From intramolecular cyclization to intermolecular hydrolysis: TMSCF2Br-enabled carbonylation of aldehydes/ketones and amines to α-hydroxyamides

Abstract

A metal-free multicomponent strategy has been developed for the synthesis of various α-hydroxyamides via carbonylation of aldehydes/ketones and amines enabled by the difluorocarbene reagent TMSCF₂Br (TMS = trimethylsilyl). The TMS-protecting group derived from TMSCF₂Br plays a crucial role in the tunability of the reaction pathways from intramolecular cyclization to intermolecular hydrolysis. The synthetic utility has been demonstrated by the late-stage modification of several drug-related molecules and the highly selective synthesis of ¹⁸O-labeled α-hydroxyamides from H₂¹⁸O.