Continuous Flow Technology for the Synthesis of 2-azabicyclo[2.2.0]hex-5-ene derivatives

The strained geometry of 2-azabicyclo[2.2.0]hex-5-enes makes them an attractive scaffold in medicinal chemistry. Their synthesis is achieved via the light-induced electrocyclization of N-carboxy-1,2-dihydropyridine derivatives, which are in turn obtained by hydride reduction of pyridines in the presence of a chloroformate. Reported batch procedures are characterized by long reaction times (up to 7 days) and generally low yields, likely as a result of inefficient light penetration and poor irradiation homogeneity. Continuous-flow technology overcomes these limitations by improving light penetration, ensuring more uniform irradiation, and enabling the straightforward scale-up of photochemical transformations. In this context, we developed a continuous flow methodology for the synthesis of 2-azabicyclo[2.2.0]-hex-5-enes that significantly reduced reaction times and increased productivity. Reaction conditions were optimized on model substrate 1a by tuning residence time, concentration, and solvent. Under the optimized conditions (30 min residence time, 0.1 M in MTBE upon 304 nm light irradiation), the desired product 2a was obtained in 93% yield, with a productivity exceeding 31 mmol/day. Compared with the corresponding batch protocol, the flow procedure delivered a 93-fold increase in productivity and a 64-fold increase in space-time yield. The scope of the reaction was subsequently expanded to a variety of chloroformates and substituted pyridines. While the nature of the chloroformate has a minimal influence on the cyclization efficiency, substitution on the pyridine ring had a pronounced impact on the reaction outcome. Electron-rich substrates afforded the desired products in good yields, whereas electron-poor substrates proved to be more challenging. In particular, 3-halo-substituted derivatives were obtained in low yields. Further investigations are currently ongoing in our laboratories.