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.

Functionalized olefin cross-coupling to construct carbon–carbon bonds

Abstract

Carbon–carbon (C–C) bonds form the backbone of many important molecules, including polymers, dyes and pharmaceutical agents. The development of new methods to create these essential connections in a rapid and practical fashion has been the focus of numerous organic chemists. This endeavour relies heavily on the ability to form C–C bonds in the presence of sensitive functional groups and congested structural environments. Here we report a chemical transformation that allows the facile construction of highly substituted and uniquely functionalized C–C bonds. Using a simple iron catalyst, an inexpensive silane and a benign solvent under ambient atmosphere, heteroatom-substituted olefins are easily reacted with electron-deficient olefins to create molecular architectures that were previously difficult or impossible to access. More than 60 examples are presented with a wide array of substrates, demonstrating the chemoselectivity and mildness of this simple reaction.

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.

Figure 1: Functionalized olefin cross-coupling as a strategy for convergent chemical synthesis.
Figure 2: Functionalized olefin cross-coupling optimization studies.
Figure 3: Adducts synthesized by functionalized olefin cross-coupling.
Figure 4: Additional functionalized olefin cross-coupling studies.
Figure 5: Functionalized olefin cross-coupling reverses conventional reactivity expectations.

References

  1. Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis (Wiley, 1995)

    Google Scholar 

  2. Isayama, S. & Mukaiyama, T. A new method for the preparation of alcohols from olefins with molecular oxygen and phenylsilane by the use of bis(acetylacetonato)cobalt(II). Chem. Lett. 18, 1071–1074 (1989)

    Google Scholar 

  3. Kato, K. & Mukaiyama, T. Iron(III) complex catalyzed nitrosation of terminal and 1,2-disubstituted olefins with butyl nitrite and phenylsilane. Chem. Lett. 21, 1137–1140 (1992)

    Google Scholar 

  4. Waser, J., Gaspar, B., Nambu, H. & Carreira, E. M. Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins. J. Am. Chem. Soc. 128, 11693–11712 (2006)

    CAS  PubMed  Google Scholar 

  5. Leggans, E. K., Barker, T. J., Duncan, K. K. & Boger, D. L. Iron(III)/NaBH4-mediated additions to unactivated alkenes: synthesis of novel 20′-vinblastine analogues. Org. Lett. 14, 1428–1431 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Shigehisa, H., Aoki, T., Yamaguchi, S., Shimizu, N. & Hiroya, K. Hydroalkoxylation of unactivated olefins with carbon radicals and carbocation species as key intermediates. J. Am. Chem. Soc. 135, 10306–10309 (2013)

    CAS  PubMed  Google Scholar 

  7. Shigehisa, H., Nishi, E., Fujisawa, M. & Hiroya, K. Cobalt-catalyzed hydrofluorination of unactivated olefins: a radical approach of fluorine transfer. Org. Lett. 15, 5158–5161 (2013)

    CAS  PubMed  Google Scholar 

  8. Girijavallabhan, V., Alvarez, C. & Njoroge, F. G. Regioselective cobalt-catalyzed addition of sulfides to unactivated alkenes. J. Org. Chem. 76, 6442–6446 (2011)

    CAS  PubMed  Google Scholar 

  9. Taniguchi, T., Goto, N., Nishibata, A. & Ishibashi, H. Iron-catalyzed redox radical cyclizations of 1,6-dienes and enynes. Org. Lett. 12, 112–115 (2010)

    CAS  PubMed  Google Scholar 

  10. Wang, L. C. et al. Diastereoselective cycloreductions and cycloadditions catalyzed by Co(dpm)2-silane (dpm) 2,2,6,6-tetramethylheptane-3,5-dionate): mechanism and partitioning of hydrometallative versus anion radical pathways. J. Am. Chem. Soc. 124, 9448–9453 (2002)

    CAS  PubMed  Google Scholar 

  11. Streuff, J. The electron-way: metal-catalyzed reductive umpolung reactions of saturated and α,β-unsaturated carbonyl derivatives. Synthesis 45, 281–307 (2013)

    CAS  Google Scholar 

  12. Zbieg, J. R., Yamaguchi, E., McInturff, E. L. & Krische, M. J. Enantioselective C–H crotylation of primary alcohols via hydrohydroxyalkylation of butadiene. Science 336, 324–327 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lo, J. C., Yabe, Y. & Baran, P. S. A practical and catalytic reductive olefin coupling. J. Am. Chem. Soc. 136, 1304–1307 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Srikanth, G. S. C. & Castle, S. L. Advances in radical conjugate additions. Tetrahedron 61, 10377–10441 (2005)

    CAS  Google Scholar 

  15. Lackner, G. L., Quasdorf, K. W. & Overman, L. E. Direct construction of quaternary carbons from tertiary alcohols via photoredox-catalyzed fragmentation of tert-alkyl N-phthalimidoyl oxalates. J. Am. Chem. Soc. 135, 15342–15345 (2013)

    CAS  PubMed  Google Scholar 

  16. Barton, D. H. R. & Crich, D. Formation of quaternary carbon centres from tertiary alcohols by free radical methods. Tetrahedron Lett. 26, 757–760 (1985)

    CAS  Google Scholar 

  17. Barton, D. H. R., Crich, D. & Kretzchmar, G. Formation of carbon-carbon bonds with radicals derived from the esters of thiohydroxamic acids. Tetrahedron Lett. 25, 1055–1058 (1984)

    CAS  Google Scholar 

  18. Iwasaki, K., Wan, K. W., Oppedisano, A., Crossley, S. W. M. & Shenvi, R. A. Simple, chemoselective hydrogenation with thermodynamic stereocontrol. J. Am. Chem. Soc. 136, 1300–1303 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. King, S. M., Ma, X. & Herzon, S. B. A method for the selective hydrogenation of alkenyl halides to alkyl halides. J. Am. Chem. Soc. 136, 6884–6887 (2014)

    CAS  PubMed  Google Scholar 

  20. Magnus, P., Waring, M. J. & Scott, D. A. Conjugate reduction of α,β-unsaturated ketones using an MnIII catalyst, phenylsilane and isopropyl alcohol. Tetrahedron Lett. 41, 9731–9733 (2000)

    CAS  Google Scholar 

  21. Zotto, C. D. et al. FeCl3-catalyzed addition of nitrogen and 1,3-dicarbonyl nucleophiles to olefins. J. Organomet. Chem. 696, 296–304 (2011)

    Google Scholar 

  22. Shigematsu, T., Matsui, M. & Utsunomiya, K. Gas chromatography of diisobutyrylmethane metal chelates. Bull. Inst. Chem. Res. Kyoto Univ. 46, 256–261 (1968)

    CAS  Google Scholar 

  23. Djerassi, C., Miramontes, L., Rosenkranz, G. & Sondheimer, F. Steroids. LIV. Synthesis of 19-nor-17α-ethynyltestosterone and 19-nor-17α-methyltestosterone. J. Am. Chem. Soc. 76, 4092–4094 (1954)

    CAS  Google Scholar 

  24. Juaristi, E., León-Romo, J. L., Reyes, A. & Escalante, J. Recent applications of α-phenylethylamine (α-PEA) in the preparation of enantiopure compounds. Part 3: α-PEA as chiral auxiliary. Part 4: α-PEA as chiral reagent in the stereodifferentiation of prochiral substrates. Tetrahedron Asymmetry 10, 2441–2495 (1999)

    CAS  Google Scholar 

  25. Mancilla, T. & Contreras, R. New bicyclic organylboronic esters derived from iminodiacetic acids. J. Organomet. Chem. 307, 1–6 (1986)

    CAS  Google Scholar 

  26. Gillis, E. P. & Burke, M. D. A simple and modular strategy for small molecule synthesis: iterative Suzuki−Miyaura coupling of B-protected haloboronic acid building blocks. J. Am. Chem. Soc. 129, 6716–6717 (2007)

    CAS  PubMed  Google Scholar 

  27. Noguchi, H., Hojo, K. & Suginome, M. Boron-masking strategy for the synthesis of oligioarenes via iterative Suzuki–Miyaura coupling. J. Am. Chem. Soc. 129, 758–759 (2007)

    CAS  PubMed  Google Scholar 

  28. Yamamoto, Y. & Maruyama, K. RCu̇BF3. 3. Conjugate addition to previously unreactive substituted enoate esters and enoic acids. J. Am. Chem. Soc. 100, 3240–3241 (1978)

    CAS  Google Scholar 

  29. Aurell, M. J., Domingo, L. R., Mestres, R., Muñoz, E. & Zaragová, R. J. Conjugate addition of organolithium reagents to α,β-unsaturated carboxylic acids. Tetrahedron 55, 815–830 (1999)

    CAS  Google Scholar 

  30. Hutchinson, D. K. & Fuchs, P. L. Amelioration of the conjugate addition chemistry of α-alkoxycopper reagents: application to the stereospecific synthesis of C-glycosides. J. Am. Chem. Soc. 109, 4930–4939 (1987)

    CAS  Google Scholar 

  31. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 44, Alcohol Drinking 71–99 (World Health Organization, 1988)

  32. Kolb, H. C. & Sharpless, K. B. The growing impact of click chemistry on drug discovery. Drug Discov. Today 8, 1128–1137 (2003)

    CAS  PubMed  Google Scholar 

  33. Chu, L., Ohta, C., Zuo, Z. & MacMillan, D. W. C. Carboxylic acids as a traceless activation group for conjugate additions: a three-step synthesis of (±)-pregabalin. J. Am. Chem. Soc. 136, 10886–10889 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ishikawa, H. et al. Total synthesis of vinblastine, vincristine, related natural products, and key structural analogs. J. Am. Chem. Soc. 131, 4904–4916 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Bullock, R. M. & Samsel, E. G. Hydrogen atom transfer reactions of transition-metal hydrides. Kinetics and mechanism of the hydrogenation of α-cyclopropylstyrene by metal carbonyl hydrides. J. Am. Chem. Soc. 112, 6886–6898 (1990)

    CAS  Google Scholar 

  36. Matsuo, J. & Murakami, M. The Mukaiyama aldol reaction: 40 years of continuous development. Angew. Chem. Int. Edn 52, 9109–9118 (2013)

    CAS  Google Scholar 

  37. Stork, G., Brizzolara, A., Landesman, H., Szmuszkovicz, J. & Terrell, R. The enamine alkylation and acylation of carbonyl compounds. J. Am. Chem. Soc. 85, 207–222 (1963)

    CAS  Google Scholar 

  38. Miyaura, N. & Suzuki, A. Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995)

    CAS  Google Scholar 

  39. Jana, R., Pathak, T. P. & Sigman, M. S. Advances in transition metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev. 111, 1417–1492 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Dubbaka, S. R. & Vogel, P. Organosulfur compounds: electrophilic reagents in transition-metal-catalyzed carbon–carbon bond-forming reactions. Angew. Chem. Int. Edn 44, 7674–7684 (2005)

    CAS  Google Scholar 

  41. Blumenkopf, T. A. & Overman, L. E. Vinylsilane- and alkynylsilane-terminated cyclization reactions. Chem. Rev. 86, 857–873 (1986)

    CAS  Google Scholar 

  42. Nakao, Y. & Hiyama, T. Silicon-based cross-coupling reaction: an environmentally benign version. Chem. Soc. Rev. 40, 4893–4901 (2011)

    CAS  PubMed  Google Scholar 

  43. Diederich F., Stang P. J., eds. Metal-catalyzed Cross-coupling Reactions (Wiley-VCH, 1998)

  44. Seebach, D. Methods of reactivity umpolung. Angew. Chem. Int. Edn Engl. 18, 239–258 (1979)

    Google Scholar 

  45. Gao, X., Soo, S. K. & Krische, M. J. Total synthesis of 6-deoxyerythronolide B via C−C bond-forming transfer hydrogenation. J. Am. Chem. Soc. 135, 4223–4226 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Werner, E. W., Mei, T.-S., Burckle, A. J. & Sigman, M. S. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy. Science 338, 1455–1458 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Financial support for this work was provided by NIH/NIGMS (GM-097444). The National Science Foundation supported a predoctoral fellowship for J.C.L.; the Shanghai Institute of Organic Chemistry, Zhejiang Medicine Co. and Pharmaron supported a postdoctoral fellowship for J.G.; and the Japan Society for the Promotion of Science supported a postdoctoral fellowship for Y.Y. We are grateful to D.-H. Huang and L. Pasternack (TSRI) for assistance with NMR spectroscopy, and A. L. Rheingold and C. E. Moore (UCSD) for X-ray crystallographic analysis. We thank R. A. Shenvi (TSRI) and Y. Ji (TSRI) for discussions.

Author information

Authors and Affiliations

Authors

Contributions

J.C.L. and P.S.B. conceived the work; J.C.L. conducted initial feasibility studies; J.C.L., J.G., Y.Y., C.-M.P. and P.S.B. designed the experiments and analysed the data; J.C.L., J.G., Y.Y. and C.-M.P. performed the experiments; and J.C.L. and P.S.B. wrote the manuscript.

Corresponding author

Correspondence to Phil S. Baran.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

Crystallographic data for the structure of Fe(dibm)3 (5) is available free of charge from the Cambridge Crystallographic Data Centre under deposition number CCDC 1022625.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary Tables 1-2, Supplementary Figures 1-30 and Supplementary References. (PDF 16782 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lo, J., Gui, J., Yabe, Y. et al. Functionalized olefin cross-coupling to construct carbon–carbon bonds. Nature 516, 343–348 (2014). https://doi.org/10.1038/nature14006

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature14006

Further reading

Comments

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.

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