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Unlocking azole chemical space via modular and regioselective N-alkylation

Nature Chemistry volume 17, pages 1576–1585 (2025)Cite this article

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Abstract

Azoles are important synthetic targets due to their diverse applications in areas ranging from human health to food security. Accordingly, access to N-functionalized azoles is an essential goal in modern synthetic chemistry. Surprisingly, however, the relied-upon azole N-alkylation strategies fundamentally limit the structural diversity of these important compounds that can be synthesized and studied. Here we introduce an approach to prepare a broad array of important but difficult-to-access N-alkyl azole compounds. We accomplish this through the introduction of a base-catalysed hydroazolation of readily accessible alkenylthianthrenium electrophiles. This strategy circumvents the classical challenge of azole alkylation regiocontrol through an unusual reversible C–N-bond-forming step that exploits the thermodynamic differences between azole N-alkylation isomers. This reaction furnishes a class of versatile azolothianthrenium building blocks that provides a general platform to investigate diverse N-alkyl azole molecules. More broadly, the distinctive approach outlined through this project is poised to impact the design and development of diverse regioselective alkylation reactions.

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Fig. 1: Importance of azoles and synthetic approaches.
Fig. 2: Brønsted base catalysis enables N-regioselective hydroazolation of alkenylthianthrenium salts.
Fig. 3: One-pot synthesis of densely functionalized azoles.
Fig. 4: Synthetic opportunities enabled by reversible hydroazolation.

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Data availability

All data supporting the findings of this paper are available within the article and its Supplementary Information files. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2393749 (4), 2393750 (50), 2393751 (51) and 2393752 (3-N1). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

We thank A. Wendlandt and M. Levin for suggestions and paper proofreading. We thank the Weix, Stahl, Yoon and Schomaker groups for sharing their chemical inventory. B. J. Thompson is acknowledged for his assistance with power supply design and fabrication. T. Drier is acknowledged for electrochemical glassware fabrication. M. Horwitz is acknowledged for initiating the collaboration and suggestions at the beginning of the project. We also acknowledge support and suggestions from all Wickens group members throughout the investigation of this project. This work was financially supported by the Office of the Vice Chancellor for Research and Graduate Education at the University of Wisconsin–Madison with funding from the Wisconsin Alumni Research Foundation and from the NIH (R01 GM149674-01). This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under grant number DGE-1747503 (A.D.M., K.T.). We acknowledge the UW-Madison Department of Chemistry SynCat Center for supporting this work. The Waters UPC2-MS instrument was supported by NIH 1S10OD036302-01, and we thank the UW-Madison Department of Chemistry SynCat Center for assisting with its operation. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. Spectroscopic instrumentation was supported by a generous gift from Paul J. and M. M. Bender, the NSF (CHE-1048642, CHE-1919350) and the NIH (1S10OD020022-1, S10 OD012245).

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Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA

    Céline Dorval, Adrian D. Matthews, Karina Targos, Sara N. Alektiar, Dylan E. Holst, Zhifeng Tan, Kyana M. Sanders, Ilia A. Guzei & Zachary K. Wickens

  2. Analytical Development Synthetics, Janssen Research & Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium

    Mikko Muuronen

  3. Global Discovery Chemistry, Janssen Research & Development LLC, Spring House, PA, USA

    Justin B. Diccianni

  4. Global Discovery Chemistry, Janssen Research & Development, Janssen-Cilag, SA, Toledo, Spain

    José Enrique Gómez

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  1. Céline Dorval
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Contributions

Z.K.W. and C.D. designed the project. D.E.H. conducted preliminary studies. C.D., A.D.M., K.T., S.N.A., D.E.H. and Z.T. performed the experiments and collected the data. M.M. conducted all computational studies. J.B.D. and J.E.G. assisted with high-throughput experimentation. K.M.S. and I.A.G. collected and analysed X-ray diffraction data. All authors analysed the data and contributed to writing the paper.

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Correspondence to Zachary K. Wickens.

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General methods and materials, supplementary data, computational studies, high-throughput experimentation set-up, characterization of N-regioselectivity, substrate preparation and characterization, general experimental procedures, and characterization data for all compounds synthesized in the preparation of this work.

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Dorval, C., Matthews, A.D., Targos, K. et al. Unlocking azole chemical space via modular and regioselective N-alkylation. Nat. Chem. 17, 1576–1585 (2025). https://doi.org/10.1038/s41557-025-01891-z

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