Mechanochemical Integration of Incompatible Reaction Environments for the One‐Pot Synthesis of Structurally Diverse N ‐Heterocycles

The integration of sequential transformations requiring mutually incompatible conditions remains a fundamental challenge in synthetic chemistry. Here, we report a liquid‐assisted mechanochemical strategy that enables the one‐pot merging of base‐ and acid‐mediated processes within a single vessel, overcoming challenges associated with their integration under conventional solution‐phase conditions. This approach provides access to valuable N ‐heterocyclic scaffolds while reducing solvent use and improving overall process efficiency. The sequence is initiated by the mechanochemical copper‐catalyzed Ullmann–Goldberg CN coupling of unprotected β‐lactams with aryl iodides, which can be paused to afford N ‐aryl β‐lactams in up to 98% yield. A strategically implemented liquid‐assisted grinding (LAG) step enables seamless integration of the CN coupling step with an acid‐mediated Fries‐type rearrangement of amides, providing access to 2,3‐dihydroquinolin‐4‐ones in moderate to excellent yields under mechanochemical conditions. The protocol exhibits broad functional group tolerance, accommodates structurally complex substrates, and enables late‐stage functionalization. Gram‐scale mechanochemical synthesis of a key 2,3‐dihydroquinolin‐4‐one intermediate, followed by its direct conversion to the WHO‐listed antimalarial drug chloroquine under solvent‐free milling conditions, highlights the scalability and practical utility of this approach.