Acid/Base-Catalyzed Functional Group Metathesis Approach to Methoxy Group Isotopic Exchange of Aryl Methyl Ethers

We report a practical method for the direct isotopic exchange of methoxy groups in aryl methyl ethers using labeled methanol as an isotope source. A base-catalyzed system (t-BuOK/18-crown-6) is effective for electron-deficient substrates, whereas an acid-catalyzed system (MeOTf) is optimal for electron-rich substrates. Both protocols afforded deuterated products in high yields with excellent deuterium incorporation. The utility is demonstrated by labeling drug molecules and serving as an internal standard for HPLC–MS/MS analysis.