Exploring Regio- and Stereoselectivity in [3+2] Cycloaddition: Molecular Electron Density Theory Approach for Novel Spirooxindole-Based Benzimidazole with Pyridine Spacer

A new ethylene derivative was synthesized as a precursor for the [3+2] cycloaddition (32CA) reaction to access a novel spirooxindole embodied with benzimidazole with a pyridine spacer. The chalcone derivatives 3a-j is obtained with condensation of the acetyl derivative with aryl aldehydes. The one-pot multi-component reaction of the ethylene derivative, 5-Cl-isatin, and octahydroindole-2-carboxylic acid enables the construction of a highly functionalized quaternary center spirooxindole scaffold in a high chemical yield. A study using the Molecular Electron Density Theory (MEDT) explains the complete regio- and stereoselectivity of the reaction, resulting in the exclusive formation of the ortho/endo-cycloadduct under kinetic control. The low activation Gibbs free energy is the result of the supernucleophilic character of the in situ-generated azomethine ylide and the strong electrophilic character of the ethylene derivatives.

Automated summary

A new ethylene derivative was synthesized as a precursor, leading to the formation of a novel spirooxindole embodied with benzimidazole and a pyridine spacer through a [3+2] cycloaddition reaction. The chalcone derivatives 3a-j were obtained by condensation of the acetyl derivative with aryl aldehydes. The reaction of the ethylene derivative, 5-Cl-isatin, and octahydroindole-2-carboxylic acid in a one-pot multi-component fashion enabled the construction of a highly functionalized quaternary center spirooxindole scaffold with a high chemical yield.