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.

A general asymmetric copper-catalysed Sonogashira C(sp3)–C(sp) coupling

Abstract

Continued development of the Sonogashira coupling has made it a well established and versatile reaction for the straightforward formation of C–C bonds, forging the carbon skeletons of broadly useful functionalized molecules. However, asymmetric Sonogashira coupling, particularly for C(sp3)–C(sp) bond formation, has remained largely unexplored. Here we demonstrate a general stereoconvergent Sonogashira C(sp3)–C(sp) cross-coupling of a broad range of terminal alkynes and racemic alkyl halides (>120 examples) that are enabled by copper-catalysed radical-involved alkynylation using a chiral cinchona alkaloid-based P,N-ligand. Industrially relevant acetylene and propyne are successfully incorporated, laying the foundation for scalable and economic synthetic applications. The potential utility of this method is demonstrated in the facile synthesis of stereoenriched bioactive or functional molecule derivatives, medicinal compounds and natural products that feature a range of chiral C(sp3)–C(sp/sp2/sp3) bonds. This work emphasizes the importance of radical species for developing enantioconvergent transformations.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Motivation and design of catalytic enantioselective Sonogashira C(sp3)−C(sp) cross-couplings.
Fig. 2: Synthetic applications of the catalytic enantioselective Sonogashira cross-coupling.
Fig. 3: Mechanistic studies of the catalytic enantioconvergent Sonogashira cross-coupling.

Data availability

All of the characterization data and experimental protocols are provided in this article and its Supplementary Information. Data are also available from the corresponding author on request.

References

  1. Knochel, P. & Molander, G. A. Comprehensive Organic Synthesis 2nd edn (Elsevier, Amsterdam, 2014).

  2. de Meijere, A., Bräse, S. & Oestreich, M. Metal-Catalyzed Cross-Coupling Reactions and More (Wiley-VCH, Weinheim, 2014).

  3. 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 

  4. Trost, B. M. & Li, C.-J. Modern Alkyne Chemistry: Catalytic and Atom-Economic Transformations (Wiley-VCH, Weinheim, 2015).

  5. Dieck, H. A. & Heck, F. R. Palladium catalyzed synthesis of aryl, heterocyclic and vinylic acetylene derivatives. J. Organomet. Chem. 93, 259–263 (1975).

    CAS  Google Scholar 

  6. Cassar, L. Synthesis of aryl- and vinyl-substituted acetylene derivatives by the use of nickel and palladium complexes. J. Organomet. Chem. 93, 253–257 (1975).

    CAS  Google Scholar 

  7. Sonogashira, K., Tohda, Y. & Hagihara, N. A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett. 16, 4467–4470 (1975).

    Google Scholar 

  8. Chinchilla, R. & Nájera, C. The Sonogashira reaction: a booming methodology in synthetic organic chemistry. Chem. Rev. 107, 874–922 (2007).

    CAS  PubMed  Google Scholar 

  9. Eckhardt, M. & Fu, G. C. The first applications of carbene ligands in cross-couplings of alkyl electrophiles: Sonogashira reactions of unactivated alkyl bromides and iodides. J. Am. Chem. Soc. 125, 13642–13643 (2003).

    CAS  PubMed  Google Scholar 

  10. Altenhoff, G., Würtz, S. & Glorius, F. The first palladium-catalyzed Sonogashira coupling of unactivated secondary alkyl bromides. Tetrahedron Lett. 47, 2925–2928 (2006).

    CAS  Google Scholar 

  11. Hornillos, V. et al. Synthesis of axially chiral heterobiaryl alkynes via dynamic kinetic asymmetric alkynylation. Chem. Commun. 52, 14121–14124 (2016).

    CAS  Google Scholar 

  12. Cui, X.-Y. et al. (Guanidine)copper complex-catalyzed enantioselective dynamic kinetic allylic alkynylation under biphasic condition. J. Am. Chem. Soc. 140, 8448–8455 (2018).

    CAS  PubMed  Google Scholar 

  13. Harada, A., Makida, Y., Sato, T., Ohmiya, H. & Sawamura, M. Copper-catalyzed enantioselective allylic alkylation of terminal alkyne pronucleophiles. J. Am. Chem. Soc. 136, 13932–13939 (2014).

    CAS  PubMed  Google Scholar 

  14. Hamilton, J. Y., Sarlah, D. & Carreira, E. M. Iridium-catalyzed enantioselective allylic alkynylation. Angew. Chem. Int. Ed. 52, 7532–7535 (2013).

    CAS  Google Scholar 

  15. Dabrowski, J. A., Gao, F. & Hoveyda, A. H. Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC–Cu-catalyzed allylic substitution reactions with (i-Bu)2(alkynyl)aluminum reagents. J. Am. Chem. Soc. 133, 4778–4781 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Choi, J. & Fu, G. C. Transition metal–catalyzed alkyl-alkyl bond formation: another dimension in cross-coupling chemistry. Science 356, eaaf7230 (2017).

    PubMed  PubMed Central  Google Scholar 

  17. Fu, G. C. Transition-metal catalysis of nucleophilic substitution reactions: a radical alternative to SN1 and SN2 processes. ACS Cent. Sci. 3, 692–700 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hazra, A., Lee, M. T., Chiu, J. F. & Lalic, G. Photoinduced copper-catalyzed coupling of terminal alkynes and alkyl iodides. Angew. Chem. Int. Ed. 57, 5492–5496 (2018).

    CAS  Google Scholar 

  20. Voronin, V. V., Ledovskaya, M. S., Bogachenkov, A. S., Rodygin, K. S. & Ananikov, V. P. Acetylene in organic synthesis: recent progress and new uses. Molecules 23, E2442 (2018).

    PubMed  Google Scholar 

  21. Trotus, I.-T., Zimmermann, T. & Schüth, F. Catalytic reactions of acetylene: a feedstock for the chemical industry revisited. Chem. Rev. 114, 1761–1782 (2014).

    CAS  PubMed  Google Scholar 

  22. Sasaki, H., Boyall, D. & Carreira, E. M. Facile, asymmetric addition of acetylene to aldehydes: in situ generation of reactive zinc acetylide. Helv. Chim. Acta 84, 964–971 (2001).

    CAS  Google Scholar 

  23. Sato, Y., Nishimata, T. & Mori, M. Asymmetric synthesis of isoindoline and isoquinoline derivatives using nickel(0)-catalyzed [2+2+2] cocyclization. J. Org. Chem. 59, 6133–6135 (1994).

    CAS  Google Scholar 

  24. Shibata, T., Arai, Y. & Tahara, Y.-k Enantioselective construction of quaternary carbon centers by catalytic [2+2+2] cycloaddition of 1,6-enynes and alkynes. Org. Lett 7, 4955–4957 (2005).

    CAS  PubMed  Google Scholar 

  25. Kong, J. R. & Krische, M. J. Catalytic carbonyl Z-dienylation via multicomponent reductive coupling of acetylene to aldehydes and α-ketoesters mediated by hydrogen: carbonyl insertion into cationic rhodacyclopentadienes. J. Am. Chem. Soc. 128, 16040–16041 (2006).

    CAS  PubMed  Google Scholar 

  26. Heller, B. et al. Phosphorus-bearing axially chiral biaryls by catalytic asymmetric cross-cyclotrimerization and a first application in asymmetric hydrosilylation. Chem. Eur. J. 13, 1117–1128 (2007).

    CAS  PubMed  Google Scholar 

  27. Skucas, E., Kong, J. R. & Krische, M. J. Enantioselective reductive coupling of acetylene to N-arylsulfonyl imines via rhodium catalyzed C–C bond-forming hydrogenation: (Z)-dienyl allylic amines. J. Am. Chem. Soc. 129, 7242–7243 (2007).

    CAS  PubMed  Google Scholar 

  28. Evano, G. & Blanchard, N. Copper-Mediated Cross-Coupling Reactions (Wiley, New Jersey, 2014).

  29. Shaughnessy, K. H., Ciganek, E. & DeVasher, R. B. Copper-Catalyzed Amination of Aryl and Alkenyl Electrophiles (Wiley, New Jersey, 2017).

  30. Díez-González, S. in Advances in Organometallic Chemistry (ed. Pérez, P. J.) 93–141 (Academic, 2016).

  31. Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Yoshikai, N. & Nakamura, E. Mechanisms of nucleophilic organocopper(i) reactions. Chem. Rev. 112, 2339–2372 (2012).

    CAS  PubMed  Google Scholar 

  33. Pérez García, P. M., Ren, P., Scopelliti, R. & Hu, X. Nickel-catalyzed direct alkylation of terminal alkynes at room temperature: a hemilabile pincer ligand enhances catalytic activity. ACS Catal. 5, 1164–1171 (2015).

    Google Scholar 

  34. Yi, J., Lu, X., Sun, Y.-Y., Xiao, B. & Liu, L. Nickel-catalyzed Sonogashira reactions of non-activated secondary alkyl bromides and iodides. Angew. Chem. Int. Ed. 52, 12409–12413 (2013).

    CAS  Google Scholar 

  35. Vechorkin, O., Barmaz, D., Proust, V. & Hu, X. Ni-catalyzed Sonogashira coupling of nonactivated alkyl halides: orthogonal functionalization of alkyl iodides, bromides, and chlorides. J. Am. Chem. Soc. 131, 12078–12079 (2009).

    CAS  PubMed  Google Scholar 

  36. Wang, Z. et al. Sonogashira reactions of alkyl halides catalyzed by NHC [CNN] pincer nickel(ii) complexes. New J. Chem. 42, 11465–11470 (2018).

    CAS  Google Scholar 

  37. Luo, F.-X. et al. Cu-catalyzed alkynylation of unactivated C(sp 3)–X bonds with terminal alkynes through directing strategy. Org. Lett. 18, 2040–2043 (2016).

    CAS  PubMed  Google Scholar 

  38. Fantin, M., Lorandi, F., Gennaro, A., Isse, A. A. & Matyjaszewski, K. Electron transfer reactions in atom transfer radical polymerization. Synthesis 49, 3311–3322 (2017).

    CAS  Google Scholar 

  39. Leophairatana, P., Samanta, S., De Silva, C. C. & Koberstein, J. T. Preventing alkyne–alkyne (i.e., Glaser) coupling associated with the ATRP synthesis of alkyne-functional polymers/macromonomers and for alkynes under click (i.e., CuAAC) reaction conditions. J. Am. Chem. Soc. 139, 3756–3766 (2017).

    CAS  PubMed  Google Scholar 

  40. Kolb, H. C., VanNieuwenhze, M. S. & Sharpless, K. B. Catalytic asymmetric dihydroxylation. Chem. Rev. 94, 2483–2547 (1994).

    CAS  Google Scholar 

  41. Sladojevich, F., Trabocchi, A., Guarna, A. & Dixon, D. J. A new family of cinchona-derived amino phosphine precatalysts: application to the highly enantio- and diastereoselective silver-catalyzed isocyanoacetate aldol reaction. J. Am. Chem. Soc. 133, 1710–1713 (2011).

    CAS  PubMed  Google Scholar 

  42. 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 

  43. Berliner, M. A., Cordi, E. M., Dunetz, J. R. & Price, K. E. Sonogashira reactions with propyne: facile synthesis of 4-hydroxy-2-methylbenzofurans from iodoresorcinols. Org. Process Res. Dev. 14, 180–187 (2010).

    CAS  Google Scholar 

  44. Schobert, H. Production of acetylene and acetylene-based chemicals from coal. Chem. Rev. 114, 1743–1760 (2014).

    CAS  PubMed  Google Scholar 

  45. John, J. Global acetylene gas market will expand revenue USD 6 Bn by 2020. SBWire (15 March 2015).

  46. Schwarzwalder, G. M., Matier, C. D. & Fu, G. C. Enantioconvergent cross-couplings of alkyl electrophiles: the catalytic asymmetric synthesis of organosilanes. Angew. Chem. Int. Ed. 58, 3571–3574 (2019).

    CAS  Google Scholar 

  47. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug design. J. Med. Chem. 54, 2529–2591 (2011).

    CAS  PubMed  Google Scholar 

  48. Armstrong, M. K., Goodstein, M. B. & Lalic, G. Diastereodivergent reductive cross coupling of alkynes through tandem catalysis: Z- and E-selective hydroarylation of terminal alkynes. J. Am. Chem. Soc. 140, 10233–10241 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Elford, T. G., Nave, S., Sonawane, R. P. & Aggarwal, V. K. Total synthesis of (+)-erogorgiaene using lithiation–borylation methodology, and stereoselective synthesis of each of its diastereoisomers. J. Am. Chem. Soc. 133, 16798–16801 (2011).

    CAS  PubMed  Google Scholar 

  50. Wu, L. et al. Asymmetric synthesis of (R)-ar-curcumene, (R)-4,7-dimethyl-l-tetralone, and their enantiomers via cobalt-catalyzed asymmetric Kumada cross-coupling. Tetrahedron: Asymmetry 27, 78–83 (2016).

    CAS  Google Scholar 

  51. Bianco, G. G. et al. (+)- and (−)-Mutisianthol: first total synthesis, absolute configuration, and antitumor activity. J. Org. Chem. 74, 2561–2566 (2009).

    CAS  PubMed  Google Scholar 

  52. Kamal, A., Shaheer Malik, M., Azeeza, S., Bajee, S. & Shaik, A. A. Total synthesis of (R)- and (S)-turmerone and (7S,9R)-bisacumol by an efficient chemoenzymatic approach. Tetrahedron: Asymmetry 20, 1267–1271 (2009).

    CAS  Google Scholar 

  53. Schaub, T. A. & Kivala, M. in Metal-Catalyzed Cross-Coupling Reactions and More (eds de Meijere, A., Bräse, S. & Oestreich, M.) 665–762 (Wiley-VCH, 2014).

  54. Zuidema, E. & Bolm, C. Sub-mol% catalyst loading and ligand-acceleration in the copper-catalyzed coupling of aryl iodides and terminal alkyenes. Chem. Eur. J. 16, 4181–4185 (2010).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China (grant nos. 21722203, 21831002 and 21801116), Shenzhen Special Funds (grant nos. JCYJ20170412152435366 and JCYJ20170307105638498) and Shenzhen Nobel Prize Scientists Laboratory Project (grant no. C17783101).

Author information

Authors and Affiliations

Authors

Contributions

X.-Y.D., Y.-F.Z., C.-L.M., Q.-S.G. and F.-L.W. designed the experiments and analysed the data. X.-Y.D., Y.-F.Z., C.-L.M., F.-L.W., Z.-L.L. and S.-P.J. performed the experiments. All authors participated in writing the manuscript. X.-Y.L. conceived and supervised the project.

Corresponding author

Correspondence to Xin-Yuan Liu.

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

Characterization data, experimental data, synthetic procedures, figures and tables.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dong, XY., Zhang, YF., Ma, CL. et al. A general asymmetric copper-catalysed Sonogashira C(sp3)–C(sp) coupling. Nat. Chem. 11, 1158–1166 (2019). https://doi.org/10.1038/s41557-019-0346-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-019-0346-2

Further reading

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