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

Nature Chemistry volume 10, pages 866–872 (2018)Cite this article

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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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Fig. 1: A quest for complementary site-selectivity in arene functionalization.
Fig. 2: Challenge and proposed strategy.
Fig. 3: An example of the ortho constraint.
Fig. 4: Use of para-substituted aryl iodides.
Fig. 5: Site-selectivity complementary to EAS reactions.

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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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Authors and 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.

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Correspondence to Guangbin Dong.

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CIF for compound 4k; CCDC reference: 1566682

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Wang, J., Li, R., Dong, Z. et al. Complementary site-selectivity in arene functionalization enabled by overcoming the ortho constraint in palladium/norbornene catalysis. Nature Chem 10, 866–872 (2018). https://doi.org/10.1038/s41557-018-0074-z

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