Continuous flow unlocks modular ketones assembly enabled by dynamic orbital selection

Cross-coupling based on diverse structural motifs offers a powerful strategy for ketone synthesis. However, existing methodologies are often hampered by a narrow substrate scope, non-neutral redox conditions, and poor scalability, particularly for sterically hindered ketones. Herein, we have developed a continuous-flow metallaphotoredox catalytic strategy driven by a dynamic orbital selection mechanism, leveraging the differential bond dissociation energies between various radicals and the metal. This approach enables efficient cross-coupling of aldehydes and carboxylic acids without the need for oxidative addition steps, thereby circumventing the reliance on stoichiometric redox reagents. It demonstrates broad substrate compatibility and excellent functional group tolerance, allowing access to a wide range of ketones, including highly sterically congested frameworks. Notably, the implementation of continuous-flow technology significantly enhances process efficiency and scalability. A successful 100 gram-scale conversion conducted in a flow microreactor within 24 h further underscores the potential of continuous-flow photocatalysis as a sustainable platform for organic synthesis.