Unraveling the mechanism of phosphine-catalyzed azetine formation and BF3-mediated ring-opening to axially chiral alkenes: a DFT study

Abstract

The recent experimental synthesis of 2-azetines and axially chiral alkenes via phosphine catalysis coupled with BF₃·Et₂O/Et₃SiH/H₂O-mediated ring-opening presents a complex mechanistic puzzle. Key questions regarding the oversimplified reaction sequence, the regioselectivity of zwitterionic intermediates, the origin of high stereocontrol, and the synergistic role of BF₃ remain unresolved. Herein, we present a comprehensive DFT study that elucidates the detailed eight-step mechanism, encompassing phosphine-initiated conjugate addition, nucleophilic attack, cyclization, catalyst dissociation, BF₃ activation, hydride transfer, ring-opening, and hydrolysis. Our analysis reveals that the nucleophilic addition step dictates the stereoselectivity, with the favoured pathway being stabilized by minimal conformational distortion and multiple C–H⋯O hydrogen bonds and lp⋯π interactions. Distortion/interaction analysis rationalizes the exclusive regioselectivity at the C4 site over the C2 site. Crucially, BF₃ not only activates the carbonyl group to facilitate hydride transfer but also generates an acidic environment that promotes efficient N–Si bond hydrolysis. This work provides a fundamental understanding of the reaction dynamics and offers theoretical guidance for designing related cascade reactions.