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

Nature volume 531, pages 459–465 (2016)Cite this article

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Abstract

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.

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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.

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, 02467, Massachusetts, USA

    Ming Joo Koh, Thach T. Nguyen, Hanmo Zhang & Amir H. Hoveyda

  2. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, 02139, Massachusetts, USA

    Richard R. Schrock

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Contributions

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.

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Correspondence to Amir H. Hoveyda.

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

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Koh, M., Nguyen, T., Zhang, H. et al. Direct synthesis of Z-alkenyl halides through catalytic cross-metathesis. Nature 531, 459–465 (2016). https://doi.org/10.1038/nature17396

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