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.

Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis


Olefin metathesis has had a large impact on modern organic chemistry, but important shortcomings remain: for example, the lack of efficient processes that can be used to generate acyclic alkenyl halides. Halo-substituted ruthenium carbene complexes decompose rapidly or deliver low activity and/or minimal stereoselectivity, and our understanding of the corresponding high-oxidation-state systems is limited. Here we show that previously unknown halo-substituted molybdenum alkylidene species are exceptionally reactive and are able to participate in high-yielding olefin metathesis reactions that afford acyclic 1,2-disubstituted Z-alkenyl halides. Transformations are promoted by small amounts of a catalyst that is generated in situ and used with unpurified, commercially available and easy-to-handle liquid 1,2-dihaloethene reagents, and proceed to high conversion at ambient temperature within four hours. We obtain many alkenyl chlorides, bromides and fluorides in up to 91 per cent yield and complete Z selectivity. This method can be used to synthesize biologically active compounds readily and to perform site- and stereoselective fluorination of complex organic molecules.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Designing catalytic CM reactions that afford Z-alkenyl halides.
Figure 2: Synthesis of Z-alkenyl chlorides and applications.
Figure 3: Z-Alkenyl bromides through catalytic CM and ROCM.
Figure 4: Z-alkenyl fluorides and late-stage fluorination.


  1. Nunnery, J. K. et al. Biosynthetically intriguing chlorinated lipophilic metabolites from geographically distant tropical marine cyanobacteria. J. Org. Chem. 77, 4198–4208 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Akiyama, T. et al. Stimulators of adipogenesis from the marine sponge Xestospongia testudinaria . Tetrahedron 69, 6560–6564 (2013)

    Article  CAS  Google Scholar 

  3. Johansson Seechurn, C. C. C., Kitching, M. O., Colacot, T. J. & Sniekus, V. Palladium-catalyzed cross-coupling: a historical contextual perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed. 51, 5062–5085 (2012)

    Article  CAS  Google Scholar 

  4. Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J. & Meanwell, N. A. Applications of fluorine in medicinal chemistry. J. Med. Chem. 58, 8315–8359 (2015)

    Article  CAS  PubMed  Google Scholar 

  5. Fujiwara, T. & O’Hagan, D. Successful fluorine-containing herbicide agrochemicals. J. Fluor. Chem. 167, 16–29 (2014)

    Article  CAS  Google Scholar 

  6. Berger, R., Resnati, G., Metrangolo, P., Weber, E. & Hulliger, J. Organic fluorine compounds: a great opportunity for enhanced materials properties. Chem. Soc. Rev. 40, 3496–3508 (2011)

    Article  CAS  PubMed  Google Scholar 

  7. Kolb, M., Barth, J., Heydt, J.-G. & Jung, M. J. Synthesis and evaluation of mono-, di-, and trifluoroethenyl-GABA derivatives as GABA-T inhibitors. J. Med. Chem. 30, 267–272 (1987)

    Article  CAS  PubMed  Google Scholar 

  8. Silverman, R. B., Bichler, K. A. & Leon, A. J. Unusual mechanistic difference in the activation of γ-aminobutyric acid aminotransferase by (E)- and (Z)-4-amino-6-fluoro-5-hexenoic acid. J. Am. Chem. Soc. 118, 1253–1261 (1996)

    Article  CAS  Google Scholar 

  9. Rosen, T. C., Yoshida, S., Kirk, K. L. & Haufe, G. Fluorinated phenylcyclopropylamines as inhibitors of monoamine oxidases. ChemBioChem 5, 1033–1043 (2004)

    Article  CAS  PubMed  Google Scholar 

  10. Morrill, C. & Grubbs, R. H. Synthesis of functionalized vinylboronates via ruthenium-catalyzed cross-metathesis and subsequent conversion to vinyl halides. J. Org. Chem. 68, 6031–6034 (2003)

    Article  CAS  PubMed  Google Scholar 

  11. Pawlu, P., Hreczycho, G., Szudkowska, J., Kubicki, M. & Marciniec, B. New one-pot synthesis of (E)-β-aryl vinyl halides from styrenes. Org. Lett. 11, 3390–3393 (2009)

    Article  CAS  Google Scholar 

  12. Bull, J. A., Mousseau, J. J. & Charette, A. B. Convenient one-pot synthesis of (E)-β-aryl vinyl halides from benzyl bromides and dihalomethanes. Org. Lett. 10, 5485–5488 (2008)

    Article  CAS  PubMed  Google Scholar 

  13. Gao, F. & Hoveyda, A. H. α-Selective Ni-catalyzed hydroalumination of aryl- and alkyl-substituted terminal alkynes: practical syntheses of internal vinyl aluminums, halides, or boronates. J. Am. Chem. Soc. 132, 10961–10963 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stork, G. & Zhao, K. A stereoselective synthesis of (Z)-1-iodo-1-alkenes. Tetrahedr. Lett . 30, 2173–2174 (1989)

    Article  ADS  CAS  Google Scholar 

  15. Zhang, X.-P. & Schlosser, M. Highly cis-selective Wittig reactions employing α-heterosubstituted ylids. Tetrahedr. Lett . 34, 1925–1928 (1993)

    CAS  Google Scholar 

  16. Crane, E. A., Zabawa, T. P., Farmer, R. L. & Scheidt, K. A. Enantioselective synthesis of (–)-exiguolide by iterative stereoselective dioxinone-directed Prins cyclizations. Angew. Chem. Int. Ed. 50, 9112–9115 (2011)

    Article  CAS  Google Scholar 

  17. Landelle, G., Turcotte-Savard, M.-C., Angers, L. & Paquin, J. F. Stereoselective synthesis of both stereoisomers of β-fluorostyrene derivatives from a common intermediate. Org. Lett. 13, 1568–1571 (2011)

    Article  CAS  PubMed  Google Scholar 

  18. Nakagawa, M., Saito, A., Soga, A., Yamamoto, N. & Taguchi, T. Chromium mediated stereoselective synthesis of (Z)-1-fluoro-2-alkenyl alkyl and trialkylsilyl ethers from dibromofluoromethylcarbinyl ethers. Tetrahedr. Lett . 46, 5257–5261 (2005)

    Article  CAS  Google Scholar 

  19. Ohmura, T., Yamamoto, Y. & Miyaura, N. Rhodium- or iridium-catalyzed trans-hydroboration of terminal alkynes, giving (Z)-1-alkenylboron compounds. J. Am. Chem. Soc. 122, 4990–4991 (2000)

    Article  CAS  Google Scholar 

  20. Molander, G. A. & Ellis, N. M. Highly stereoselective synthesis of cis-alkenyl pinacolatoboronates and potassium cis-alkenyltrifluoroborates via a hydroboration/protodeboronation approach. J. Org. Chem. 73, 6841–6844 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kiesewetter, E. T. et al. Synthesis of Z-(pinacolato)allylboron and Z-(pinacolato)alkenylboron compounds through stereoselective catalytic cross-metathesis. J. Am. Chem. Soc. 135, 6026–6029 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bronner, S. M., Herbert, M. B., Patel, P. R., Marx, V. M. & Grubbs, R. H. Ruthenium-catalyzed Z-selective metathesis catalysts with modified cyclometalated carbene ligands. Chem. Sci. 5, 4091–4098 (2014)

    Article  CAS  PubMed  Google Scholar 

  23. Brown, H. C., Larock, R. C., Gupta, S. K., Rajagopalan, S. & Bhat, N. G. Vinylic organoboranes. 15. Mercuration of 2-alkenyl-1,3,2-benzodioxaboroles and boronic acids. A convenient stereospecific procedure for the conversion of alkynes into (E)-1-halo-1-alkenes via mercuric salts. J. Org. Chem. 54, 6079–6084 (1989)

    Article  CAS  Google Scholar 

  24. Petasis, N. A. & Zavialov, I. A. Mild conversion of alkenyl boronic acids to alkenyl halides with halosuccinimides. Tetrahedr. Lett . 37, 567–570 (1996)

    Article  CAS  Google Scholar 

  25. Gensch, K. H., Pitman, I. H. & Higuchi, T. Oxidation of thioesters to sulfoxides by iodine. II. Catalytic role of some carboxylic acid anions. J. Am. Chem. Soc. 90, 2096–2104 (1968)

    Article  CAS  Google Scholar 

  26. Hamri, S., Rodríguez, J., Basset, J., Guillaumet, G. & Pujol, M. D. A convenient iodination of indoles and derivatives. Tetrahedron 68, 6269–6275 (2012)

    Article  CAS  Google Scholar 

  27. Speed, A. W. H., Mann, S. J., O’Brien, R. V., Schrock, R. R. & Hoveyda, A. H. Catalytic Z-selective cross-metathesis in complex molecule synthesis: a convergent stereoselective route to disorazole C1 . J. Am. Chem. Soc. 136, 16136–16139 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hanh, T. T. H., Hang, D. T. T., Minh, C. V. & Dat, N. T. Anti-inflammatory effects of fatty acids isolated from Chromolaena odorata . Asian Pac. J. Trop. Med. 4, 760–763 (2011)

    Article  CAS  PubMed  Google Scholar 

  29. López, S., Fernández-Trillo, F., Midón, P., Castedo, L. & Saá, C. First stereoselective syntheses of (–)-siphonodiol and (–)-tetrahydrosiphonodiol, bioactive polyacetylenes from marine sponges. J. Org. Chem. 70, 6346–6352 (2005)

    Article  PubMed  CAS  Google Scholar 

  30. Campbell, M. G. & Ritter, T. Late-stage fluorination: from fundamentals to application. Org. Process Res. Dev. 18, 474–480 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Imaizumi, Y. et al. Molecular basis of pimarane compounds as novel activators of large-conductance Ca2+-activated channel α-subunit. Mol. Pharmacol. 62, 836–846 (2002)

    Article  CAS  PubMed  Google Scholar 

  32. Macnaughtan, M. L., Johnson, M. J. A. & Kampf, J. W. Olefin metathesis reactions with vinyl halides: formation, observation, interception, and fate of the ruthenium–monohalomethylidene moiety. J. Am. Chem. Soc. 129, 7708–7709 (2007)

    Article  CAS  PubMed  Google Scholar 

  33. Sashuk, V., Samojlowicz, C., Szadkowska, A. & Grela, K. Olefin cross-metathesis with vinyl halides. Chem. Commun. 2468–2470 (2008)

  34. Macnaughtan, M. L., Gary, J. B., Gerlach, D. L., Johnson, M. J. A. & Kamf, J. W. Cross-metathesis of vinyl halides. Scope and limitations of ruthenium-based catalysts. Organometallics 28, 2880–2887 (2009)

    Article  CAS  Google Scholar 

  35. Meek, S. J., O’Brien, R. V., Llaveria, J., Schrock, R. R. & Hoveyda, A. H. Catalytic Z-selective olefin metathesis for natural product synthesis. Nature 471, 461–466 (2011)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  36. Vasiliu, M., Li, S., Arduengo, A. J. III & Dixon, D. A. Bond energies in models of the Schrock metathesis catalyst. J. Phys. Chem. C 115, 12106–12120 (2011)

    Article  CAS  Google Scholar 

  37. Rosebrugh, L. E., Herbert, M. B., Marx, V. M., Keitz, B. K. & Grubbs, R. H. Highly active ruthenium metathesis catalysts exhibiting unprecedented activity and Z selectivity. J. Am. Chem. Soc. 135, 1276–1279 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Koh, M. J. et al. High-value alcohols and higher-oxidation-state compounds by catalytic Z-selective cross-metathesis. Nature 517, 181–186 (2015)

    Article  ADS  CAS  PubMed  Google Scholar 

  39. Silverio, D. L. et al. Simple organic molecules as catalysts for enantioselective synthesis of amines and alcohols. Nature 494, 216–221 (2013)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hoye, R. C., Andersen, G. L., Brown, S. G. & Schultz, E. E. Total synthesis of clathculins A and B. J. Org. Chem. 75, 7400–7403 (2010)

    Article  CAS  PubMed  Google Scholar 

  41. Jang, H., Zhugralin, A. R., Lee, Y. & Hoveyda, A. H. Highly selective methods for synthesis of internal (α-) vinylboronates through efficient NHC–Cu-catalyzed hydroboration of terminal alkynes. Utility in synthesis and mechanistic basis for selectivity. J. Am. Chem. Soc. 133, 7859–7871 (2011)

    Article  CAS  PubMed  Google Scholar 

  42. Hoveyda, A. H. Evolution of catalytic enantioselective olefin metathesis: from ancillary transformation to purveyor of stereochemical identity. J. Org. Chem. 79, 4763–4792 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fustero, S., Simón-Fuentes, A., Barrio, P. & Haufe, G. Olefin metathesis reactions with fluorinated substrates, catalysts, and solvents. Chem. Rev. 115, 871–930 (2015)

    Article  CAS  PubMed  Google Scholar 

  44. Zhang, H., Yu, E. C., Torker, S., Schrock, R. R. & Hoveyda, A. H. Preparation of macrocyclic Z-enoates and (E,Z)- or (Z,E)-dienoates through catalytic stereoselective ring-closing metathesis. J. Am. Chem. Soc. 136, 16493–16496 (2014)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gillingham, D. G. & Hoveyda, A. H. Chiral N-heterocyclic carbenes in natural product synthesis: application of Ru-catalyzed asymmetric ring-opening/cross-metathesis and Cu-catalyzed allylic alkylation to total synthesis of baconipyrone C. Angew. Chem. Int. Ed. 46, 3860–3864 (2007)

    Article  CAS  Google Scholar 

  46. Addington, D. E. et al. Impact of second-generation anti-psychotics and perphenazine on depressive symptoms in a randomized trial for chronic schizophrenia. J. Clin. Psychiatry 72, 75–80 (2011)

    Article  CAS  PubMed  Google Scholar 

  47. English, A. R., Girard, D., Jasys, V. J., Martingano, R. J. & Kellogg, M. S. Orally effective acid prodrugs of the β-lactamase inhibitor sulbactam. J. Med. Chem. 33, 344–347 (1990)

    Article  CAS  PubMed  Google Scholar 

  48. Furuya, T. & Ritter, T. Fluorination of boronic acids mediated by silver(I) triflate. Org. Lett. 11, 2860–2863 (2009)

    Article  CAS  PubMed  Google Scholar 

  49. Haginaka, J., Yasuda, H., Uno, T. & Nakagawa, T. Alkaline degradation and determination by high-performance liquid chromatography. Chem. Pharm. Bull. 32, 2752–2758 (1984)

    Article  CAS  Google Scholar 

  50. Townsend, E. M. et al. High oxidation state molybdenum imido heteroatom-substituted alkyliene complexes. Organometallics 32, 4612–4617 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


This research was supported by the United States National Institutes of Health, Institute of General Medical Sciences (GM-59426 and in part GM-57212).

Author information

Authors and Affiliations



M.J.K., T.T.N. and H.Z. were involved in the discovery, design and development of the new Z-selective cross-metathesis strategies and their applications. A.H.H., M.J.K., T.T.N. and H.Z. conceived the research programme. A.H.H. designed and directed the investigations. A.H.H. and R.R.S. conceived the studies that led to the development of Mo MAP complexes. A.H.H. wrote the manuscript with revisions provided by M.J.K., T.T.N. and H.Z.

Corresponding author

Correspondence to Amir H. Hoveyda.

Ethics declarations

Competing interests

The catalysts and technologies developed are licensed by a company that was founded by A.H.H. and R.R.S.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data (see Contents for more details). (PDF 10349 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Koh, M., Nguyen, T., Zhang, H. et al. Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis. Nature 531, 459–465 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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