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Iridium nitrenoid-enabled arene C−H functionalization

Nature Catalysis volume 7, pages 934–943 (2024)Cite this article

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Abstract

Direct arene C−H functionalization via nucleophilic aromatic substitution remains a challenging task. Here we report an iridium nitrenoid-catalysed arene C−H functionalization strategy, making use of readily available aryl azides as electrophiles to react with different nucleophilic reaction partners. The practicality of this methodology is demonstrated by enantioselective synthesis of chiral 2-amino-2′-hydroxy-1,1′-binaphthyl, a class of building blocks, ligands and catalysts in asymmetric transformation, using β-naphthols and β-naphthyl azides as starting materials under the catalysis of a tailored oxazoline-chelated iridium complex. Mechanistic studies and density functional theory calculations show that the reaction proceeds through an iridium nitrenoid-mediated C−H functionalization pathway. The reported arene C−H functionalization strategy serves as a blueprint to expand the applicability of nucleophilic aromatic substitution reactions and is particularly valuable for the synthesis of aniline-containing molecules.

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Fig. 1: Introduction to arene C–H functionalization and metal nitrenoid in activation.
Fig. 2: Iridium nitrenoid-mediated C–H functionalization of aryl azides with different nucleophiles.
Fig. 3: Asymmetric synthesis of NOBINs via an iridium nitrenoid-mediated C–H functionalization of β-naphthyl azides with β-naphthols.
Fig. 4: Generality of the reaction.
Fig. 5: Mechanistic studies.

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Data availability

The X-ray crystallographic coordinates for structures of 3a-a and Ir16 reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition numbers 2299324 (3a-a) and 2237480 (Ir16). These data can be obtained free of charge from http://www.ccdc.cam.ac.uk/data_request/cif. Reaction optimization, experimental procedures, characterization of new compounds and mechanistic studies are available in the Supplementary Information or from the corresponding authors upon reasonable request.

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Acknowledgements

We gratefully acknowledge generous support by the Alexander von Humboldt Foundation (Feodor Lynen fellowship, T.R.) and the National Science Foundation (CHE-1764328, K.N.H.). Y.L. thanks the Singapore National Research Foundation (NRF), Prime Minister’s Office for the NRF Investigatorship Award (A-0004067-00-00) and the National University of Singapore (A-8001466-00-00) and Ministry of Education (MOE) of Singapore (A-0008481-00-00) for generous financial support.

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Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Liang-Wen Qi & Yixin Lu

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Torben Rogge & K. N. Houk

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Contributions

L.-W.Q. carried out the experiments and wrote the first draft of the paper. T.R. performed the DFT calculation. L.-W.Q., K.N.H. and Y.L. conceived the project. The paper was written through contributions from all authors. Y.L. supervised the project.

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Correspondence to K. N. Houk or Yixin Lu.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–12 and Tables 1–9.

Supplementary Data 1

Crystallographic data of 3aa.

Supplementary Data 2

Crystallographic data of Ir16.

Supplementary Data 3

Cartesian coordinates.

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Qi, LW., Rogge, T., Houk, K.N. et al. Iridium nitrenoid-enabled arene C−H functionalization. Nat Catal 7, 934–943 (2024). https://doi.org/10.1038/s41929-024-01207-3

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