Biocatalyzed aza-michael addition via continuous flow technology: a game-changer for the facile synthesis of N-alkylated pyrazole derivatives.

N-Alkylated pyrazole derivatives are widely used in the treatment of prostate cancer, depression, epilepsy and sickle cell disease due to their remarkable anti-tumor, anti-depressant and anti-bacterial activity. In this work, a convenient synthesis of N-alkylated pyrazole derivatives from pyrazoles and α,β-unsaturated compounds catalyzed by Lipozyme® TL IM/K2CO3 in a continuous-flow microreactor was studied. Through the study of reaction parameters such as enzyme type, the Lipozyme® TL IM/K2CO3 mixed catalyst ratio, reaction solvent, substrate molar ratio, temperature, residence time, etc., the best reaction conditions for the enzymatic synthesis of N-alkylated pyrazole derivatives were obtained. The effects of electronic effects and steric hindrance of donors and acceptors were explored. The reaction was conducted in a shaker reactor and a continuous-flow microreactor respectively, and their space-time yields were compared. This research provides a novel technology for the facile synthesis of N-alkylated pyrazole derivatives and a versatile compound library to support subsequent research in pharmaceuticals and related domains.