Mechanistic Divergence in Rh(III)-Catalyzed Cascades: How Substrate Identity Switches Between Cyclization and Migratory Insertion

Abstract

Density functional theory (DFT) calculations provide a detailed mechanistic understanding of Rh(III)-catalyzed cyclization reactions involving 8-methylquinoline or 2-methylquinoline-N-oxide and 2-alkynylaniline. The results show that the activation of C-H bonds initiates the reaction, leading to the formation of five-membered rhodacycles, with regioselectivity determined by the Mayer bond order. For 8-methylquinoline, the nucleophilic cyclization pathway predominates, producing coupled products through reductive elimination. In contrast, 2-methylquinoline-N-oxide undergoes a regioselective migratory insertion, followed by oxygen atom transfer and tautomerization to generate indole oxides. Distortion/interaction analysis reveals that spatial factors are key in controlling migratory insertion selectivity, while Intermolecular Geometry and Molecular Hydrogen (IGMH) and Atoms in Molecules (AIM) analyses uncover significant noncovalent interactions (e.g., O-H···π) in the transition states. These findings offer a predictive framework for understanding selectivity in Rh(III)-catalyzed cascade reactions, which can inform the rational design of catalysts for heterocyclic synthesis.