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:

Site-selective arene C–H amination with iron-aminyl radical

Nature Catalysis (2024)Cite this article

Subjects

Abstract

Homolytic aromatic substitution is an enabling strategy for arene C–H functionalization with numerous important synthetic applications. However, despite notable advances, exerting control over site selectivity remains a formidable challenge. Here we report a unified highly site-selective arene C–H amination of various electronically distinct arenes using an iron-aminyl radical. Unlike the conventionally employed free nitrogen-centred radicals, the metal-supported aminyl radical possesses a general attractive interaction with diverse inherent functional groups in arene substrates, engendering extraordinary regioselectivity through substrate chelation. Importantly, this approach has the ability to override the inherent influences of polar and steric effects that typically dictate regiochemical control in homolytic aromatic substitution, leading to high site selectivity. The broad scope of applicable directing groups renders this method a powerful tool to streamline the synthesis of various important aniline building blocks and pharmaceuticals, and allows for the late-stage C–H amination of structurally diverse drugs and other bioactive molecules.

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: Background of site-selective HAS for arene C–H functionalization and our design.
Fig. 2: Optimized conditions and site selectivity comparison with the existing methods.
Fig. 3: Mechanistic studies.
Fig. 4: Proposed reaction pathway and the calculated energy landscape.
Fig. 5: Reaction scope.
Fig. 6: Synthetic utility.

Similar content being viewed by others

Data availability

Experimental procedures and characterization data along with computational information are included in the Supplementary Information. All other data are available from the corresponding authors upon reasonable request.

References

  1. Mortier, J. (ed.) Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds (Wiley, 2015).

  2. Ruffoni, A., Mykura, R., Bietti, M. & Leonori, D. The interplay of polar effects in controlling the selectivity of radical reactions. Nat. Synth. 1, 682–695 (2022).

    Article  Google Scholar 

  3. Bowman, W. R. & Storey, J. M. D. Synthesis using aromatic homolytic substitution—recent advances. Chem. Soc. Rev. 36, 1803–1822 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Proctor, R. S. J. & Phipps, R. J. Recent advances in Minisci-type reactions. Angew. Chem. Int. Ed. 58, 13666–13699 (2019).

    Article  CAS  Google Scholar 

  5. Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ruffoni, A. et al. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 11, 426–433 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Fan, W.-T., Li, Y., Wang, D., Ji, S.-J. & Zhao, Y. Iron-catalyzed highly para-selective difluoromethylation of arenes. J. Am. Chem. Soc. 142, 20524–20530 (2020).

    Article  CAS  PubMed  Google Scholar 

  8. Choi, J., Laudadio, G., Godineau, E. & Baran, P. S. Practical and regioselective synthesis of C-4-alkylated pyridines. J. Am. Chem. Soc. 143, 11927–11933 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ricci, A. (ed.) Amino Group Chemistry: from Synthesis to the Life Sciences (Wiley-VCH, 2008).

  10. Schaefer, T. et al. 4H-Imidazo[1,2-a]imidazole derivatives for electronic applications. World Intellectual Property Organization WO2013068376A1 (2013).

  11. Zavialov, K. V. et al. Preparation of substituted pyrrolopyridines and pyrrolopyrimidines as epidermal growth factor receptor inhibitors. World Intellectual Property Organization WO2022146201A1 (2022).

  12. Mellini, P. et al. Identification of diketopiperazine-containing 2‑anilinobenzamides as potent sirtuin 2 (SIRT2)-selective inhibitors targeting the “selectivity pocket”, substrate-binding site, and NAD+‑binding site. J. Med. Chem. 62, 5844–5862 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Weintraub, P. M. et al. Preparation of substituted pyridinones and pyridines as inhibitors of poly(ADP-ribose) polymerases (PARP). World Intellectual Property Organization WO2005097750A1 (2005).

  14. Alonso, C. et al. Novel topoisomerase I inhibitors. Syntheses and biological evaluation of phosphorus substituted quinoline derivates with antiproliferative activity. Eur. J. Med. Chem. 149, 225–237 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Tejería, A. et al. Antileishmanial activity of new hybrid tetrahydroquinoline and quinoline derivatives with phosphorus substituents. Eur. J. Med. Chem. 162, 18–31 (2019).

    Article  PubMed  Google Scholar 

  16. Shen, Q. & Hartwig, J. F. Palladium-catalyzed coupling of ammonia and lithium amide with aryl halides. J. Am. Chem. Soc. 128, 10028–10029 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Surry, D. S. & Buchwald, S. L. Selective palladium-catalyzed arylation of ammonia: synthesis of anilines as well as symmetrical and unsymmetrical di- and triarylamines. J. Am. Chem. Soc. 129, 10354–10355 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Kim, J. & Chang, S. Ammonium salts as an inexpensive and convenient nitrogen source in the Cu-catalyzed amination of aryl halides at room temperature. Chem. Commun. 2008, 3052−3054 (2008).

  19. Jiao, J., Murakami, K. & Itami, K. Catalytic methods for aromatic C−H amination: an ideal strategy for nitrogen-based functional molecules. ACS Catal. 6, 610–633 (2016).

    Article  CAS  Google Scholar 

  20. Park, Y., Kim, Y. & Chang, S. Transition metal-catalyzed C−H amination: scope, mechanism, and applications. Chem. Rev. 117, 9247–9301 (2017).

    Article  CAS  Google Scholar 

  21. Morofuji, T., Shimizu, A. & Yoshida, J.-I. Electrochemical C–H amination: synthesis of aromatic primary amines via N-arylpyridinium ions. J. Am. Chem. Soc. 135, 5000–5003 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Ham, W. S., Hillenbrand, J., Jacq, J., Genicot, C. & Ritter, T. Divergent late-stage (hetero)aryl C−H amination by the pyridinium radical cation. Angew. Chem. Int. Ed. 58, 532–536 (2019).

    Article  CAS  Google Scholar 

  23. Rössler, S. L. et al. Pyridyl radical cation for C−H amination of arenes. Angew. Chem. Int. Ed. 58, 526–531 (2019).

    Article  Google Scholar 

  24. Zheng, Y.-W. et al. Photocatalytic hydrogen-evolution cross-couplings: benzene C–H amination and hydroxylation. J. Am. Chem. Soc. 138, 10080–10083 (2016).

    Article  CAS  PubMed  Google Scholar 

  25. Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C–H amination via photoredox catalysis. Science 349, 1326–1330 (2015).

    Article  CAS  PubMed  Google Scholar 

  26. Paudyal, M. P. et al. Dirhodium-catalyzed C−H arene amination using hydroxylamines. Science 353, 1144–1147 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, T. et al. A metal-free direct arene C−H amination. Adv. Synth. Catal. 363, 2783–2795 (2021).

    Article  CAS  Google Scholar 

  28. Kim, H., Heo, J., Kim, J., Baik, M.-H. & Chang, S. Copper-mediated amination of aryl C–H bonds with the direct use of aqueous ammonia via a disproportionation pathway. J. Am. Chem. Soc. 140, 14350–14356 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Yu, L. et al. Ammonia as ultimate amino source in synthesis of primary amines via nickel-promoted C–H bond amination. Org. Lett. 21, 5634–5638 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Anugu, R. R., Munnuri, S. & Falck, J. R. Picolinate-directed arene meta-C−H amination via FeCl3 catalysis. J. Am. Chem. Soc. 142, 5266–5271 (2020).

    Article  CAS  PubMed  Google Scholar 

  31. Xu, L.-L. et al. Copper mediated C–H amination with oximes: en route to primary anilines. Chem. Sci. 9, 5160–5164 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li, Z., Yu, H. & Bolm, C. Dibenzothiophene sulfoximine as an NH3 surrogate in the synthesis of primary amines by copper-catalyzed C−X and C−H bond amination. Angew. Chem. Int. Ed. 56, 9532–9535 (2017).

    Article  CAS  Google Scholar 

  33. Matsubara, T., Asako, S., Ilies, L. & Nakamura, E. Synthesis of anthranilic acid derivatives through iron-catalyzed ortho amination of aromatic carboxamides with N‑chloroamines. J. Am. Chem. Soc. 136, 646–649 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Peng, J., Chen, M., Xie, Z., Luo, S. & Zhu, Q. Copper-mediated C(sp2)–H amination using TMSN3 as a nitrogen source: redox-neutral access to primary anilines. Org. Chem. Front. 1, 777–781 (2014).

    Article  CAS  Google Scholar 

  35. Tezuka, N. et al. Direct hydroxylation and amination of arenes via deprotonative cupration. J. Am. Chem. Soc. 138, 9166–9171 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Pratley, C., Fenner, S. & Murphy, J. A. Nitrogen-centered radicals in functionalization of sp2 systems: generation, reactivity, and applications in synthesis. Chem. Rev. 122, 8181–8260 (2022).

    Article  CAS  PubMed  Google Scholar 

  37. Minisci, F., Galli, R. & Cecere, M. Homolytic amination of aromatic compounds by redox systems. Reactivity and orientation. Tetrahedron Lett. 6, 4663–4667 (1965).

    Article  Google Scholar 

  38. Legnani, L., Cerai, G. P. & Morandi, B. Direct and practical synthesis of primary anilines through iron-catalyzed C−H bond amination. ACS Catal. 6, 8162–8165 (2016).

    Article  CAS  Google Scholar 

  39. Liu, J. et al. Iron-catalyzed amination of (hetero)arenes with a redox-active aminating reagent under mild conditions. Chem. Eur. J. 23, 563–567 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. D’Amato, E. M., Börgel, J. & Ritter, T. Aromatic C–H amination in hexafluoroisopropanol. Chem. Sci. 10, 2424–2428 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  41. See, Y. Y. & Sanford, M. S. C−H amination of arenes with hydroxylamine. Org. Lett. 22, 2931–2934 (2020).

    Article  CAS  PubMed  Google Scholar 

  42. Gillespie, J. E., Morrill, C. & Phipps, R. J. Regioselective radical arene amination for the concise synthesis of ortho-phenylenediamines. J. Am. Chem. Soc. 143, 9355–9360 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Morrill, C., Gillespie, J. E. & Phipps, R. J. An aminative rearrangement of O-(arenesulfonyl)hydroxylamines: facile access to ortho-sulfonyl anilines. Angew. Chem. Int. Ed. 61, e202204025 (2022).

    Article  CAS  Google Scholar 

  44. Gillespie, J. E., Lam, N. & Phipps, R. J. Ortho-selective amination of arene carboxylic acids via rearrangement of acyl O-hydroxylamines. Chem. Sci. 14, 10103–10111 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Qiu, X. et al. Cleaving arene rings for acyclic alkenylnitrile synthesis. Nature 597, 64–69 (2021).

    Article  CAS  PubMed  Google Scholar 

  46. Olivos Suarez, A. I., Lyaskovskyy, V., Reek, J. N. H., van der Vlugt, J. I. & de Bruin, B. Complexes with nitrogen-centered radical ligands: classification, spectroscopic features, reactivity, and catalytic applications. Angew. Chem. Int. Ed. 52, 12510–12529 (2013).

    Article  Google Scholar 

  47. 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 

  48. Li, J. et al. Site-specific allylic C–H bond functionalization with a copper-bound N-centred radical. Nature 574, 516–521 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Nakafuku, K. M. et al. Enantioselective radical C–H amination for the synthesis of β-amino alcohols. Nat. Chem. 12, 697–704 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Xu, P., Xie, J.-J., Wang, D.-S. & Zhang, X. P. Metalloradical approach for concurrent control in intermolecular radical allylic C−H amination. Nat. Chem. 15, 498–507 (2023).

    Article  CAS  PubMed  Google Scholar 

  51. Wiese, S. et al. Catalytic C–H amination with unactivated amines through copper(II) amides. Angew. Chem. Int. Ed. 49, 8850–8855 (2010).

    Article  CAS  Google Scholar 

  52. Gephart, R. T. III et al. Catalytic C–H amination with aromatic amines. Angew. Chem. Int. Ed. 51, 6488–6492 (2012).

    Article  CAS  Google Scholar 

  53. Sambiagio, C. et al. A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry. Chem. Soc. Rev. 47, 6603–6743 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chatterjee, S. et al. A combined spectroscopic and computational study on the mechanism of iron-catalyzed aminofunctionalization of olefins using hydroxylamine derived N−O reagent as the “amino” source and “oxidant”. J. Am. Chem. Soc. 144, 2637–2656 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhou, Y. et al. Mechanism and reaction channels of iron-catalyzed primary amination of alkenes by hydroxylamine reagents. ACS Catal. 13, 1863–1874 (2023).

    Article  CAS  Google Scholar 

  56. Fürstner, A. Iron catalysis in organic synthesis: a critical assessment of what it takes to make this base metal a multitasking champion. ACS Cent. Sci. 2, 778–789 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ndubaku, C. O. et al. Pyrazolopyrimidinone compounds and uses thereof. World Intellectual Property Organization WO2019055750A1 (2019).

  58. Liu, Y.-J. et al. Overcoming the limitations of directed C–H functionalizations of heterocycles. Nature 515, 389–393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge the National Natural Science Foundation of China (nos 22101140, 22371143 and 22188101 to F.W. and no. 22073067 to Y.D.), the Fundamental Research Funds for the Central Universities (no. 63223009 to F.W.) and the Haihe Laboratory of Sustainable Chemical Transformations, Frontiers Science Center for New Organic Matter at Nankai University (no. 63181206 to F.W.) for financial support. We thank S.-Y. Xin and J.-K. Cheng from the F.W. group for the experimental assistance. We acknowledge S. S. Stahl (University of Wisconsin–Madison), J. A. Buss (University of Michigan) and D. Wang (Marquette University) for the manuscript proofreading and helpful discussions.

Author information

Author notes

  1. These authors contributed equally: Chao-Rui Ma, Guan-Wang Huang, Hui Xu.

Authors and Affiliations

  1. State Key Laboratory of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, China

    Chao-Rui Ma, Guan-Wang Huang, Zhan-Lin Wang, Zheng-Hao Li, Yin Yang & Fei Wang

  2. Tianjin Key Laboratory of Molecular Optoelectronic Sciences, Department of Chemistry, Tianjin University, Tianjin, China

    Hui Xu & Yanfeng Dang

  3. Tianjin Key Laboratory of Biosensing and Molecular Recognition, Research Center for Analytical Science, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin, China

    Jun Liu & Gongyu Li

Authors
  1. Chao-Rui Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guan-Wang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhan-Lin Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zheng-Hao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yin Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gongyu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanfeng Dang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.-R.M. and G.-W.H. carried out experimental work with support from Z.-L.W. and Z.-H.L.; H.X. and Y.D. performed density functional theory calculations. C.-R.M. and Y.Y. carried out electron paramagnetic resonance measurements. J.L. and G.L. carried out high-resolution mass spectrometry measurements. F.W. handled the project administration. Y.D. and F.W. supervised the project.

Corresponding authors

Correspondence to Yanfeng Dang or Fei Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks John Falck, Anthony J. Fernandes and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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 Figs. 1–25, Tables 1–10, Methods and References.

Supplementary Data 1

Cartesian coordinates of optimized structures.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, CR., Huang, GW., Xu, H. et al. Site-selective arene C–H amination with iron-aminyl radical. Nat Catal (2024). https://doi.org/10.1038/s41929-024-01140-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41929-024-01140-5

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