N-Substituted Auxiliaries for Aerobic Dehydrogenation of Tetrahydro-isoquinoline: A Theory-Guided Photo-Catalytic Design.

Visible-light mediated aerobic dehydrogenation of N-heterocyclic compounds is a reaction with enormous potential for application. Herein, we report the first complete aerobic dehydrogenation pathway to large-scale production of isoquinolines. The discovery of this visible light photoredox reaction was enabled through the combination of mathematical simulations and real-time quantitative mass spectrometry screening. The theoretical calculations showed that hyper-conjugation, the main underlying factor hindering the aerobic oxidation of tetrahydroisoquinolines, is relieved both by π- and σ-donating substituents. This mechanistic insight provided a novel photocatalytic route based on N-substituted auxiliaries that facilitated the conversion of tetrahydroisoquinolines into the corresponding isoquinolines in just three simple steps (yield 71.7% in bulk-solution phase), using unmodified Ru(bpy)Cl photocatalyst, sun energy, atmospheric O, and at ambient temperature.