Expedited access to β-lactams via a telescoped three-component Staudinger reaction in flow

Abstract

The Staudinger reaction is widely used for the generation of β-lactams via the thermal cycloaddition of imines with ketenes. Traditionally, it cannot be performed as a multicomponent reaction between aldehydes, amines and ketenes, thus limiting its versatility. Recently we reported for the first time a three-component Staudinger reaction in batch, exploiting a photochemical Wolff rearrangement of diazoketones and an in situ generation of the imine. Here we report an expedited continuous flow approach that generates the crucial ketene intermediate prior to its telescoped reaction with an imine component at ambient temperatures. The imine is prepared by an in situ dehydration between amines and aldehydes in a packed bed reactor containing basic alumina as drying agent. The resulting telescoped flow approach features a fast dehydration reaction (t_Res ca. 3 min) as well as an efficient Wolff rearrangement using LEDs (420 nm) to afford the desired β-lactam products in less than 30 min which compares favorably with reaction times of several days in batch mode. Flow processing thereby affords a safe and streamlined entry to these important targets and allows their effective generation on gram scale. Moreover, this approach exploits several homogeneous and heterogeneous transformations under mild conditions that generate water and nitrogen gas as the only by-products.

Graphical abstract