Azo Methine Ylide Cycloadditions Involving Isatin And Substituted Nitroethylenes And Their Biological Activity

Abstract

Variously substituted isatins and several and#945;,and#946;-disubstituted nitroethylenes were used in a highly regio and diastereoselective [3+2]-cycloaddition approach. Consequently, a variety of and#945;-amino acids were used to generate azo-methine ylides under thermal conditions, yielding two regioisomers simply by altering the and#945;-substituents of the and#945;-amino acids. On oxindoles and nitroethylenes, the reaction tolerates a variety of sterically demanding, electron-rich and electron-deficient aryl and nitrogen substituents. The reaction delivered the cycloadducts in good yield (80-94%) and excellent diastereoselectivities (up to 98:2) in favor of (cis,cis)-spirooxindoles with opposite regioselectivity. The scale-up and transformation reactions were also demonstrated for two of the cycloadducts. newlineThe molecular electron density theory (MEDT) studies for the [3+2]-cycloaddition reactions were performed. The correct regioselectivity from two-centre interactions was anticipated through Parr function analysis. The reaction is kinetically controlled and has a negative free energy, making it irreversible. The nucleophilic nature of azo-methine ylide controls the bond formation, according to electron localization function topological characterization throughout the reaction route, which suggested a two-stage one-step chemical process. The systematic biological studies were performed for the several cycloadducts. Two of the cycloadducts displayed significant activity against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) strain. These two actives were further exhibited excellent minimum inhibitory concentration values comparable with the standard antibiotics. In subsequent dose response assays, there was negative response towards the haemolytic activity against human red blood cells. newlineWe aimed for the regioselective mono-chlorination of electron-sufficient nitroolefin which was achieved by iodobenzene dichloride reagent. Regioselective chlorination was attempted at ambient temperature.