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:

Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization

Nature volume 517, pages 600–604 (2015)Cite this article

Subjects

Abstract

Many enzymes oxidize unactivated aliphatic C–H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C–H bonds1,2. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the –N(Me)CH2– group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time3,4. For such reasons, synthetic chemists have sought catalysts that directly convert C–H bonds to C–N bonds. Most currently used catalysts for C–H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C–H bonds, or reagents containing specialized groups on the nitrogen atom5,6,7,8,9,10,11,12,13,14. Among C–H bond amination reactions, those forming a C–N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation15. Here we report a mild, selective, iron-catalysed azidation of tertiary C–H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen ‘click’ cycloadditions and the Staudinger ligation16,17,18,19. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment—for example, to fluorescent tags or ‘handles’ for affinity chromatography—directly on complex molecular structures.

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: Development of a catalyst for the azidation of aliphatic C–H bonds.
Figure 2: Evaluation of the effect of the steric and electronic environment on site selectivity for the azidation of aliphatic tertiary C–H bonds.
Figure 3: Introduction of a series of nitrogen-containing functionalities via C–H bond azidation.

Similar content being viewed by others

References

  1. Bollinger, J. M. & Broderick, J. B. Frontiers in enzymatic C-H-bond activation. Curr. Opin. Chem. Biol. 13, 51–57 (2009)

    Article  CAS  Google Scholar 

  2. Lewis, J. C., Coelho, P. S. & Arnold, F. H. Enzymatic functionalization of carbon-hydrogen bonds. Chem. Soc. Rev. 40, 2003–2021 (2011)

    Article  CAS  Google Scholar 

  3. Plouffe, J. et al. Clinical efficacy of intravenous followed by oral azithromycin monotherapy in hospitalized patients with community-acquired pneumonia. Antimicrob. Agents Chemother. 44, 1796–1802 (2000)

    Article  CAS  Google Scholar 

  4. O’Doherty, B., Muller, O. & Grp, A. S. Randomized, multicentre study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of adults with mild to moderate community-acquired pneumonia. Eur. J. Clin. Microbiol. Infect. Dis. 17, 828–833 (1998)

    Article  Google Scholar 

  5. Jeffrey, J. L. & Sarpong, R. Intramolecular C(sp3)-H amination. Chem. Sci. 4, 4092–4106 (2013)

    Article  CAS  Google Scholar 

  6. Ochiai, M., Miyamoto, K., Kaneaki, T., Hayashi, S. & Nakanishi, W. Highly regioselective amination of unactivated alkanes by hypervalent sulfonylimino-Λ3-bromane. Science 332, 448–451 (2011)

    Article  ADS  CAS  Google Scholar 

  7. Louillat, M. L. & Patureau, F. W. Oxidative C-H amination reactions. Chem. Soc. Rev. 43, 901–910 (2014)

    Article  CAS  Google Scholar 

  8. Roizen, J. L., Harvey, M. E. & Du Bois, J. Metal-catalyzed nitrogen-atom transfer methods for the oxidation of aliphatic C-H bonds. Acc. Chem. Res. 45, 911–922 (2012)

    Article  CAS  Google Scholar 

  9. Dequirez, G., Pons, V. & Dauban, P. Nitrene chemistry in organic synthesis: still in its infancy? Angew. Chem. Int. Edn Engl. 51, 7384–7395 (2012)

    Article  CAS  Google Scholar 

  10. Lescot, C., Darses, B., Collet, F., Retailleau, P. & Dauban, P. Intermolecular C-H amination of complex molecules: insights into the factors governing the selectivity. J. Org. Chem. 77, 7232–7240 (2012)

    Article  CAS  Google Scholar 

  11. Roizen, J. L., Zalatan, D. N. & Du Bois, J. Selective intermolecular amination of C-H bonds at tertiary carbon centers. Angew. Chem. Int. Edn Engl. 52, 11343–11346 (2013)

    Article  CAS  Google Scholar 

  12. Michaudel, Q., Thevenet, D. & Baran, P. S. Intermolecular Ritter-type C-H amination of unactivated sp3 carbons. J. Am. Chem. Soc. 134, 2547–2550 (2012)

    Article  CAS  Google Scholar 

  13. Li, J. et al. Simultaneous structure-activity studies and arming of natural products by C-H amination reveal cellular targets of eupalmerin acetate. Nature Chem. 5, 510–517 (2013)

    Article  ADS  CAS  Google Scholar 

  14. McNally, A., Haffemayer, B., Collins, B. S. L. & Gaunt, M. J. Palladium-catalysed C-H activation of aliphatic amines to give strained nitrogen heterocycles. Nature 510, 129–133 (2014)

    Article  ADS  CAS  Google Scholar 

  15. Pronin, S. V., Reiher, C. A. & Shenvi, R. A. Stereoinversion of tertiary alcohols to tertiary-alkyl isonitriles and amines. Nature 501, 195–199 (2013)

    Article  ADS  CAS  Google Scholar 

  16. Bräse, S., Gil, C., Knepper, K. & Zimmermann, V. Organic azides: an exploding diversity of a unique class of compounds. Angew. Chem. Int. Edn Engl. 44, 5188–5240 (2005)

    Article  Google Scholar 

  17. Schilling, C. I., Jung, N., Biskup, M., Schepers, U. & Brase, S. Bioconjugation via azide-Staudinger ligation: an overview. Chem. Soc. Rev. 40, 4840–4871 (2011)

    Article  CAS  Google Scholar 

  18. Lallana, E., Riguera, R. & Fernandez-Megia, E. Reliable and efficient procedures for the conjugation of biomolecules through Huisgen azide-alkyne cycloadditions. Angew. Chem. Int. Edn Engl. 50, 8794–8804 (2011)

    Article  CAS  Google Scholar 

  19. Hennessy, E. T. & Betley, T. A. Complex N-heterocycle synthesis via iron-catalyzed, direct C-H bond amination. Science 340, 591–595 (2013)

    Article  ADS  CAS  Google Scholar 

  20. Zhdankin, V. V. Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic Applications of Polyvalent Iodine Compounds (Wiley & Sons, 2013)

    Book  Google Scholar 

  21. Zhdankin, V. V. et al. Preparation, X-ray crystal structure, and chemistry of stable azidoiodinanes — Derivatives of benziodoxole. J. Am. Chem. Soc. 118, 5192–5197 (1996)

    Article  CAS  Google Scholar 

  22. Hill, C. L., Smegal, J. A. & Henly, T. J. Catalytic replacement of unactivated alkane carbon-hydrogen bonds with carbon-X bonds (X = nitrogen, oxygen, chlorine, bromine, or iodine) — Coupling of intermolecular hydrocarbon activation by MnIIITPPX complexes with phase-transfer catalysis. J. Org. Chem. 48, 3277–3281 (1983)

    Article  CAS  Google Scholar 

  23. Kojima, T., Leising, R. A., Yan, S. P. & Que, L. Alkane functionalization at nonheme iron centers. Stoichiometric transfer of metal-bound ligands to alkane. J. Am. Chem. Soc. 115, 11328–11335 (1993)

    Article  CAS  Google Scholar 

  24. Costas, M. Selective C-H oxidation catalyzed by metalloporphyrins. Coord. Chem. Rev. 255, 2912–2932 (2011)

    Article  CAS  Google Scholar 

  25. Kim, C., Chen, K., Kim, J. H. & Que, L. Stereospecific alkane hydroxylation with H2O2 catalyzed by an iron(II)-tris(2-pyridylmethyl)amine complex. J. Am. Chem. Soc. 119, 5964–5965 (1997)

    Article  CAS  Google Scholar 

  26. 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 

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

    Article  CAS  Google Scholar 

  28. Davies, H. M. L. & Morton, D. Guiding principles for site selective and stereoselective intermolecular C-H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev. 40, 1857–1869 (2011)

    Article  CAS  Google Scholar 

  29. Demko, Z. P. & Sharpless, K. B. A click chemistry approach to tetrazoles by Huisgen 1,3-dipolar cycloaddition: synthesis of 5-acyltetrazoles from azides and acyl cyanides. Angew. Chem. Int. Edn Engl. 41, 2113–2116 (2002)

    Article  CAS  Google Scholar 

  30. Trippier, P. C. Synthetic strategies for the biotinylation of bioactive small molecules. ChemMedChem 8, 190–203 (2013)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the US NIH (4R37GM055382 to J.F.H.) and the Swiss National Science Foundation (SNSF; PBGEP2_145544 to AS) for financial support. We thank A. DiPasquale for assistance with crystallographic data and acknowledge US NIH shared instrumentation grant S10-RR027172.

Author information

Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    Ankit Sharma & John F. Hartwig

Authors
  1. Ankit Sharma
    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

A.S. conducted the experiments. A.S. and J.F.H. conceived and designed the project, analysed the data and prepared this manuscript. X-ray crystal structures are deposited in the Cambridge Crystallographic Data Centre (CCDC 1027821–1027822).

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 Text and Data, Supplementary Tables 1-3 and Supplementary References. (PDF 8932 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sharma, A., Hartwig, J. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015). https://doi.org/10.1038/nature14127

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature14127

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