Facile and High‐Yielding Synthesis of C(3)‐Aminoisoindolinones Under Metal Catalyst‐Free Conditions

Abstract C(3)‐Aminoisoindolinones have attracted the attention of medicinal chemists due to their unique and stable N−C−N substructure and possibilities for facile and scalable synthesis of combinatorial libraries. We discovered that para ‐toluenesulfonic acid (PTSA), an organic protic acid, efficiently catalyzes condensation of isoindolinone‐3‐ols with primary and secondary amines to furnish C(3) N‐substituted isoindolinones in high yields. The N−C bond formation reaction is highly efficient and experimentally simple. The method replaces known transition metal catalysts involving Cu, Pt, Pd or Au. It works efficiently for both intra‐ and inter‐molecular variants. Furthermore, it is amenable for synthesis of C(3)‐aminoisoindolinones with free N(2) via photolytic deprotection of the 2‐nitrobenzyl group. We have demonstrated application of the method for synthesis of a variety of medicinally relevant bicyclic and tricyclic C(3)‐aminoisoindolinones.