DFT-investigated Rh-catalyzed [4+1] annulation of N-methoxybenzamides with nitriles to synthesize different isoindolinones under solvent control

Abstract

We report the mechanism of Rh-catalyzed amination and alkenylation of N-methoxybenzamides for the synthesis of isoindolinone derivatives, as revealed by density functional theory calculations. Computational studies revealed that the catalytic cycle began with Rh(III)-catalyzed N–H deprotonation, the concerted metalation–deprotonation (CMD), followed by the formation of a seven-membered rhodacycle through cyano group insertion. The catalyst was then regenerated via two protonation steps, simultaneously generating the key intermediate 2-(phenoxymethylimide)-N-methoxybenzamide. Both the amination and alkenylation isoindolinone products were derived from this key intermediate. We designed four pathways for the formation of the amino-isoindolinone product: base-assisted, solvent-assisted, without external assistance, and Rh(III) catalyst-assisted hydrogen transfer. The alkenylated isoindolinone product was obtained via base-assisted or solvent-assisted hydrogen transfer. The calculation results showed that the pathway A-a-1 involving the base CF₃CH₂ONa is the most favorable path for generating the amino-isoindolinone product in 2,2,2-trifluoroethanol (TFE). On the other hand, the pathway A-a′-1 involving the base (CF₃)₂CHONa is the most favorable for generating the alkenylated isoindolinone product in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP).