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Direct C–H metallation of tetrahydrofuran and application in flow

Nature Synthesis volume 1, pages 558–564 (2022)Cite this article

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Abstract

The direct C–H metallation of tetrahydrofuran (THF) to generate α-anionic THF is one of the most straightforward methods for the functionalization of THF. However, the stability of THF makes it difficult to activate the α-proton and the instability of α-anionic THF leads to an uncontrollably rapid cleavage. These factors are well-known challenges for both the generation and utilization of α-anionic THF. Here we develop a reaction for the direct metallation of THF using a strong base as well as precise control of the temperature and reaction time in a microfluidic system. Various electrophiles, which include those with complex structures, were introduced to give products in high yields. Also, transmetallations to α-cuprated THF and α-borylated THF were successfully achieved and α-borylated THF was further functionalized via cross-coupling reactions, which demonstrates the value of this microfluidic approach.

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Fig. 1: Methods for α-functionalization of THF through an anionic reaction pathway.
Fig. 2: Generation and utilization of α-anionic THF in flow.
Fig. 3: Cupration and borylation of α-anionic THF in the integrated flow microreactor.
Fig. 4: Synthetic applications of α-borylated THF and plausible mechanisms.

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Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2098707 (9e). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data that support the findings of this study, which include experimental procedures and compound characterization, are available within the paper and its Supplementary Information.

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Acknowledgements

We acknowledge the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (no. 2020R1C1C1014408 for H.K. and 2020R1I1A1A01067730 for H.-J.L.). We are grateful to the Chiral Technology Korea (CTK) corporation for help with HPLC analysis and H.-J. Lee (Seoul Women’s University) for X-ray crystallography.

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Author notes

  1. These authors contributed equally: Dongyong Kim, Hyune-Jea Lee.

  2. Deceased: Jun-ichi Yoshida.

Authors and Affiliations

  1. Department of Chemistry, College of Science, Korea University, Seoul, South Korea

    Dongyong Kim, Hyune-Jea Lee & Heejin Kim

  2. Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto, Japan

    Yutaka Shimizu

  3. National Institution of Technology, Suzuka College, Suzuka, Japan

    Jun-ichi Yoshida

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Contributions

H.K., J.Y. and H.-J.L. designed and directed the project. H.K., H.-J.L. and D.K. conceived and designed the experiments. D.K. and Y.S. assisted in conducting and analysing the chemical experiments. H.-J.L. and H.K. wrote the manuscript with contributions from D.K. All the authors contributed to discussions.

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Correspondence to Heejin Kim.

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Nature Synthesis thanks Varinder Aggarwal and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details, Supplementary Figs. 1–4 and Tables 1–7.

Supplementary Data 1

Crystallographic data for Compound 9e, CCDC 2098707

Source data

Source Data Fig. 1

Source data for graphs in Fig. 2b.

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Kim, D., Lee, HJ., Shimizu, Y. et al. Direct C–H metallation of tetrahydrofuran and application in flow. Nat. Synth 1, 558–564 (2022). https://doi.org/10.1038/s44160-022-00100-w

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