Computational Insightsinto BF3-Catalyzed[2π + 2σ] Cycloadditions: Catalyst, Substrate, Solvent,and Electric Field Effects

Abstract Bridged bicyclic scaffolds, particularly azacycle-fused bicyclo[2.1.1]hexanes, are three-dimensional bioisosteres of benzene in medicinal chemistry. We reported a computational study of BF3-catalyzed [2π + 2σ] cycloaddition between dihydropyridines (DHPs) and bicyclo[1.1.0]butanes (BCBs). Experimentally, this reaction exclusively affords the azacycle-fused product P1 (bond formation adjacent to the DHP nitrogen). To understand this selectivity, we also examined the hypothetical regioisomeric pathway to P2 (bond formation at the remote double bond). Our DFT and DLPNO–CCSD(T)/CBS calculations reveal a concerted BCB ring-opening and nucleophilic attack, revising the initially proposed stepwise mechanism. BF3 plays two distinct roles: it lowers the overall barrier via enhanced orbital interactions and reduced Pauli repulsion, and it reverses the intrinsic selectivity. Under catalyst-free conditions, P2 is unexpectedly favored due to superior dispersion interactions. Upon BF3 coordination, this dispersion advantage is eliminated through conformational changes, and differential electrostatic effects favor P1 over P2. Bulky C3 substituents such as t-Bu restore P2 preference with a moderate barrier, outperforming electron-withdrawing groups. An applied electric field lowers barriers without altering selectivity, while low-polarity solvents narrow the P1/P2 barrier gap. Synergistically combining these parameters enables P2 formation with improved kinetics. This work provides mechanistic novelty and a multifactor strategy for rational selectivity control in strained-ring annulations.