Amide Synthesis via Molecular Shuffling of Carboxylic Acids

The amide bond represents the most fundamental functional group in chemistry and biology. Amides are key building blocks of peptides, pharmaceuticals, polymers, advanced materials and biologically active compounds. The synthesis of amides has been ranked as the most common reaction performed by synthetic chemists in the last century. While the most common approach by far involves the condensation of carboxylic acids and amines, this approach has been historically limited by the positional connectivity of the key carboxylic acid group. Herein, we report a new approach to amide synthesis that relies on molecular shuffling of carboxylic acid functional group. It is found that amino benzoic acids engage in oxidative addition to a Pd(0) complex, and CO generated by decarbonylation undergoes transfer insertion into the C–Pd bond formed by alkene insertion before the last reductive elimination, achieving carbonyl shuttle amidation. The carbonyl shuttle amide synthesis is precisely controlled by ligand selection, where the reaction pathway can be fully switched to a divergent amine synthesis by decarbonylative amination. This approach is characterized by a particularly wide substrate scope and excellent functional group tolerance, including bioactive molecules and late-stage functionalization. The method is scalable, which highlights the practical utility of this new method for the synthesis of amides. Moreover, this strategy is applicable to the synthesis of linear amides. The study opens new avenues for the synthesis of amides by carbonyl reshuffling and advances an accelerated utilization of amides as critical building blocks in chemical science.