Abstract
C–H activation is the most direct way of functionalizing organic molecules. Many advances in this field still require specific directing groups to achieve the necessary activity and selectivity. Developing C–H activation reactions directed by native functional groups is essential for their broad application in synthesis1. Over the past decade, several generations of bifunctional ligands developed have enabled C(sp3)–H activation reactions of free carboxylic acids2, free aliphatic amines3, native amides4,5 and alcohols6. However, an effective catalyst for ketones and carboxylic esters remains to be realized. Here we report diverse methyl β-C−H functionalizations, including intermolecular arylation, hydroxylation and intramolecular C(sp3)–H/C(sp2)–H coupling of ketones and carboxylic esters with a monoprotected amino neutral amide (MPANA) ligand. The in situ generation of cationic Pd(II) complexes by the combination MPANA ligand and HBF4 is crucial for achieving the reactivity. The compatibility of these reactions with cyclic ketones and lactams provides a method to access spirocyclic and fused ring systems. Mechanistic experiments and density functional theory studies support the role of cationic Pd complexes with MPANA ligands in enhancing catalyst–substrate affinity and facilitating the C−H cleavage step.
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Data availability
Crystallographic data for compound 7eb are available in Supplementary Information files and from the Cambridge Crystallographic Data Center under reference numbers CCDC 2355481. All other data supporting the findings of this study are available in the Article and Supplementary Information.
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Acknowledgements
We thank the Scripps Research Institute and the NIH (National Institute of General Medical Sciences grants 2R01GM084019). We also thank D. A. Strassfeld for assistance with automated conformational searches and discussions throughout this project. We thank J. Chen, B. Sanchez, Q. N. Wong and J. Lee of the Scripps Automated Synthesis Facility for assistance with mass spectrometry. We also thank M. Gembicky and J. Bailey of the UCSD Crystallography Facility for X-ray crystallographic analysis.
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J.-Q.Y. conceived the project. Y.-H.L. developed the MPANA ligand, reaction conditions and substrates scope. N.C. and Y.L. performed the DFT studies. J.-Q.Y. and Y.-H.L. prepared the paper. J.-Q.Y. directed the project.
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Extended data figures and tables
Extended Data Fig. 1 Ineffective ligands for intermolecular methyl β-C–H arylation.
Reaction conditions: substrate (0.1 mmol), Pd(OAc)2 (10 mol%), with or without ligand (10 mol%), 4-iodotoluene (2.0 equiv.), Ag2CO3 (2.0 equiv.), Et2O·HBF4 (1.5 equiv.), HFIP (2.0 ml), 80 °C, 12 h.
Extended Data Fig. 2 Mechanistic investigations.
A, Deuterium incorporation experiments condition: 1a (0.1 mmol), Pd(OAc)2 (10 mol%), ArI (2.0 equiv.), ligand L1 (10 mol%), Ag2CO3 (2.0 equiv.), DOTf (1.5 equiv.), HFIP-OD (2.0 ml), 80 °C, 12 h. B, Parallel kinetic isotopic effect (KIE) studies condition: 1f or [D3]1f (0.1 mmol), Pd(OAc)2 (10 mol%), ArI (2.0 equiv.), ligand L1 (10 mol%), Ag2CO3 (2.0 equiv.), Et2O·HBF4 (1.5 equiv.), HFIP (2.0 ml), 80 °C, 3-75 min. C, Palladium charge and ligand effects on the C(sp3)−H cleavage step. i) Effect of cationic Pd on substrate coordination. ii) Ligand effect on C(sp3)−H cleavage transition state (TS). All quasi-harmonic free energies are reported at 353 K relative to separated reactants. D, C(sp3)−H hydroxylation with water as a solo hydroxyl source. Reaction conditions: 1s (0.1 mmol), PdCl2(PPh3)2 (10 mol%), ligand L3 (10 mol%), Selectfluor (2.5 equiv.), Ag2CO3 (1.5 equiv.), Et2O·HBF4 (1.5 equiv.), water (2.0 equiv.), HFIP (2.0 ml), 50 °C, 48 h, under N2.
Supplementary information
Supplementary Information
Supplementary Sections 1–15; see Contents for details.
Crystallographic Data (7b)
Crystallographic data for compound 7b
Crystallographic Data (7eb)
Crystallographic data for compound 7eb
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Li, YH., Chekshin, N., Lu, Y. et al. β-C−H bond functionalization of ketones and esters by cationic Pd complexes. Nature 637, 608–614 (2025). https://doi.org/10.1038/s41586-024-08281-4
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DOI: https://doi.org/10.1038/s41586-024-08281-4
