Fluoroalkylated enamides are attractive scaffolds in drug discovery owing to the ability of fluoroalkyl groups to enhance pharmacokinetic properties and the prevalence of enamide motifs in bioactive compounds. In addition, enamides serve as versatile intermediates in organic synthesis. However, stereoselective access to fluoroalkylated enamides, especially the thermodynamically disfavored Z-isomers, remains a significant challenge. Herein, we report a Z-selective copper-catalyzed allylic fluoroalkylation of allylamides using a fluorinated carboxylic anhydride/H2O2 system as a radical fluoroalkylating reagent, delivering a broad range of fluoroalkylated Z-enamides in high yields. Allylic fluoroalkylations of alkenes are typically E-selective, and fluoroalkylations of allylamides often yield intramolecularly cyclized products. These inherent reactivity and selectivity issues have limited access to fluoroalkylated Z-enamides. Our strategy addresses these challenges by enabling the stereoselective synthesis of thermodynamically disfavored fluoroalkylated Z-enamides. The synthetic utility of this reaction is demonstrated by late-stage functionalization and product derivatization. Mechanism studies, supported by experimental and computational data, suggest that a heterovalent dinuclear cupracyclic intermediate is responsible for the observed Z-selectivity.
Tagami et al. (Thu,) studied this question.