Mechanistic Insights into Scandium-Catalyzed Cascade Cyclization of Aromatic Aldimines with Tethered Alkenes via C-H Activation

Rare-earth catalyzed C-H activation offers a uniquely powerful platform for atom-economical ring construction, yet the mechanistic foundations of cascade processes that assemble polycyclic frameworks remain poorly understood. Herein, a computational investigation is reported to elucidate the mechanism of a scandium-catalyzed diastereoselective cascade cyclization of aromatic aldimines bearing tethered alkenes. The calculations establish a catalytic sequence involving the formation of active species, stereoselective intramolecular alkene insertion, intramolecular nucleophilic addition, and a rate-determining protonolysis step. The diastereoselectivity originates from a distortion-minimized alkene insertion transition state and a conformationally rigid postinsertion intermediate that enforces facial selectivity during the second cyclization. Moreover, the decisive influence of the tether architecture is uncovered. Short tethers enable low-strain six- or seven-membered ring formation, whereas tether elongation imposes prohibitive substrate distortion penalties that suppress reactivity. In addition, the oxygen atom in the tether plays an important role in the protonolysis step by alleviating steric congestion and providing a weak stabilizing O···H interaction, effects that are absent in amino- or all-carbon-tethers. These results highlight how tether-enabled preorganization governs reactivity and selectivity, providing valuable mechanistic insights for the development of new atom-efficient C-H activation strategies to access complex polycyclic compounds.