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

In this investigation, molecular electron density theory (MEDT) is used to study the [3 + 2] cycloaddition (32CA) reaction between 1-(furan-2-yl)-<i>N</i>-phenylmethanimine oxide (1) and styrene (2). 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, 1 is a moderate electrophile and a strong nucleophile, while 2 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 meta-endo 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 <i>via</i> 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 meta-endo 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.