Development of a Continuous Flow Baldwin Rearrangement Process and Its Comparison to Traditional Batch Mode

Abstract

A new and highly efficient continuous flow process is presented for the synthesis of aziridines via the thermal Baldwin rearrangement. The process was initially explored using traditional batch synthesis techniques but suffered from moderate yields, long reaction times, and moderate diastereoselectivities. Here we demonstrate that the process can be greatly improved upon its transfer to continuous flow, which afforded the aziridine targets in high yields, short reaction times, and consistently high diastereoselectivities, with the high-throughput process rendering multigram quantities of product in short periods of time. In addition, flow processing extended the substrate scope including several examples that had failed in batch mode, thus demonstrating the value of this overlooked entry into valuable aziridine species.

Advances in the Continuous Flow Synthesis of 3‐ and 4‐Membered Ring Systems

“…Another recent example demonstrating the advantages of continuous flow technology for high temperature reactions was published by Bonner and Baumann in 2023, who described a continuous flow Baldwin rearrangement to access aziridines from 2,3-dihydroisoxazoles. [19] During this study, it was determined that high temperatures were required to achieve full conversion, with toluene at 110 °C requiring 3 hours in batch to access the product in poor to moderate yields. By transferring the reaction to flow, a reduced reaction time of 10 minutes could be achieved by superheating the mixture to 135 °C, which led to improved yields due to a decrease in the quantity of impurities being formed.…”

“…Exploiting this approach, a range of epoxides was synthesised in good to excellent yield. This method was then applied towards the synthesis of Fluconazole (19), a drug used for the treatment of fungal infections, yielding key intermediate 18 in 78 % yield on a multigram scale using a Lonza Flow Plate microreactor (Scheme 9). Similar to the above example, in 2020 the Kappe group also published their work on using flow generated halomagnesium intermediates and their reactivity with aldehydes.…”

“…Another recent example demonstrating the advantages of continuous flow technology for high temperature reactions was published by Bonner and Baumann in 2023, who described a continuous flow Baldwin rearrangement to access aziridines from 2,3‐dihydroisoxazoles [19] . During this study, it was determined that high temperatures were required to achieve full conversion, with toluene at 110 °C requiring 3 hours in batch to access the product in poor to moderate yields.…”