Toward a Safe, High-Throughput, and Scalable Continuous-Flow Process for the Azide-Mediated Schmidt Reaction of Ketones

Abstract

The Schmidt reaction is a valuable method for converting common functional groups such as ketones, carboxylic acids, and aldehydes into nitrogen-containing products, but its use on scale is restricted by the extreme hazards associated with the key reagent, hydrazoic acid. To address this challenge, we developed a continuous-flow strategy designed to mitigate risk while enabling preparatively useful throughput. A microscale flow reactor was first constructed to study the influence of temperature, pressure, and residence time on the Schmidt reaction of ketones, identifying conditions that balance high conversion with an acceptable regioselectivity. An exogenous nitrogen cofeed was implemented as an additional safety measure to control the concentration of HN₃ in the gas phase. Guided by these insights, a mesoscale reactor constructed entirely from compatible polymeric materials delivered over 22 g of amide product in an hour with performance comparable to that of the microscale system. Important limitations, safety considerations, and design challenges associated with HN₃ remain unresolved and are discussed to inform future efforts toward larger-scale continuous-flow Schmidt reactions for pharmaceutical and fine-chemical manufacturing.