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:

Rapid functionalization of multiple C–H bonds in unprotected alicyclic amines

Nature Chemistry volume 12, pages 545–550 (2020)Cite this article

Subjects

Abstract

The synthesis of valuable bioactive alicyclic amines containing variable substituents in multiple ring positions typically relies on multistep synthetic sequences that frequently require the introduction and subsequent removal of undesirable protecting groups. Although a vast number of studies have aimed to simplify access to such materials through the C–H bond functionalization of feedstock alicyclic amines, the simultaneous introduction of more than one substituent to unprotected amines has never been accomplished. Here we report an advance in C–H bond functionalization methodology that enables the introduction of up to three substituents in a single operation. Lithiated amines are first exposed to a ketone oxidant, generating transient imines that are subsequently converted to endocyclic 1-azaallyl anions, which can be processed further to furnish β-substituted, α,β-disubstituted, or α,β,α′-trisubstituted amines. This study highlights the unique utility of in situ-generated endocyclic 1-azaallyl anions, elusive intermediates in synthetic chemistry.

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: Selected methods for the β-C–H bond functionalization of alicyclic amines and a new strategy for the multifunctionalization of secondary alicyclic amines.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available within the paper and its Supplementary Information. Crystallographic data for structures (±)-13a and (±)-13q have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. 1935815 ((±)-13a) and 1935816 ((±)-13q). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/

References

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  3. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    CAS  PubMed  Google Scholar 

  4. Campos, K. R. Direct sp 3 C–H bond activation adjacent to nitrogen in heterocycles. Chem. Soc. Rev. 36, 1069–1084 (2007).

    CAS  PubMed  Google Scholar 

  5. Mitchell, E. A., Peschiulli, A., Lefevre, N., Meerpoel, L. & Maes, B. U. W. Direct α-functionalization of saturated cyclic amines. Chem. Eur. J. 18, 10092–10142 (2012).

    CAS  PubMed  Google Scholar 

  6. Vo, C.-V. T. & Bode, J. W. Synthesis of saturated N-heterocycles. J. Org. Chem. 79, 2809–2815 (2014).

    CAS  PubMed  Google Scholar 

  7. Girard, S. A., Knauber, T. & Li, C.-J. The cross-dehydrogenative coupling of Csp 3-H bonds: a versatile strategy for C–C bond formations. Angew. Chem. Int. Ed. 53, 74–100 (2014).

    CAS  Google Scholar 

  8. Seidel, D. The azomethine ylide route to amine C–H functionalization: redox-versions of classic reactions and a pathway to new transformations. Acc. Chem. Res. 48, 317–328 (2015).

    CAS  PubMed  Google Scholar 

  9. Beatty, J. W. & Stephenson, C. R. J. Amine functionalization via oxidative photoredox catalysis: methodology development and complex molecule synthesis. Acc. Chem. Res. 48, 1474–1484 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Cheng, M.-X. & Yang, S.-D. Recent advances in the enantioselective oxidative α-C–H functionalization of amines. Synlett 28, 159–174 (2017).

    CAS  Google Scholar 

  11. Payne, P. R., Garcia, P., Eisenberger, P., Yim, J. C. H. & Schafer, L. L. Tantalum catalyzed hydroaminoalkylation for the synthesis of α- and β-substituted N-heterocycles. Org. Lett. 15, 2182–2185 (2013).

    CAS  PubMed  Google Scholar 

  12. Chen, W., Ma, L., Paul, A. & Seidel, D. Direct α-C–H bond functionalization of unprotected cyclic amines. Nat. Chem. 10, 165–169 (2018).

    PubMed  Google Scholar 

  13. Lennox, A. J. J. et al. Electrochemical aminoxyl-mediated α-cyanation of secondary piperidines for pharmaceutical building block diversification. J. Am. Chem. Soc. 140, 11227–11231 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Paul, A. & Seidel, D. α-Functionalization of cyclic secondary amines: Lewis acid promoted addition of organometallics to transient imines. J. Am. Chem. Soc. 141, 8778–8782 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Takasu, N., Oisaki, K. & Kanai, M. Iron-catalyzed oxidative C(3)–H functionalization of amines. Org. Lett. 15, 1918–1921 (2013).

    CAS  PubMed  Google Scholar 

  16. Griffiths, R. J. et al. Oxidative β-C–H sulfonylation of cyclic amines. Chem. Sci. 9, 2295–2300 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Xu, G.-Q. et al. Dual C(sp 3)−H bond functionalization of N-heterocycles through sequential visible-light photocatalyzed dehydrogenation/[2+2] cycloaddition reactions. Angew. Chem. Int. Ed. 57, 5110–5114 (2018).

    CAS  Google Scholar 

  18. Zhang, J., Park, S. & Chang, S. Catalytic access to bridged sila-N-heterocycles from piperidines via cascade sp 3 and sp 2 C–Si bond formation. J. Am. Chem. Soc. 140, 13209–13213 (2018).

    CAS  PubMed  Google Scholar 

  19. Sundararaju, B. et al. Ruthenium-catalyzed cascade N- and C(3)-dialkylation of cyclic amines with alcohols involving hydrogen autotransfer processes. Adv. Synth. Catal. 352, 3141–3146 (2010).

    CAS  Google Scholar 

  20. Sundararaju, B., Achard, M., Sharma, G. V. M. & Bruneau, C. sp 3 C–H bond activation with ruthenium(ii) catalysts and C(3)-alkylation of cyclic amines. J. Am. Chem. Soc. 133, 10340–10343 (2011).

    CAS  PubMed  Google Scholar 

  21. Millet, A., Larini, P., Clot, E. & Baudoin, O. Ligand-controlled beta-selective C(sp 3)–H arylation of N-Boc-piperidines. Chem. Sci. 4, 2241–2247 (2013).

    CAS  Google Scholar 

  22. Affron, D. P., Davis, O. A. & Bull, J. A. Regio- and stereospecific synthesis of C-3 functionalized proline derivatives by palladium catalyzed directed C(sp 3)–H Arylation. Org. Lett. 16, 4956–4959 (2014).

    CAS  PubMed  Google Scholar 

  23. Ye, S. et al. N-Heterocyclic carbene ligand-enabled C(sp 3)−H arylation of piperidine and tetrahydropyran derivatives. Chem. Eur. J. 22, 4748–4752 (2016).

    CAS  PubMed  Google Scholar 

  24. Van Steijvoort, B. F., Kaval, N., Kulago, A. A. & Maes, B. U. W. Remote functionalization: palladium-catalyzed C5(sp 3)–H arylation of 1-Boc-3-aminopiperidine through the use of a bidentate directing group. ACS Catal. 6, 4486–4490 (2016).

    Google Scholar 

  25. Maetani, M. et al. Synthesis of a bicyclic azetidine with in vivo antimalarial activity enabled by stereospecific, directed C(sp 3)–H arylation. J. Am. Chem. Soc. 139, 11300–11306 (2017).

    CAS  PubMed  Google Scholar 

  26. Antermite, D., Affron, D. P. & Bull, J. A. Regio- and stereoselective palladium-catalyzed C(sp 3)–H arylation of pyrrolidines and piperidines with C(3) directing groups. Org. Lett. 20, 3948–3952 (2018).

    CAS  PubMed  Google Scholar 

  27. Chen, W., Kang, Y., Wilde, R. G. & Seidel, D. Redox-neutral α,β-difunctionalization of cyclic amines. Angew. Chem. Int. Ed. 53, 5179–5182 (2014).

    CAS  Google Scholar 

  28. Ma, L., Paul, A., Breugst, M. & Seidel, D. Redox-neutral aromatization of cyclic amines: mechanistic insights and harnessing of reactive intermediates for amine α- and β-C−H functionalization. Chem. Eur. J. 22, 18179–18189 (2016).

    CAS  PubMed  Google Scholar 

  29. Topczewski, J. J., Cabrera, P. J., Saper, N. I. & Sanford, M. S. Palladium-catalysed transannular C–H functionalization of alicyclic amines. Nature 531, 220–224 (2016).

    CAS  PubMed  Google Scholar 

  30. Cabrera, P. J., Lee, M. & Sanford, M. S. Second-generation palladium catalyst system for transannular C–H functionalization of azabicycloalkanes. J. Am. Chem. Soc. 140, 5599–5606 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Willems, L. I. & IJzerman, A. P. Small molecule antagonists for chemokine CCR3 receptors. Med. Res. Rev. 30, 778–817 (2010).

    CAS  PubMed  Google Scholar 

  32. Jia, L. et al. Discovery of VTP-27999, an alkyl amine renin inhibitor with potential for clinical utility. ACS Med. Chem. Lett. 2, 747–751 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Schönherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C–H methylation reactions. Angew. Chem. Int. Ed. 52, 12256–12267 (2013).

    Google Scholar 

  34. Ye, Z., Gettys, K. E. & Dai, M. Opportunities and challenges for direct C–H functionalization of piperazines. Beilstein J. Org. Chem. 12, 702–715 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Källström, S. & Leino, R. Synthesis of pharmaceutically active compounds containing a disubstituted piperidine framework. Bioorg. Med. Chem. 16, 601–635 (2008).

    PubMed  Google Scholar 

  36. Rao, G. A. & Periasamy, M. Cycloaddition of enamine and iminium ion intermediates formed in the reaction of N-arylpyrrolidines with T-HYDRO. Synlett 26, 2231–2236 (2015).

    CAS  Google Scholar 

  37. Shu, X.-Z. et al. Selective functionalization of sp 3 C−H bonds adjacent to nitrogen using (diacetoxyiodo)benzene (DIB). J. Org. Chem. 74, 7464–7469 (2009).

    CAS  PubMed  Google Scholar 

  38. Wittig, G. & Hesse, A. Hydrid-übertragung von lithium-pyrrolidid auf azomethine. Liebigs Ann. Chem. 746, 174–184 (1971).

    CAS  Google Scholar 

  39. Wittig, G. & Hesse, A. Zur reaktionsweise N‐metallierter acyclischer und cyclischer sekundärer amine. Liebigs Ann. Chem. 746, 149–173 (1971).

    CAS  Google Scholar 

  40. Pal, K., Behnke, M. L. & Tong, L. A general stereocontrolled synthesis of cis-2,3-disubstituted pyrrolidines and piperidines. Tetrahedron Lett. 34, 6205–6208 (1993).

    CAS  Google Scholar 

  41. Nenajdenko, V. G., Pronin, S. V. & Balenkova, E. S. Synthesis of aminoalkylpyrazoles and-isoxazoles from cyclic β-(trifluoroacetyl) enamines. Russ. Chem. Bull. 56, 336–344 (2007).

    CAS  Google Scholar 

  42. Whitesell, J. K. & Whitesell, M. A. Alkylation of ketones and aldehydes via their nitrogen derivatives. Synthesis 1983, 517–536 (1983).

    Google Scholar 

  43. Mangelinckx, S., Giubellina, N. & De Kimpe, N. 1-Azaallylic anions in heterocyclic chemistry. Chem. Rev. 104, 2353–2400 (2004).

    CAS  PubMed  Google Scholar 

  44. Fandrick, D. R. et al. Copper-catalyzed asymmetric propargylation of cyclic aldimines. Org. Lett. 18, 6192–6195 (2016).

    CAS  PubMed  Google Scholar 

  45. De Lucca, G. V. et al. Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency. J. Med. Chem. 48, 2194–2211 (2005).

    PubMed  Google Scholar 

Download references

Acknowledgements

Financial support from the NIH–NIGMS (grant no. R01GM101389) is gratefully acknowledged. We thank I. Ghiviriga (University of Florida) for assistance with NMR experiments. Mass spectrometry instrumentation was supported by a grant from the NIH (S10 OD021758-01A1). We further acknowledge the National Science Foundation (grant no. 1828064) and the University of Florida for funding the purchase of the X-ray equipment.

Author information

Authors and Affiliations

  1. Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL, USA

    Weijie Chen, Anirudra Paul & Daniel Seidel

  2. Center for X-Ray Crystallography, Department of Chemistry, University of Florida, Gainesville, FL, USA

    Khalil A. Abboud

Authors
  1. Weijie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anirudra Paul
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Khalil A. Abboud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Daniel Seidel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

W.C. developed the amine β- and multifunctionalization and explored the scope. A.P. performed initial studies on the amine β-functionalization and α,β-difunctionalization. K.A.A. performed crystallographic analyses for compounds (±)-13a and (±)-13q. D.S. conceived and supervised the project. D.S. and W.C. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Daniel Seidel.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Information

Materials and methods, evaluation of reaction conditions, characterization data, GCOSY and NOESY analyses, crystallographic summaries and NMR spectra.

Crystallographic data

Crystallographic data of compound (±)-13a. CCDC reference 1935815.

Crystallographic data

Crystallographic data of compound (±)-13q. CCDC reference 1935816.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, W., Paul, A., Abboud, K.A. et al. Rapid functionalization of multiple C–H bonds in unprotected alicyclic amines. Nat. Chem. 12, 545–550 (2020). https://doi.org/10.1038/s41557-020-0438-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-020-0438-z

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