Mechanistic insight on water and substrate catalyzed the synthesis of 3-(1H-indol-3-yl)-2-(4-methoxybenzyl)isoindolin-1-one: Driving by noncovalent interactions.

The mechanisms of the synthesis of 2-substituted-3-(1H-indol-3-yl)-isoindolin-1-one derivatives have been investigated theoretically under unassisted, self-assisted, and water-assisted conditions. Being different from previously proposed catalyst-free by Hu et al., our results show that the title mechanism can be altered and accelerated by solvent and substrate 2. Two types of mechanisms have been developed by DFT calculations differ in the reaction sequence of substrates 1 with 3 (M1) or 2 (M2) followed by 2 (M1) or 3 (M2), and water-assisted M1 is the most favored one. It was found that the nucleophilicity of substrate 3 is stronger than that of 2. Our calculations suggest that the water-assisted pathway in M1 is the most favorable case, which undergoes nucleophilic addition and H-shift, C-N bond formation and water elimination, and intramolecular cyclization and water elimination. The rate-determining step is the nucleophilic attack process. Moreover, we also explored the effect of nucleophilic attack of the nitrogen of (4-methoxyphenyl)methanamine on hydroxyl or carbonyl group carbon of phthalaldehydic acid on the activation energy. More importantly, we found that water molecules play a critical role in the whole reaction, not only act as solvent but also as an efficient catalyst, proton shuttle, and stabilizer to stabilize the structures of transition states and intermediates via π···H-O, O···H-N, O···H-C, and O···H-O interactions. The origin of the different reactivity of M1 and M2 is ascribed to the pivotal noncovalent interactions exist between catalyst (water and substrate 2) and reactants. © 2018 Wiley Periodicals, Inc.