N-Heterocyclic Carbene-Diboron-Substrate Cooperatively Facilitate Direct Amidation of Carboxylic Acids and Amines

Abstract

Herein, we report that an efficient and practical organocatalyzed strategy enables direct amidation of a wide range of carboxylic acids and variety of amines. The organocatalyzed system is proved to be suitable for the synthesis of small molecular peptides from protected amino acids, and the method was successfully applied to the late stage functionalization of drug molecules or pharmaceutical intermediates. Mechanistic studies by control experiments, in situ infrared spectroscopy, 11B nuclear magnetic resonance (11B NMR), and density functional theory (DFT) calculation, reveal that N-propyl-N-(2-(pyridin-2-ylamino)phenyl) formamide reacts with B2pin2 to form the N-heterocyclic carbene (NHC)-diboron adduct, and the boron atom of NHC-diboron adduct is able to coordinate to the carboxyl oxygen atom of the carboxylic acid to generate the true active species of NHC-diboron-carboxylic acid for catalyzing the amidation of carboxylic acids and amines. The discovery of in situ generation of catalytic system in combination of multi-catalytic components with substrates may open the door to cooperative catalysis for the synthesis of important organic molecules.