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

## TL;DR

This paper introduces a new continuous-flow method using enzymes to efficiently synthesize N-alkylated pyrazole compounds, which are important for treating various diseases.

## Contribution

The study presents a novel continuous-flow biocatalytic approach for synthesizing N-alkylated pyrazoles with optimized reaction conditions.

## Key findings

- The best reaction conditions for enzymatic synthesis were determined using Lipozyme® TL IM/K2CO3 in a continuous-flow microreactor.
- The method successfully produced 25 N-alkylated pyrazole derivatives, demonstrating its broad applicability.
- Space-time yields were compared between shaker and continuous-flow reactors, highlighting the efficiency of the latter.

## Abstract

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.

An efficient continuous-flow biocatalytic synthesis of N-alkylated pyrazoles was established, with 25 derivatives prepared to verify applicability and supply pharmaceutical parameters.