Spirocyclic scaffolds are found in many pharmacologically active natural and synthetic compounds. From time to time, efforts have been undertaken to develop new and better processes for the synthesis of spirocyclic compounds. We have uncovered some remarkable benefits through our research on the synthesis of spirocyclic compounds using aqueous and mechanochemical conditions (Scheme 1, 2). Spiro[indole-pyrrolidine] (4) was readily synthesized in high yields using Michael condensation of 3-dicyanomethylene-2H-indol-2-ones (2) with various isothiocyanate derivatives (3), while piperidine is used as the catalyst under aqueous and mechanochemical reaction conditions. (2) was synthesized in situ by Knoevenagel condensation of indole-2,3-dione (1) and malononitrile in the absence of a catalyst. The advantages of this protocol are that it is a solvent-free reaction, occurs at ambient temperature, requires short reaction times, has experimental simplicity, and produces excellent yields of 85-94 and 90-98% respectively. These environmentally-friendly reaction media are useful alternatives to volatile organic solvents.

Aqua/mechanochemical mediated synthesis of novel spiro[indole-pyrrolidine] derivatives

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ACS Fall 2022

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