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Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis

Nature Chemistryvolume 10pages866872 (2018) | Download Citation

Abstract

Achieving site-selectivity in arene functionalization that is complementary to the site-selectivity from electrophilic aromatic substitution reactions has been a long-standing quest in organic synthesis. Palladium/norbornene cooperative catalysis potentially offers a unique approach to this problem, but its use has been hampered by the ortho constraint, which is the requirement of an ortho substituent for mono ortho functionalization of haloarenes. Here, we show that such a challenge could be addressed using a new class of bridgehead-modified norbornenes, thereby enabling a broadly useful strategy for arene functionalization with complementary site-selectivity. A range of ortho-unsubstituted aryl iodides, previously problematic substrates, can now be employed to provide mono ortho-functionalized products effectively. This method is applicable for late-stage functionalization of complex bioactive molecules at positions that are difficult to reach by conventional approaches.

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Acknowledgements

The authors thank the University of Chicago for research support. G. Lu is thanked for discussions of the DFT results, and K.-y. Yoon is thanked for checking the experiments and X-ray crystallography.

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Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    • Jianchun Wang
    • , Renhe Li
    • , Zhe Dong
    •  & Guangbin Dong
  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    • Peng Liu

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Contributions

J.W. and G.D. conceived and designed the experiments. J.W. performed experiments. R.L. and Z.D. helped perform the experiments during the revision. J.W. and P.L. performed calculations. J.W. and G.D. co-wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Guangbin Dong.

Supplementary information

  1. Supplementary information

    Supplementary experimental details, supplementary data and supplementary figures

  2. Crystallographic data

    CIF for compound 4k; CCDC reference: 1566682

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https://doi.org/10.1038/s41557-018-0074-z