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Molecular editing of aza-arene C–H bonds by distance, geometry and chirality


Direct molecular editing of heteroarene carbon–hydrogen (C–H) bonds through consecutive selective C–H functionalization has the potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry1. In contrast to electronically biased heterocyclic C–H bonds2,3,4,5,6,7,8,9, remote benzocyclic C–H bonds on bicyclic aza-arenes are especially difficult to differentiate because of the lack of intrinsic steric/electronic biases10,11,12. Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C–H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C–H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different orders to suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage ‘molecular editing’ strategy to directly modify bicyclic aza-arenes at any given site in different orders.

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Fig. 1: Molecular editing of heterocycles.
Fig. 2: C6 (and related)-selective C–H olefination reactions of quinoline and other heterocycles.
Fig. 3: C7 (and related)-selective C–H olefination reactions of quinoline and other heterocycles.
Fig. 4: Synthetic applications.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information, and free of charge from the Cambridge Crystallographic Data Centre ( under reference numbers CCDC 2078170–2078173 and 2132680.


  1. Wencel-Delord, J. & Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 5, 369–375 (2013).

    Article  CAS  Google Scholar 

  2. Takagi, J., Sato, K., Hartwig, J. T., 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).

    Article  CAS  Google Scholar 

  3. 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 

  4. 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).

    Article  CAS  Google Scholar 

  5. 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 

  6. Tsai, C.-C. et al. Bimetallic nickel aluminun mediated para-selective alkenylation of pyridine: direct observation of η21-pyridine Ni(0)-Al(III) intermediates prior to C–H bond activation. J. Am. Chem. Soc. 132, 11887–11889 (2010).

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. Chen, Q., du Jourdin, X. M. & Knochel, P. Transition-metal-free BF3-mediated regioselective direct alkylation and arylation of functionalized pyridines using Grignard or organozinc reagents. J. Am. Chem. Soc. 135, 4958–4961 (2013).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. 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 

  11. 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).

    Article  CAS  Google Scholar 

  12. Murai, M., Nishinaka, N. & Takai, K. Iridium-catalyzed sequential silylation and borylation of heteroarenes cased on regioselective C–H bond activation. Angew. Chem. Int. Ed. 57, 5843–5847 (2018).

    Article  CAS  Google Scholar 

  13. 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  ADS  CAS  Google Scholar 

  14. Wilson, R. M. & Danishefsky, S. J. Small molecule natural products in the discovery of therapeutic agents: the synthesis connection. J. Org. Chem. 71, 8329–8351 (2006).

    Article  CAS  Google Scholar 

  15. Szpilman, A. M. & Carreira, E. M. Probing the biology of natural products: molecular editing by diverted total synthesis. Angew. Chem. Int. Ed. 49, 9592–9628 (2010).

    Article  CAS  Google Scholar 

  16. 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 

  17. 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 

  18. Davis, H. J., Mihai, M. T. & Phipps, R. J. Ion pair-directed regiocontrol in transition-metal catalysis: a meta-selective C–H borylation of aromatic quaternary ammonium salts. J. Am. Chem. Soc. 138, 12759–12762 (2016).

    Article  CAS  Google Scholar 

  19. Hoque, M. E., Bisht, R., Haldar, C. & Chattopadhyay, B. Noncovalent interactions in Ir-catalyzed C–H activation: L-shaped ligand for para-selective borylation of aromatic esters. J. Am. Chem. Soc. 139, 7745–7748 (2017).

    Article  CAS  Google Scholar 

  20. Zhang, T. et al. A directive Ni catalyst overrides conventional site selectivity in pyridine C–H alkenylation. Nat. Chem. 13, 1207–1213 (2021).

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  22. Ramakrishna, K. et al. Coordination assisted distal C–H alkylation of fused heterocycles. Angew. Chem. Int. Ed. 58, 13808–13812 (2019).

    Article  CAS  Google Scholar 

  23. Shi, H. et al. Differentiation and functionalization of remote C–H bonds in adjacent positions. Nat. Chem. 12, 399–404 (2020).

    Article  CAS  Google Scholar 

  24. Lewis, C. A. & Miller, S. J. Site-selective derivatization and remodeling of erythromycin A by using simple peptide-based chiral catalysts. Angew. Chem. Int. Ed. 45, 5616–5619 (2006).

    Article  CAS  Google Scholar 

  25. Tay, J.-H. et al. Regiodivergent glycosylations of 6-deoxy-erythronolide B and oleandomycin-derived macrolactones enabled by chiral acid catalysis. J. Am. Chem. Soc. 139, 8570–8578 (2017).

    Article  CAS  Google Scholar 

  26. Dimakos, V. & Taylor, M. S. Site-selective functionalization of hydroxyl groups in carbohydrate derivatives. Chem. Rev. 118, 11457–11517 (2018).

    Article  CAS  Google Scholar 

  27. 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 

  28. Lerchen, A. et al. Non‐directed cross‐dehydrogenative (hetero)arylation of allylic C(sp3)–H bonds enabled by C–H activation. Angew. Chem. Int. Ed. 57, 15248–15252 (2018).

    Article  CAS  Google Scholar 

  29. Fu, L., Zhang, Z., Chen, P., Lin, Z. & Liu, G. Enantioselective copper-catalyzed alkynylation of benzylic C–H bonds via radical relay. J. Am. Chem. Soc. 142, 12493–12500 (2020).

    Article  CAS  Google Scholar 

  30. Porey, S. et al. Alkyne linchpin strategy for drug: pharmacophore conjugation: experimental and computational realization of a meta-selective inverse sonogashira coupling. J. Am. Chem. Soc. 142, 3762–3774 (2020).

    Article  CAS  Google Scholar 

  31. Pan, P. et al. Structure-based drug design and identification of H2O-soluble and low toxic hexacyclic camptothecin derivatives with improved efficacy in cancer and lethal inflammation models in vivo. J. Med. Chem. 61, 8613–8624 (2018).

    Article  CAS  Google Scholar 

  32. Krajewska, J., Olczyk, T. & Jarzab, B. Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer. Expert Rev. Clin. Pharmacol. 9, 69–79 (2016).

    Article  CAS  Google Scholar 

  33. Personeni, N., Rimassa, L., Pressiani, T., Smiroldo, V. & Santoro, A. Cabozantinib for the treatment of hepatocellular carcinoma. Expert Rev. Anticancer Ther. 19, 847–855 (2019).

    Article  CAS  Google Scholar 

  34. Hwang, J. Y. et al. Synthesis and evaluation of 7-substituted 4-aminoquinoline analogues for antimalarial activity. J. Med. Chem. 54, 7084–7093 (2011).

    Article  CAS  Google Scholar 

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We acknowledge The Scripps Research Institute and the National Institutes of Health (National Institute of General Medical Sciences grant no. R01 GM102265) for their financial support. Computations were performed on the Hoffman2 cluster at University of California Los Angeles (UCLA) and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the National Science Foundation (NSF) (grant no. OCI-1053575). We are grateful for financial support of the UCLA work from the NSF (grant no. CHE-1764328 to K.N.H.) and the NSF under the NSF Center for Selective C–H Functionalization (grant no. CHE-1700982). J. Chen, B. Sanchez and E. Sturgell are acknowledged for their assistance with liquid chromatography–mass spectrometry analysis. We thank M. Gembicky, J. Bailey and the University of California San Diego Crystallography Facility for X-ray crystallographic analysis.

Author information

Authors and Affiliations



Z.F. developed the templates, optimized the conditions and investigated the substrate scope. X.C. and J.J.W. performed the DFT calculations. Z.F. and K.T. developed the template chaperones. H.S.P. and N.Y.S.L. prepared part of the substrates and reagents. K.N.H supervised the mechanistic study. J.-Q.Y., K.N.H., Z.F. and N.Y.S.L. prepared the manuscript. J.-Q.Y. directed the project.

Corresponding authors

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

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Competing interests

J.-Q.Y. and Z.F. are inventors on a patent application related to this work (US Patent application 63/334,828) filed by The Scripps Research Institute. The authors declare no other competing interests.

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Nature thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Additional olefin scope for C6 (and related)-selective C–H olefination reactions of quinoline and other heterocycles.

All yields are isolated yields. aUsing conditions in Extended Data Fig. 3b. nPr, n-propyl; iBu, isobutyl; Hex, n-hexyl.

Extended Data Fig. 2 Additional olefin scope for C7 (and related)-selective C–H olefination reactions of quinoline and other heterocycles.

All yields are isolated yields.

Extended Data Fig. 3 Site-selective C–H alkynylation and allylation of aza-arenes.

a, C6 (and related)-selective C–H alkynylation of aza-arenes. b, C6 (and related)-selective C–H allylation of aza-arenes. c, C7 (and related)-selective C–H alkynylation of aza-arenes. All yields are isolated yields. aUsing trans-5-decene (3 equiv). bUsing trans-4-methyl-2-pentene (3 equiv). cUsing 1-hexene (3 equiv). dUsing (S,S)-T25 (0.3 equiv), Pd(OAc)2 (20 mol%), Ac-L-Phe-OH (40 mol%), alkynylation reagent (4 equiv), 100 °C. TBAF, tetra-n-butylammonium fluoride.

Supplementary information

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Fan, Z., Chen, X., Tanaka, K. et al. Molecular editing of aza-arene C–H bonds by distance, geometry and chirality. Nature 610, 87–93 (2022).

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