DFT studies on the mechanism of one-pot α,γ-difunctionalization of β-ketoesters: regio-, chemo-, and stereoselectivity promoted by DBU/MeOH.

Abstract

Context: 1,3-Dicarbonyl derivatives, such as β-ketoesters, are inexpensive and readily available building blocks widely applied in organic synthesis for the preparation of bioactive molecules. Nevertheless, the mechanistic origins of their regio-, chemo-, and stereoselectivity in multicomponent transformations remain insufficiently understood. Here, the α,γ-difunctionalization of cyclic β-ketoesters with benzaldehyde, allyl bromide, DBU, and methanol was investigated via density functional theory (DFT) to elucidate these selectivities. The reaction follows a five-step mechanism comprising deprotonation, alkylation, γ-deprotonation, aldol condensation, and dehydration. Energetic analysis revealed that the initial deprotonation is kinetically favored through a bimolecular pathway ( ${\Delta G}^{\#}$ = 8.35 kcal/mol), whereas alkylation occurs stereoselectively via the Si face and aldol condensation via the Re face. Methanol cooperates with DBU by stabilizing enolates through hydrogen bonding and lowering activation barriers. These insights rationalize the observed experimental selectivity and provide a theoretical framework for the rational design of new selective multicomponent reactions in organic synthesis.

Methods: All quantum chemical calculations were performed via Gaussian 16 at the B3LYP/6-31G(d,p) level of theory, with Grimme's D3 dispersion correction. Transition states were confirmed by harmonic frequency analysis and connected to their reactants and products via intrinsic reaction coordinate (IRC) calculations. Solvent effects (THF) were modeled using the IEFPCM approach. Conceptual DFT descriptors were computed at the B3LYP/6-311++G(d,p) level to assess the electronic properties. Natural bond orbital (NBO) analysis was conducted with NBO. The topological features of the electron density were examined using Multiwfn (version 3.8) through QTAIM and IGMH analyses, and the molecular structures were visualized using VMD.