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Transition-metal-free C(sp2)–C(sp3) cross-coupling of α-(pseudo)halo aliphatic ketones with boronic acids via a 1,4-metallate shift

Nature Synthesis volume 2, pages 1211–1221 (2023)Cite this article

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Abstract

Suzuki-type cross-coupling is one of the most common strategies for the construction of C–C bonds. Despite great progress on the preparation of C(sp2)–C(sp2) bonds, C(sp2)–C(sp3) cross-coupling with aliphatic halides remains rare, especially with tertiary aliphatic halides and under transition-metal-free conditions. Here we report an efficient C(sp2)–C(sp3) cross-coupling between α-(pseudo)halo aliphatic ketones and arylboronic acids via a 1,4-metallate shift. The α-arylated ketones obtained from this protocol under transition-metal-free and additive-free conditions in the presence of base are formed when the key intermediate enolate traps the arylboronic acid, leading to a tetracoordinate boron intermediate. A subsequent 1,4-metallate shift affords the Suzuki-type coupling products. This strategy provides a practical, scalable and operationally straightforward method for the synthesis of C(sp2)–C(sp3) bonds, and is compatible with challenging tertiary aliphatic halides, allowing for the preparation of 1,3-disubstituted target products.

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Fig. 1: Previous work on Suzuki–Miyaura cross-couplings and our strategy.
Fig. 2: Downstream applications and transformations.
Fig. 3: Scale-up and control experiments.
Fig. 4: Calculated free-energy profiles for the α-arylation of chlorocyclohexanone.

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Data availability

The data that support the findings of this study are available within the article and its Supplementary Information files. The X-ray crystallographic coordinates for structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2085418 (3a). The data can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/datarequest/cif.

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Acknowledgements

Financial support from National Natural Science Foundation of China (21931013 and 22271105), the Natural Science Foundation of Fujian Province (2022J02009), the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University and numerical computations at the Hefei advanced computing centre is gratefully acknowledged. Dedicated to Professor Zhenfeng Xi on the occasion of his 60th birthday.

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Authors and Affiliations

  1. Institute of Next Generation Matter Transformation, College of Material Sciences Engineering, Huaqiao University, Xiamen, China

    Xue Li, Hao Wang, Qiaohui Zhang, Heyun Sheng & Qiuling Song

  2. School of Chemistry and Chemical Engineering, State Key Laboratory of Antiviral Drugs, Henan Normal University, Xinxiang, China

    Haohua Chen, Yu Lan & Qiuling Song

  3. Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, China

    Yu Lan

  4. College of Chemistry and Institute of Green Catalysis, Zhengzhou University, Zhengzhou, China

    Yu Lan

  5. Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou University, Fuzhou, China

    Qiuling Song

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Contributions

Q.S. designed and directed the project. X.L. performed the experiments and developed the reactions. Q.Z., H.W. and H.S. helped collecting some of the experimental data. X.L. prepared the Supplementary Information. Y.L. directed the DFT calculations, H.C. performed DFT calculations and drafted the DFT sections. Q.S. and X.L. wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Yu Lan or Qiuling Song.

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Nature Synthesis thanks the anonymous reviewers 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

Experimental details, Supplementary Figs. 1–184 and Tables 1 and 2.

Supplementary Data 1

Crystallographic data for compound 3a, CCDC 2085418.

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Li, X., Chen, H., Wang, H. et al. Transition-metal-free C(sp2)–C(sp3) cross-coupling of α-(pseudo)halo aliphatic ketones with boronic acids via a 1,4-metallate shift. Nat. Synth 2, 1211–1221 (2023). https://doi.org/10.1038/s44160-023-00373-9

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