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Tritiation of aryl thianthrenium salts with a molecular palladium catalyst

Author

Listed:
  • Da Zhao

    (Max-Planck-Institut für Kohlenforschung)

  • Roland Petzold

    (Max-Planck-Institut für Kohlenforschung)

  • Jiyao Yan

    (Max-Planck-Institut für Kohlenforschung
    RWTH Aachen University)

  • Dieter Muri

    (Roche Innovation Center Basel)

  • Tobias Ritter

    (Max-Planck-Institut für Kohlenforschung)

Abstract

Tritium labelling is a critical tool for investigating the pharmacokinetic and pharmacodynamic properties of drugs, autoradiography, receptor binding and receptor occupancy studies1. Tritium gas is the preferred source of tritium for the preparation of labelled molecules because it is available in high isotopic purity2. The introduction of tritium labels from tritium gas is commonly achieved by heterogeneous transition-metal-catalysed tritiation of aryl (pseudo)halides. However, heterogeneous catalysts such as palladium supported on carbon operate through a reaction mechanism that also results in the reduction of other functional groups that are prominently featured in pharmaceuticals3. Homogeneous palladium catalysts can react chemoselectively with aryl (pseudo)halides but have not been used for hydrogenolysis reactions because, after required oxidative addition, they cannot split dihydrogen4. Here we report a homogenous hydrogenolysis reaction with a well defined, molecular palladium catalyst. We show how the thianthrene leaving group—which can be introduced selectively into pharmaceuticals by late-stage C–H functionalization5—differs in its coordinating ability to relevant palladium(II) catalysts from conventional leaving groups to enable the previously unrealized catalysis with dihydrogen. This distinct reactivity combined with the chemoselectivity of a well defined molecular palladium catalyst enables the tritiation of small-molecule pharmaceuticals that contain functionality that may otherwise not be tolerated by heterogeneous catalysts. The tritiation reaction does not require an inert atmosphere or dry conditions and is therefore practical and robust to execute, and could have an immediate impact in the discovery and development of pharmaceuticals.

Suggested Citation

  • Da Zhao & Roland Petzold & Jiyao Yan & Dieter Muri & Tobias Ritter, 2021. "Tritiation of aryl thianthrenium salts with a molecular palladium catalyst," Nature, Nature, vol. 600(7889), pages 444-449, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7889:d:10.1038_s41586-021-04007-y
    DOI: 10.1038/s41586-021-04007-y
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    Citations

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    Cited by:

    1. Kai Sun & Chang Ge & Xiaolan Chen & Bin Yu & Lingbo Qu & Bing Yu, 2024. "Energy-transfer-enabled photocatalytic transformations of aryl thianthrenium salts," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    2. Rui Li & Yongmeng Wu & Changhong Wang & Meng He & Cuibo Liu & Bin Zhang, 2022. "One-pot H/D exchange and low-coordinated iron electrocatalyzed deuteration of nitriles in D2O to α,β-deuterio aryl ethylamines," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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