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.