Skip to main content

Thank you for visiting 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:

Asymmetric O-propargylation of secondary aliphatic alcohols

A Publisher Correction to this article was published on 08 June 2020


The asymmetric O-alkylation of secondary aliphatic alcohols remains a substantial challenge in chemistry. Such a challenge largely stems from the steric demand of each reactant, in addition to the relatively low nucleophilicity of alcohols. Here, we report the development of a base-free, Cu-catalysed propargylic substitution reaction that enables the efficient, asymmetric O-propargylation of secondary aliphatic alcohols. Mechanistic studies implied key factors to slow down the undesired decomposition process of electrophiles in this reaction, which opened up the possibility of using secondary aliphatic alcohols as nucleophilic substrates. This asymmetric O-alkylation reaction proceeds under almost neutral conditions, tolerates a broad scope of functional groups and shows remarkable chemoselectivities. This method is amenable to the modification of natural products and commercial drugs. The products obtained could be readily elaborated to various classes of enantioenriched α,α′-disubstituted ethers that are difficult to access by other methods.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Synthetic challenges to asymmetric alkylation of secondary aliphatic alcohols, and our approach.
Fig. 2: Mechanistic insights into the Cu-catalysed APS reaction provided by kinetic studies.
Fig. 3: Substrate scope of the Cu-catalysed asymmetric O-propargylation of secondary aliphatic alcohols.
Fig. 4: Product derivatization.
Fig. 5: Mechanistic studies.
Fig. 6: Role of Ph2SiF2 in this reaction.

Similar content being viewed by others

Data availability

The data supporting the findings of this study are available within the manuscript and its Supplementary Information file. Experimental details and full spectroscopic characterization data for all new compounds, as well as copies of NMR spectra, are provided in the Supplementary Information. Crystallographic data relating to this study have been deposited in the Cambridge Crystallographic Data Centre (CCDC) database under deposition numbers 1951205 and 1952086. These data can be obtained free of charge from the CCDC via


  1. Brown, W. H., Iverson, B. L., Anslyn, E. V. & Foote, C. S. Organic Chemistry 7th edn Ch. 11 (Cengage, 2013).

  2. Williamson, A. W. XXII.—On etherification. J. Chem. Soc. 106, 229–239 (1852).

    Google Scholar 

  3. Xiang, J. et al. Hindered dialkyl ether synthesis with electrogenerated carbocations. Nature 573, 398–402 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Trost, B. M., McEachern, E. J. & Toste, D. F. A two-component catalyst system for asymmetric allylic alkylations with alcohol pronucleophiles. J. Am. Chem. Soc. 120, 12702–12703 (1998).

    Article  CAS  Google Scholar 

  5. Xie, J., Guo, W., Cai, A., Escudero-Adán, E. C. & Kleij, A. W. Pd-catalyzed enantio- and regioselective formation of allylic aryl ethers. Org. Lett. 19, 6388–6391 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Liu, W.-B., Xia, J.-B. & You, S.-L. Iridium-catalyzed asymmetric allylic substitutions. Top. Organomet. Chem. 38, 155–207 (2012).

    Article  CAS  Google Scholar 

  7. Trost, B. M., Zhang, T. & Sieber, J. D. Catalytic asymmetric allylic alkylation employing heteroatom nucleophiles: a powerful method for C–X bond formation. Chem. Sci. 1, 427–440 (2010).

    Article  CAS  Google Scholar 

  8. Shu, C. & Hartwig, J. F. Iridium-catalyzed intermolecular allylic etherification aliphatic alkoxides: asymmetric synthesis of dihydropyrans and dihydrofurans. Angew. Chem. Int. Ed. 43, 4794–4797 (2004).

    Article  CAS  Google Scholar 

  9. Ueno, S. & Hartwig, J. F. Direct, iridium-catalyzed enantioselective and regioselective allylic etherification with aliphatic alcohols. Angew. Chem. Int. Ed. 47, 1928–1931 (2008).

    Article  CAS  Google Scholar 

  10. Barker, G., Johnson, D. G., Young, P. C., Macgregor, S. A. & Lee, A. L. Chirality transfer in gold(i)-catalysed direct allylic etherifications of unactivated alcohols: experimental and computational study. Chem. Eur. J. 21, 13748–13757 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Liu, Z. & Breit, B. Rhodium‐catalyzed enantioselective intermolecular hydroalkoxylation of allenes and alkynes with alcohols: synthesis of branched allylic ethers. Angew. Chem. Int. Ed. 55, 8440–8443 (2016).

    Article  CAS  Google Scholar 

  12. Zhu, S.-F., Cai, Y., Mao, H.-X., Xie, J.-H. & Zhou, Q.-L. Enantioselective iron-catalysed O–H bond insertions. Nat. Chem. 2, 546–551 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Kang, Q. K., Wang, L., Liu, Q. J., Li, J. F. & Tang, Y. Asymmetric H2O-nucleophilic ring opening of D–A cyclopropanes: catalyst serves as a source of water. J. Am. Chem. Soc. 137, 14594–14597 (2015).

    Article  CAS  PubMed  Google Scholar 

  14. Xia, Y. et al. Asymmetric ring‐opening of cyclopropyl ketones with thiol, alcohol, and carboxylic acid nucleophiles catalyzed by a chiral N,N′‐dioxide–scandium (iii) complex. Angew. Chem. Int. Ed. 54, 13748–13752 (2015).

    Article  CAS  Google Scholar 

  15. Ziegler, D. T. & Fu, G. C. Catalytic enantioselective carbon–oxygen bond formation: phosphine-catalyzed synthesis of benzylic ethers via the oxidation of benzylic C–H bonds. J. Am. Chem. Soc. 138, 12069–12072 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Imada, Y., Yuasa, M., Nakamura, I. & Murahashi, S. I. Copper(i)-catalyzed amination of propargyl esters. Selective synthesis of propargylamines, 1-alken-3-ylamines, and (Z)-allylamines. J. Org. Chem. 59, 2282–2284 (1994).

    Article  CAS  Google Scholar 

  17. Detz, R. J., Hiemstra, H. & van Maarseveen, J. H. Catalyzed propargylic substitution. Eur. J. Org. Chem. 2009, 6263–6276 (2009).

    Article  CAS  Google Scholar 

  18. Miyake, Y., Uemura, S. & Nishibayashi, Y. Catalytic propargylic substitution reactions. ChemCatChem 1, 342–356 (2009).

    Article  CAS  Google Scholar 

  19. Nishibayashi, Y. Transition-metal-catalyzed enantioselective propargylic substitution reactions of propargylic alcohol derivatives with nucleophiles. Synthesis 2012, 489–503 (2012).

    Article  CAS  Google Scholar 

  20. Sakata, K. & Nishibayashi, Y. Mechanism and reactivity of catalytic propargylic substitution reactions via metal–allenylidene intermediates: a theoretical perspective. Catal. Sci. Technol. 8, 12–25 (2018).

    Article  CAS  Google Scholar 

  21. Zhang, D.-Y. & Hu, X.-P. Recent advances in copper-catalyzed propargylic substitution. Tetrahedron Lett. 56, 283–295 (2015).

    Article  CAS  Google Scholar 

  22. Trost, B. M. & Li, C. J. Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations (Wiley, 2014).

  23. Nakajima, K., Shibata, M. & Nishibayashi, Y. Copper-catalyzed enantioselective propargylic etherification of propargylic esters with alcohols. J. Am. Chem. Soc. 137, 2472–2475 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Taylor, M. S. Catalysis based on reversible covalent interactions of organoboron compounds. Acc. Chem. Res. 48, 295–305 (2015).

    Article  CAS  PubMed  Google Scholar 

  25. Li, R.-Z. et al. Enantioselective propargylation of polyols and desymmetrization of meso 1,2-diols by copper/borinic acid dual catalysis. Angew. Chem. Int. Ed. 56, 7213–7217 (2017).

    Article  CAS  Google Scholar 

  26. Li, R.-Z. et al. Site-divergent delivery of terminal propargyls to carbohydrates by synergistic catalysis. Chem 3, 834–845 (2017).

    Article  CAS  Google Scholar 

  27. Tsuchida, K., Yuki, M., Nakajima, K. & Nishibayashi, Y. Copper- and borinic acid-catalyzed propargylic etherification of propargylic carbonates with benzyl alcohols. Chem. Lett. 47, 671–673 (2018).

    Article  CAS  Google Scholar 

  28. Blackmond, D. G. Kinetic profiling of catalytic organic reactions as a mechanistic tool. J. Am. Chem. Soc. 137, 10852–10866 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Kumar, A., Geng, Y. & Schmidt, R. R. Silicon fluorides for acid–base catalysis in glycosidations. Adv. Synth. Catal. 354, 1489–1499 (2012).

    Article  CAS  Google Scholar 

  30. Shao, L., Zhang, D.-Y., Wang, Y.-H. & Hu, X.-P. Enantioselective copper-catalyzed propargylic etherification of propargylic esters with phenols promoted by inorganic base additives. Adv. Synth. Catal. 358, 2558–2563 (2016).

    Article  CAS  Google Scholar 

  31. Cox, N., Dang, H., Whittaker, A. M. & Lalic, G. NHC–copper hydrides as chemoselective reducing agents: catalytic reduction of alkynes, alkyl triflates, and alkyl halides. Tetrahedron 70, 4219–4231 (2014).

    Article  CAS  Google Scholar 

  32. Sonogashira, K. Development of Pd–Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon halides. J. Organomet. Chem. 653, 46–49 (2002).

    Article  CAS  Google Scholar 

  33. Hari Babu, M., Ranjith Kumar, G., Kant, R. & Sridhar Reddy, M. Ni-catalyzed regio- and stereoselective addition of arylboronic acids to terminal alkynes with a directing group tether. Chem. Commun. 53, 3894–3897 (2017).

    Article  CAS  Google Scholar 

  34. Sun, Y., Abdukader, A., Lu, D., Zhang, H. & Liu, C. Synthesis of (E)-β-iodo vinylsulfones via iodine-promoted iodosulfonylation of alkynes with sodium sulfinates in an aqueous medium at room temperature. Green Chem. 19, 1255–1258 (2017).

    Article  CAS  Google Scholar 

  35. Coombs, J. R., Zhang, L. & Morken, J. P. Enantiomerically enriched tris(boronates): readily accessible conjunctive reagents for asymmetric synthesis. J. Am. Chem. Soc. 136, 16140–16143 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lee, S., Li, D. & Yun, J. Copper-catalyzed synthesis of 1,1-diborylalkanes through regioselective dihydroboration of terminal alkynes. Chem. Asian J. 9, 2440–2443 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Shi, S. L. & Buchwald, S. L. Copper-catalysed selective hydroamination reactions of alkynes. Nat. Chem. 7, 38–44 (2015).

    Article  CAS  PubMed  Google Scholar 

  38. Cho, S. H., Yoo, E. J., Bae, I. & Chang, S. Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water. J. Am. Chem. Soc. 127, 16046–16047 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Larock, R. C. & Yum, E. K. Synthesis of indoles via palladium-catalyzed heteroannulation of internal alkynes. J. Am. Chem. Soc. 113, 6689–6690 (1991).

    Article  CAS  Google Scholar 

  40. Aggarwal, V. K., de Vicente, J. & Bonnert, R. V. A novel one-pot method for the preparation of pyrazoles by 1,3-dipolar cycloadditions of diazo compounds generated in situ. J. Org. Chem. 68, 5381–5383 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Heaney, F. Nitrile oxide/alkyne cycloadditions—a credible platform for synthesis of bioinspired molecules by metal‐free molecular clicking. Eur. J. Org. Chem. 2012, 3043–3058 (2012).

    Article  CAS  Google Scholar 

  42. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).

    Article  CAS  Google Scholar 

  43. Zhang, K. et al. Enantioconvergent copper catalysis: in situ generation of the chiral phosphorus ylide and its Wittig reactions. J. Am. Chem. Soc. 139, 12847–12854 (2017).

    Article  CAS  PubMed  Google Scholar 

  44. Panera, M., Diez, J., Merino, I., Rubio, E. & Gamasa, M. P. Synthesis of copper(i) complexes containing enantiopure pybox ligands. First assays on enantioselective synthesis of propargylamines catalyzed by isolated copper(i) complexes. Inorg. Chem. 48, 11147–11160 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Hattori, G. et al. Copper-catalyzed enantioselective propargylic amination of propargylic esters with amines: copper–allenylidene complexes as key intermediates. J. Am. Chem. Soc. 132, 10592–10608 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Hattori, H. Heterogeneous basic catalysis. Chem. Rev. 95, 537–558 (1995).

    Article  CAS  Google Scholar 

Download references


This work is supported by funding from the National Key Research and Development Program (2018YFA0903300) and National Natural Science Foundation of China (21922106 and 21772125), and start-up funding from Sichuan University and The Open Project of the State Key Laboratory of Natural Medicines (3144060211). We acknowledge J. J. Chruma (Sichuan University) for helpful discussions and manuscript revision. We thank D. Luo from the Analytical and Testing Center of Sichuan University for help with X-ray analysis.

Author information

Authors and Affiliations



D.N. conceived of the idea, guided the project and wrote the manuscript, with feedback from the other authors. R.-Z.L. and D.-Q.L. conducted the experiments and analysed the results.

Corresponding author

Correspondence to Dawen Niu.

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

Supplementary methods, Figs. 1–6, references and spectra.

Supplementary Data 1

Crystallographic Data of 26ah in Fig. 3

Supplementary Data 2

Crystallographic data of the copper complex in Fig. 5c.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, RZ., Liu, DQ. & Niu, D. Asymmetric O-propargylation of secondary aliphatic alcohols. Nat Catal 3, 672–680 (2020).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


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