Palladium-catalyzed difluorocarbene transfer enables access to enantioenriched chiral spirooxindoles

Abstract

We disclose herein an unprecedented Pd-catalyzed difluorocarbene transfer reaction, which assembles a series of structurally interesting chiral spiro ketones with generally over 90% ee. Commercially available BrCF₂CO₂K serves as the difluorocarbene precursor, which is harnessed as a user-friendly and safe carbonyl source in this transformation. Preliminary mechanistic studies exclude the formation of free CO in the reaction process, and importantly, we also find that BrCF₂CO₂K outcompete gaseous CO and several common CO surrogates in this asymmetric process. The reaction mechanism, including the in-situ progressive release of the difluorocarbene, the rapid migratory insertion of ArPd(II) = CF₂ species, and subsequent defluorination hydrolysis by water to introduce the carbonyl group, accounts for the overall high efficiency and uniqueness. This work clearly showcases the advantage and potential of the difluorocarbene in synthesis and supplies a mechanistically distinct route for asymmetric carbonylative cyclization reactions.

Difluorocarbenes are versatile synthetic intermediates, used for both generating fluorinated products as well as modulating organometallic catalytic reaction pathways. Here, the authors introduce a palladium/chiral ligand system that applies the metal–difluorocarbene intermediate toward a carbonylative spirocyclization.