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

Ferdinand H. Lutter, Lucie Grokenberger, Luca Alessandro Perego, Diego Broggini, Sébastien Lemaire, Simon Wagschal () and Paul Knochel ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18188-z

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