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

Abstract

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.

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 (https://www.ccdc.cam.ac.uk/structures) under reference numbers CCDC 2078170–2078173 and 2132680.

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Acknowledgements

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

Authors

Contributions

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.

Ethics declarations

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

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 (2022). https://doi.org/10.1038/s41586-022-05175-1

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