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Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets

Author

Listed:
  • Ferdinand H. Lutter

    (Department Chemie)

  • Lucie Grokenberger

    (Department Chemie)

  • Luca Alessandro Perego

    (Janssen Pharmaceutica)

  • Diego Broggini

    (Janssen Pharmaceutica)

  • Sébastien Lemaire

    (Janssen Pharmaceutica)

  • Simon Wagschal

    (Janssen Pharmaceutica)

  • Paul Knochel

    (Department Chemie)

Abstract

Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

Suggested Citation

  • Ferdinand H. Lutter & Lucie Grokenberger & Luca Alessandro Perego & Diego Broggini & Sébastien Lemaire & Simon Wagschal & Paul Knochel, 2020. "Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18188-z
    DOI: 10.1038/s41467-020-18188-z
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    Cited by:

    1. Yu Chang & Chuandong Xie & Hong Liu & Shengli Huang & Pengfei Wang & Wenling Qin & Hailong Yan, 2022. "Organocatalytic atroposelective construction of axially chiral N, N- and N, S-1,2-azoles through novel ring formation approach," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

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