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:

Catalytic access to carbocation intermediates via nitrenoid transfer leading to allylic lactams

Nature Catalysis volume 4, pages 79–88 (2021)Cite this article

Subjects

Abstract

Carbocation intermediacy is postulated in numerous organic transformations and provides the foundation for retrosynthetic logics in chemical synthesis. Although a number of catalytic approaches are designed to generate transient carbocations under mild conditions, there is room for improvement in the context of selectivity control and synthetic utility. Here we present an approach that enables catalytic access to carbocation intermediates via metal-nitrenoid transfer into alkenes, which subsequently allows a regiocontrolled elimination reaction. Customized catalysts are capable of bypassing competing pathways of the reactive intermediates to furnish valuable allylic lactams with excellent regioselectivity. Mechanistic investigations suggest that the ligand plays a critical role as an internal base in the selectivity-determining proton transfer process. This protocol is broadly applicable for preparing both five- and the more challenging four-membered allylamides. The virtue of this platform is further demonstrated by achieving the enantioselective construction of γ-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: Carbocation intermediacy.
Fig. 2: General applicability.
Fig. 3: Further advances in Ir-catalysed cyclization.
Fig. 4: DFT calculations for the proposed mechanism.
Fig. 5: Experimental support for the proposed carbocation intermediacy.

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 nos. 1999590–1999595. 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. Norris, J. F. On the nonexistence of trivalent carbon. Am. Chem. J. 25, 117–122 (1901).

    CAS  Google Scholar 

  2. Kehrmann, F. W. & Ueber, F. Die basischen eigenschaften des kohlenstoffs und die constitution des sogennanten triphenylmeths. Ber. Dtsch. Chem. Ges. 34, 3815–3819 (1901).

    Article  CAS  Google Scholar 

  3. Olah, G. A. 100 years of carbocations and their significance in chemistry. J. Org. Chem. 66, 5943–5957 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Naredla, R. R. & Klumpp, D. A. Contemporary carbocation chemistry: applications in organic synthesis. Chem. Rev. 113, 6905–6948 (2013).

    Article  CAS  PubMed  Google Scholar 

  5. Olah, G. A. & Lukas, J. Stable carbonium ions. XXXIX. Formation of alkylcarbonium ions via hydride ion abstraction from alkanes in fluorosulfonic acid–antimony pentafluoride solution. Isolation of some crystalline alkylcarbonium ion salts. J. Am. Chem. Soc. 89, 2227–2228 (1967).

    Article  CAS  Google Scholar 

  6. Zhang, F. et al. Cu-catalyzed cascades to carbocycles: union of diaryliodonium salts with alkenes or alkynes exploiting remote carbocations. J. Am. Chem. Soc. 136, 8851–8854 (2014).

    Article  CAS  PubMed  Google Scholar 

  7. Nitsch, D. et al. Chiral propargylic cations as intermediates in SN1-type reactions: substitution pattern, nuclear magnetic resonance studies, and origin of the diastereoselectivity. J. Am. Chem. Soc. 136, 2851–2857 (2014).

    Article  CAS  PubMed  Google Scholar 

  8. Zhu, Q., Gentry, E. C. & Knowles, R. R. Catalytic carbocation generation enabled by the mesolytic cleavage of alkoxyamine radical cations. Angew. Chem. Int. Ed. 55, 9969–9973 (2016).

    Article  CAS  Google Scholar 

  9. Shao, B., Bagdasarian, A. L., Popov, S. & Nelson, H. M. Arylation of hydrocarbons enabled by organosilicon reagents and weakly coordinating anions. Science 355, 1403–1407 (2017).

    Article  CAS  PubMed  Google Scholar 

  10. Phipps, R. J., McMurray, L., Ritter, S., Duong, H. A. & Gaunt, M. J. Copper-catalyzed alkene arylation with diaryliodonium salts. J. Am. Chem. Soc. 134, 10773–10776 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Wigman, B. et al. Vinyl carbocations generated under basic conditions and their intramolecular C–H insertion reactions. J. Am. Chem. Soc. 141, 9140–9144 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Kutateladze, D. A., Strassfeld, D. A. & Jacobsen, E. N. Enantioselective tail-to-head cyclizations catalyzed by dual-hydrogen-bond donors. J. Am. Chem. Soc. 142, 6951–6956 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wendlandt, A. E., Vangal, P. & Jacobsen, E. N. Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. Nature 556, 447–451 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Isomura, M., Petrone, D. A. & Carreira, E. M. Coordination-induced stereocontrol over carbocations: asymmetric reductive deoxygenation of racemic tertiary alcohols. J. Am. Chem. Soc. 141, 4738–4748 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. Degennaro, L., Trinchera, P. & Luisi, R. Recent advances in the stereoselective synthesis of aziridines. Chem. Rev. 114, 7881–7929 (2014).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, S., Lei, H. & Rovis, T. A Rh(iii)-catalyzed formal [4+1] approach to pyrrolidines from unactivated terminal alkenes and nitrene sources. J. Am. Chem. Soc. 141, 12536–12540 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rigoli, J. W., Weatherly, C. D., Alderson, J. M., Vo, B. T. & Schomaker, J. M. Tunable, chemoselective amination via silver catalysis. J. Am. Chem. Soc. 135, 17238–17241 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Stokes, B. J., Liu, S. & Driver, T. G. Rh2(ii)-catalyzed nitro-group migration reactions: selective synthesis of 3-nitroindoles from β-nitro styryl azides. J. Am. Chem. Soc. 133, 4702–4705 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kong, C., Jana, N. & Driver, T. G. Rh2(ii)-catalyzed selective aminomethylene migration from styryl azides. Org. Lett. 15, 824–827 (2013).

    Article  CAS  PubMed  PubMed Central  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  PubMed  Google Scholar 

  21. Nay, B., Riache, N. & Evanno, L. Chemistry and biology of non-tetramic γ-hydroxy-γ-lactams and γ-alkylidene-γ-lactams from natural sources. Nat. Prod. Rep. 26, 1044–1062 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Kambe, T. et al. Discovery of novel prostaglandin analogs as potent and selective EP2/EP4 dual agonists. Bioorg. Med. Chem. 20, 2235–2251 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Meiries, S. & Marquez, R. Convergent synthesis of (2R,3R,8R,9R)-N-Boc-ADDA. J. Org. Chem. 73, 5015–5021 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Griesbeck, A. G., Bondock, S. & Lex, J. Synthesis of erythro-α-amino β-hydroxy carboxylic acid esters by diastereoselective photocycloaddition of 5-methoxyoxazoles with aldehydes. J. Org. Chem. 68, 9899–9906 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Ferreira, P. M. T., Monteiro, L. S. & Pereira, G. Synthesis of substituted oxazoles from N-acyl-β-hydroxyamino acid derivatives. Eur. J. Org. Chem. 2008, 4676–4683 (2008).

    Article  CAS  Google Scholar 

  26. Shigehisa, H., Aoki, T., Yamaguchi, S., Shimizu, N. & Hiroya, K. Hydroalkoxylation of unactivated olefins with carbon radicals and carbocation species as key intermediates. J. Am. Chem. Soc. 135, 10306–10309 (2013).

    Article  CAS  PubMed  Google Scholar 

  27. Whitmore, F. C. The common basis of intramolecular rearrangements. J. Am. Chem. Soc. 54, 3274–3283 (1932).

    Article  CAS  Google Scholar 

  28. Fujita, K.-i, Tanino, N. & Yamaguchi, R. Ligand-promoted dehydrogenation of alcohols catalyzed by Cp*Ir complexes. A new catalytic system for oxidant-free oxidation of alcohols. Org. Lett. 9, 109–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Royer, A. M., Rauchfuss, T. B. & Gray, D. L. Organoiridium pyridonates and their role in the dehydrogenation of alcohols. Organometallics 29, 6763–6768 (2010).

    Article  CAS  Google Scholar 

  30. Hong, S. Y. et al. Selective formation of γ-lactams via C–H amidation enabled by tailored iridium catalysts. Science 359, 1016–1021 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Hong, S. Y., Son, J., Kim, D. & Chang, S. Ir(iii)-catalyzed stereoselective haloamidation of alkynes enabled by ligand participation. J. Am. Chem. Soc. 140, 12359–12363 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Hwang, Y., Park, Y., Kim, Y. B., Kim, D. & Chang, S. Revisiting arene C(sp2)−H amidation by intramolecular transfer of iridium nitrenoids: evidence for a spirocyclization pathway. Angew. Chem. Int. Ed. 57, 13565–13569 (2018).

    Article  CAS  Google Scholar 

  34. Filler, R. & Schure, R. M. Highly acidic perhalogenated alcohols. A new synthesis of perfluoro-tert-butyl alcohol. J. Org. Chem. 32, 1217–1219 (1967).

    Article  CAS  Google Scholar 

  35. Park, Y., Park, K. T., Kim, J. G. & Chang, S. Mechanistic studies on the Rh(iii)-mediated amido transfer process leading to robust C–H amination with a new type of amidating reagent. J. Am. Chem. Soc. 137, 4534–4542 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Fisher, J. F., Meroueh, S. O. & Mobashery, S. Bacterial resistance to β-lactam antibiotics: compelling opportunism, compelling opportunity. Chem. Rev. 105, 395–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Fernandes, R., Amador, P. & Prudêncio, C. β-Lactams: chemical structure, mode of action and mechanisms of resistance. Rev. Med. Microbiol. 24, 7–17 (2013).

    Article  Google Scholar 

  38. Minatti, A. & Muñiz, K. Intramolecular aminopalladation of alkenes as a key step to pyrrolidines and related heterocycles. Chem. Soc. Rev. 36, 1142–1152 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Xiong, P., Xu, H.-H. & Xu, H.-C. Metal- and reagent-free intramolecular oxidative amination of tri- and tetrasubstituted alkenes. J. Am. Chem. Soc. 139, 2956–2959 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Race, N. J., Hazelden, I. R., Faulkner, A. & Bower, J. F. Recent developments in the use of aza-Heck cyclizations for the synthesis of chiral N-heterocycles. Chem. Sci. 8, 5248–5260 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shuler, S. A., Yin, G., Krause, S. B., Vesper, C. M. & Watson, D. A. Synthesis of secondary unsaturated lactams via an Aza–Heck reaction. J. Am. Chem. Soc. 138, 13830–13833 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, H. et al. Iridium-Catalysed enantioselective C(sp3)–H amidation controlled by attractive noncovalent interactions. J. Am. Chem. Soc. 141, 7194–7201 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Dolan, N. S., Scamp, R. J., Yang, T., Berry, J. F. & Schomaker, J. M. Catalyst-controlled and tunable, chemoselective silver-catalyzed intermolecular nitrene transfer: experimental and computational studies. J. Am. Chem. Soc. 138, 14658–14667 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lebel, H., Huard, K. & Lectard, S. N-Tosyloxycarbamates as a source of metal nitrenes: rhodium-catalyzed C−H insertion and aziridination reactions. J. Am. Chem. Soc. 127, 14198–14199 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Jiang, H., Lang, K., Lu, H., Wojtas, L. & Zhang, X. P. Asymmetric radical bicyclization of allyl azidoformates via cobalt(ii)-based metalloradical catalysis. J. Am. Chem. Soc. 139, 9164–9167 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction–activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).

    Article  CAS  Google Scholar 

  47. Olah, G. A. Stable carbocations, 189. The σ-bridged 2-norbornyl cation and its significance to chemistry. Acc. Chem. Res. 9, 41–52 (1976).

    Article  CAS  Google Scholar 

  48. Hammett, L. P. The effect of structure upon the reactions of organic compounds. Benzene derivatives. J. Am. Chem. Soc. 59, 96–103 (1937).

    Article  CAS  Google Scholar 

  49. Lee, J. et al. Versatile Cp*Co(iii)(LX) catalyst system for selective intramolecular C–H amidation reactions. J. Am. Chem. Soc. 142, 12324–12332 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Thai, T.-T., Therrien, B. & Süss-Fink, G. Pentamethylcyclopentadienyl rhodium and iridium complexes containing oxinato ligands. Inorg. Chem. Commun. 12, 806–807 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by the Institute for Basic Science (IBS-R010-D1) in Korea. The authors thank S. Seo (Institute for Basic Science) for helpful discussions and critical reading.

Author information

Authors and Affiliations

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

    Seung Youn Hong, Dongwook Kim & Sukbok Chang

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

    Seung Youn Hong, Dongwook Kim & Sukbok Chang

Authors
  1. Seung Youn Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongwook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sukbok Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.Y.H. and S.C. conceived and designed the project and wrote the manuscript. S.Y.H. carried out the experiments and DFT calculations. D.K. performed the X-ray crystallographic analysis. S.C. organized the research. All the authors analysed the data, discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Sukbok Chang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Catalysis thanks Forrest Michael and the other, anonymous, reviewer(s) 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

Supplementary Figs. 1–21 and Tables 1–9.

Supplementary Data 1

Cartesian coordinates of DFT-optimized structures.

Supplementary Data 2

Crystallographic Data for compound 40 (CCDC 1999590).

Supplementary Data 3

Crystallographic Data of compound 36 (CCDC 1999591).

Supplementary Data 4

Crystallographic Data of compound 19 (CCDC 1999592).

Supplementary Data 5

Crystallographic Data of compound Ir11 (CCDC 1999593).

Supplementary Data 6

Crystallographic Data of compound 6-OAc (CCDC 1999594).

Supplementary Data 7

Crystallographic Data of compound 29 (CCDC 1999595).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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). https://doi.org/10.1038/s41929-020-00558-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-020-00558-x

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