Heteroaromatic Swapping in Aromatic Ketones

The modification of aromatic rings to heteroaromatic rings is a widely employed strategy in medicinal chemistry, often used to modulate lipophilicity and improve metabolic stability1,2. However, achieving a one-step, generalizable transformation of aromatic rings into diverse heteroaromatic rings—termed "Heteroaromatic Swapping"—has been a persistent challenge. Ex-isting methods, including skeletal editing3 and transition-metal-catalyzed aromatic ring exchange4,5, face significant limita-tions in substrate scope. Here, we report an efficient approach to Heteroaromatic Swapping via a Claisen/retro-Claisen mech-anism6, utilizing heteroaryl esters and aromatic ketones. This method enables the selective exchange of aromatic rings with heteroaromatic rings across a broad substrate range. Notably, it overcomes the substrate restrictions of current techniques, allowing high-yield conversions of bioactive aromatic ketones into their heteroaromatic analogs. This strategy expands the molecular editing toolkit, providing a practical and versatile approach for synthesizing bioactive compounds with improved pharmacokinetic properties.