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:

Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of β-lactams via transposed NiH catalysis

Nature Catalysis volume 6, pages 784–795 (2023)Cite this article

Subjects

A preprint version of the article is available at arXiv.

Abstract

Synthetic methods for constructing enantioenriched β-lactams are highly valuable given their ubiquity in bioactive compounds, most notably in antibiotics such as penicillins and carbapenems. Intramolecular hydroamidation of β,γ-unsaturated amides would provide a convenient means to reach this alluring chemical space, yet it remains limited due to the regioselectivity issue arising from the difficulty associated with the formation of strained four-membered rings. Here we describe a NiH-catalysed strategy that addresses this challenge through the use of readily accessible alkenyl dioxazolone derivatives. The reaction transcends the conventional NiH operation mode via a transposed mechanism initiated by N-activation, thus allowing for proximal C–N bond formation with excellent regioselectivity, regardless of the electronic properties of substituents. This mechanistic platform is also highly effective for the enantioselective intramolecular hydroamidation of alkenes to enable a convenient access to enantioenriched β-lactams.

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: Intramolecular umpolung hydroamination of alkenes harnessing TMH.
Fig. 2: Reaction development and preliminary mechanistic investigations.
Fig. 3: Experimental investigations towards the feasibility of stepwise mechanism.
Fig. 4: Mechanistic considerations of the concerted insertion mode.
Fig. 5: Reaction scope of the NiH-catalysed intramolecular hydroamidation.
Fig. 6: NiH-catalysed enantioselective hydroamidation of alkenyl dioxazolones.
Fig. 7: Synthetic applications of the NiH-catalysed enantioselective hydroamidation.

Similar content being viewed by others

Data availability

The X-ray crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC2236294 (2), CCDC2236394 (15), CCDC2236312 (17) and CCDC2236313 ((R)-22). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. All other data are available from the authors upon reasonable request.

References

  1. Jordan, A. J., Lalic, G. & Sadighi, J. P. Coinage metal hydrides: synthesis, characterization, and reactivity. Chem. Rev. 116, 8318–8372 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Eberhardt, N. A. & Guan, H. Nickel hydride complexes. Chem. Rev. 116, 8373–8426 (2016).

    Article  CAS  PubMed  Google Scholar 

  3. Hu, Y., Shaw, A. P., Estes, D. P. & Norton, J. R. Transition-metal hydride radical cations. Chem. Rev. 116, 8427–8462 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Crossley, S. W. M., Obradors, C., Martinez, R. M. & Shenvi, R. A. Mn-, Fe-, and Co-catalyzed radical hydrofunctionalizations of olefins. Chem. Rev. 116, 8912–9000 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Green, S. A. et al. The high chemofidelity of metal-catalyzed hydrogen atom transfer. Acc. Chem. Res. 51, 2628–2640 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen, J., Guo, J. & Lu, Z. Recent advances in hydrometallation of alkenes and alkynes via the first row transition metal catalysis. Chin. J. Chem. 36, 1075–1109 (2018).

    Article  CAS  Google Scholar 

  7. Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences (Wiley‐VCH, 2007).

  8. Hirano, K. & Miura, M. Hydroamination, aminoboration, and carboamination with electrophilic amination reagents: Umpolung-enabled regio- and stereoselective synthesis of N-containing molecules from alkenes and alkynes. J. Am. Chem. Soc. 144, 648–661 (2022).

    Article  CAS  PubMed  Google Scholar 

  9. Miki, Y., Hirano, K., Satoh, T. & Miura, M. Copper-catalyzed intermolecular regioselective hydroamination of styrenes with polymethylhydrosiloxane and hydroxylamines. Angew. Chem. Int. Ed. 52, 10830–10834 (2013).

    Article  CAS  Google Scholar 

  10. Zhu, S., Niljianskul, N. & Buchwald, S. L. Enantio- and regioselective CuH-catalyzed hydroamination of alkenes. J. Am. Chem. Soc. 135, 15746–15749 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Müller, T. E., Hultzsch, K. C., Yus, M., Foubelo, F. & Tada, M. Hydroamination: direct addition of amines to alkenes and alkynes. Chem. Rev. 108, 3795–3892 (2008).

    Article  PubMed  Google Scholar 

  12. Huang, L., Arndt, M., Gooßen, K., Heydt, H. & Gooßen, L. J. Late transition metal-catalyzed hydroamination and hydroamidation. Chem. Rev. 115, 2596–2697 (2015).

    Article  CAS  PubMed  Google Scholar 

  13. Liu, R. Y. & Buchwald, S. L. CuH-catalyzed olefin functionalization: from hydroamination to carbonyl addition. Acc. Chem. Res. 53, 1229–1243 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gui, J. et al. Practical olefin hydroamination with nitroarenes. Science 348, 886–891 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Song, H., Yang, Z., Tung, C.-H. & Wang, W. Iron-catalyzed reductive coupling of nitroarenes with olefins: Intermediate of iron–nitroso complex. ACS Catal. 10, 276–281 (2020).

    Article  CAS  Google Scholar 

  16. Chen, J., Shen, X. & Lu, Z. Cobalt-catalyzed Markovnikov selective sequential hydrogenation/hydrohydrazidation of aliphatic terminal alkynes. J. Am. Chem. Soc. 142, 14455–14460 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Shen, X. et al. Ligand-promoted cobalt-catalyzed radical hydroamination of alkenes. Nat. Commun. 11, 783 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang, Y., He, Y. & Zhu, S. NiH-catalyzed functionalization of remote and proximal olefins: new reactions and innovative strategies. Acc. Chem. Res. 55, 3519–3536 (2022).

    Article  CAS  PubMed  Google Scholar 

  19. Dai, X.-J., Engl, O. D., León, T. & Buchwald, S. L. Catalytic asymmetric synthesis of α-arylpyrrolidines and benzo-fused nitrogen heterocycles. Angew. Chem. Int. Ed. 58, 3407–3411 (2019).

    Article  CAS  Google Scholar 

  20. Xi, Y., Butcher, T. W., Zhang, J. & Hartwig, J. F. Regioselective, asymmetric formal hydroamination of unactivated internal alkenes. Angew. Chem. Int. Ed. 55, 776–780 (2016).

    Article  CAS  Google Scholar 

  21. Ichikawa, S., Dai, X.-J. & Buchwald, S. L. Regio- and enantioselective synthesis of 1,2-diamine derivatives by copper-catalyzed hydroamination. Org. Lett. 21, 4370–4373 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Shigehisa, H. et al. Catalytic hydroamination of unactivated olefins using a Co catalyst for complex molecule synthesis. J. Am. Chem. Soc. 136, 13534–13537 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Osato, A., Fujihara, T. & Shigehisa, H. Constructing four-membered heterocycles by cycloisomerization. ACS Catal. 13, 4101–4110 (2023).

    Article  CAS  Google Scholar 

  24. Wang, H., Yang, J. C. & Buchwald, S. L. CuH-catalyzed regioselective intramolecular hydroamination for the synthesis of alkyl-substituted chiral aziridines. J. Am. Chem. Soc. 139, 8428–8431 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gao, D.-W. et al. Cascade CuH-catalysed conversion of alkynes into enantioenriched 1,1-disubstituted products. Nat. Catal. 3, 23–29 (2020).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Banik, B. K. Beta-Lactams: Novel Synthetic Pathways and Applications (Springer Cham, 2017).

  28. 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 

  29. van Vliet, K. M. & de Bruin, B. Dioxazolones: Stable substrates for the catalytic transfer of acyl nitrenes. ACS Catal. 10, 4751–4769 (2020).

    Article  Google Scholar 

  30. Hong, S. Y., Hwang, Y., Lee, M. & Chang, S. Mechanism-guided development of transition-metal-catalyzed C–N bond-forming reactions using dioxazolones as the versatile amidating source. Acc. Chem. Res. 54, 2683–2700 (2021).

    Article  CAS  PubMed  Google Scholar 

  31. Lyu, X., Zhang, J., Kim, D., Seo, S. & Chang, S. Merging NiH catalysis and inner-sphere metal-nitrenoid transfer for hydroamidation of alkynes. J. Am. Chem. Soc. 143, 5867–5877 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Choi, H., Lyu, X., Kim, D., Seo, S. & Chang, S. Endo-selective intramolecular alkyne hydroamidation enabled by NiH catalysis incorporating alkenylnickel isomerization. J. Am. Chem. Soc. 144, 10064–10074 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Meng, L., Yang, J., Duan, M., Wang, Y. & Zhu, S. Facile synthesis of chiral arylamines, alkylamines and amides by enantioselective NiH-catalyzed hydroamination. Angew. Chem. Int. Ed. 60, 23584–23589 (2021).

    Article  CAS  Google Scholar 

  34. Zhang, Y., Qiao, D., Duan, M., Wang, Y. & Zhu, S. Enantioselective synthesis of α-aminoboronates by NiH-catalysed asymmetric hydroamidation of alkenyl boronates. Nat. Commun. 13, 5630 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li, Y. et al. A general strategy for the synthesis of α-trifluoromethyl- and α-perfluoroalkyl-β-lactams via palladium-catalyzed carbonylation. Chem. Sci. 12, 10467–10473 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fischer, D. M., Balkenhohl, M. & Carreira, E. M. Cobalt-catalyzed cyclization of unsaturated N-acyl sulfonamides: a diverted Mukaiyama hydration reaction. JACS Au 2, 1071–1077 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Marson, C. M. & Fallah, A. Preparation of γ- and δ-lactams by ring closure of β,γ-unsaturated amides using trifluoromethanesulfonic acid. Tetrahedron Lett. 35, 293–296 (1994).

    Article  CAS  Google Scholar 

  38. Qi, C., Hasenmaile, F., Gandon, V. & Lebœuf, D. Calcium(II)-catalyzed intra- and intermolecular hydroamidation of unactivated alkenes in hexafluoroisopropanol. ACS Catal. 8, 1734–1739 (2018).

    Article  CAS  Google Scholar 

  39. Wang, H. et al. Regioselective intramolecular Markovnikov and anti-Markovnikov hydrofunctionalization of alkenes via photoredox catalysis. Chem. Commun. 55, 11426–11429 (2019).

    Article  CAS  Google Scholar 

  40. Jeon, J., Lee, C., Seo, H. & Hong, S. NiH-catalyzed proximal-selective hydroamination of unactivated alkenes. J. Am. Chem. Soc. 142, 20470–20480 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Lee, C., Seo, H., Jeon, J. & Hong, S. γ-Selective C(sp3)–H amination via controlled migratory hydroamination. Nat. Commun. 12, 5657 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Du, B., Ouyang, Y., Chen, Q. & Yu, W.-Y. Thioether-directed NiH-catalyzed remote γ-C(sp3)–H hydroamidation of alkenes by 1,4,2-dioxazol-5-ones. J. Am. Chem. Soc. 143, 14962–14968 (2021).

    Article  CAS  PubMed  Google Scholar 

  43. Lee, C., Kang, H.-J., Seo, H. & Hong, S. Nickel-catalyzed regio- and enantioselective hydroamination of unactivated alkenes using carbonyl directing groups. J. Am. Chem. Soc. 144, 9091–9100 (2022).

    Article  CAS  PubMed  Google Scholar 

  44. Du, B. et al. NiH-catalyzed anti-Markovnikov hydroamidation of unactivated alkenes with 1,4,2-dioxazol-5-ones for the direct synthesis of N-alkyl amides. Commun. Chem. 5, 176 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hong, S. Y. & Chang, S. Stereodefined access to lactams via olefin difunctionalization: iridium nitrenoids as a motif of LUMO-controlled dipoles. J. Am. Chem. Soc. 141, 10399–10408 (2019).

    Article  CAS  PubMed  Google Scholar 

  46. Hong, S. Y., Kim, D. & Chang, S. Catalytic access to carbocation intermediates via nitrenoid transfer leading to allylic lactams. Nat. Catal. 4, 79–88 (2021).

    Article  CAS  Google Scholar 

  47. Kim, S., Kim, D., Hong, S. Y. & Chang, S. Tuning orbital symmetry of iridium nitrenoid enables catalytic diastereo- and enantioselective alkene difunctionalizations. J. Am. Chem. Soc. 143, 3993–4004 (2021).

    Article  CAS  PubMed  Google Scholar 

  48. Kweon, J., Kim, D., Kang, S. & Chang, S. Access to β-lactams via iron-catalyzed olefin oxyamidation enabled by the π-accepting phthalocyanine ligand. J. Am. Chem. Soc. 144, 1872–1880 (2022).

    Article  CAS  PubMed  Google Scholar 

  49. Polse, J. L., Andersen, R. A. & Bergman, R. G. Reactivity of a terminal Ti(IV) imido complex toward alkenes and alkynes: cycloaddition vs C–H activation. J. Am. Chem. Soc. 120, 13405–13414 (1998).

    Article  CAS  Google Scholar 

  50. Day, C. S. et al. Elucidating electron-transfer events in polypyridine nickel complexes for reductive coupling reactions. Nat. Catal. 6, 244–253 (2023).

    Article  CAS  Google Scholar 

  51. Brandi, A., Cicchi, S. & Cordero, F. M. Novel syntheses of azetidines and azetidinones. Chem. Rev. 108, 3988–4035 (2008).

    Article  CAS  PubMed  Google Scholar 

  52. Hodous, B. L. & Fu, G. C. Enantioselective Staudinger aynthesis of β-lactams catalyzed by a planar-chiral nucleophile. J. Am. Chem. Soc. 124, 1578–1579 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Khangarot, R. K. & Kaliappan, K. P. Kinugasa reaction: a direct one-pot route to highly functionalized β-lactams. Eur. J. Org. Chem. 2013, 7664–7677 (2013).

    Article  CAS  Google Scholar 

  54. Ye, Y. et al. Using enzymes to tame nitrogen-centred radicals for enantioselective hydroamination. Nat. Chem. 15, 206–212 (2022).

    Article  PubMed  Google Scholar 

  55. Fujioka, H., Yamanaka, T., Matsunaga, N., Fuji, M. & Kita, Y. Asymmetric synthesis of carbapenems using chiral acetals: synthesis of a key intermediate to (+)-PS-5. Synlett 1992, 35–36 (1992).

    Article  Google Scholar 

  56. Starcevic, S., Mrak, P. & Kopitar, G. An enzymatic route for the preparation of chiral γ-aryl-β-aminobutyric acid derivatives. WO2014096375 (2014).

  57. Momoi, Y. et al. Total synthesis of (−)-Haouamine B pentaacetate and structural revision of Haouamine B. Angew. Chem. Int. Ed. 53, 13215–13219 (2014).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Institute for Basic Science (IBS-R010-Y2 (S.S.) and IBS-R010-D1 (S.C.)) in South Korea. S.S. also acknowledges support from the DGIST Start-up Fund Program of the Ministry of Science and ICT (2023040012). Computational works for this research were performed on the High Performance Computing Resources in the IBS Research Solution Center.

Author information

Authors and Affiliations

  1. Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, Republic of Korea

    Xiang Lyu, Changhyeon Seo, Hoimin Jung, Dongwook Kim, Sangwon Seo & Sukbok Chang

  2. Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea

    Xiang Lyu, Changhyeon Seo, Hoimin Jung, Dongwook Kim & Sukbok Chang

  3. Westfälische Wilhelms-Universität Münster, Organisch-Chemisches Institut, Münster, Germany

    Teresa Faber

  4. Department of Physics and Chemistry, DGIST, Daegu, Republic of Korea

    Sangwon Seo

Authors
  1. Xiang Lyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Changhyeon Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hoimin Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Teresa Faber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dongwook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sangwon Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sukbok Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.S. and S.C. conceived and designed the project. X.L. optimized the reaction conditions for asymmetric hydroamination, and performed and analysed the experiments for the reaction scope and mechanistic investigations. X.L. and C.S. carried out experiments for the synthetic applications. T.F. contributed to the initial findings and reaction optimization of the standard hydroamidation reaction. D.K. performed the X-ray crystallographic analysis. H.J. carried out the DFT calculations. S.S and S.C. organized the research and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Sangwon Seo or Sukbok Chang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks Cristina Trujillo and the other, anonymous, reviewers 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 Methods, Tables 1–15, Figs. 1–22 and references.

Supplementary Data 1

Crystallographic data for compound 2.

Supplementary Data 2

Crystallographic data for compound 15.

Supplementary Data 3

Crystallographic data for compound 17.

Supplementary Data 4

Crystallographic data for compound (R)-22.

Supplementary Data 5

Cartesian coordinates of DFT-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

Lyu, X., Seo, C., Jung, H. et al. Intramolecular hydroamidation of alkenes enabling asymmetric synthesis of β-lactams via transposed NiH catalysis. Nat Catal 6, 784–795 (2023). https://doi.org/10.1038/s41929-023-01014-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-023-01014-2

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