Asymmetric Reductive Three-Component Annulation Reaction for Constructing Fused N-Heterocycles With Contiguous...

The development of efficient methods for the diverse synthesis of optically active fused N-heterocycles is vital for advancing medicinal chemistry. Hydrodearomative annulation of weakly reactive azaarenes presents a promising yet challenging strategy to fulfil such a synthetic purpose. Herein, we report a reductive three-component reaction for the construction of fused N-heterocycles with contiguous quaternary and tertiary carbon stereocenters, enabled by a simple chiral phosphoric acid/PhSiH₃ catalytic system. A wide variety of isoquinolinium salts were transformed in combination with formaldehyde and N-alkyl anilines into the target products with good isolated yields (up to 88%), and high diastereoselectivities (>20:1 dr) and enantioselectivities (up to 96.5:3.5 er). The reaction proceeds through sequential hydrodearomatization, C₄-methylation, and asymmetric annulation, in which the chiral phosphoric acid participates in both the formation of intermediates and the stereocontrolling steps. DFT calculations further reveal that the observed enantioselectivity arises from C-H···O interactions between the substrate and catalyst, with steric repulsion effects playing a decisive role.