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Conformation-induced remote meta-C–H activation of amines


Achieving site selectivity in carbon–hydrogen (C–H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C–H bonds in any given organic molecule can lead to the activation of undesired C–H bonds by a non-selective catalyst. One solution to this problem is to distinguish C–H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C–H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied1,2,3,4,5,6,7,8,9,10,11,12,13. However, the directed activation of C–H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C–H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation14,15. Here we report a recyclable template that directs the olefination and acetoxylation of distal meta-C–H bonds—as far as 11 bonds away—of anilines and benzylic amines. This template is able to direct the meta-selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho- to meta-selectivity.

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Figure 1: Design of a versatile template to direct meta-C–H activation.
Figure 2: Development of templates to direct meta-C–H olefination.
Figure 3: Template-directed remote C–H olefination of N-methylanilines.
Figure 4: Meta-C–H acetoxylation of N-methylanilines and benzylamine derivatives.

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  1. 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 

  2. Hartung, C. G. & Snieckus, V. in Modern Arene Chemistry (ed. Astruc, D. ) 330–367 (Wiley-VCH, 2004)

    Google Scholar 

  3. 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 

  4. 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 

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

  6. 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 

  7. 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 

  8. Desai, L. V., Hull, K. L. & Sanford, M. S. Palladium-catalyzed oxygenation of unactivated sp3 C−H bonds. J. Am. Chem. Soc. 126, 9542–9543 (2004)

    Article  CAS  Google Scholar 

  9. Satoh, T. & Miura, M. Oxidative coupling of aromatic substrates with alkynes and alkenes under rhodium catalysis. Chemistry 16, 11212–11222 (2010)

    Article  CAS  Google Scholar 

  10. Guimond, N., Gorelsky, S. I. & Fagnou, K. Rhodium(III)-catalyzed heterocycle synthesis using an internal oxidant: improved reactivity and mechanistic studies. J. Am. Chem. Soc. 133, 6449–6457 (2011)

    Article  CAS  Google Scholar 

  11. Rakshit, S., Grohmann, C., Besset, T. & Glorius, F. Rh(III)-catalyzed directed C–H olefination using an oxidizing directing group: mild, efficient, and versatile. J. Am. Chem. Soc. 133, 2350–2353 (2011)

    Article  CAS  Google Scholar 

  12. Park, S. H., Kim, J. Y. & Chang, S. Rhodium-catalyzed selective olefination of arene esters via C–H bond activation. Org. Lett. 13, 2372–2375 (2011)

    Article  CAS  Google Scholar 

  13. Ackermann, L. & Pospech, J. Ruthenium-catalyzed oxidative C–H bond alkenylations in water: expedient synthesis of annulated lactones. Org. Lett. 13, 4153–4155 (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  CAS  ADS  Google Scholar 

  15. Wan, L., Dastbaravardeh, N., Li, G. & Yu, J.-Q. Cross-coupling of remote meta-C–H bonds directed by a U-shaped template. J. Am. Chem. Soc. 135, 18056–18059 (2013)

    Article  CAS  Google Scholar 

  16. Schwarz, H. Remote functionalization of C–H and C–C bonds by naked transition-metal ions (cosi fan tutte). Acc. Chem. Res. 22, 282–287 (1989)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. 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 

  19. Boele, M. D. K. et al. Selective Pd-catalyzed oxidative coupling of anilides with olefins through C−H bond activation at room temperature. J. Am. Chem. Soc. 124, 1586–1587 (2002)

    Article  CAS  Google Scholar 

  20. Paul, S., Schweizer, W. B., Ebert, M.-O. & Gilmour, R. A novel fluorinated gold(I) N-heterocyclic carbene complex: exploiting fluorine stereoelectronic effects to control molecular topology. Organometallics 29, 4424–4427 (2010)

    Article  CAS  Google Scholar 

  21. Banks, J. W. et al. The preferred conformation of α-fluoroamides. J. Chem. Soc. Perkin Trans. 2 2409–2411 (1999)

  22. Wang, D.-H., Engle, K. M., Shi, B.-F. & Yu, J.-Q. Ligand-enabled reactivity and selectivity in a synthetically versatile aryl C–H olefination. Science 327, 315–319 (2010)

    Article  CAS  ADS  Google Scholar 

  23. Cho, J.-Y., Tse, M. K., Holmes, D., Maleczka, R. E., Jr & Smith, M. R., III Remarkably selective iridium catalysts for the elaboration of aromatic C–H bonds. Science 295, 305–308 (2002)

    Article  CAS  ADS  Google Scholar 

  24. Ishiyama, T. et al. Mild iridium-catalyzed borylation of arenes. High turnover numbers, room temperature reactions, and isolation of a potential intermediate. J. Am. Chem. Soc. 124, 390–391 (2002)

    Article  CAS  Google Scholar 

  25. Zhang, Y.-H., Shi, B.-F. & Yu, J.-Q. Pd(II)-catalyzed olefination of electron-deficient arenes using 2,6-dialkylpyridine ligands. J. Am. Chem. Soc. 131, 5072–5074 (2009)

    Article  CAS  Google Scholar 

  26. 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 

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

    Article  CAS  Google Scholar 

  28. Duong, H. A., Gilligan, R. E., Cooke, M. L., Phipps, R. J. & Gaunt, M. J. Copper(II)-catalyzed meta-selective direct arylation of α-aryl carbonyl compounds. Angew. Chem. Int. Ed. 50, 463–466 (2011)

    Article  CAS  Google Scholar 

  29. Hull, K. L. & Sanford, M. S. Catalytic and highly regioselective cross-coupling of aromatic C−H substrates. J. Am. Chem. Soc. 129, 11904–11905 (2007)

    Article  CAS  Google Scholar 

  30. 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 

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We gratefully acknowledge The Scripps Research Institute and the NIH (NIGMS, 1R01 GM102265) for their financial support. R.-Y.T. is a visiting scholar from Wenzhou University and is sponsored by the National Natural Science Foundation of China (21202121).

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R.-Y.T. and G.L. performed the experiments and developed the reactions. R.-Y.T. and J.-Q.Y. designed the templates. J.-Q.Y. had the idea for this work and prepared this manuscript with feedback from R.-Y.T. and G.L.

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Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Tang, RY., Li, G. & Yu, JQ. Conformation-induced remote meta-C–H activation of amines. Nature 507, 215–220 (2014).

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