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Mechanochemical Integration of Incompatible Reaction Environments for the One-Pot Synthesis of Structurally Diverse N-Heterocycles
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DOI：10.1002/cssc.70938.png)
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Abstract
En 中文
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 CN 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 CN 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.
Keywords:
C<span class='icomoon'>?</span>N coupling
Fries rearrangement
liquid-assisted grinding
mechanochemistry
one-pot synthesis
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