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

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.