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Directed Aromatic Deuteration and Tritiation of Pharmaceuticals by Heavy Alkali Metal Amide Catalysts

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    Research Article

    Directed Aromatic Deuteration and Tritiation of Pharmaceuticals by Heavy Alkali Metal Amide Catalysts
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    ACS Catalysis

    Cite this: ACS Catal. 2024, 14, 13, 9640–9647
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    https://doi.org/10.1021/acscatal.4c01807
    Published June 12, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Deuterium- and tritium-labeled compounds play a significant role in the pharmaceutical development process. Ortho-directed hydrogen isotope exchange (HIE) with transition metal catalysts is one of the most well-developed methods for the labeling of various aromatic compounds, but met with limited success with aromatic ethers and fluorides. Herein, we present a practical method for the directed HIE of aromatic ethers and fluorides with D2/T2 gas catalyzed by heavy alkali metal amides. Using commercially available potassium amide KN(SiMe3)2 as an HIE catalyst, we successfully achieved tritiations of complex pharmaceutical compounds with high specific activities. This straightforward and practical method provides a valuable complement to transition metal-catalyzed HIE, enabling expanded substrate scope and broadening the HIE toolbox for efficient isotope labeling. Control experiments and density functional theory (DFT) calculations reveal an intriguing kinetic deprotonative equilibrium between aromatic C–H bonds and alkali amides and well explain the obviously different behaviors of the alkali amide catalysts MN(SiMe3)2 (M = Cs, K, and Na).

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acscatal.4c01807.

    • General information; condition optimization; additional substrates with other directing groups; experimental procedures; mechanistic studies; NMR spectra for all compounds, control experiments; and DFT calculation (PDF)

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    Cited By

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    This article is cited by 2 publications.

    1. Hui-Zhen Du, Bing-Tao Guan. Alkali Metal Amide-Catalyzed α-Deuteration of Sulfides. Organic Letters 2024, Article ASAP.
    2. Rajendra Maity, Otto Dungan, Frédéric A. Perras, Jingwei Li, Daohua Liu, Sumei Ren, Dan Lehnherr, Zheng Huang, Eric M. Phillips, Moses Adeyemo, Joseph Frimpong, Timothy Quainoo, Zhen-Fei Liu, Long Luo. Hydrogen Isotope Labeling of Pharmaceuticals Via Dual Hydrogen Isotope Exchange Pathways Using CdS Quantum Dot Photocatalyst. Journal of the American Chemical Society 2024, Article ASAP.
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    ACS Catalysis

    Cite this: ACS Catal. 2024, 14, 13, 9640–9647
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acscatal.4c01807
    Published June 12, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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