Robust and general late-stage methylation of aryl chlorides : application to isotopic labeling of drug-like scaffolds

Davenport, Elliot and Negru, Daniela E. and Badman, Geoff and Lindsay, David M. and Kerr, William J. (2023) Robust and general late-stage methylation of aryl chlorides : application to isotopic labeling of drug-like scaffolds. ACS Catalysis, 13 (17). pp. 11541-11547. ISSN 2155-5435 (https://doi.org/10.1021/acscatal.3c02761)

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Abstract

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.

  • Item type:Article
    ID code:86642
    Dates:
    Date
    Event
    1 September 2023
    Published
    16 August 2023
    Published Online
    4 August 2023
    Accepted
    Subjects:Science > Chemistry
    Department:Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:31 Aug 2023 15:09
    Last modified:25 Apr 2024 01:35
    URI:https://strathprints.strath.ac.uk/id/eprint/86642
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