Synthesis of novel isoindolone derivatives via cascade reactions. Contrasting diastereoselectivity under solution-phase vis-a-vis solvent-free ball-milling reaction conditions

The highly diastereoselective synthesis, crystallographic analysis, and full characterization of several novel heterocycle-fused isoindolones is described. The synthetic strategy involves a cascade Michael/aldol-like cyclization reaction between N-substituted phthalimides rac-1 or 2 and several alpha,beta-unsaturated electrophiles to afford the tricyclic systems pyrrolo[2,1-a]isoindolone and tetrahydropyrido[2,1-a] isoindolone. This synthetic strategy offers a convenient alternative to existing procedures for the preparation of isoindolone derivatives fused to five- and six-membered rings. X-ray crystallographic analysis allowed the determination of relative configurations and revealed that the synthesized compounds exhibit significant structural distortion, especially in the five membered rings. Relevantly, the diastereomeric distribution of products depends substantially on whether the cascade reaction is carried out under solution vis-a-vis solvent-free conditions. (C) 2019 Elsevier Ltd. All rights reserved.