Work

Safe by Design Flow Technology for Diazoacetonitrile Generation and Direct Conversion to Pyrazoles

Year: 2026

Type: article

Abstract: Diazo compounds enable short and efficient synthetic routes but their broader adoption is limited by hazards associated with their preparation, storage, and handling. Here, a safe by design continuous flow process is presented in which diazoacetonitrile (DAN) is generated in aqueous solution, transferred into an organic phase with minimal hold up, and immediately consumed in a telescoped [3 + 2] cycloaddition with activated alkynes to obtain 3 cyano 1H pyrazoles. Operating windows for solvent choice, temperature, residence time, and pressure are established, and the influence of added HCl on nitrosation efficiency and DAN decay is observed. Dichloromethane and benzonitrile are compared as extraction and reaction media: benzonitrile enables higher organic phase DAN concentrations, whereas dichloromethane facilitates isolation. Under optimized conditions, NMR yields of ∼60%-80% are obtained for reactions with methyl propiolate, and a 2 h telescoped run affords a 37% isolated yield after recrystallization. The workflow prevents isolation or accumulation of DAN, improving the safety of processes involving this energetic intermediate and illustrating how continuous flow and biphasic extraction can support greener synthesis by avoiding reaction steps.

Source: ChemistryOpen

DOI: 10.1002/open.202600006

Authors: Dušan Bošković, Stefan Loebbecke, Calogero Giancarlo Piscopo, Ligia Johanna Radulescu, Maud Schwarzer

Institution: Fraunhofer Institute for Chemical Technology

Language: English

Topic: Innovative Microfluidic and Catalytic Techniques Innovation

Subfield: Biomedical Engineering

Field: Engineering

Domain: Physical Sciences

SDG: Responsible consumption and production

Open Access status: gold

Estimated APC paid: $2,790