<p>The modification of aromatic rings to heteroaromatic rings is a widely employed strategy in medicinal chemistry, often used to modulate lipophilicity and improve metabolic stability. However, achieving a one-step, generalizable transformation of aromatic rings into diverse heteroaromatic rings—termed “heteroaromatic swapping”—remains a persistent challenge. Existing methods, such as skeletal editing and transition-metal-catalyzed aromatic ring exchange, are limited in substrate scope and efficiency. Here, we present an efficient strategy for heteroaromatic swapping via a Claisen/retro-Claisen mechanism, utilizing heteroaryl esters and aromatic ketones. This approach enables the selective exchange of aromatic rings with heteroaromatic rings across a broad substrate range, overcoming the limitations of existing techniques. Notably, it achieves high-yield conversions of bioactive aromatic ketones into their heteroaromatic counterparts. This method expands the molecular editing toolkit, offering a practical and versatile platform for synthesizing bioactive compounds with enhanced physicochemical properties.</p>