Halogen bonding accelerated aerobic dehydrogenative aromatization for 4-aminoquinoline preparation

Org Biomol Chem. 2024 Dec 3. doi: 10.1039/d4ob01700e. Online ahead of print.

Abstract

This study presents a highly efficient method for 4-aminoquinoline derivative preparation under transition metal-free conditions. The process involves an aerobic oxidative dehydrative coupling of 2,3-dihydroquinolin-4(1H)-ones with various amines, including ammonia, resulting in high yields of the desired products. The method is also applicable to substituted 4-aminoquinoline derivative construction through a cyclization/dehydrative coupling cascade process starting from 2'-amino chalcones. Mechanistic studies reveal that iodine (I2) is consumed to produce 3-iodoquinolin-4-ol, which acts as a true catalyst with high catalytic efficacy (as low as 0.5 mol%). The presence of halogen bonding is critical in the inter-molecular transfer hydrogenation process to generate inactive quinolin-4-ol. Subsequently, using air/oxygen as the terminal oxidant, the iodine anion was oxidized to I2 to regenerate the 3-iodoquinolin-4-ol from quinolin-4-ol in the catalytic cycle. Key benefits of this methodology include its simplicity, transition metal-free conditions, environmentally-benign oxidant, and high atom economy, making it a valuable approach for synthesizing medicinally significant 4-aminoquinoline derivatives.