Mechanochemical Integration of Incompatible Reaction Environments for the One-Pot Synthesis of Structurally Diverse...

Area of Science:

• Synthetic Chemistry
• Green Chemistry
• Mechanochemistry

Background:

• Integrating base- and acid-mediated reactions is challenging in conventional solution-phase synthesis.
• Developing efficient and sustainable synthetic routes for N-heterocyclic compounds is crucial.

Purpose of the Study:

• To develop a one-pot liquid-assisted mechanochemical strategy merging incompatible base- and acid-mediated reactions.
• To provide an efficient and scalable synthesis for valuable N-heterocyclic scaffolds, including precursors for pharmaceuticals.

Main Methods:

• Utilized liquid-assisted grinding (LAG) for mechanochemical synthesis.
• Employed copper-catalyzed Ullmann-Goldberg C-N coupling followed by an acid-mediated Fries-type rearrangement.
• Performed reactions under solvent-reduced or solvent-free conditions.

Main Results:

• Achieved one-pot merging of base- and acid-mediated processes.
• Synthesized N-aryl β-lactams in up to 98% yield.
• Produced 2,3-dihydroquinolin-4-ones in moderate to excellent yields with broad functional group tolerance.
• Demonstrated gram-scale synthesis of a chloroquine precursor.

Conclusions:

• The liquid-assisted mechanochemical strategy offers an efficient and sustainable alternative to conventional methods.
• This approach enables the synthesis of complex N-heterocycles and facilitates late-stage functionalization.
• The method is scalable and has practical utility, as shown by the synthesis of a chloroquine intermediate.