Robust and General Late-Stage Methylation of Aryl Chlorides: Application to Isotopic Labeling of Drug-like Scaffolds

The preparation of isotopically labeled compounds for drug discovery and development presents a unique challenge. Both stable and radioactive isotopes must be incorporated into complex bioactive molecules as efficiently as possible, using precious, and often expensive, isotopically enriched reagents. Due to the ubiquity and importance of methyl groups in drug molecules, there is a requirement for a general, late-stage methylation that allows for the incorporation of both carbon and hydrogen isotopes. Herein, we report a highly efficient, robust palladium-catalyzed approach, optimized via high-throughput experimentation, for the methylation of aryl chlorides using potassium methyltrifluoroborate. A practically straightforward route to isotopically labeled methylating agents has also been developed, and the methodology applied to isotopologue synthesis, including the installation of isotopic labels in a range of drug-like scaffolds.

Automated summary

The preparation of isotopically labeled compounds for drug discovery and development is challenging due to the need to incorporate both stable and radioactive isotopes efficiently into complex bioactive molecules. A highly efficient, robust palladium-catalyzed approach for the methylation of aryl chlorides using potassium methyltrifluoroborate has been reported in this study, optimized via high-throughput experimentation. Additionally, a straightforward route to isotopically labeled methylating agents has been developed and applied to isotopologue synthesis in a range of drug-like scaffolds.