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

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          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-1 H-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.

          Abstract

          Aryl azoles are common scaffolds in pharmaceutically relevant molecules. Here, the authors report the mild and highly regioselective ortho magnesiation of aryl azoles using a tailored magnesium amide base in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation.

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          Most cited references 42

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          Aryl-aryl bond formation by transition-metal-catalyzed direct arylation.

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            Ruthenium(II)-catalyzed C-H bond activation and functionalization.

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              Formal SN-Type Reactions in Rhodium(III)-Catalyzed CH Bond Activation

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                Author and article information

                Contributors
                swagscha@its.jnj.com
                paul.knochel@cup.uni-muenchen.de
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                7 September 2020
                7 September 2020
                2020
                : 11
                Affiliations
                [1 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Ludwig-Maximilians-Universität München, , Department Chemie, ; Butenandtstrasse 5-13, Haus F, 81377 München, Germany
                [2 ]Discovery Product Development and Supply, Janssen Pharmaceutica, Hochstrasse 201, 8200 Schaffhausen, Switzerland
                [3 ]GRID grid.419619.2, ISNI 0000 0004 0623 0341, Discovery Product Development and Supply, , Janssen Pharmaceutica, ; Turnhoutseweg 30, B-2340 Beerse, Belgium
                Article
                18188
                10.1038/s41467-020-18188-z
                7477575
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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