Direct Acylation of Unactivated Alkyl Halides with Aldehydes through N-Heterocyclic Carbene Organocatalysis

Abstract

Catalytic acylation of organohalides with aldehydes is an ideal strategy for the direct synthesis of ketones. However, the utilization of unactivated alkyl halides in such a transformation remains a formidable challenge. In this study, we developed a cross-coupling reaction of aldehydes with unactivated alkyl halides through N-heterocyclic carbene catalysis. With this protocol, various ketones could be rapidly synthesized from readily available starting materials under mild conditions. This organocatalytic system was successfully applied in the late-stage functionalization of pharmaceutical derivatives. Mechanistic investigations suggest a closed-shell nucleophilic substitution mechanism for this reaction.

Keywords: Direct Acylation; Ketone Synthesis; N-Heterocyclic Carbene Organocatalysis; Umpolung Chemistry; Unactivated Alkyl Halides.