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On-demand synthesis of organozinc halides under continuous flow conditions

Nature Protocols volume 13, pages 324334 (2018) | Download Citation

Abstract

Organozinc reagents are versatile building blocks for introducing C(sp2)-C(sp3) and C(sp3)-C(sp3) bonds into organic structures. However, despite their ample synthetic versatility and broad functional group tolerance, the use of organozinc reagents in the laboratory is limited because of their instability, exothermicity and water sensitivity, as well as their labor-intensive preparation. Herein, we describe an on-demand synthesis of these useful reagents under continuous flow conditions, overcoming these primary limitations and supporting widespread adoption of these reagents in synthetic organic chemistry. To exemplify this procedure, a solution of ethyl zincbromoacetate is prepared by flowing ethyl bromoacetate through a column containing metallic zinc. The temperature of the column is controlled by a heating jacket and a thermocouple in close contact with it. Advice on how to perform the procedure using alternative equipment is also given to allow a wider access to the methodology. Here we describe the preparation of 50 ml of solution, which takes 1 h 40 min, although up to 250–300 ml can be prepared with the same column setup at a rate of 30 ml per h. The procedure provides the reagent as a clean solution with reproducible concentration. Organozinc solutions generated in flow can be coupled to a second flow reactor to perform a Reformatsky reaction or can be collected over a flask containing the required reagents for a batch Negishi reaction.

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Acknowledgements

We thank D.T. McQuade, Z. Miller, J. de Mata Muñoz, N. Alonso, A. de la Hoz and Á. Díaz Ortiz for their input in the progress of developing this methodology. We also thank O. Kappe for his advice.

Author information

Affiliations

  1. Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Toledo, Spain.

    • Mateo Berton
    • , Lena Huck
    •  & Jesús Alcázar
  2. Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Ciudad Real, Spain.

    • Lena Huck

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Contributions

M.B. and L.H. carried out the experiments. All authors designed the protocol and J.A. supervised the project. All authors contributed to the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jesús Alcázar.

Supplementary information

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    Supplementary Methods

    Preparation of ethyl 3-hydroxy-3-(3-ethoxyphenyl)butanoate and ethyl 2-(4-bromophenyl)acetate.

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DOI

https://doi.org/10.1038/nprot.2017.141

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