Continuous Process to Safely Manufacture an Aryldiazoacetate and Its Direct Use in a Dirhodium-Catalyzed Enantioselective Cyclopropanation

We report the development and demonstration of a continuous-flow process for the safe formation, extraction, and drying of aryldiazoacetate 2, which enables direct use in a fed-batch dirhodium-catalyzed enantioselective cyclopropanation reaction to provide cyclopropane 4. Designing this process with safety as a primary objective, we identified the appropriate arylsulfonyl hydrazone starting material and organic soluble base to facilitate a Bamford-Stevens diazo-generating flow process at 30 degrees C, well below the thermal onset temperature (Tonset = 57 degrees C), while also minimizing accumulation of the highly energetic diazo intermediate (AHD = -729 J/g). The Bamford-Stevens reaction byproducts are efficiently removed via a continuous aqueous extraction utilizing a liquid-liquid hydrophobic membrane separator. Continuous molecular sieve drying of the organic layer was demonstrated to maintain water levels <100 ppm in the final aryldiazoacetate solution, thereby ensuring acceptable reactivity, selectivity, and purity in the water sensitive cyclopropanation reaction. The full process was successfully executed on a 100 g scale, setting the foundation for the wider application of this and related chemistries on a kilogram scale.