High-speed circulation microflow synthesis facilitating practical large-scale heterogeneous photocatalysis

Abstract

Although continuous-flow synthesis using microtubing reactors has provided a wealth of opportunities for photochemical synthesis and has proven particularly beneficial in scaling up processes, handling solids and slow reactions remains major hurdles that have hampered its broad application. 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 microflow reactor overcomes solid sedimentation to prevent clogging and improve 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 microflow reactor that significantly outperformed conventional batch reactors. The photocatalyst was recycled and reused 10 times to achieve kg-scale synthesis without obvious deactivation. Even though the reaction occurred in batch mode, semi-continuous production was achieved via automated feeding and collection, and a photo-promoted gas/liquid/solid three-phase trifluoromethylation reaction was employed to produce the drug trifluridine on a kg scale. Our study suggests that a circulation flow reactor with high flow speed will become a crucial tool in the synthetic chemist’s toolbox, owing to its simple infrastructure, ease of operation and automation, significant efficiency improvement compared to conventional batch reactors, scalability, improved safety and tolerance of solids.

High-Speed Circulation Flow Platform Facilitating Practical Large-Scale Heterogeneous Photocatalysis

“…The high-speed circulation flow reactor promises to become a critical component in supplementing existing reaction setups because of its simple infrastructure, ease of operation, and excellent efficiencies for mixing, heating, and light irradiation. In addition, the system overcomes clogging issues, facilitates effective slow reactions, enables scale-up, and achieves automation …”

Photocatalytic Reductive Functionalization of Aryl Alkynes via Alkyne Radical Anions

“…Given the poor solubility of oxalates in MeCN, a simple high-speed circulation flow was employed to scale up the photocatalytic reductive hydrocarboxylation reaction, affording the desired product 8a in 76% yield at gramscale. 21 Then, methylation of 8a with MeLi resulted in the formation of nabumetone in 68% overall yield, providing a practical approach for scaling up photoreactions that involve reagents with low solubility (Figure 4). 22 Mechanistic Studies.…”