Capturing CO: Palladium-Catalyzed, BrCF2COOK-Mediated One-Pot Carbonylative Coupling for the Synthesis of Oxindoles

Abstract

We herein report an unprecedented palladium-catalyzed difluorocarbene transfer reaction that enables the one-pot carbonylative coupling for the construction of structurally diverse and functionalized oxindole derivatives. The transformation proceeds under mild reaction conditions employing a palladium catalyst in combination with potassium bromodifluoroacetate (BrCF₂CO₂K), which serves as a bench-stable difluorocarbene precursor and an in situ carbon monoxide (CO) source. This dual functionality of BrCF₂CO₂K eliminates the need for external CO gas, thereby enhancing safety, cost-effectiveness, and operational simplicity. The reaction efficiently incorporates various coupling partners, including boronic acids, amines, alcohols, and alkynes, enabling the simultaneous introduction of carbonyl and functional groups into the oxindole core. The methodology exhibits broad substrate scope, excellent functional group tolerance, and good to excellent yields, offering a versatile and practical approach to access valuable oxindole frameworks. Furthermore, basic hydrolysis of the reaction mixture (when methacryloyl was employed for double protection) furnished the free N-H products, which can serve as versatile intermediates for subsequent derivatization or functionalization, unlike their N-methyl-protected counterparts that lack such synthetic flexibility. Mechanistic insights and control experiments suggest the involvement of key Pd(II) intermediates and in situ generated difluorocarbene species, which mediate sequential alkene insertion, carbene transfer, and carbonylation steps.