Transition-Metal-Free Activation of Amides by N−C Bond Cleavage

The amide bond N−C activation represents a powerful strategy in organic synthesis to functionalize the historically inert amide linkage. This personal account highlights recent remarkable advances in transition-metal-free activation of amides by N−C bond cleavage, focusing on both (1) mechanistic aspects of ground-state-destabilization of the amide bond enabling formation of tetrahedral intermediates directly from amides with unprecedented selectivity, and (2) synthetic utility of the developed transformations. Direct nucleophilic addition to amides enables a myriad of powerful methods for the formation of C−C, C−N, C−O and C−S bonds, providing a straightforward and more synthetically useful alternative to acyl-metals.