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Functional-group translocation of cyano groups by reversible C–H sampling

Nature volume 620, pages 1007–1012 (2023)Cite this article

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Abstract

Chemical transformations that introduce, remove or manipulate functional groups are ubiquitous in synthetic chemistry1. Unlike conventional functional-group interconversion reactions that swap one functionality for another, transformations that alter solely the location of functional groups are far less explored. Here, by photocatalytic, reversible C–H sampling, we report a functional-group translocation reaction of cyano (CN) groups in common nitriles, allowing for the direct positional exchange between a CN group and an unactivated C−H bond. The reaction shows high fidelity for 1,4-CN translocation, frequently contrary to inherent site selectivity in conventional C−H functionalizations. We also report the direct transannular CN translocation of cyclic systems, providing access to valuable structures that are non-trivial to obtain by other methods. Making use of the synthetic versatility of CN and a key CN translocation step, we showcase concise syntheses of building blocks of bioactive molecules. Furthermore, the combination of C–H cyanation and CN translocation allows access to unconventional C–H derivatives. Overall, the reported reaction represents a way to achieve site-selective C–H transformation reactions without requiring a site-selective C–H cleavage step.

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Fig. 1: Direct FG translocation to unactivated C–H sites with no accompanying variations of the molecule.
Fig. 2: Design and optimization of the CN translocation reaction.
Fig. 3: Substrate scope with linear nitriles.
Fig. 4: Direct transannular CN translocation.
Fig. 5: Applications of the direct CN translocation reaction.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Additional data are available from the corresponding author upon request. Metrical parameters for the structures of 83 and 91 are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC 2238601 and 2238605.

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Acknowledgements

This project was supported by the Natural Science Foundation of China (22201015), BNLMS and Peking University Li Ge Zhao Ning Youth Research Fund for Life Sciences (LGZNQN202204). We thank X. Zhang (PKU) and H. Fu (PKU) for assistance with NMR spectroscopy; Y. Qiu (PKU) for assistance with X-ray crystallography; and G. Dong (Uchicago) and X.-Y. Liu (SUSTech) for discussions and suggestions.

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  1. These authors contributed equally: Ken Chen, Qingrui Zeng

Authors and Affiliations

  1. Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, China

    Ken Chen, Qingrui Zeng, Longhuan Xie, Zisheng Xue, Jianbo Wang & Yan Xu

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Contributions

Y.X. proposed the transformation. K.C., Q.Z., L.X., Z.X. and Y.X. conceived and conducted the experimental investigation. K.C., Q.Z. and Y.X. wrote the paper. J.W. and Y.X. directed the research. K.C. and Q.Z. contributed equally.

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Correspondence to Yan Xu.

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Extended data figures and tables

Extended Data Fig. 1 Additional substrate scope.

All yields are isolated yields. General condition: NaDT (2 mol%), T1 (40 mol%), MeCN:acetone (1:1, 0.375 M), N2 atmosphere, 365 nm LED irradiation. a Using TBPDT (3 mol%) instead of NaDT and 5 mol% of T1. For detailed experimental procedures, see Section 4 of Supplementary Information.

Extended Data Fig. 2 Additional applications of the direct CN translocation reaction.

a. An exemplary case of using CN translocation reactions to promote continuous C–C bond construction. b. Examples of expedited synthesis of cycloheptane building blocks using CN translocation reactions. a Mixed with ca. 10% of inseparable impurity and directly used in the next step. For details, see Section 5 of Supplementary Information.

Supplementary information

Supplementary Information

This Supplementary Information file contains the following 9 sections: 1. General consideration; 2. Substrate synthesis; 3. The optimal reaction condition and study on the impact of reaction parameters; 4. Substrate scope study; 5. Further study on the direct CN translocation reaction; 6. Additional analysis of the reaction design, deuterium labelling experiments, and further studies; 7. XRD analysis of compounds S33, S36, 83 and 91; 8. References; and 9. Spectra.

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Chen, K., Zeng, Q., Xie, L. et al. Functional-group translocation of cyano groups by reversible C–H sampling. Nature 620, 1007–1012 (2023). https://doi.org/10.1038/s41586-023-06347-3

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