Ruthenium-catalyzed late-stage C–H alkenylation of N-arylpyridazino[4,5-b]quinolin-1(2H)-ones

Abstract

A ruthenium-catalyzed one-pot sequential cascade has been developed for the synthesis of functionalized pyridazino[4,5-b]quinolin-1(2H)-ones. The sequence comprises Ru/Cu-catalyzed C(sp³)–H oxidation, cyclization with hydrazine hydrate, Chan–Lam N–H arylation, and Ru/Cu-mediated ortho-selective C(sp²)–H alkenylation in a single operation. Mechanistic studies highlight the crucial role of ruthenium in C–H activation and alkenylation. The N-aryl substitution of pyridazino[4,5-b]quinolin-1(2H)-one resulted in steric hindrance, which prevents free rotation around the C–N single bond (CN nature due to the amide, phenyl, and ortho bulky substituents), and hence showed inherent atropisomerism, as revealed by specific optical rotation (SOR) studies. Furthermore, the alkenylation at the o-position enhanced the restriction of free rotation and the atropisomeric products were obtained, as revealed by chiral HPLC analysis and SOR studies. However, further detailed chiral synthetic studies are required to understand the enantioselective versions, which are in progress in our laboratory and will be communicated separately. SC-XRD studies revealed that the crystallization of products occurs in centrosymmetric space groups. This efficient cascade offers a concise route to structurally diverse atropisomeric and functionalized pyridazinoquinolinones.