Synthesis of Functionalized Benzo[h]Quinolines via Base‐Catalyzed 1,4‐Addition/Intramolecular Annulation Cascade

Abstract Benzo[ h ]quinoline (BhQ) is an important scaffold in biologically active natural products and synthetic molecules. However, current synthetic methods for BhQs require multiple steps, harsh conditions, and/or long reaction times. In this study, we developed an atom‐ and step‐economical approach for the one‐pot synthesis of functionalized BhQs. The key transformation is the formation of new 2C─C and 1C─N bonds via the lithium‐hexamethyldisilazane‐catalyzed double annulation cascade reaction of benzonitriles and diynones, leading to the synthesis of thirty‐four BhQs in up to quantitative yield. Exploration of the substrate scope under the optimized conditions revealed the reactivity of 2‐(cyanomethyl)benzonitriles and regioselectivity of unsymmetrical diynones, which were significantly influenced by electronic and steric effects. Building on density functional theory calculations, we proposed a putative reaction mechanism that provides insights into the origin of the observed regioselectivity. Practical gram‐scale synthesis and modification of functional groups around the BhQ core gave direct access to seven BhQ derivatives, demonstrating the benefits of our one‐pot approach for the construction of complex molecules for synthetic and pharmaceutical applications.