A continuous-flow synthesis of 1,4-benzodiazepin-5-ones, privileged scaffolds for drug discovery.

To date, compound collections based on ‘privileged structures’ play a key role in the hit discovery and the hit-to-lead processes. The term, coined by Evans in the late 1980s, was originally referring to the 1,4-benzodiazepine nucleus. Despite the impressive diversity of ,3-dihydro- benzo[e][1,4]-diazepin-2-ones prepared to date, the corresponding 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one isomer has been only rarely explored. The traditional synthetic strategies to this scaffold are affected by the formation of undesired byproducts and/or by low to moderate yields. Moreover, the need for impractical and costly purifications procedures makes these approaches inadequate to be run on larger scales. Following our interest in exploiting modern synthetic technologies to improve classical organic reactions, we investigated a continuous-flow hydrogenation protocol employing a fixed-bed catalyst (H-Cube Pro™, Thales Nanotechnology Inc.) and performed a thorough screening of different catalysts and reaction conditions in order to identify the suitable method for the reduction and concomitant cyclization of substrates (Scheme 1). Our efforts led to an improved continuous-flow synthetic protocol for the preparation of 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one derivatives, that is highly preferable over traditional metal mediated non-catalytic reduction procedure, due to its efficiency, high yielding, and ease in scale-up. As no purification steps are required, it could be successfully exploited for the rapid construction of the 3,4-dihydro-5H-benzo[e]-[1,4]diazepin-5-one privileged structures, useful for the generation of compound libraries for drug discovery.