Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol

Nature volume 483, pages 70–73 (2012)Cite this article

Subjects

Abstract

New synthetic methods for the catalytic functionalization of C–H bonds have the potential to revolutionize the synthesis of complex molecules1,2,3,4. However, the realization of this synthetic potential requires the ability to functionalize selectively one C–H bond in a compound containing many such bonds and an array of functional groups. The site-selective functionalization of aliphatic C–H bonds is one of the greatest challenges that must be met for C–H bond functionalization to be used widely in complex-molecule synthesis1,3,5,6, and processes catalysed by transition-metals provide the opportunity to control selectivity7,8. Current methods for catalytic, aliphatic C–H bond functionalization typically rely on the presence of one inherently reactive C–H bond9,10, or on installation and subsequent removal of directing groups that are not components of the desired molecule8. To overcome these limitations, we sought catalysts and reagents that would facilitate aliphatic C–H bond functionalization at a single site, with chemoselectivity derived from the properties of the catalyst and site-selectivity directed by common functional groups11 contained in both the reactant and the desired product. Here we show that the combination of an iridium-phenanthroline catalyst and a dihydridosilane reagent leads to the site-selective γ-functionalization of primary C–H bonds controlled by a hydroxyl group, the most common functional group in natural products12. The scope of the reaction encompasses alcohols and ketones bearing many substitution patterns and auxiliary functional groups; this broad scope suggests that this methodology will be suitable for the site-selective and diastereoselective functionalization of complex natural products.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Hydroxyl-directed γ-oxygenation of secondary and tertiary alcohols and ketones.
Figure 2: Functional-group tolerance of hydroxyl-directed γ-oxygenation.
Figure 3: Directed aliphatic C–H functionalization of natural products.

Similar content being viewed by others

References

  1. Gutekunst, W. R. & Baran, P. S. C–H functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011)

    Article  CAS  Google Scholar 

  2. McMurray, L., O'Hara, F. & Gaunt, M. J. Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation. Chem. Soc. Rev. 40, 1885–1898 (2011)

    Article  CAS  Google Scholar 

  3. Chen, K. & Baran, P. S. Total synthesis of eudesmane terpenes by site-selective C–H oxidations. Nature 459, 824–828 (2009)

    Article  ADS  CAS  Google Scholar 

  4. Godula, K. & Sames, D. C–H bond functionalization in complex organic synthesis. Science 312, 67–72 (2006)

    Article  ADS  CAS  Google Scholar 

  5. Feng, Y. & Chen, G. Total synthesis of celogentin C by stereoselective C–H activation. Angew. Chem. Int. Ed. 49, 958–961 (2010)

    Article  CAS  Google Scholar 

  6. Giannis, A., Heretsch, P., Sarli, V. & Stößel, A. Synthesis of cyclopamine using a biomimetic and diastereoselective approach. Angew. Chem. Int. Ed. 48, 7911–7914 (2009)

    Article  CAS  Google Scholar 

  7. Yu, J.-Q. & Shi, Z. in Topics in Current Chemistry Vol. 292 (Springer, 2010)

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

    Article  CAS  Google Scholar 

  9. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007)

    Article  ADS  CAS  Google Scholar 

  10. Newhouse, T. & Baran, P. S. If C–H bonds could talk: selective C–H bond oxidation. Angew. Chem. Int. Ed. 50, 3362–3374 (2011)

    Article  CAS  Google Scholar 

  11. Lu, Y., Wang, D.-H., Engle, K. M. & Yu, J.-Q. Pd(II)-catalyzed hydroxyl-directed C–H olefination enabled by monoprotected amino acid ligands. J. Am. Chem. Soc. 132, 5916–5921 (2010)

    Article  CAS  Google Scholar 

  12. Henkel, T., Brunne, R. M., Müller, H. & Reichel, F. Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew. Chem. Int. Ed. 38, 643–647 (1999)

    Article  CAS  Google Scholar 

  13. Simmons, E. M. & Hartwig, J. F. Iridium-catalyzed arene ortho-silylation by formal hydroxyl-directed C−H activation. J. Am. Chem. Soc. 132, 17092–17095 (2010)

    Article  CAS  Google Scholar 

  14. Boebel, T. A. & Hartwig, J. F. Silyl-directed, iridium-catalyzed ortho-borylation of arenes. A one-pot ortho-borylation of phenols, arylamines, and alkylarenes. J. Am. Chem. Soc. 130, 7534–7535 (2008)

    Article  CAS  Google Scholar 

  15. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010)

    Article  CAS  Google Scholar 

  16. Crotti, C. et al. Evaluation of the donor ability of phenanthrolines in iridium complexes by means of synchrotron radiation photoemission spectroscopy and DFT calculations. Dalton Trans. 133–142 (2007)

  17. Corriu, R. J. P. & Moreau, J. J. E. Selective catalytic route to bifunctional silanes. Catalysis by rhodium and ruthenium complexes of the alcoholysis of diarylsilanes and the hydrosilylation of carbonyl compounds. J. Chem. Soc. Chem. Commun. 38–39 (1973)

  18. Bosworth, N. & Magnus, P. D. Studies on terpenes. Part I. Rearrangement of 7-oxatricyclo[4,3,0,0]nonanes into 8-substituted 1,3,3-trimethylnorbornane derivatives. J. Chem. Soc. Perkin Trans. I 943–948 (1972)

  19. Miyazawa, M. & Miyamoto, Y. Biotransformation of (+)-(1R,2S)-fenchol by the larvae of common cutworm (Spodoptera litura). Tetrahedron 60, 3091–3096 (2004)

    Article  CAS  Google Scholar 

  20. Deng, J. G., Jiang, Y. Z., Liu, G. L., Wu, L. J. & Mi, A. Q. A practical method for the synthesis of homochiral 2,10-camphanediols. Synthesis 963–965 (1991)

  21. Plé, K., Chwalek, M. & Voutquenne-Nazabadioko, L. Synthesis of α-hederin, δ-hederin, and related triterpenoid saponins. Eur. J. Org. Chem. 2004, 1588–1603 (2004)

    Article  Google Scholar 

  22. García-Granados, A., López, P. E., Melguizo, E., Parra, A. & Simeó, Y. Remote hydroxylation of methyl groups by regioselective cyclopalladation. Partial synthesis of hyptatic acid-A. J. Org. Chem. 72, 3500–3509 (2007)

    Article  Google Scholar 

  23. Kitagawa, I., Hori, K., Sakagami, M., Zhou, J. L. & Yoshikawa, M. Saponin and sapogenol. XLVIII. On the constituents of the roots of Glycyrrhiza uralensis Fischer from northeastern China. (2). Licorice-saponins D3, E2, F3, G2, H2, J2, and K2. Chem. Pharm. Bull. (Tokyo) 41, 1337–1345 (1993)

    Article  CAS  Google Scholar 

  24. Majetich, G. & Wheless, K. Remote intramolecular free radical functionalizations: an update. Tetrahedron 51, 7095–7129 (1995)

    Article  CAS  Google Scholar 

  25. Chen, K., Richter, J. M. & Baran, P. S. 1,3-diol synthesis via controlled, radical-mediated C−H functionalization. J. Am. Chem. Soc. 130, 7247–7249 (2008)

    Article  CAS  Google Scholar 

  26. Kasuya, S., Kamijo, S. & Inoue, M. Direct construction of 1,3-diaxial diol derivatives by C−H hydroxylation. Org. Lett. 11, 3630–3632 (2009)

    Article  CAS  Google Scholar 

  27. 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 

  28. Giri, R. et al. Pd-catalyzed stereoselective oxidation of methyl groups by inexpensive oxidants under mild conditions: a dual role for carboxylic anhydrides in catalytic C−H bond oxidation. Angew. Chem. Int. Ed. 44, 7420–7424 (2005)

    Article  CAS  Google Scholar 

  29. Litvinas, N. D., Brodsky, B. H. & Du Bois, J. C−H hydroxylation using a heterocyclic catalyst and aqueous H2O2 . Angew. Chem. Int. Ed. 48, 4513–4516 (2009)

    Article  CAS  Google Scholar 

  30. Zalatan, D. N. & Du Bois, J. in Topics in Current Chemistry Vol. 292 (eds Yu, J.-Q. & Shi, Z. ) 347–378 (Springer, 2010)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the US National Science Foundation (CHE-0910641 to J.F.H.) and the US National Institutes of Health (GM087901 to E.M.S.) for funding this work, and Johnson Matthey for a gift of [Ir(cod)OMe]2.

Author information

Author notes

  1. Eric M. Simmons & John F. Hartwig

    Present address: Present address: Department of Chemistry, University of California, Berkeley, California 91820, USA,

Authors and Affiliations

  1. Department of Chemistry, University of Illinois, Urbana, 61801, Illinois, USA

    Eric M. Simmons & John F. Hartwig

Authors
  1. Eric M. Simmons
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John F. Hartwig
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.M.S. and J.F.H. conceived the work and designed the experiments. E.M.S. performed the experiments. Both authors analysed the data and wrote the manuscript.

Corresponding author

Correspondence to John F. Hartwig.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Materials and Method, Supplementary Experimental Procedures and Spectral Data , 1H and 13 C NMR Spectra and additional references. (PDF 3547 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Simmons, E., Hartwig, J. Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012). https://doi.org/10.1038/nature10785

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature10785

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing