Decoding the [3 + 2] cycloaddition of a furan–imine oxide with styrene: mechanism, selectivity and bioactivity†

Abstract

In this investigation, molecular electron density theory (MEDT) is used to study the [3 + 2] cycloaddition (32CA) reaction between 1-(furan-2-yl)-N-phenylmethanimine oxide () and styrene (). In fact, density functional theory (DFT) calculations at the M06-2X-D3/6-311G(d,p) level of theory in benzene at room temperature were performed to describe the regio- and stereoselectivity and the mechanism of the 32CA reaction studied. Using the CDFT approach, is a moderate electrophile and a strong nucleophile, while is classified as a moderate electrophile and a moderate nucleophile. As a consequence, the 32CA reaction under study is characterized by a non-polar characteristic. Analysis of thermodynamic data indicates that the compound is both thermodynamically and kinetically more favored than the other compounds, which aligns perfectly with the experimental results. BET analysis shows that this reaction takes place via a non-polar one-step cycloaddition with low asynchronous transition states. The QTAIM and ELF approaches further confirmed this asynchronous characteristic. Molecular docking analysis revealed that the product exhibited notable binding affinity to the 1CIN protease, highlighting its potential as a therapeutic inhibitor. Although drug-likeness evaluations confirmed compliance with Lipinski's rule of five, suggesting favorable pharmacokinetic properties, the PASS analysis indicated a limited range of predicted biological activities for the compound.