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Remote site-selective C–H activation directed by a catalytic bifunctional template

Nature volume 543, pages 538–542 (2017)Cite this article

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Abstract

In chemical syntheses, the activation of carbon–hydrogen (C–H) bonds converts them directly into carbon–carbon or carbon–heteroatom bonds without requiring any prior functionalization. C–H activation can thus substantially reduce the number of steps involved in a synthesis. A single specific C–H bond in a substrate can be activated by using a ‘directing’ (usually a functional) group to obtain the desired product selectively1,2,3,4,5. The applicability of such a C–H activation reaction can be severely curtailed by the distance of the C–H bond in question from the directing group, and by the shape of the substrate, but several approaches have been developed to overcome these limitations6,7,8,9,10,11,12. In one such approach, an understanding of the distal and geometric relationships between the functional groups and C–H bonds of a substrate has been exploited to achieve meta-selective C–H activation by using a covalently attached, U-shaped template13,14,15,16,17. However, stoichiometric installation of this template has not been feasible in the absence of an appropriate functional group on which to attach it. Here we report the design of a catalytic, bifunctional nitrile template that binds a heterocyclic substrate via a reversible coordination instead of a covalent linkage. The two metal centres coordinated to this template have different roles: one reversibly anchors substrates near the catalyst, and the other cleaves remote C–H bonds. Using this strategy, we demonstrate remote, site-selective C–H olefination of heterocyclic substrates that do not have the necessary functional groups for covalently attaching templates.

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Figure 1: Design of a cooperative bimetallic approach for remote, site-selective C–H activation.
Figure 2: Discovery of a template that enables site-selective, remote C–H activation.
Figure 3: Results of remote, site-selective C–H olefination of heterocycle-containing substrates using a catalytic template.
Figure 4: Extending the reaction principle to the site-selective C–H olefination of quinolines and other heterocycles.

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References

  1. Snieckus, V. Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics. Chem. Revc. 90, 879–933 (1990)

    Article  CAS  Google Scholar 

  2. Flemming, J. P., Berry, M. B. & Brown, J. M. Sequential ortho-lithiations; the sulfoxide group as a relay to enable meta-substitution. Org. Biomol. Chem. 6, 1215–1221 (2008)

    Article  CAS  Google Scholar 

  3. Daugulis, O., Do, H.-Q. & Shabashov, D. Palladium- and copper-catalyzed arylation of carbon-hydrogen bonds. Acc. Chem. Res. 42, 1074–1086 (2009)

    Article  CAS  Google Scholar 

  4. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C-H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010)

    Article  CAS  Google Scholar 

  5. Colby, D. A., Bergman, R. G. & Ellman, J. A. Rhodium-catalyzed C-C bond formation via heteroatom-directed C-H bond activation. Chem. Rev. 110, 624–655 (2010)

    Article  CAS  Google Scholar 

  6. Breslow, R. Biomimetic control of chemical selectivity. Acc. Chem. Res. 13, 170–177 (1980)

    Article  CAS  Google Scholar 

  7. Das, S., Incarvito, C. D., Crabtree, R. H. & Brudvig, G. W. Molecular recognition in the selective oxygenation of saturated C-H bonds by a dimanganese catalyst. Science 312, 1941–1943 (2006)

    Article  CAS  ADS  Google Scholar 

  8. Martínez-Martínez, A. J., Kennedy, A. R., Mulvey, R. E. & O’Hara, C. T. Directed ortho-meta′- and meta-meta′-dimetalations: a template base approach to deprotonation. Science 346, 834–837 (2014)

    Article  ADS  Google Scholar 

  9. Phipps, R. J. & Gaunt, M. J. A meta-selective copper-catalyzed C-H bond arylation. Science 323, 1593–1597 (2009)

    Article  CAS  ADS  Google Scholar 

  10. Saidi, O. et al. Ruthenium-catalyzed meta sulfonation of 2-phenylpyridines. J. Am. Chem. Soc. 133, 19298–19301 (2011)

    Article  CAS  Google Scholar 

  11. Hofmann, N. & Ackermann, L. Meta-selective C-H bond alkylation with secondary alkyl halides. J. Am. Chem. Soc. 135, 5877–5884 (2013)

    Article  CAS  Google Scholar 

  12. Li, J. et al. N-acyl amino acid ligands for ruthenium(II)-catalyzed meta-C–H tert-alkylation with removable auxiliaries. J. Am. Chem. Soc. 137, 13894–13901 (2015)

    Article  CAS  Google Scholar 

  13. Leow, D., Li, G., Mei, T.-S. & Yu, J.-Q. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012)

    Article  CAS  ADS  Google Scholar 

  14. Lee, S., Lee, H. & Tan, K. L. Meta-selective C-H functionalization using a nitrile-based directing group and cleavable Si-tether. J. Am. Chem. Soc. 135, 18778–18781 (2013)

    Article  CAS  Google Scholar 

  15. Tang, R.-Y., Li, G. & Yu, J.-Q. Conformation-induced remote meta-C–H activation of amines. Nature 507, 215–220 (2014)

    Article  CAS  ADS  Google Scholar 

  16. Bera, M., Maji, A., Sahoo, S. K. & Maiti, D. Palladium(II)-catalyzed meta-C–H olefination: constructing multisubstituted arenes through homo-diolefination and sequential hetero-diolefination. Angew. Chem. Int. Ed. 54, 8515–8519 (2015)

    Article  CAS  Google Scholar 

  17. Chu, L. et al. Remote meta-C–H activation using a pyridine-based template: achieving site-selectivity via the recognition of distance and geometry. ACS Cent. Sci. 1, 394–399 (2015)

    Article  CAS  Google Scholar 

  18. Kuninobu, Y., Ida, H., Nishi, M. & Kanai, M. A meta-selective C-H borylation directed by a secondary interaction between ligand and substrate. Nat. Chem. 7, 712–717 (2015)

    Article  CAS  Google Scholar 

  19. Shibasaki, M. & Yoshikawa, N. Lanthanide complexes in multifunctional asymmetric catalysis. Chem. Rev. 102, 2187–2210 (2002)

    Article  CAS  Google Scholar 

  20. Van den Beuken, E. K. & Feringa, B. L. Bimetallic catalysis by late transition metal complexes. Tetrahedron 54, 12985–13011 (1998)

    Article  CAS  Google Scholar 

  21. Konsler, R. G., Karl, J. & Jacobsen, E. N. Cooperative asymmetric catalysis with dimeric Salen complexes. J. Am. Chem. Soc. 120, 10780–10781 (1998)

    Article  CAS  Google Scholar 

  22. Park, J. & Hong, S. Cooperative bimetallic catalysis in asymmetric transformations. Chem. Soc. Rev. 41, 6931–6943 (2012)

    Article  CAS  Google Scholar 

  23. Alvarado, R. J. et al. Structural insights into the coordination and extraction of Pb(ii) by disulfonamide ligands derived from o-phenylenediamine. Inorg. Chem. 44, 7951–7959 (2005)

    Article  CAS  Google Scholar 

  24. Cheng, P.-H., Cheng, H.-Y., Lin, C.-C. & Peng, S.-M. Oxidations of N,N′-disubstituted o-phenylenediamine in the presence of metal ions and the crystal structure of N,N′-dimethylbenzimidazolium perchlorate, pyridine-bis(o-benzosemiquinonediimine)cobalt(iii) chloride and bis(pyridine)(N,N′-bistoluene-p-sulfonyl-o-phenylenediiminato)-copper(ii). Inorg. Chim. Acta 169, 19–21 (1990)

    Article  CAS  Google Scholar 

  25. Nakao, Y., Kanyiva, K. S. & Hiyama, T. A strategy for C-H activation of pyridines: direct C-2 selective alkenylation of pyridines by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 130, 2448–2449 (2008)

    Article  CAS  Google Scholar 

  26. Tsai, C.-C. et al. Bimetallic nickel aluminum mediated para-selective alkenylation of pyridine: direct observation of η2,η1-pyridine Ni(0)-Al(III) intermediates prior to C-H bond activation. J. Am. Chem. Soc. 132, 11887–11889 (2010)

    Article  CAS  Google Scholar 

  27. Yang, Y.-F. et al. Palladium-catalyzed meta-selective C-H bond activation with a nitrile-containing template: computational study on mechanism and origins of selectivity. J. Am. Chem. Soc. 136, 344–355 (2014)

    Article  CAS  Google Scholar 

  28. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014)

    Article  CAS  Google Scholar 

  29. Taylor, R. D., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014)

    Article  CAS  Google Scholar 

  30. Stork, G. & Schultz, A. G. The total synthesis of dl-camptothecin. J. Am. Chem. Soc. 93, 4074–4075 (1971)

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge The Scripps Research Institute and the United States National Institutes of Health (the National Institute of General Medical Sciences, grant no. 1R01 GM102265) for financial support. We thank the Ito Foundation for International Education Exchange (predoctoral fellowship to K.T.).

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Author notes

  1. Zhipeng Zhang and Keita Tanaka: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Zhipeng Zhang, Keita Tanaka & Jin-Quan Yu

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  1. Zhipeng Zhang
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  2. Keita Tanaka
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Contributions

Z.Z. developed the catalytic bidentate template for 3-phenylpyridine and other heterocycles. K.T. developed the non-covalent tridentate template for quinoline and other heterocycles. J.-Q.Y. conceived the concept and prepared the manuscript with feedback from Z.Z. and K.T.

Corresponding author

Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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This file contains Supplementary Text and Data, Supplementary Tables 1-32 and Supplementary References. (PDF 39269 kb)

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Zhang, Z., Tanaka, K. & Yu, JQ. Remote site-selective C–H activation directed by a catalytic bifunctional template. Nature 543, 538–542 (2017). https://doi.org/10.1038/nature21418

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