Theoretical studies on cycloaddition reactions of N-allyl substituted polycyclic Isoindole-1,3-dione with nitrones and nitrile oxides

Abstract

Bridged polycyclic molecular skeletons and related systems are key structural motifs in medicinal chemistry. The most efficient and widely accepted method for the syntheses of the bridged molecular polycyclic scaffolds is the 1,3-dipolar cycloaddition reactions. Herein, a systematic study on (3 + 2) cycloaddition reaction (32CA) of norbornene imide A with three-atom components (TACs), nitrile oxides and nitrones are presented at the M06-2X/6–311++G(d,p)-PCM(toluene), M06-2X-D3/6–311++G(d,p)-PCM(toluene) and MPWB1K/6–311++G(d,p)-PCM(toluene) levels of theory. The different reactivities of the strained endocyclic CC bond in the carbocyclic fragment and the less hindered N-allyl imide double bond in the alkene are evaluated. In the reaction of A and the nitrile oxides, four reaction pathways are characterized whereas eight distinctive reactive channels are located for nitrones. Trends in the calculated activation energies show that the 32CA reaction between A and nitrile oxides competitively occur at the endocyclic CC bond in the carbocyclic fragment and the N-allyl imide double bond. The cycloaddition of the nitrones favorably add across the less hindered N-allyl imide double bond. The trends in reactivity are in perfect agreement with local reactivity descriptors. Evaluation of TS geometries and bond distances validate that these 32CA reactions follow a one-step asynchronous molecular mechanism as proposed by Domingo. The activation energies suggest favored exo approach along all the reaction pathways, for that leads to better stabilization. Frontier molecular orbital analysis and global reactivity descriptors demonstrate that all the 32CA reactions proceed via an inverse electron demand character. Results from the local electrophilic (PK+) and nucleophilic (PK-) Parr functions show that the 32CA takes place at the atomic centers with the largest radical atomic spin densities in complete agreement with experimental outcomes.