Abstract
Methylene-selective C–H functionalization at distal positions is a challenge in the field of Pd(II) catalysis. We have previously reported a ligand-enabled β,γ-C–H coupling with dihaloarenes for the synthesis of benzocyclobutenes (BCBs) as a promising class of scaffolds in drug discovery. Here we report a Pd(II)-catalysed method for the γ,δ-methylene C–H activation of free aliphatic acids and subsequent coupling with dihaloarenes, which offers an efficient route for the synthesis of diversely functionalized BCBs. The development of a carboxyl-pyridone ligand is crucial for the remote C(sp3)–H activation. Notably, previous γ,δ-methylene C–H activation reactions of monoaliphatic acids are limited to carbocyclic substrates. The site-selective activation of γ,δ-C–H bonds installs the BCB pharmacophores that are one carbon atom further away from the carboxyl group than in previous studies. Given the carboxyl group can serve as hydrogen-bond donor or acceptor, such alternation of distance between two interactions can impact bioactivity.
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Data availability
The data that support the findings of this study are available within the Article and its Supplementary Information. The crystallographic data for the structure reported in this study for compounds 4o have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under accession number 2357735. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.
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Acknowledgements
We thank Z. Li for help with ligand synthesis. We thank M. Gembicky and J. Bailey for X-ray crystallographic analysis. We thank L. Pasternack and G. Kroon for their assistance with NMR analysis. We gratefully acknowledge the National Institutes of Health (National Institute of General Medical Sciences, R01GM084019) and The Scripps Research Institute for financial support.
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J.-Q.Y. conceived the concept. L.H. discovered and developed the reaction. L.H., J.-L.Y. and Y.-K.L. developed the substrate scope. L.H., D.A.S. and J.-Q.Y. wrote the manuscript. J.-Q.Y. directed the project.
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Nature Synthesis thanks Gong Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.
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Supplementary Information
Supplementary Tables 1–5, experimental procedures, additional reaction optimization and characterization data.
Supplementary Data 1
Crystallographic data for compound 4o, CCDC 2357735.
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Hu, L., Yan, JL., Lin, YK. et al. Regiocontrollable [2 + 2] benzannulation of γ,δ-C(sp3)–H bonds with dihaloarenes using palladium catalysis. Nat. Synth 4, 1556–1564 (2025). https://doi.org/10.1038/s44160-025-00883-8
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DOI: https://doi.org/10.1038/s44160-025-00883-8
