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:

Nickel-catalysed enantioselective hydrosulfenation of alkynes

Nature Catalysis volume 6, pages 487–494 (2023)Cite this article

Subjects

Abstract

Enantioenriched sulfoxides have found ever-increasing applications in marketed drugs or as candidates in clinical trials. They are also frequently used as key motifs in chiral ligands or as organocatalysts in asymmetric catalysis. However, the asymmetric synthesis of such a functionality poses a significant challenge. Here, by harnessing the strong backbonding donation of Ni(0) to alkynes, we report a Ni-catalysed hydrosulfenation reaction of unactivated alkynes with in situ-generated sulfenic acids, enabling the reaction to proceed in an enantioselective stepwise mechanism that is contrary to the well-established uncatalysed concerted mechanism. A plethora of alkenyl sulfoxides were synthesized with high enantioselectivity and a broad substrate scope. The products could be easily elaborated into structurally diverse sulfoxides that could serve as chiral ligands, catalysts and useful pharmacophores for the late-stage modification of drugs.

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: Sulfoxide medicines, ligands and synthetic strategies.
Fig. 2: Substrate scope.
Fig. 3: Applications of chiral sulfoxides.
Fig. 4: Mechanistic investigations.

Similar content being viewed by others

Data availability

All information relating to optimization studies, experimental procedures, mechanistic studies, DFT calculations, high-performance liquid chromatography spectra, NMR spectra, high-resolution mass spectrometry and optical rotation data are available in Supplementary Information. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2117922 (3g), CCDC 2178299 (7) and CCDC 2124800 (8′). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available from the corresponding authors upon request.

References

  1. Gupta, V. & Carroll, K. S. Sulfenic acid chemistry, detection and cellular lifetime. Biochim. Biophys. Acta 1840, 847–875 (2014).

    CAS  PubMed  Google Scholar 

  2. Carreno, M. C. Applications of sulfoxides to asymmetric synthesis of biologically active compounds. Chem. Rev. 95, 1717–1760 (1995).

    CAS  Google Scholar 

  3. Fernández, I. & Khiar, N. Recent developments in the synthesis and utilization of chiral sulfoxides. Chem. Rev. 103, 3651–3706 (2003).

    PubMed  Google Scholar 

  4. Wojaczynska, E. & Wojaczynski, J. Modern stereoselective synthesis of chiral sulfinyl compounds. Chem. Rev. 120, 4578–4611 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Robak, M. T., Herbage, M. A. & Ellman, J. A. Synthesis and applications of tert-butanesulfinamide. Chem. Rev. 110, 3600–3740 (2010).

    CAS  PubMed  Google Scholar 

  6. Trost, B. M. & Rao, M. Development of chiral sulfoxide ligands for asymmetric catalysis. Angew. Chem. Int. Ed. 54, 5026–5043 (2015).

    CAS  Google Scholar 

  7. Sipos, G., Drinkel, E. E. & Dorta, R. The emergence of sulfoxides as efficient ligands in transition metal catalysis. Chem. Soc. Rev. 44, 3834–3860 (2015).

    CAS  PubMed  Google Scholar 

  8. Otocka, S., Kwiatkowska, M., Madalinska, L. & Kielbasinski, P. Chiral organosulfur ligands/catalysts with a stereogenic sulfur atom: applications in asymmetric synthesis. Chem. Rev. 117, 4147–4181 (2017).

    CAS  PubMed  Google Scholar 

  9. Pitchen, P., Dunach, E., Deshmukh, M. N. & Kagan, H. B. An efficient asymmetric oxidation of sulfides to sulfoxides. J. Am. Chem. Soc. 106, 8188–8193 (1984).

    CAS  Google Scholar 

  10. Ma, L.-j et al. Chiral Brønsted-acid-catalyzed asymmetric oxidation of sulfenamide by using H2O2: a versatile access to sulfinamide and sulfoxide with high enantioselectivity. ACS Catal. 9, 1525–1530 (2019).

    CAS  Google Scholar 

  11. Maitro, G. et al. Enantioselective synthesis of aryl sulfoxides via palladium-catalyzed arylation of sulfenate anions. Org. Lett. 9, 5493–5496 (2007).

    CAS  PubMed  Google Scholar 

  12. Zong, L., Ban, X., Kee, C. W. & Tan, C. H. Catalytic enantioselective alkylation of sulfenate anions to chiral heterocyclic sulfoxides using halogenated pentanidium salts. Angew. Chem. Int. Ed. 53, 11849–11853 (2014).

    CAS  Google Scholar 

  13. Jia, T. et al. Palladium-catalyzed enantioselective arylation of aryl sulfenate anions: a combined experimental and computational study. J. Am. Chem. Soc. 139, 8337–8345 (2017).

    CAS  PubMed  Google Scholar 

  14. Wang, L., Chen, M., Zhang, P., Li, W. & Zhang, J. Palladium/PC-Phos-catalyzed enantioselective arylation of general sulfenate anions: scope and synthetic applications. J. Am. Chem. Soc. 140, 3467–3473 (2018).

    CAS  PubMed  Google Scholar 

  15. Wu, C., Berritt, S., Liang, X. & Walsh, P. J. Palladium-catalyzed enantioselective alkenylation of sulfenate anions. Org. Lett. 21, 960–964 (2019).

    CAS  PubMed  Google Scholar 

  16. Andersen, K. K. Synthesis of (+)-ethyl p-tolyl sulfoxide from (−)-menthyl (−)-p-toluenesulfinate. Tetrahedron Lett. 3, 93–95 (1962).

    Google Scholar 

  17. Andersen, K. K., Gaffield, W., Papanikolaou, N. E., Foley, J. W. & Perkins, R. I. Optically active sulfoxides. The synthesis and rotatory dispersion of some diaryl sulfoxides. J. Am. Chem. Soc. 86, 5637–5646 (1964).

    CAS  Google Scholar 

  18. Han, Z. et al. A highly selective and practical method for enantiopure sulfoxides utilizing activated and functionally differentiated N-sulfonyl-1,2,3-oxathiazolidine-2-oxide derivatives. Angew. Chem. Int. Ed. 42, 2032–2035 (2003).

    CAS  Google Scholar 

  19. Han, Z. et al. Development of a preparative-scale asymmetric synthesis of (R)-p-tolyl methyl sulfoxide for use in a one-pot synthesis of a drug intermediate containing a trifluoromethyl-substituted alcohol functionality. Org. Process Res. Dev. 11, 605–608 (2007).

    CAS  Google Scholar 

  20. Zhang, X., Ang, E. C. X., Yang, Z., Kee, C. W. & Tan, C. H. Synthesis of chiral sulfinate esters by asymmetric condensation. Nature 604, 298–303 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Shelton, J. R. & Davis, K. E. t-Butylsulfenic acid. J. Am. Chem. Soc. 89, 718–719 (1967).

    CAS  Google Scholar 

  22. Allison, W. S. Formation and reactions of sulfenic acids in proteins. Acc. Chem. Res. 9, 293–299 (1976).

    CAS  Google Scholar 

  23. Neville Jones, D., Cottam, P. D. & Davies, J. Addition of sulphenic acids to unactivated alkynes to give alkenyl sulphoxides. Tetrahedron Lett. 20, 4977–4980 (1979).

    Google Scholar 

  24. Guihaumé, J., Halbert, S., Eisenstein, O. & Perutz, R. N. Hydrofluoroarylation of alkynes with Ni Catalysts. C–H activation via ligand-to-ligand hydrogen transfer, an alternative to oxidative addition. Organometallics 31, 1300–1314 (2011).

    Google Scholar 

  25. Zhang, Y.-Q. et al. Ni-catalyzed asymmetric hydrophosphinylation of conjugated enynes and mechanistic studies. Chem. Sci. 13, 4095–4102 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Chatt, J. & Duncanson, L. A. 586. Olefin co-ordination compounds. Part III. Infra-red spectra and structure: attempted preparation of acetylene complexes. J. Chem. Soc. 2939–2947 (1953).

  27. Chatt, J., Duncanson, L. A. & Venanzi, L. M. Directing effects in inorganic substitution reactions. Part I. A hypothesis to explain the trans effect. J. Chem. Soc. 4456–4460 (1955).

  28. Allen, S. R., Green, M., Orpen, A. G. & Williams, I. D. The role of metallacyclopropenes in the formation of alkylidyne complexes; evidence for a 1,2-trimethylsilyl shift and the X-ray crystal structure of [Mo=C(SiMe3)CH2{P(OMe)3}2(η5-C9H7)]. J. Chem. Soc. Chem. Commun. 826–828 (1982).

  29. Boatz, J. A., Gordon, M. S. & Sita, L. R. Theoretical studies of the metallacyclopropenes c-[MX2C2H2] (M = C, Si, Ge, Sn; X = H, F). J. Phys. Chem. 94, 5488–5493 (1990).

    CAS  Google Scholar 

  30. Edelbach, B. L., Lachicotte, R. J. & Jones, W. D. Catalytic carbon−carbon bond activation and functionalization by nickel complexes. Organometallics 18, 4040–4049 (1999).

    CAS  Google Scholar 

  31. Jemmis, E. D. et al. Are metallocene−acetylene (M = Ti, Zr, Hf) complexes aromatic metallacyclopropenes? Organometallics 29, 76–81 (2009).

    Google Scholar 

  32. Tasker, S. Z., Standley, E. A. & Jamison, T. F. Recent advances in homogeneous nickel catalysis. Nature 509, 299–309 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bakewell, C., White, A. J. P. & Crimmin, M. R. Reversible alkene binding and allylic C-H activation with an aluminium(I) complex. Chem. Sci. 10, 2452–2458 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Wheeler, O. W., Coates, R. A., Lapoutre, V. J. F., Bakker, J. M. & Armentrout, P. B. Metallacyclopropene structures identified by IRMPD spectroscopic investigation of the dehydrogenation reactions of Ta+ and TaO+ with ethene. Int. J. Mass Spectrom. 442, 83–94 (2019).

    CAS  Google Scholar 

  35. Lv, Z. J., Chai, Z., Zhu, M., Wei, J. & Zhang, W. X. Selective coupling of lanthanide metallacyclopropenes and nitriles via azametallacyclopentadiene and η2-pyrimidine metallacycle. J. Am. Chem. Soc. 143, 9151–9161 (2021).

    CAS  PubMed  Google Scholar 

  36. He, Q. et al. Palladium-catalyzed modular and enantioselective cis-difunctionalization of 1,3-enynes with imines and boronic reagents. J. Am. Chem. Soc. 143, 17989–17994 (2021).

    CAS  PubMed  Google Scholar 

  37. Standley, E. A., Tasker, S. Z., Jensen, K. L. & Jamison, T. F. Nickel catalysis: synergy between method development and total synthesis. Acc. Chem. Res. 48, 1503–1514 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Xiao, L. J. et al. Nickel(0)-catalyzed hydroalkenylation of imines with styrene and its derivatives. Angew. Chem. Int. Ed. 57, 3396–3400 (2018).

    CAS  Google Scholar 

  39. Montgomery, J. Nickel-catalyzed cyclizations, couplings, and cycloadditions involving three reactive components. Acc. Chem. Res. 33, 467–473 (2000).

    CAS  PubMed  Google Scholar 

  40. Orsino, A. F., Gutierrez Del Campo, M., Lutz, M. & Moret, M. E. Enhanced catalytic activity of nickel complexes of an adaptive diphosphine–benzophenoneligand in alkyne cyclotrimerization. ACS Catal. 9, 2458–2481 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Hao, J., Mougang-Soume, B., Vabre, B. & Zargarian, D. On the stability of a POCsp3OP-type pincer ligand in nickel(II) complexes. Angew. Chem. Int. Ed. 53, 3218–3222 (2014).

    CAS  Google Scholar 

  42. Linden, A. et al. ‘Chiral-at-metal’ hemilabile nickel complexes with a latent d10-ML2 configuration: receiving substrates with open arms. Organometallics 31, 6162–6171 (2012).

    CAS  Google Scholar 

  43. Bonrath, B. W., Porschke, K. R., Wilke, C., Angermund, K. & Kruger, C. Mono- and dinuclear nickel(0) complexes of butadiyne. Angew. Chem. Int. Ed. 27, 833–835 (1988).

    Google Scholar 

  44. Jiang, J., Fu, M., Li, C., Shang, R. & Fu, Y. Theoretical investigation on nickel-catalyzed hydrocarboxylation of alkynes employing formic acid. Organometallics 36, 2818–2825 (2017).

    CAS  Google Scholar 

  45. Ren, X., Lu, Y., Lu, G. & Wang, Z.-X. Density functional theory mechanistic study of Ni-catalyzed reductive alkyne-alkyne cyclodimerization: oxidative cyclization versus outer-sphere proton transfer. Org. Lett. 22, 2454–2459 (2020).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful for financial support from NSFC (22071224 and 21901235 to Q.-W.Z. and 21973055 to G.L.) and USTC Research Funds of the Double First-Class Initiative (YD2060002010 to Q.-W.Z.). We acknowledge the Taishan Scholar of Shandong Province (No. tsqn201812013 to G.L.) and the Qilu Young Scholar of Shandong University (to G.L.). The numerical calculations in this paper were performed on the supercomputing system in the Supercomputing Center of the University of Science and Technology of China and the HPC Cloud Platform of Shandong University.

Author information

Authors and Affiliations

  1. Key Laboratory of Precision and Intelligent Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei, China

    Ya-Qian Zhang, Liyan Yuwen & Qing-Wei Zhang

  2. School of Chemistry and Chemical Engineering, Key Laboratory of Colloid and Interface Chemistry, Ministry of Education, Shandong University, Jinan, China

    Lingfei Hu & Gang Lu

Authors
  1. Ya-Qian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lingfei Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liyan Yuwen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gang Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing-Wei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Q.-W.Z. conceived and supervised the project. Y.-Q.Z. performed the experiments and analysed the data. L.Y. carried out the synthesis of sulfoxide starting materials and collected the data. Q.-W.Z. and L.H. carried out the DFT calculations. Q.-W.Z. and G.L. co-wrote the paper.

Corresponding authors

Correspondence to Gang Lu or Qing-Wei Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Catalysis thanks the 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 Tables 1–4, Figs. 1–9, Methods, copies of NMR and high-performance liquid chromatography data and References.

Supplementary Data 1

cif file of 3g.

Supplementary Data 2

cif file of 7.

Supplementary Data 3

cif file of 8′.

Supplementary Data 4

Cartesian coordinates of 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

Zhang, YQ., Hu, L., Yuwen, L. et al. Nickel-catalysed enantioselective hydrosulfenation of alkynes. Nat Catal 6, 487–494 (2023). https://doi.org/10.1038/s41929-023-00966-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-023-00966-9

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research