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.

Skeletal editing through direct nitrogen deletion of secondary amines

Abstract

Synthetic chemistry aims to build up molecular complexity from simple feedstocks1. However, the ability to exert precise changes that manipulate the connectivity of the molecular skeleton itself remains limited, despite possessing substantial potential to expand the accessible chemical space2,3. Here we report a reaction that ‘deletes’ nitrogen from organic molecules. We show that N-pivaloyloxy-N-alkoxyamides, a subclass of anomeric amides, promote the intermolecular activation of secondary aliphatic amines to yield intramolecular carbon–carbon coupling products. Mechanistic experiments indicate that the reactions proceed via isodiazene intermediates that extrude the nitrogen atom as dinitrogen, producing short-lived diradicals that rapidly couple to form the new carbon–carbon bond. The reaction shows broad functional-group tolerance, which enables the translation of routine amine synthesis protocols into a strategy for carbon–carbon bond constructions and ring syntheses. This is highlighted by the use of this reaction in the syntheses and skeletal editing of bioactive compounds.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Background.
Fig. 2: Development of an anomeric amide reagent.
Fig. 3: Scope of the nitrogen-deletion reaction promoted by reagent 1c.
Fig. 4: Mechanistic experiments.

Data availability

All data are available from the corresponding author upon reasonable request.

References

  1. 1.

    Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1995).

  2. 2.

    Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    CAS  Article  Google Scholar 

  3. 3.

    Huigens, R. W., III et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem. 5, 195–202 (2013).

    CAS  Article  Google Scholar 

  4. 4.

    Szpilman, A. M. & Carreira, E. M. Probing the biology of natural products: molecular editing by diverted total synthesis. Angew. Chem. Int. Ed. 49, 9592–9628 (2010).

    CAS  Article  Google Scholar 

  5. 5.

    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).

    CAS  Article  Google Scholar 

  6. 6.

    Hu, Y., Stumpfe, D. & Bajorath, J. Recent advances in scaffold hopping. J. Med. Chem. 60, 1238–1246 (2017).

    CAS  Article  Google Scholar 

  7. 7.

    Mahjour, B., Shen, Y., Liu, W. & Cernak, T. A map of the amine–carboxylic acid coupling system. Nature 580, 71–75 (2020).

    ADS  CAS  Article  Google Scholar 

  8. 8.

    Cao, Z.-C. & Shi, Z.-J. Deoxygenation of ethers to form carbon–carbon bonds via nickel catalysis. J. Am. Chem. Soc. 139, 6546–6549 (2017).

    CAS  Article  Google Scholar 

  9. 9.

    Roque, J. B., Kuroda, Y., Göttemann, L. T. & Sarpong, R. Deconstructive diversification of cyclic amines. Nature 564, 244–248 (2018).

    ADS  CAS  Article  Google Scholar 

  10. 10.

    Smaligo, A. J. et al. Hydrodealkenylative C(sp3)–C(sp2) bond fragmentation. Science 364, 681–685 (2019).

    ADS  CAS  Article  Google Scholar 

  11. 11.

    Fier, P. S., Kim, S. & Maloney, K. M. Reductive cleavage of secondary sulfonamides: converting terminal functional groups into versatile synthetic handles. J. Am. Chem. Soc. 141, 18416–18420 (2019).

    CAS  Article  Google Scholar 

  12. 12.

    Xu, Y. et al. Deacylative transformations of ketones via aromatization-promoted C–C bond activation. Nature 567, 373–378 (2019).

    ADS  CAS  Article  Google Scholar 

  13. 13.

    Silva Jr, L. F. in Stereoselective Synthesis of Drugs and Natural Products Vol. 1 (eds Andrushko, N. & Andrushko, V.) Ch. 18 (Wiley, 2013).

  14. 14.

    Donald, J. R. & Unsworth, W. P. Ring-expansion reactions in the synthesis of macrocycles and medium-sized rings. Chem. Eur. J. 23, 8780–8799 (2017).

    CAS  Article  Google Scholar 

  15. 15.

    Glover, S. A. Anomeric amides — Structure, properties and reactivity. Tetrahedron 54, 7229–7271 (1998).

    CAS  Article  Google Scholar 

  16. 16.

    Glover, S. A. & Mo, G. Hindered ester formation by SN2 azidation of N-acetoxy-N-alkoxyamides and N-alkoxy-N-chloroamides—novel application of HERON rearrangements. J. Chem. Soc., Perkin Trans. 2 1728–1739 (2002).

    Article  Google Scholar 

  17. 17.

    Hinman, R. L. & Hamm, K. L. The oxidation of 1,1-dibenzylhydrazines. J. Am. Chem. Soc. 81, 3294–3297 (1959).

    CAS  Article  Google Scholar 

  18. 18.

    Hinsberg, W. D. & Dervan, P. B. Synthesis and direct spectroscopic observation of a 1,1-dialkyldiazene. Infrared and electronic spectrum of N-(2,2,6,6-tetramethylpiperidyl)nitrene. J. Am. Chem. Soc. 100, 1608–1610 (1978).

    CAS  Article  Google Scholar 

  19. 19.

    Kuznetsov, M. A. & Ioffe, B. V. The present state of the chemistry of aminonitrenes and oxynitrenes. Russ. Chem. Rev. 58, 732 (1989).

    ADS  Article  Google Scholar 

  20. 20.

    Urry, W. H., Kruse, H. W. & McBride, W. R. Novel organic reactions of the intermediate from the two-electron oxidation of 1,1-dialkyl hydrazines in acid. J. Am. Chem. Soc. 79, 6568–6569 (1957).

    CAS  Article  Google Scholar 

  21. 21.

    Lemal, D. M. & Rave, T. W. Diazenes from Angeli’s Salt. J. Am. Chem. Soc. 87, 393–394 (1965).

    CAS  Article  Google Scholar 

  22. 22.

    Zou, X., Zou, J., Yang, L., Li, G. & Lu, H. Thermal rearrangement of sulfamoyl azides: reactivity and mechanistic study. J. Org. Chem. 82, 4677–4688 (2017).

    CAS  Article  Google Scholar 

  23. 23.

    Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    CAS  Article  Google Scholar 

  24. 24.

    Berger, K. J. & Levin, M. D. Reframing primary alkyl amines as aliphatic building blocks. Org. Biomol. Chem. 19, 11–36 (2021).

    CAS  Article  Google Scholar 

  25. 25.

    Plunkett, S., Basch, C. H., Santana, S. O. & Watson, M. P. Harnessing alkylpyridinium salts as electrophiles in deaminative alkyl–alkyl cross-couplings. J. Am. Chem. Soc. 141, 2257–2262 (2019).

    CAS  Article  Google Scholar 

  26. 26.

    Brown, H. C. & Okamoto, Y. Electrophilic substituent constants. J. Am. Chem. Soc. 80, 4979–4987 (1958).

    CAS  Article  Google Scholar 

  27. 27.

    Banert, K. et al. Steric hindrance underestimated: it is a long, long way to tri-tert-alkylamines. J. Org. Chem. 83, 5138–5148 (2018).

    CAS  Article  Google Scholar 

  28. 28.

    Procopiou, G., Lewis, W., Harbottle, G. & Stockman, R. A. Cycloaddition of chiral tert-butanesulfinimines with trimethylenemethane. Org. Lett. 15, 2030–2033 (2013).

    CAS  Article  Google Scholar 

  29. 29.

    Chandrasekaran, R. Y. & Wager, T. T. Histamine-3 receptor modulators. US patent US2005171181A1 (2005).

  30. 30.

    Wager, T. T. et al. Discovery of two clinical histamine H3 receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764). J. Med. Chem. 54, 7602–7620 (2011).

    CAS  Article  Google Scholar 

  31. 31.

    Taylor, E. C. in Successful Drug Discovery (eds Fischer, J. & Rotella, D. P.) 157–180 (John Wiley & Sons, Ltd, 2015).

  32. 32.

    Barrett, T. N., Braddock, D. C., Monta, A., Webb, M. R. & White, A. J. P. Total synthesis of the marine metabolite (±)-polysiphenol via highly regioselective intramolecular oxidative coupling. J. Nat. Prod. 74, 1980–1984 (2011).

    CAS  Article  Google Scholar 

  33. 33.

    Moy, B., Kirkpatrick, P., Kar, S. & Goss, P. Lapatinib. Nat. Rev. Drug Discov. 6, 431–432 (2007).

    CAS  Article  Google Scholar 

  34. 34.

    Ayer, W. A. & Habgood, T. E. in The Alkaloids: Chemistry and Physiology Vol. 11 (ed. Manske, R. H. F.) Ch. 12, 459–510 (Academic Press, 1968).

  35. 35.

    Münch, G. et al. The cognition-enhancing drug tenilsetam is an inhibitor of protein crosslinking by advanced glycosylation. J Neural Transm. Park. Dis. Dement. Sect. 8, 193–208 (1994).

    Article  Google Scholar 

  36. 36.

    De Almeida, M. V. et al. Preparation and thermal decomposition of N,N′-diacyl-N,N′-dialkoxyhydrazines: synthetic applications and mechanistic insights. J. Am. Chem. Soc. 117, 4870–4874 (1995).

    Article  Google Scholar 

  37. 37.

    Glover, S. A. et al. The HERON reaction — origin, theoretical background, and prevalence. Can. J. Chem. 83, 1492–1509 (2005).

    CAS  Article  Google Scholar 

  38. 38.

    Strick, B. F., Mundal, D. A. & Thomson, R. J. An oxidative [2,3]-sigmatropic rearrangement of allylic hydrazides. J. Am. Chem. Soc. 133, 14252–14255 (2011).

    CAS  Article  Google Scholar 

  39. 39.

    Nwachukwu, C. I., McFadden, T. P. & Roberts, A. G. Ni-catalyzed iterative alkyl transfer from nitrogen enabled by the in situ methylation of tertiary amines. J. Org. Chem. 85, 9979–9992 (2020).

    CAS  Article  Google Scholar 

  40. 40.

    Newcomb, M. in Encyclopedia of Radicals in Chemistry, Biology and Materials (eds Chatgilialoglu, C. & Studer, A.) (Wiley, 2012).

  41. 41.

    Herk, L., Feld, M. & Szwarc, M. Studies of “Cage” Reactions. J. Am. Chem. Soc. 83, 2998–3005 (1961).

    CAS  Article  Google Scholar 

  42. 42.

    Carpenter, B. K. Dynamic behavior of organic reactive intermediates. Angew. Chem. Int. Ed. 37, 3340–3350 (1998).

    Article  Google Scholar 

Download references

Acknowledgements

We thank D. Nagib, F. D. Toste, M. Johnson and Z. Wickens for discussions. Financial support for this work was provided by start-up funding from the University of Chicago.

Author information

Affiliations

Authors

Contributions

S.H.K., K.J.B. and B.D.D. designed and conducted experiments, and collected and analysed the data. M.D.L. supervised the research, conceived of the project and wrote the manuscript with input from all authors.

Corresponding author

Correspondence to Mark D. Levin.

Ethics declarations

Competing interests

Reagent 1c is under development for commercialization with Sigma-Aldrich (product number 919799), but the authors have retained no financial interest and no patents have been filed.

Additional information

Peer review information Nature thanks the anonymous reviewers for their contribution to the peer review of this work.

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

Supplementary information

Supplementary Information

This file contains Supplementary Sections 1-59, including Supplementary Materials and Methods, Procedures, Supplementary Figures 1-17, Supplementary References and NMR Spectra data – see contents page for details.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kennedy, S.H., Dherange, B.D., Berger, K.J. et al. Skeletal editing through direct nitrogen deletion of secondary amines. Nature 593, 223–227 (2021). https://doi.org/10.1038/s41586-021-03448-9

Download citation

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

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