Facile Synthesis of Sterically Hindered and Electron-Deficient Secondary Amides from Isocyanates

摘要

Amide bond formation is widely regarded as the most used chemical reaction in drug discovery. Despite the importance of amides, nearly all are formed by reactions operating under a single mechanistic approach: dehydrative condensation of amines and carboxylic acids by the action of a coupling agent. This approach has proven to be highly suitable, albeit often wasteful and expensive, for the majority of amides. An exception is the preparation of highly hindered and electron-deficient amides, for which difficulty in their formation by condensation is well known. Although a number of mechanistically unique amide bond forming reactions have been reported, including work from our own labs, none of these new reactions addresses the challenge of preparing amides from hindered acids or those derived from bulky or electron-deficient amines.