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Overcoming the limitations of directed C–H functionalizations of heterocycles


In directed C–H activation reactions, any nitrogen or sulphur atoms present in heterocyclic substrates will coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C–H functionalization at an undesired position, limits the application of C–H activation reactions in heterocycle-based drug discovery1,2,3,4,5, in which regard they have attracted much interest from pharmaceutical companies3,4,5. Here we report a robust and synthetically useful method that overcomes the complications associated with performing C–H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand that promotes the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is localized near the target C–H bond, avoiding interference from any nitrogen or sulphur atoms present in the heterocyclic substrates. This reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulphur and phosphorus. Thus, this operationally simple aerobic reaction demonstrates that it is possible to bypass a fundamental limitation that has long plagued applications of directed C–H activation in medicinal chemistry.

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Figure 1: Development of a catalytic system to overcome fundamental limitations of heterocyclic C–H bond functionalizations.
Figure 2: Discovery of an efficient aerobic C–H activation reaction.
Figure 3: Scope of the reaction.
Figure 4: Overriding the conventional positional selectivity dictated by heterocycles.


  1. Meanwell, N. A. Improving drug candidates by design: a focus on physicochemical properties as a means of improving compound disposition and safety. Chem. Res. Toxicol. 24, 1420–1456 (2011)

    Article  CAS  Google Scholar 

  2. Ritchie, T. J., Macdonald, S. J. F., Young, R. J. & Pickett, S. D. The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types. Drug Discov. Today 16, 164–171 (2011)

    Article  CAS  Google Scholar 

  3. Schönherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Edn Engl. 52, 12256–12267 (2013)

    Article  Google Scholar 

  4. Bryan, M. C. et al. Sustainable practices in medicinal chemistry: current state and future directions. J. Med. Chem. 56, 6007–6021 (2013)

    Article  CAS  Google Scholar 

  5. Davies, I. W. & Welch, C. J. Looking forward in pharmaceutical process chemistry. Science 325, 701–704 (2009)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Kakiuchi, F. et al. Catalytic addition of aromatic carbon–hydrogen bonds to olefins with the aid of ruthenium complexes. Bull. Chem. Soc. Jpn 68, 62–83 (1995)

    Article  CAS  Google Scholar 

  8. Jun, C.-H., Hong, J.-B. & Lee, D.-Y. Chelation-assisted hydroacylation. Synlett 1–12 (1999)

  9. 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 

  10. 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 

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

    Article  CAS  Google Scholar 

  12. Engle, K. M., Mei, T.-S., Wasa, M. & Yu, J.-Q. Weak coordination as a powerful means for developing broadly useful C–H functionalization reactions. Acc. Chem. Res. 45, 788–802 (2012)

    Article  CAS  Google Scholar 

  13. Yeung, C. S. & Dong, V. M. Catalytic dehydrogenative cross-coupling: forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds. Chem. Rev. 111, 1215–1292 (2011)

    Article  CAS  Google Scholar 

  14. 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  ADS  CAS  Google Scholar 

  15. Wasa, M., Worrell, B. T. & Yu, J.-Q. Pd(0)/PR3-catalyzed arylation of nicotinic acid and isonicotinic acid derivatives. Angew. Chem. Int. Edn Engl. 49, 1275–1277 (2010)

    Article  CAS  Google Scholar 

  16. Ackermann, L. & Lygin, A. V. Ruthenium-catalyzed direct C–H bond arylations of heteroarenes. Org. Lett. 13, 3332–3335 (2011)

    Article  CAS  Google Scholar 

  17. Cho, J.-Y., Iverson, C. N. & Smith, M. R., III Steric and chelate directing effects in aromatic borylation. J. Am. Chem. Soc. 122, 12868–12869 (2000)

    Article  CAS  Google Scholar 

  18. Malik, H. A. et al. Non-directed allylic C–H acetoxylation in the presence of Lewis basic heterocycles. Chem. Sci. 5, 2352–2361 (2014)

    Article  CAS  Google Scholar 

  19. 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. Tetrahedr. Lett. 43, 5649–5651 (2002)

    Article  CAS  Google Scholar 

  20. Hurst, T. E. et al. Iridium-catalyzed C–H activation versus directed ortho metalation: complementary borylation of aromatics and heteroaromatics. Chemistry 16, 8155–8161 (2010)

    Article  CAS  Google Scholar 

  21. 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)

    Article  CAS  Google Scholar 

  22. 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 

  23. 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)

    Article  CAS  Google Scholar 

  24. Wencel-Delord, J., Nimphius, C., Wang, H. & Glorius, F. Rhodium(III) and hexabromobenzene — a catalyst system for the cross-dehydrogenative coupling of simple arenes and heterocycles with arenes bearing directing groups. Angew. Chem. Int. Edn 51, 13001–13005 (2012)

    Article  CAS  Google Scholar 

  25. Fu, H. Y., Chen, L. & Doucet, H. Phosphine-free palladium-catalyzed direct arylation of imidazo[1,2-a]pyridines with aryl bromides at low catalyst loading. J. Org. Chem. 77, 4473–4478 (2012)

    Article  CAS  Google Scholar 

  26. Kuznetsov, A., Onishi, Y., Inamoto, Y. & Gevorgyan, V. Fused heteroaromatic dihydrosiloles: synthesis and double-fold modification. Org. Lett. 15, 2498–2501 (2013)

    Article  CAS  Google Scholar 

  27. Wang, D.-H., Wasa, M., Giri, R. & Yu, J.-Q. Pd(II)-catalyzed cross-coupling of sp3 C–H bonds with sp2 and sp3 boronic acids using air as the oxidant. J. Am. Chem. Soc. 130, 7190–7191 (2008)

    Article  CAS  Google Scholar 

  28. Campbell, A. N. & Stahl, S. S. Overcoming the “oxidant problem”: strategies to use O2 as the oxidant in organometallic C–H oxidation reactions catalyzed by Pd (and Cu). Acc. Chem. Res. 45, 851–863 (2012)

    Article  CAS  Google Scholar 

  29. Lang, S. Unravelling the labyrinth of palladium-catalysed reactions involving isocyanides. Chem. Soc. Rev. 42, 4867–4880 (2013)

    Article  CAS  Google Scholar 

  30. Ito, Y., Suginome, M., Matsuura, T. & Murakami, M. Palladium-catalyzed insertion of isocyanides into the silicon-silicon linkages of oligosilanes. J. Am. Chem. Soc. 113, 8899–8908 (1991)

    Article  CAS  Google Scholar 

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We thank the following for financial support: the Shanghai Institute of Organic Chemistry, the Chinese Academy of Sciences, the CAS/SAFEA International Partnership Program for Creative Research Teams, the National Natural Science Foundation of China (grant NSFC-21121062), the Recruitment Program of Global Experts, the Scripps Research Institute and the NIH (NIGMS, 1R01 GM102265).

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Authors and Affiliations



Y.-J.L. and H.X. performed the reaction discovery experiments and contributed equally. W.-J.K., H.X. and M.S. performed the reactions with the heterocyclic substrates. H.-X.D. and J.-Q.Y. conceived the concept, directed the project and prepared this manuscript.

Corresponding authors

Correspondence to Hui-Xiong Dai or Jin-Quan Yu.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Text, Supplementary Methods, Supplementary Data and additional references - see Contents for details. (PDF 36081 kb)

Supplementary Data

This zipped file contains the 'cif' files for the X-ray crystallographic data for compounds: complex E, complex F, 3a, and 5i. (ZIP 98 kb)

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Liu, YJ., Xu, H., Kong, WJ. et al. Overcoming the limitations of directed C–H functionalizations of heterocycles. Nature 515, 389–393 (2014).

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