Recent advances in the cleavage of non-activated amides

The amide bond is one of the most fundamental and widely utilized functional groups in organic chemistry, central to the structures of pharmaceuticals, bioactive molecules, and advanced materials. However, its exceptional resonance stabilization renders the C-N bond highly inert, posing a persistent synthetic challenge for its transformation. While twisted amides with distorted C-N bonds have offered useful reactivity enhancements, the selective activation of conventional, non-activated amides remains far more difficult. This review summarizes recent advances over the past decade in the activation and cleavage of non-activated amide C-N bonds for their conversion into diverse carboxylic acid derivatives. Key strategies covered include transition-metal catalysis, electrophilic activation, strong base-counter-cation systems, and <i>N</i>-based activating groups that enable chemoselective bond cleavage. Together, these developments provide powerful tools for amide functionalization and offer new opportunities for efficient, practical, and selective syntheses.