Copper-catalyzed direct amide bond formation from amines and carboxylic acids <i>via</i> isothiocyanate activation

An efficient catalytic method for the direct synthesis of amides from non-activated carboxylic acids under mild conditions is described. Amines couple with isothiocyanates to form thiourea intermediates, followed by copper-mediated desulfurization to generate reactive carbodiimides <i>in situ</i>, which can rapidly combine with unactivated acids to form amides. The influence of the electronic effects of substituents on carbodiimides on reaction selectivity is discussed. This protocol exhibits broad functional group compatibility, is applicable to the late-stage functionalization of pharmaceuticals and peptides, and provides a new approach for late-stage functionalization.