ISATIN (1H-indole-2,3-dione), which is derived from the oxidative breakdown of the natural indigo dye, has been proven to be one of the most efficient carbonyl synthons in the field of heterocyclic chemistry. Isatin has been shown to participate in electrophilic reaction of its C-3 carbonyl with various active methylene reagents, including barbituric acid, thiobarbituric acid, malononitrile, cyanoacetamide, pyrazolones, rhodanine, thiazolidinedione and 4-hydroxycoumarin, to furnish various biologically relevant arylidene, spirooxindoles, and indolinone scaffolds. The current review compiles some recent trends on green and sustainable synthesis of isatin active methylene hybrids, where green and sustainable catalytic systems have been used for the synthesis, which include aqueous media and water-on-media reactions, ionic liquids, deep eutectic solvents (DES), reusable magnetic nano-catalysts, grinding and mechanochemical methods, and microwave/ultrasound techniques. Comparing reaction yield, reaction time, and green chemistry parameters, such as E-factor and atom economy, shows that green methods not only excel conventional synthesis by reflux, but also improve the pharmacological potential of synthesized heterocycles. The data obtained through biological testing from the literature indicate that these hybrids have good anticancer, antimicrobial, antidiabetic, antiviral and anti-inflammatory properties, thus making green synthesized isatin-active methylene hybrids good candidates for use in future drug development programs. This review further analyzes the structure activity relationship, Knoevenagel condensation mechanism, and other critical issues that need to be resolved to commercialize green chemistry methods.
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