α-Fluoro-α,β-unsaturated Amides from 1-Bromo-1-fluoroalkenes via Palladium-Catalyzed Carbonylation Reactions

Abstract

The highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z approximately 1:1), which are readily available starting materials, have been found to isomerize to high E/Z ratios after storage at -20 degrees C for 1 week or by photolysis at 254 nm. Since the (E)-isomers have been found to react faster than the corresponding (Z)-isomers at room temperature in Pd(0)-catalyzed reactions, the palladium-catalyzed carboalkoxylation of high E/Z 1-bromo-1-fluoroalkenes lead to a high Z/E (Z/E >/= 98:2) ratio of the alpha-fluoro-alpha,beta-unsaturated esters. When 1-bromo-1-fluoroalkenes (E/Z approximately 1:1) were reacted with HCOOH/NBu(3)/Pd(II)/DMF, the (E)-isomer was selectively reduced, and the remaining (Z)-1-bromo-1-fluoroalkenes were recovered in essentially pure isomeric form. The resulting mixture of (Z)-1-bromo-1-fluoroalkenes and the reduced products underwent similar palladium-catalyzed carboalkoxylation reactions at 70 degrees C, and the (E)-alpha-fluoro-alpha,beta-unsaturated esters were stereospecifically obtained. This methodology was also successfully applied for the stereospecific synthesis of (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides: the palladium-catalyzed carboamidation reaction of high E/Z and (Z)-1-bromo-1-fluoroalkenes lead to pure (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides, respectively.

Transition metals in organic synthesis: Highlights for the year 2005

“…Formation of medium-sized lactones, lactams, and thiolactones using a palladium catalyst was reported [501]. Mixtures of 1-bromo-1-fluoro-1-alkenes (Z/E ≈ 1:1) were transformed into (Z)-2-fluoro-2-enoic acid esters and amides having a Z/E ratio > 98:2 [502].…”

Site-specific preparation of 4-substituted-6-fluoro(carboalkoxyl)benzo[b]furans and benzo[b]thiophenes via base-catalyzed cyclization of enyne derivatives

“…(2)). The reduced olefin can be readily separated after the cyclization process has been completed [21,32,33].…”

Stereospecific preparation of symmetrical (1Z, 3Z)- and (1E, 3E)-2,3-difluoro-1,4-disubstituted-buta-1,3-dienes from 1-bromo-1-fluoroalkenes

“…Recently, we reported the preparation of (Z)-1-bromo-1-fluoroalkenes by kinetic reduction of 1 (Scheme 3) [32]. (Z)-1-Bromo-1-fluoroalkenes 4 can be obtained in pure form, however most of them were utilized with the corresponding reduced products 5 in a mixture to avoid tedious isolation and to improve the overall yield [29][30][31][32]. Therefore (Z)-1-bromo-1-fluoro-2-phenylethene 4a was reacted with Bu 3 SnSnBu 3 (1.2 equiv.…”

“…to high E/Z ratios [29,32]; for 1 (R = aryl groups), high E/Z ratios (E/Z > 75:25) were obtained after storage in a freezer (À20 8C) for 1 week (Scheme 1). Alternatively, the isomerization readily occurs when 1 undergoes photolysis at 254 nm for approximately 1 h. The isomerization is very clean and is most likely due to a trace amount of bromine in the mixture.…”