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.

  • Article
  • Published:

Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

Nature Chemistry volume 10, pages 583–591 (2018)Cite this article

Subjects

Abstract

Reactions that directly install nitrogen into C–H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C–H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C–H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C–H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Brønsted or Lewis acid, the [MnIII(ClPc)]-catalysed C–H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C–H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C–H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base–metal-catalysed C–H aminations and provide new opportunities for tunable selectivities.

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

Fig. 1: Converting C–H bonds to C–N bonds.
Fig. 2: Intermolecular benzylic C–H amination substrate scope.
Fig. 3: Late-stage benzylic C–H amination of bioactive molecules.
Fig. 4: Late-stage benzylic C–H amination of natural products.
Fig. 5: Mechanism of [MnIII(ClPc)]-catalysed benzylic C–H amination.

Similar content being viewed by others

References

  1. Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Acred, P., Brown, D. M., Turner, D. H. & Wilson, M. J. Pharmacology and chemotherapy of ampicillin—a new broad-spectrum penicillin. Br. J. Pharmacol. 18, 356–369 (1962).

    CAS  Google Scholar 

  3. McGrath, N. A., Brichacek, M. & Njardarson, J. T. A graphical journey of innovative organic architectures that have improved our lives. J. Chem. Educ. 87, 1348–1349 (2010).

    Article  CAS  Google Scholar 

  4. Hili, R. & Yudin, A. K. Making carbon–nitrogen bonds in biological and chemical synthesis. Nat. Chem. Biol. 2, 284–287 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Hubbard, B. K., Thomas, M. G. & Walsh, C. T. Biosynthesis of l-p-hydroxyphenylglycine, a non-proteinogenic amino acid constituent of peptide antibiotics. Chem. Biol. 7, 931–942 (2000).

    CAS  Google Scholar 

  6. Carey, J. S., Laffan, D., Thomson, C. & Williams, M. T. Analysis of the reactions used for the preparation of drug candidate molecules. Org. Biomol. Chem. 4, 2337–2347 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Dugger, R. W., Ragan, J. A. & Ripin, D. H. B. Survey of GMP bulk reactions run in a research facility between 1985 and 2002. Org. Process Res. Dev. 9, 253–258 (2005).

    Article  CAS  Google Scholar 

  8. Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Li, J. W. H. & Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier? Science 325, 161–165 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. DeCorte, B. L. Underexplored opportunities for natural products in drug discovery. J. Med. Chem. 59, 9295–9304 (2016).

    Article  CAS  PubMed  Google Scholar 

  11. 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  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Huard, K. & Lebel, H. N-tosyloxycarbamates as reagents in rhodium-catalyzed C–H amination reactions. Chem. Eur. J. 14, 6222–6230 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Fiori, K. W. & Du Bois, J. Catalytic intermolecular amination of C–H bonds: method development and mechanistic insights. J. Am. Chem. Soc. 129, 562–568 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Liang, C. et al. Efficient diastereoselective intermolecular rhodium-catalyzed C–H amination. Angew. Chem. Int. Ed. 45, 4641–4644 (2006).

    Article  CAS  Google Scholar 

  17. Bess, E. N. et al. Analyzing site selectivity in Rh2(esp)2-catalyzed intermolecular C–H amination reactions. J. Am. Chem. Soc. 136, 5783–5789 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Paradine, S. M. & White, M. C. Iron-catalyzed intramolecular allylic C–H amination. J. Am. Chem. Soc. 134, 2036–2039 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Paradine, S. M. et al. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp 3) –H amination. Nat. Chem. 7, 987–994 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Hennessy, E. T., Liu, R. Y., Iovan, D. A., Duncan, R. A. & Betley, T. A. Iron-mediated intermolecular N-group transfer chemistry with olefinic substrates. Chem. Sci. 5, 1526–1532 (2014).

    Article  CAS  Google Scholar 

  23. Liu, Y. et al. Nonheme iron-mediated amination of C(sp 3)–H bonds. Quinquepyridine-supported iron-imide/nitrene intermediates by experimental studies and DFT calculations. J. Am. Chem. Soc. 135, 7194–7204 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Lu, H., Subbarayan, V., Tao, J. & Zhang, X. P. Cobalt(II)-catalyzed intermolecular benzylic C–H amination with 2,2,2-trichloroethoxycarbonyl azide (TrocN3). Organometallics 29, 389–393 (2010).

    Article  CAS  Google Scholar 

  25. Lu, H., Hu, Y., Jiang, H., Wojtas, L. & Zhang, X. P. Stereoselective radical amination of electron deficient C(sp 3)–H bonds by Co(II)-based metalloradical catalysis: direct synthesis of α-amino acid derivatives via α-C–H amination. Org. Lett. 14, 5158–5161 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gephart, R. T. III & Warren, T. H. Copper-catalyzed sp 3 C–H amination. Organometallics 31, 7728–7752 (2012).

    Article  CAS  Google Scholar 

  27. Fructos, M. R., Trofimenko, S., Díaz-Requejo, M. M. & Pérez, P. J. Facile amine formation by intermolecular catalytic amidation of carbon–hydrogen bonds. J. Am. Chem. Soc. 128, 11784–11791 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Huang, X., Bergsten, T. M. & Groves, J. T. Manganese-catalyzed late-stage aliphatic C–H azidation. J. Am. Chem. Soc. 137, 5300–5303 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Karimov, R. R., Sharma, A. & Hartwig, J. F. Late stage azidation of complex molecules. ACS Cent. Sci. 2, 715–724 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ruppel, J. V., Kamble, R. M. & Zhang, X. P. Cobalt-catalyzed intramolecular C–H amination with arylsulfonyl azides. Org. Lett. 9, 4889–4892 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Safari, N. et al. Rapid and efficient synthesis of metallophthalocyanines in ionic liquid. J. Porphyr. Phthalocyanines 9, 256–261 (2005).

    Article  CAS  Google Scholar 

  32. Du Bois, J. 2,2,2-Trichloroethoxysulfonamide. e-EROS Encyclopedia of Reagents for Organic Synthesis (2009). https://doi.org/10.1002/047084289X.rn01072

  33. Asensio, G., González-Núñez, M. E., Bernardini, C. B., Mello, R. & Adam, W. Regioselective oxyfunctionalization of unactivated tertiary and secondary C–H bonds of alkylamines by methyl(trifluoromethyl)dioxirane in acid medium. J. Am. Chem. Soc. 115, 7250–7253 (1993).

    Article  CAS  Google Scholar 

  34. Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C. Remote oxidation of aliphatic C–H bonds in nitrogen-containing molecules. J. Am. Chem. Soc. 137, 14590–14593 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, M. & Sanford, M. S. Platinum-catalyzed, terminal selective C(sp 3 )–H oxidation of aliphatic amines. J. Am. Chem. Soc. 137, 12796–12799 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Taylor, R. D., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Stepan, A. F., Mascitti, V., Beaumont, K. & Kalgutkar, A. S. Metabolism-guided drug design. Med. Chem. Commun. 4, 631–652 (2013).

    Article  CAS  Google Scholar 

  38. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Lund, B. W. et al. Discovery of a potent, orally available, and isoform-selective retinoic acid β2 receptor agonist. J. Med. Chem. 48, 7517–7519 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Alibert, S. et al. Effects of a series of dihydroanthracene derivatives on drug efflux in multidrug resistant cancer cells. Eur. J. Med. Chem. 38, 253–263 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Chambers, M. S. et al. Spiropiperidines as high-affinity, selective σ ligands. J. Med. Chem. 35, 2033–2039 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Wikström, H. et al. N-substituted 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines and 3-phenylpiperidines: effects on central dopamine and σ receptors. J. Med. Chem. 30, 2169–2174 (1987).

    Article  PubMed  Google Scholar 

  43. Morgan, B. P. et al. Discovery of potent, nonsteroidal, and highly selective glucocorticoid receptor antagonists. J. Med. Chem. 45, 2417–2424 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Krishnegowda, G. et al. Synthesis and biological evaluation of a novel class of isatin analogs as dual inhibitors of tubulin polymerization and Akt pathway. Bioorg. Med. Chem. 19, 6006–6014 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hille, U. E., Zimmer, C., Vock, C. A. & Hartmann, R. W. First selective CYP11B1 inhibitors for the treatment of cortisol-dependent diseases. ACS Med. Chem. Lett. 2, 2–6 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Jiang, X., Song, Z., Xu, C., Yao, Q. & Zhang, A. (d,l)-10-Camphorsulfonic-acid-catalysed synthesis of diaryl-fused 2,8-dioxabicyclo[3.3.1]nonanes from 2-hydroxychalcones and naphthol derivatives. Eur. J. Org. Chem. 418–425 (2014).

  47. Lu, H., Jiang, H., Hu, Y., Wojtas, L. & Zhang, X. P. Chemoselective intramolecular allylic C–H amination versus C=C aziridination through Co(II)-based metalloradical catalysis. Chem. Sci. 2, 2361–2366 (2011).

    Article  CAS  Google Scholar 

  48. Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies Ch. 3 (CRC, Boca Raton, FL, 2007).

    Book  Google Scholar 

  49. Greenwood, N. N. & Earnshaw, A. Chemistry of the Elements. 2nd edn, Ch. 24. (Butterworth-Heinemann, Oxford, 1997).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial support for this work was provided by the NIGMS Maximizing Investigators’ Research Award MIRA (R35 GM122525). J.R.C. is an NIH Ruth Kirschstein Postdoctoral Fellow (1 F32GM112501-01A1). The authors thank D.L. Gray and T.J. Woods for crystallographic analysis of compounds 36, 37, 38 and 44. The authors thank L. Zhu for assistance with NMR spectroscopy and T. Nanjo, R. Ma, W. Liu and J. Griffin for checking the experimental procedures.

Author information

Author notes

  1. These authors contributed equally: Kaibo Feng and Anasheh Sookezian.

Authors and Affiliations

  1. Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL, USA

    Joseph R. Clark, Kaibo Feng, Anasheh Sookezian & M. Christina White

Authors
  1. Joseph R. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaibo Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anasheh Sookezian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Christina White
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.C.W. and J.R.C. conceived and designed the project. J.R.C., K.F. and A.S. conducted the experiments and, with M.C.W., analysed the data. M.C.W. and J.R.C. prepared the manuscript with input from K.F. and A.S.

Corresponding author

Correspondence to M. Christina White.

Ethics declarations

Competing interests

The University of Illinois has filed a patent application on the [Mn(ClPc)] catalyst for intermolecular C–H functionalization. The [Mn(ClPc)] catalyst (product # 901425) will be offered by MilliporeSigma through a licence from the University of Illinois.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information

Supplementary experimental data, synthetic procedures and chemical compound characterization data

Crystallographic data

CIF for compound (±)-36 with embedded structure factors; CCDC reference: 1587014

Crystallographic data

CIF for compound (±)-37 with embedded structure factors; CCDC reference: 1587015

Crystallographic data

CIF for compound (-)-38; CCDC reference: 1587016

Crystallographic data

Structure factors for compound (-)-38; CCDC reference: 1587016

Crystallographic data

Description: CIF for compound (-)-44; CCDC reference: 1587017

Crystallographic data

Structure factors for compound (-)-44; CCDC reference: 1587017

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Clark, J.R., Feng, K., Sookezian, A. et al. Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization. Nature Chem 10, 583–591 (2018). https://doi.org/10.1038/s41557-018-0020-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-018-0020-0

This article is cited by

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