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:

Benzazetidine synthesis via palladium-catalysed intramolecular C−H amination

Nature Chemistry volume 8, pages 1131–1136 (2016)Cite this article

Subjects

Abstract

Small-sized N-heterocycles are important structures in organic synthesis and medicinal chemistry. Palladium-catalysed intramolecular aminations of the C−H bonds of unfunctionalized amine precursors have recently emerged as an attractive new method for N-heterocycle synthesis. However, the way to control the reactivity of high-valent Pd intermediates to form the desired C−N cyclized products selectively remains poorly addressed. Herein we report a strategy to control the reductive elimination (RE) pathways in high-valent Pd catalysis and apply this strategy to achieve the synthesis of highly strained four-membered benzazetidines via the Pd-catalysed intramolecular C−H amination of N-benzyl picolinamides. These reactions represent the first practical synthetic method for benzazetidines and enable access to a range of complex benzazetidines from easily obtainable starting materials. The use of a newly designed phenyliodonium dimethylmalonate reagent is critical, as oxidation of Pd(II) palladacycles with this reagent favours a kinetically controlled C−N RE pathway to give strained ring-closed products.

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

Figure 1: Strategy for the synthesis of small-sized N-heterocycles via Pd-catalysed IDCA.
Figure 2: Synthesis of benzazetidine via Pd-catalysed IDCA of PA-coupled benzylamine.
Figure 3: Substrate scope of benzazetidine synthesis.
Figure 4: Facile removal of the PA group.
Figure 5: Computational studies of Pd-catalysed IDCAs of N-benzyl PAs with PhI(OAc)2 and PhI(DMM) (R, CF3).

Similar content being viewed by others

References

  1. Sweeney, J. B. Aziridines: epoxides’ ugly cousins? Chem. Soc. Rev. 31, 247–258 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Alcaide, B., Almendros, P. & Aragoncillo, C. Highly reactive 4-membered ring nitrogen-containing heterocycles: synthesis and properties. Curr. Opin. Drug Discov. Devel. 13, 685–697 (2010).

    CAS  PubMed  Google Scholar 

  4. Espino, C. G. & Du Bois, J. A Rh-catalyzed C−H insertion reaction for the oxidative conversion of carbamates to oxazolidinones. Angew. Chem. Int. Ed. 40, 598–600 (2001).

    Article  CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Jeffrey, J. L. & Sarpong, R. Intramolecular C(sp3)–H amination. Chem. Sci. 4, 4092–4106 (2013).

    Article  CAS  Google Scholar 

  7. Tsang, P. W. C., Zheng, N. & Buchwald, S. L. Combined C–H functionalization/C–N bond formation route to carbazoles. J. Am. Chem. Soc. 127, 14560–14561 (2005).

    Article  CAS  Google Scholar 

  8. Wasa, M. & Yu, J.-Q. Synthesis of β, γ and δ-lactams via Pd(II)-catalyzed C–H activation reactions. J. Am. Chem. Soc. 130, 14058–14059 (2008).

    Article  CAS  Google Scholar 

  9. McNally, A., Haffemayer, B., Collins, B. S. L. & Gaunt, M. J. Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature 510, 129–133 (2014).

    Article  CAS  Google Scholar 

  10. Chen, X., Engle, K. M., Wang, D.-H. & Yu, J.-Q. Palladium(II)-catalyzed C–H activation/C–C cross-coupling reactions: versatility and practicality. Angew. Chem. Int. Ed. 48, 5094–5115 (2009).

    Article  CAS  Google Scholar 

  11. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    Article  CAS  Google Scholar 

  12. Hickman, A. J. & Sanford, M. S. High-valent organometallic copper and palladium in catalysis. Nature 484, 177–185 (2012).

    Article  CAS  Google Scholar 

  13. Engle, K. M., Mei, T.-S., Wang, X. & Yu, J.-Q. Bystanding F+ oxidants enable selective reductive elimination from high-valent metal centers in catalysis. Angew. Chem. Int. Ed. 50, 1478–1491 (2011).

    Article  CAS  Google Scholar 

  14. Wojciechowski, K. Aza-ortho-xylylenes in organic synthesis. Eur. J. Org. Chem. 3587–3605 (2001).

    Article  Google Scholar 

  15. Sadana, A. K., Saini, R. K. & Billups, W. E. Cyclobutarenes and related compounds. Chem. Rev. 1539–1602 (2003).

  16. Burgess, E. M. & McCullagh, L. N-Phenylbenzoazetine. J. Am. Chem. Soc. 88, 1580–1581 (1966).

    Article  CAS  Google Scholar 

  17. Beak, P. & Selling, G. W. Displacements at the nitrogen of lithio-alkoxylamides by organometallic reagents. J. Org. Chem. 54, 5574–5580 (1989).

    Article  CAS  Google Scholar 

  18. Lancaster, M. & Smith, D. J. H. Preparation and some reactions of benzazetidines. Chem. Commun. 471–472 (1980).

  19. Nadres, E. T. & Daugulis, O. Heterocycle synthesis via direct C−H/N−H coupling. J. Am. Chem. Soc. 134, 7–10 (2012).

    Article  CAS  Google Scholar 

  20. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of azetidines, pyrrolidines, and indolines via palladium-catalyzed intramolecular amination of C(sp3)–H and C(sp2)–H bonds at the γ and δ positions. J. Am. Chem. Soc. 134, 3–6 (2012).

    Article  CAS  Google Scholar 

  21. He, G., Zhang, S., Nack, W. A. & Chen, G. Use of a readily removable auxiliary group for the synthesis of pyrrolidones by the palladium-catalyzed intramolecular amination of unactivated γ C(sp3)−H bonds. Angew. Chem. Int. Ed. 52, 11124–11128 (2013).

    Article  CAS  Google Scholar 

  22. Engle, K. M. & Yu., J.-Q. Developing ligands for palladium(II)-catalyzed C–H functionalization. J. Org. Chem. 78, 8927–8955 (2013).

    Article  CAS  Google Scholar 

  23. Gou, F.-R. et al. Palladium-catalyzed aryl C–H bonds activation/acetoxylation utilizing a bidentate system. Org. Lett. 11, 5726–5729 (2009).

    Article  CAS  Google Scholar 

  24. Gary, J. B. & Sanford, M. S. Participation of carbonyl oxygen in carbon–carboxylate bond-forming reductive elimination from palladium. Organometallics 30, 6143–6149 (2011).

    Article  CAS  Google Scholar 

  25. Nielsen, M. C., Lyngvi, E. & Schoenebeck, F. Chemoselectivity in the reductive elimination from high oxidation state palladium complexes—scrambling mechanism uncovered. J. Am. Chem. Soc. 135, 1978–1985 (2013).

    Article  CAS  Google Scholar 

  26. Zhdankin, V. V. & Stang, P. J. Chemistry of polyvalent iodine. Chem. Rev. 108, 5299–5358 (2008).

    Article  CAS  Google Scholar 

  27. Shabashov, M. & Daugulis, O. Auxiliary-assisted palladium-catalyzed arylation and alkylation of sp2 and sp3 carbon–hydrogen bonds. J. Am. Chem. Soc. 132, 3965–3972 (2010).

    Article  CAS  Google Scholar 

  28. Deprez, N. R. & Sanford, M. S. Synthetic and mechanistic studies of Pd-catalyzed C−H arylation with diaryliodonium salts: evidence for a bi-metallic high oxidation state Pd intermediate. J. Am. Chem. Soc. 131, 11234–11241 (2009).

    Article  CAS  Google Scholar 

  29. Powers, D. C., Benitez, D., Tkatchouk, E., Goddard, W. A. III & Ritter, T. Bimetallic reductive elimination from dinuclear Pd(III) complexes. J. Am. Chem. Soc. 132, 14092–14103 (2010).

    Article  CAS  Google Scholar 

  30. Powers, D. C. et al. Connecting binuclear Pd(III) and mononuclear Pd(IV) chemistry by Pd−Pd bond cleavage. J. Am. Chem. Soc. 134, 12002–12009 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

G.C. thanks the State Key Laboratory of Elemento-Organic Chemistry at Nankai University and the Pennsylvania State University for financial support for the experimental part of this work. P.L. thanks the University of Pittsburgh for financial support for the computational part of the work. Calculations were performed at the Center for Simulation and Modeling at the University of Pittsburgh and the Extreme Science and Engineering Discovery Environment (XSEDE) supported by the National Science Foundation.

Author information

Authors and Affiliations

  1. State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300071, China

    Gang He, Zhengwei Guo & Gong Chen

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, 15260, Pennsylvania, USA

    Gang Lu & Peng Liu

  3. Department of Chemistry, The Pennsylvania State University, University Park, 16802, Pennsylvania, USA

    Gong Chen

Authors
  1. Gang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhengwei Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.H. discovered the benzazetidine synthesis via the Pd-catalysed IDCA reaction of benzylamines, introduced the PhI(DMM) reagent, carried out most of the reaction optimization and structural determination of the reaction products and prepared the Supplementary Information. Z.G. helped in the preparation of some benzylamine substrates and contributed to the reaction optimization. G.L. conducted the computations. P.L. directed the computational studies. P.L. and G.L. prepared the computational sections of the manuscript. G.C. formulated the initial ideas of this work, supervised all the experiments, coordinated with P.L. on the computational studies and prepared most of the manuscript.

Corresponding authors

Correspondence to Gang He, Peng Liu or Gong Chen.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 20978 kb)

Supplementary information

Crystallographic data for compound 5. (CIF 13 kb)

Supplementary information

Structure factors file for compound 5. (FCF 157 kb)

Supplementary information

Crystallographic data for complexA. (CIF 16 kb)

Supplementary information

Structure factors file for complexA. (FCF 179 kb)

Supplementary information

Crystallographic data for compound 21N. (CIF 15 kb)

Supplementary information

Structure factors file for compound 21N. (FCF 178 kb)

Supplementary information

Crystallographic data for compound 26. (CIF 11 kb)

Supplementary information

Structure factors file for compound 26. (FCF 62 kb)

Supplementary information

Crystallographic data for palladacycle complexE. (CIF 25 kb)

Supplementary information

Structure factors file for palladacycle complexE. (FCF 351 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

He, G., Lu, G., Guo, Z. et al. Benzazetidine synthesis via palladium-catalysed intramolecular C−H amination. Nature Chem 8, 1131–1136 (2016). https://doi.org/10.1038/nchem.2585

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2585

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