Theoretical investigation of the regio-, enantio-, and stereo-selectivities of the (3 + 2) cycloaddition reactions of N-vinylindoles with nitrones and nitrile oxides

Abstract

The 1,3-dipolar cycloadditions of nitrones and nitrile oxides to N-vinylindole afford isoxazolidines and 5-indolyl-substituted isoxazolines which are structural components of a wide range of natural and pharmaceutically active compounds. In these reactions, there are several regio-, enantio-, and stereo-chemical possibilities, leading to several potential pathways, and these pathways are studied with density functional theory calculations at the M06/6-311G(d,p) level of theory. The results show that the electron-withdrawing substituents on the dipolarophile accelerate the (3 + 2) cycloaddition reactions of nitrones with N-vinylindole by lowering the activation barriers of the reaction. The (3 + 2) cycloaddition of electron-withdrawing and electron-donating substituted nitrones with N-vinylindole proceeds with the preferential formation of cis-stereoisomers, and this is due to the Z-configuration of the nitrone and the trans-periplanar orientation of the substituents and the indolyl group on the transition state. The reactions of nitrile oxides with N-vinylindole proceed regioselectively at the exocyclic double bond in the indole to form 5-indolyl-substituted-isoxazolines. It has been established that the (3 + 2) cycloaddition of electron-donating and electron-withdrawing substituted nitrones and nitrile oxides to N-vinylindole is not enantioselective. The global electrophilicity indices (ω) and maximum electronic charge transfer (ΔN max ) computed for various nitrones and nitrile oxides considered in this work are consistent with energetic trends and experimental outcomes. The analysis of the electrophilic (P k + ) and nucleophilic (P k −) Parr functions at the reactive centers shows that the cycloaddition will happen in such a way as to unite the atoms with the highest molecular orbital coefficients because this would lead to the greatest stabilization, and this is in good agreement with the energetic trends and the experimental outcome.