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Ortho-C–H methoxylation of aryl halides enabled by a polarity-reversed N–O reagent


Oxygen-substituted arenes widely exist in biologically important molecules and can serve as versatile handles to install other functional groups. However, direct and site-selective installation of oxygen groups to common aromatic compounds remains challenging, especially when additional arene functionalization is simultaneously required. Current arene C−H oxidation strategies generally require directing groups or precisely prefunctionalized substrates to control site-selectivity. While palladium/norbornene cooperative catalysis is promising for site-specific arene vicinal difunctionalization through simultaneous reactions with an electrophile and a nucleophile, the electrophile scope has been limited to species based on relatively ‘soft’ elements, such as carbon, nitrogen and sulfur. Here we report the development of an ortho oxygenation reaction with common aryl halides to rapidly deliver diverse aryl ethers. The coupling of the ‘hard’ oxygen electrophile is enabled by a stable, polarity-reversed, conformationally predistorted N−O reagent and facilitated by a C7-bromo-substituted norbornene mediator. Mechanistic studies reveal a unique SN2-type pathway between the N−O reagent as the oxygen electrophile and an electron-rich Pd(II) nucleophile.

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Fig. 1: Alkyl aryl ethers and their preparations.
Fig. 2: Computational study of the Pd/NBE-catalysed ortho-C–H oxygenation reaction.
Fig. 3: Synthetic applications.
Fig. 4: Rapid access to challenging substitution patterns of benzenoids via a relay C–H functionalization strategy.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 2209874 (4m) and 2209875 (2a). Copies of the data can be obtained free of charge via


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We acknowledge the financial support from the University of Chicago, the National Institute of General Medical Sciences (R01GM124414, G.D.) and the National Science Foundation (CHE-2247505, P.L.). We thank J. Huo (University of Chicago) for checking the experimental procedure. We thank Z. Wu and Y. Xue (University of Chicago) for helpful discussions. We acknowledge Z. Zhang and S. Ochi (University of Chicago) for the X-ray crystallography. Density functional theory calculations were performed at the Center for Research Computing of the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation grant number ACI-1548562 (P.L.).

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Authors and Affiliations



X.L. and G.D. conceived and designed the experiments. X.L. and Z.C. performed the experiments. Y.F. and P.L. designed and conducted the density functional theory calculations. X.L., Y.F., P.L. and G.D. wrote the manuscript. P.L. and G.D. directed the research.

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Correspondence to Peng Liu or Guangbin Dong.

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Nature Chemistry thanks Wei Guan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–11, Tables 1–3, experimental procedures and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 2a; CCDC reference no. 2209875.

Supplementary Data 2

Crystallographic data for compound 4m; CCDC reference no. 2209874.

Supplementary Data 3

Computational data including xyz coordinates.

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Liu, X., Fu, Y., Chen, Z. et al. Ortho-C–H methoxylation of aryl halides enabled by a polarity-reversed N–O reagent. Nat. Chem. 15, 1391–1399 (2023).

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