DMAP-Catalyzed Direct Conversion of Cbz/Boc-Protected Amines to Amides with Carboxylic Acids as the Acylating Agent

Abstract

Carbamate-protected amines, such as Cbz and Boc derivatives, are ubiquitous synthetic intermediates that classically require deprotection prior to acylation. We report a 4-dimethylaminopyridine (DMAP)-catalyzed protocol that directly converts these protected amines into amides using carboxylic acids. This method bypasses the traditional deprotection step, operates under mild conditions, and delivers a wide range of amides in moderate-to-excellent yields (up to 85%). Mechanism studies support a pathway involving transient activation of the carbamate via a mixed anhydride-like intermediate. The reaction's broad scope and operational simplicity redefine protected amines as versatile, direct synthons for streamlined amide assembly, overturning the long-held perception that protected amino groups are intrinsically inert toward nucleophilic acyl substitution. This strategy holds particular promise for peptide synthesis, where it could eliminate the repetitive deprotection–acylation cycle that has long been a bottleneck in both solution- and solid-phase peptide assemblies.