Catalyst-free, scalable heterocyclic flow photocyclopropanation

Abstract

Industrial process development is driven by several factors, including safety, cost, robustness and environmental aspects. However, attempts to establish aryl diazo esters – which are highly valued in academic research for their reactivity as carbene precursors – in the chemical industry have been limited by their explosivity and toxicity. Their catalyst-free photolysis in continuous flow improves safety, sustainability and scalability compared to batch reactions. Herein, we report the continuous flow catalyst-free photocyclopropanation of heterocycles in up to grams per h productivity in a non-chlorinated, biodegradable solvent. Highly-functionalized cyclopropanated products are key intermediates in the synthesis of drugs and pharmaceutically-relevant compounds. Optimal conditions and process understanding were obtained by a Design of Experiments approach. In comparison with a large scale batch experiment, continuous flow conditions improved yield, productivity and process safety.