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

Abstract

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.

Photocatalytic Reductive Functionalization of Aryl Alkynes via Alkyne Radical Anions

“…To showcase the practicality of this method, we conducted a two-step gram-scale synthesis of anti-inflammatory drug nabumetone from commercially available 2-ethynyl-6-methoxynaphthalene ( 7w ) using our reductive hydrocarboxylation reaction. 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 gram-scale . 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 ).…”

Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow

“…A segmented flow was observed through the flow of both the solution of reagents and gas (oxygen); finally, the coil photoreactor was subjected to LED irradiation (365 nm), resulting in 0.56 g of the desired product, with a high turnover frequency (835.2 µmol g −1 h −1 ). Recently, Wu and coworkers reported on a practical and very efficient approach to carry out photocatalyzed reactions in continuous flow by employing mpg-CN [73]. The authors demonstrated that switching from continuous flow mode to a high-speed circulation flow mode can strongly enhance productivity, allowing the photocatalyzed reaction mediated by solid-phase catalysts to be quickly scaled up.…”

“…The nickel/mesoporous graphitic carbon nitride (mpg-CN) blended catalyst was selected for the photo-mediated ligand-free Buchwald−Hartwig C−N coupling reaction. A capillary photoreactor packed with nickel/mpg-CN was tested, with scarce results in terms of conversion and yield (12% Recently, Wu and coworkers reported on a practical and very efficient approach to carry out photocatalyzed reactions in continuous flow by employing mpg-CN [73]. The authors demonstrated that switching from continuous flow mode to a high-speed circulation flow mode can strongly enhance productivity, allowing the photocatalyzed reaction mediated by solid-phase catalysts to be quickly scaled up.…”