Palladium-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes: Switching Regioselectivity via Simple Hydrazones

Conventional approaches for Pd-catalyzed ring-opening cross-couplings of gem-difluorocyclopropanes with nucleophiles predominantly deliver the beta-fluoroalkene scaffolds (linear selectivity). Herein, we report a cooperative strategy that can completely switch the reaction selectivity to give the alkylated alpha-fluoroalkene skeletons (branched selectivity). The unique reactivity of hydrazones that enables analogous inner-sphere 3,3 '-reductive elimination driven by denitrogenation, as well as the assistance of steric-embedded N-heterocyclic carbene ligand, are the key to switch the regioselectivity. A wide range of hydrazones derived from naturally abundant aryl and alkyl aldehydes are well applicable, and various gem-difluorocyclopropanes, including modified pharmaceutical and biological molecules, can be efficiently functionalized with high value alkylated alpha-fluorinated alkene motifs under mild conditions.

Automated summary

A cooperative strategy has been developed to switch the reaction selectivity from beta-fluoroalkene scaffolds to alkylated alpha-fluoroalkene skeletons. Key factors include the unique reactivity of hydrazones and the assistance of a steric-embedded N-heterocyclic carbene ligand. This approach allows for efficient functionalization of various gem-difluorocyclopropanes under mild conditions, including modified pharmaceutical and biological molecules.