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On-demand synthesis of organozinc halides under continuous flow conditions

Nature Protocols volume 13, pages 324–334 (2018)Cite this article

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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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Figure 1: Reaction of organozinc halides with a variety of electrophiles.
Figure 2: Range of reactions possible in which alkyl zincbromoacetates are presented using a zinc column.
Figure 3
Figure 4: Equipment for assembly and setup of zinc column reactor.
Figure 5: Materials used for zinc activation.
Figure 6
Figure 7: Preparation of the zinc column.
Figure 8
Figure 9: Setup of the reactor module.
Figure 10
Figure 11: Reaction conditions and setup for the zinc activation.
Figure 12: Setup and conditions for preparation of organozinc reagent.
Figure 13
Figure 14
Figure 15: Color change observed during the fast titration.

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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.

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Authors and Affiliations

  1. Lead Discovery, Janssen Research and Development,

    Mateo Berton, Lena Huck & Jesús Alcázar

  2. , Janssen-Cilag, S.A., Toledo, Spain

    Mateo Berton, Lena Huck & Jesús Alcázar

  3. Facultad de Ciencias Químicas, Universidad de Castilla-La Mancha, Ciudad Real, Spain

    Lena Huck

Authors
  1. Mateo Berton
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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.

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Correspondence to Jesús Alcázar.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

Preparation of ethyl 3-hydroxy-3-(3-ethoxyphenyl)butanoate and ethyl 2-(4-bromophenyl)acetate. (PDF 354 kb)

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Berton, M., Huck, L. & Alcázar, J. On-demand synthesis of organozinc halides under continuous flow conditions. Nat Protoc 13, 324–334 (2018). https://doi.org/10.1038/nprot.2017.141

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