Differentiation and functionalization of remote C–H bonds in adjacent positions


Site-selective functionalization of C–H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C–H bonds that are distal from a functional group. In this context, distinguishing remote C–H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C–H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Remote site-selective C–H functionalization.
Fig. 2: Density functional theory optimized transition state structures.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Metrical parameters for the structure of 2ah (see Supplementary Information) are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference number CCDC 1890836.


  1. 1.

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

    CAS  Article  Google Scholar 

  2. 2.

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

    CAS  Article  Google Scholar 

  3. 3.

    Abrams, D. J., Provencher, P. A. & Sorensen, E. J. Recent applications of C–H functionalization in complex natural product synthesis. Chem. Soc. Rev. 47, 8925–8967 (2018).

    CAS  Article  Google Scholar 

  4. 4.

    Li, J., Sarkar, S. D. & Ackermann, L. meta- and para-selective C–H functionalization by C–H activation. Top. Organomet. Chem. 55, 217–257 (2016).

    CAS  Article  Google Scholar 

  5. 5.

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

    CAS  Article  Google Scholar 

  6. 6.

    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).

    CAS  Article  Google Scholar 

  7. 7.

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

    CAS  Article  Google Scholar 

  8. 8.

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

    CAS  Article  Google Scholar 

  9. 9.

    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).

    CAS  Article  Google Scholar 

  10. 10.

    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).

    CAS  Article  Google Scholar 

  11. 11.

    Bag, S. et al. Remote para-C–H functionalization of arenes by a D-shaped biphenyl template-based assembly. J. Am. Chem. Soc. 137, 11888–11891 (2015).

    CAS  Article  Google Scholar 

  12. 12.

    Okumura, S. et al. Para-selective alkylation of benzamides and aromatic ketones by cooperative nickel/aluminum catalysis. J. Am. Chem. Soc. 138, 14699–14704 (2016).

    CAS  Article  Google Scholar 

  13. 13.

    Stephens, D. E. & Larionov, O. V. Recent advances in the C–H-functionalization of the distal positions in pyridines and quinolines. Tetrahedron 71, 8683–8716 (2015).

    CAS  Article  Google Scholar 

  14. 14.

    Berman, A. M., Lewis, J. C., Bergman, R. G. & Ellman, J. A. Rh(i)-catalyzed direct arylation of pyridines and quinolines. J. Am. Chem. Soc. 130, 14926–14927 (2008).

    CAS  Article  Google Scholar 

  15. 15.

    Takagi, J., Sato, K., Hartwig, J. F., Ishiyama, T. & Miyaura, N. Iridium-catalyzed C–H coupling reaction of heteroaromatic compounds with bis(pinacolato)diboron: regioselective synthesis of heteroarylboronates. Tetrahedron Lett. 43, 5649–5651 (2002).

    CAS  Article  Google Scholar 

  16. 16.

    Ye, M., Gao, G.-L. & Yu, J.-Q. Ligand-promoted C-3 selective C–H olefination of pyridines with Pd catalysts. J. Am. Chem. Soc. 133, 6964–6967 (2011).

    CAS  Article  Google Scholar 

  17. 17.

    Nakao, Y., Yamada, Y., Kashihara, N. & Hiyama, T. Selective C-4 alkylation of pyridine by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 132, 13666–13668 (2010).

    CAS  Article  Google Scholar 

  18. 18.

    Tsai, C.-C. et al. Bimetallic nickel aluminun mediated para-selective alkenylation of pyridine: direct observation of η 2,η 1-pyridine Ni(0)-Al(iii) intermediates prior to C–H bond activation. J. Am. Chem. Soc. 132, 11887–11889 (2010).

    CAS  Article  Google Scholar 

  19. 19.

    Yamamoto, S., Saga, Y., Andou, T., Matsunaga, S. & Kanai, M. Cobalt-catalyzed C-4 selective alkylation of quinolines. Adv. Synth. Catal. 356, 401–405 (2014).

    CAS  Article  Google Scholar 

  20. 20.

    Kwak, J., Kim, M. & Chang, S. Rh(NHC)-catalyzed direct and selective arylation of quinolines at the 8-position. J. Am. Chem. Soc. 133, 3780–3783 (2011).

    CAS  Article  Google Scholar 

  21. 21.

    Konishi, S. et al. Site-selective C−H borylation of quinolines at the C8 position catalyzed by a silica-supported phosphane-iridium system. Chem. Asian J. 9, 434–438 (2014).

    CAS  Article  Google Scholar 

  22. 22.

    Zhang, Z., Tanaka, K. & Yu, J.-Q. Remote site-selective C–H activation directed by a catalytic bifunctional template. Nature 543, 538–542 (2017).

    CAS  Article  Google Scholar 

  23. 23.

    Wang, X.-C. et al. Ligand-enabled meta-C–H activation using a transient mediator. Nature 519, 334–338 (2015).

    CAS  Article  Google Scholar 

  24. 24.

    Dong, Z., Wang, J. & Dong, G. Simple amine-directed meta-selective C–H arylation via Pd/norbornene catalysis. J. Am. Chem. Soc. 137, 5887–5890 (2015).

    CAS  Article  Google Scholar 

  25. 25.

    Shen, P.-X., Wang, X.-C., Wang, P., Zhu, R.-Y. & Yu, J.-Q. Ligand-enabled meta-C–H alkylation and arylation using a modified norbornene. J. Am. Chem. Soc. 137, 11574–11577 (2015).

    CAS  Article  Google Scholar 

  26. 26.

    Ye, J. & Lautens, M. Palladium-catalysed norbornene-mediated C−H functionalization of arenes. Nat. Chem. 7, 863–870 (2015).

    CAS  Article  Google Scholar 

  27. 27.

    Della, Ca’N., Fontana, M., Motti, E. & Catellani, M. Pd/norbornene: a winning combination for selective aromatic functionalization via C–H bond activation. Acc. Chem. Res. 49, 1389–1400 (2016).

    Article  Google Scholar 

  28. 28.

    Shi, H., Herron, A. N., Shao, Y., Shao, Q. & Yu, J.-Q. Enantioselective remote meta-C–H arylation and alkylation via a chiral transient mediator. Nature 558, 581–586 (2018).

    CAS  Article  Google Scholar 

  29. 29.

    Wang, P. et al. Ligand-accelerated non-directed C–H functionalization of arenes. Nature 551, 489–493 (2017).

    CAS  Article  Google Scholar 

  30. 30.

    Bracher, F. & Tremmel, T. From lead to drug utilizing a Mannich reaction: the topotecan story. Arch. Pharm. Chem. Life Sci. 350, e1600236 (2017).

    Article  Google Scholar 

Download references


We acknowledge Scripps Research, the NIH (National Institute of General Medical Sciences grant no. R01GM102265), the National Science Foundation (NSF, CHE-1764328 to K.N.H.) and the CCI Center for Selective C–H Functionalization (CHE-1700982 to K.N.H) for financial support. Computational studies were also supported by the NSF (OCI-1053575 to K.N.H.). Y.L. and J.W. thank the China Scholarship Council for support.

Author information




J.-Q.Y. and H.S. conceived the concept. H.S. developed the remote site-selective arylation of benzoazines. H.S. and Y.L. developed the remote site-selective arylation of arenes. H.S., Y.L., J.W. and K.T. prepared templates and reaction substrates. P.V., K.L.B., X.C. and K.N.H. performed the density functional theory calculations. J.-Q.Y. directed the project.

Corresponding authors

Correspondence to Kendall N. Houk or Jin-Quan Yu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information

Supplementary experimental details, compound characterization data, Supplementary tables, Supplementary figure, computational study.

Crystallographic data

Crystallographic data for compound 2ah. CCDC reference 1890836.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shi, H., Lu, Y., Weng, J. et al. Differentiation and functionalization of remote C–H bonds in adjacent positions. Nat. Chem. 12, 399–404 (2020). https://doi.org/10.1038/s41557-020-0424-5

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing