The present work establishes a sustainable and environmentally benign biocatalytic strategy for the construction of multisubstituted cyanopyrazoles via 3+2 cycloaddition, employing lipase as a highly efficient and practical catalyst. Under the optimized mild reaction conditions, this protocol enables the preparation of structurally diverse cyanopyrazole derivatives with high to excellent isolated yields. The substrate used in this method is the in situ-generated diazoacetonitrile. The corresponding conversion was carried out under mild aqueous conditions, avoiding the flammable and explosive characteristics of diazoacetonitrile. The established protocol exhibits a representative substrate scope and good functional group compatibility. Molecular docking was employed to investigate the reaction, highlighting the significant impact of the active-site architecture of the lipase on this reaction. This biocatalytic approach not only enriches the synthetic toolbox for the preparation of valuable cyanopyrazole scaffolds but also highlights the potential of lipase-catalyzed promiscuous reactions in the green synthesis of pharmaceutically relevant heterocyclic compounds.
Zhang et al. (Mon,) studied this question.