Activation of remote meta-C–H bonds assisted by an end-on template

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Abstract

Functionalization of unactivated carbon–hydrogen (C–H) single bonds is an efficient strategy for rapid generation of complex molecules from simpler ones. However, it is difficult to achieve selectivity when multiple inequivalent C–H bonds are present in the target molecule. The usual approach is to use σ-chelating directing groups, which lead to ortho-selectivity through the formation of a conformationally rigid six- or seven-membered cyclic pre-transition state1,2,3,4,5,6,7,8,9,10,11,12,13,14. Despite the broad utility of this approach, proximity-driven reactivity prevents the activation of remote C–H bonds. Here we report a class of easily removable nitrile-containing templates that direct the activation of distal meta-C–H bonds (more than ten bonds away) of a tethered arene. We attribute this new mode of C–H activation to a weak ‘end-on’ interaction15 between the linear nitrile group and the metal centre. The ‘end-on’ coordination geometry relieves the strain of the cyclophane-like pre-transition state of the meta-C–H activation event. In addition, this template overrides the intrinsic electronic and steric biases as well as ortho-directing effects with two broadly useful classes of arene substrates (toluene derivatives and hydrocinnamic acids).

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Figure 1: A template strategy for the activation of distal meta -C–H bonds (more than ten bonds away).
Figure 2: Template-directed meta -selective C–H olefination of toluene derivatives.
Figure 3: Template-directed meta -selective C–H olefination of hydrocinnamic acid derivatives.

References

  1. 1

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

  2. 2

    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)

  3. 3

    Ryabov, A. D. Cyclopalladated complexes in organic synthesis. Synthesis 233–252 (1985)

  4. 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)

  5. 5

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

  6. 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)

  7. 7

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

  8. 8

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

  9. 9

    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. (2011)

  10. 10

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

  11. 11

    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)

  12. 12

    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)

  13. 13

    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)

  14. 14

    Ackermann, L. & Pospech, J. Ruthenium-catalyzed oxidative C–H bond alkenylations in water: expedient synthesis of annulated lactones. Org. Lett. 13, 4153–4155 (2011)

  15. 15

    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)

  16. 16

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

  17. 17

    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)

  18. 18

    Li, J.-J., Giri, R. & Yu, J.-Q. Remote C–H bond functionalization reveals the distance-dependent isotope effect. Tetrahedron 64, 6979–6987 (2008)

  19. 19

    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)

  20. 20

    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)

  21. 21

    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)

  22. 22

    Wang, X., Leow, D. & Yu, J.-Q. Pd(II)-catalyzed para-selective C–H arylation of monosubstituted arenes. J. Am. Chem. Soc. 133, 13864–13867 (2011)

  23. 23

    Ueda, K., Yanagisawa, S., Yamaguchi, J. & Itami, K. A general catalyst for the β-selective C–H bond arylation of thiophenes with iodoarenes. Angew. Chem. Int. Edn 49, 8946–8949 (2010)

  24. 24

    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)

  25. 25

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

  26. 26

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

  27. 27

    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. Edn 50, 463–466 (2011)

  28. 28

    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)

  29. 29

    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)

  30. 30

    Gürtler, C. & Buchwald, S. L. A phosphane-free catalyst system for the Heck arylation of disubstituted alkenes: application to the synthesis of trisubstituted olefins. Chem. Eur. J. 5, 3107–3112 (1999)

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Acknowledgements

We thank The Scripps Research Institute and the NIH (NIGMS, 1 R01 GM084019-03) for their financial support. We also thank the Agency for Science, Technology and Research (A*STAR) in Singapore for a postdoctoral fellowship (to D.L.).

Author information

D.L., G.L. and T.-S.M. performed the experiments and analysed the data. D.L., G.L. and J.-Q.Y. designed the templates and developed the reactions. J.-Q.Y. conceived this concept and prepared this manuscript with feedback from D.L. and G.L.

Correspondence to Jin-Quan Yu.

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The authors declare no competing financial interests.

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Leow, D., Li, G., Mei, T. et al. Activation of remote meta-C–H bonds assisted by an end-on template. Nature 486, 518–522 (2012) doi:10.1038/nature11158

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