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Although continuous flow synthesis using microtubing reactors has provided a wealth of opportunities for homogeneous photochemical synthesis and has proven particularly beneficial in scaling up processes, employing continuous flow technology to scale up heterogeneous photoreactions is challenging due to the issues including handling of solids, poor light penetration, and commonly lengthy reaction time. Here we present a solution to these issues by changing the continuous flow mode to a high-speed circulation flow mode. The high flow rate set in a circulation flow reactor overcomes solid sedimentation to prevent clogging and improve the mixing efficiency. We successfully conducted 100 g-scale C–N and C–S cross-couplings using a heterogeneous photocatalyst and a nickel catalyst in the flow reactor that significantly outperformed conventional batch reactors. The photocatalyst was recycled and reused 10 times to achieve a kilogram-scale synthesis without obvious deactivation. Semicontinuous production was achieved via automated feeding and collection, and a photopromoted gas/liquid/solid three-phase trifluoromethylation reaction was employed. A kilogram-scale amount of starting material was successfully transformed, resulting in a 43.2% yield of trifluridine. Our study suggests that a circulation flow reactor with high flow speed will become a crucial tool in the synthetic chemist's toolbox because of its simple infrastructure, ease of operation and automation, significant efficiency improvement compared to conventional batch reactors, scalability, improved safety, and tolerance of solids.
Liu et al. (Wed,) studied this question.