Computational exploration of the 1,3‐dipolar cycloaddition reaction of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives

Abstract The synthesis of isoxazolidine and isoxazole derivatives, versatile building blocks for the construction of a wide range of complex heterocyclic architectures in synthetic organic and medicinal chemistry, is efficiently achieved via the 1,3‐dipolar cycloaddition reaction (1,3‐DC). Herein, we report an extensive theoretical study on the peri‐, regio‐, stereo, and enantio‐selectivities of 1,3‐DC of 7‐isopropylidenebenzonorbornadiene with nitrile oxide and cyclic nitrone derivatives using density functional theory calculations. Acetophenone‐substituted nitrile oxide periselectively adds across the endocyclic olefinic bond of the dipolarophile to furnish the exo ‐cycloadduct as the major product, a reaction that has a rate constant of 1.88 × 10 9 s −1 . The endo approach of this periselective path is the closest competing pathway with a rate constant of 4.59 × 10 7 s −1 . Different substituents on the nitrile oxide do not affect the peri‐ and stereo‐selectivity of the reaction. Diethyl ether solvation has no substantial effect on the energetic patterns observed in the gas phase computation. Also, we report a novel 1,3‐DC between cyclic nitrone derivatives and 7‐isopropylidenebenzonorbornadiene as an efficient way to generate isoxazolidine derivatives. Even though the reactions of the cyclic nitrone derivatives have slightly higher activation barriers than the acyclic nitrile oxide derivatives, the former is more enantioselective than the latter. Whereas electron‐donating groups (EDGs) on the cyclic nitrone favor the formation of the exo ‐cycloadduct, electron‐withdrawing groups (EWGs) favor the formation of the endo ‐cycloadduct. Both 1,3‐dipoles add across the dipolarophile via a concerted asynchronous mechanism.