Transforming 2D azolium salts to 3D caged tertiary amines <i>via</i> stereoselective dearomative cascade annulation

Three-dimensional fused-ring frameworks, especially those incorporating heteroatoms, are fundamental to expanding chemical space and unlocking unique properties critical for drug discovery and functional materials, yet their synthesis remains a formidable challenge. Herein, we report for the first time the union of two distinct azolium salts as an efficient synthetic platform to access tertiary amine-caged frameworks under mild conditions. The strategy combines the masked nucleophilic and electrophilic properties of isoquinolinium and pyridinium salts, and avails double dearomatization guided inverse electron demand (4 + 2) or (3 + 2) annulation in a highly regio- and diastereoselective manner to construct the nitrogen caged motifs. Our methodology creates two new rings and four new bonds in a single operation and transforms flat-aromatic compounds into structurally unprecedented three-dimensional architectures with contiguous stereocenters in very high yields. DFT studies have shed light on the reaction mechanism, indicating that the annulation step is rate-limiting, with (4 + 2) annulation proceeding stepwise and (3 + 2) annulation following a concerted pathway.