During our efforts towards the identification of a lead compound in one of our medicinal chemistry projects, we became interested in the incorporation of a CF<sub>3</sub>-cyclopropane moiety. A common method to access this functionality relies on the reaction of an olefin with trifluoromethyl diazomethane. Upon scale-up though, this method presents significant drawbacks due to the safety hazards associated with the production and handling of large quantities of this reagent. Here we present a simple, safe and scalable procedure for the generation of trifluoromethyl diazomethane solution in continuous flow from inexpensive 2,2,2-trifluoroethyl amine hydrochloride and sodium nitrite. The flow system is based on commercially available Syrris Asia syringe pumps, PTFE tubing, static mixers, and Zaiput’s membrane liquid-liquid phase separator. The process starts with mixing aqueous streams of 2,2,2-trifluoroethyl amine hydrochloride and sodium nitrite followed by the introduction of an organic solvent. A solution of trifluoromethyl diazomethane in an organic solvent is obtained after extraction of the resulting biphasic mixture in a plug flow reactor and efficient in-line phase separation. Optimization data for residence time, concentration of the aqueous solutions, ratio of reagents and organic solvent will be presented. Under the optimized conditions, the method allows for generation of the CF<sub>3</sub>-diazomethane solution at various concentrations (up to 0.48 M). Adjustment of the flow rate translates into the trifluoromethyl diazomethane productivity in the range of 0.23-0.79 mmol/min. Such a controlled flexibility was found to be particularly useful in the enantioselective cyclopropanation of styrenes that proceeds with high ee’s and good yields.

Scalable method for preparation of trifluoromethyl diazomethane in continuous flow using in-line membrane phase separation

ACS Fall 2020 Virtual Meeting

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