Synthesis of isoindolinones: Intramolecular [4+2] cycloaddition/retro [4+2] of pyridone propiolamides

A new synthesis of isoindolinones was discovered during a screening campaign aimed at the development of novel methods for the synthesis of pyridone-EZH2 inhibitor analogues. The reaction proceeds via an intramolecular [4+2] cycloaddition of a pyridone with a tethered propiolamide moiety followed by extrusion of isocyanic acid. The discovery, optimization, and scope of the methodology are described.