Scale-Up of Continuous Metallaphotoredox Catalyzed C–O Coupling to a 10 kg-Scale Using Small Footprint Photochemical Taylor Vortex Flow Reactors

We report the development and optimization of a scalable flow process for metallaphotoredox (Ir/Ni) C-O coupling, a mild and efficient approach for forming alkyl-aryl ethers, a common motif in medicinal and process chemistry settings. Time-resolved infrared spectroscopy (TRIR) highlighted the amine as the major quencher of the photocatalyst triplet excited state, along with the formation of an Ir(II) species that, in the presence of the Ni cocatalyst, has its lifetime shortened, suggesting reductive quenching of Ir(III)*, followed by reoxidation facilitated by the Ni cocatalyst. TRIR and batch reaction screening was used to develop conditions transferrable to flow, and many processing benefits of performing the reaction in flow were then demonstrated using a simple to construct/operate, small-footprint FEP coil flow reactor, including short (<10 min) space times and reduced catalyst loadings (down to 0.1 mol % Ir, 1 mol % Ni) while retaining good yield/conversion. Scalability was demonstrated by increasing the length or diameter of the FEP coil flow reactor tubing, however, due to suspected mass transfer/mixing limitations, the yield decreased upon scale-up in some cases. Therefore, we applied a modified version of our previously reported photochemical Taylor Vortex Flow Reactor (PhotoVortex), where Taylor vortices and a short-irradiated path length allow photochemical reactions to be performed efficiently via excellent mixing. In a small PhotoVortex (8 mL irradiated volume), we have demonstrated projected productivities around 1 kg day-1 and >10 kg day-1 in a large PhotoVortex (185 mL irradiated volume) with good product yields (>90%) and low catalyst loadings (0.1 to 0.5 mol % of [Ir{dF(CF3)ppy}2dtbbpy]PF6), enabled by excellent mixing ensuring sufficient mass transfer between short-lived photoexcited and other transient species.