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Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis

Nature Catalysis (2024)Cite this article

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Abstract

Catalytic site-selective functionalization of distal C–H bonds represents a formidable challenge in organic synthesis. Particularly, the precise functionalization of distal aromatic C(sp2)–H bonds remains largely unexplored. Here we present a highly para-selective acylation strategy to target ultraremote aryl C(sp2)–H bonds, eight chemical bonds away from an activated functionality, through radical N-heterocyclic carbene organocatalysis. This method is developed on the basis of a unique single-electron pathway involving the site-selective activation of aryl C–H bonds by a nitrogen-centred radical generated in situ. Importantly, this organocatalytic approach shows potential for the functionalization of drugs, amino acids and peptides, thus highlighting its importance for medicinal chemistry. Our investigation encompassed meticulous mechanistic studies, including control experiments and density functional theory calculations, to unravel the intricacies behind the observed site selectivity and shed light on the mechanism of radical N-heterocyclic carbene organocatalysis.

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Fig. 1: Background and discovery of N-radical-directed remote arene C–H functionalization.
Fig. 2: Reaction condition assessment.
Fig. 3: Aldehyde scope of the organocatalytic remote acylation.
Fig. 4: Amide scope of the organocatalytic remote acylation.
Fig. 5: Late-stage functionalization of drugs and biologically active molecules.
Fig. 6: Site-selective functionalization of amino acid derivatives and peptides.
Fig. 7: Further experimental studies.
Fig. 8: DFT calculations.

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Data availability

The data supporting the findings of this study are available within this Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2245194 (3a), 2355142 (3bu) and 2245196 (3ch). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Data are available from the corresponding authors upon request.

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Acknowledgements

We are grateful for the financial support from the NSFC (no. 22271028 to J.-L.L., 22071011 to Q.-Z.L. and 22203010 to Z.-Y.Y.), the Science & Technology Department of Sichuan Province (no. 2023NSFSC2001 to J.-L.L.) and Longquan Talents Program, Key-Area Research and Development Program of Guangdong Province (no. 2022B1111050003 to J.-L.L.). We express our profound gratitude for the insightful discussions with Y. Lan and X.-T. Qi regarding the DFT calculations in this study.

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  1. These authors contributed equally: Qing-Zhu Li, Wen-Lin Zou.

Authors and Affiliations

  1. Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu, China

    Qing-Zhu Li, Wen-Lin Zou, Zhao-Yuan Yu, Xin-Xin Kou, Yan-Qing Liu, Xiang Zhang, Yu He & Jun-Long Li

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Contributions

J.-L.L. supervised this study. Q.-Z.L. and W.-L.Z. conducted the main experiments and prepared the supplementary information of the experimental section. X.-X.K. and Y.-Q.L. prepared some substrates and performed the synthetic and mechanistic experiments. Y.H. and X.Z. helped with characterizing some compounds. Z.-Y.Y. performed the DFT calculations. Z.-Y.Y. and X.Z. prepared the supplementary information of the calculation section. J.-L.L. and Q.-Z.L. designed the project and wrote the manuscript. Q.-Z.L. and W.-L.Z. contributed equally to this work.

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Correspondence to Jun-Long Li.

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Nature Catalysis thanks Jan Philipp Götze, Liliana Dobrzańska, Xiangyang Liu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary methods, discussion, note and references.

Supplementary Data 1

The atomic coordinates of the optimized computational models studied in this paper.

Supplementary Data 2

CIF file of 3a.

Supplementary Data 3

CIF file of 3bu.

Supplementary Data 4

CIF file of 3ch.

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Li, QZ., Zou, WL., Yu, ZY. et al. Remote site-selective arene C–H functionalization enabled by N-heterocyclic carbene organocatalysis. Nat Catal (2024). https://doi.org/10.1038/s41929-024-01194-5

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