C(3)-Aryl Isoindolinones: a PTSA-mediated Access and Improved Synthesis of ()-Nuevamine

We achieved a facile and scalable synthesis of N(2)-free C(3)-aryl isoindolinones in three steps from the corresponding phthalimides and electron-rich aromatic compounds. The reduction of one of the two carbonyls in N(2)-2-nitrobenzyl phthalimides with sodium borohydride followed by organo-catalysed (PTSA, 10 mol%) condensation with electron-rich aromatic compounds furnished C(3)-aryl isoindolinones. The subsequent removal of the 2-nitrobenzyl group under neutral photolytic conditions delivered N(2)-free C(3)-aryl isoindolinones in excellent overall yields. The intramolecular version of condensation delivered tetracyclic isoindolinones, for example nuevamine, in excellent yields with an extremely favourable E-factor, thus paving the way for the scalable and green synthesis of the alkaloid and its analogues. We achieved a facile synthesis of some C(3)-aryl isoindolinones with free N(2)H from isoindolinone-3-ols and electron-rich aromatic compounds in a two-step method. In continuation we demonstrated a high yielding synthesis of the tetracyclic alkaloid nuevamine.