Reversing conventional site-selectivity in C(sp3)–H bond activation

Abstract

One of the core barriers to developing C–H activation reactions is the ability to distinguish between multiple C–H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp2)–H bonds have been selectively activated in the presence of proximate ones. Yet achieving such unconventional site selectivity with C(sp3)–H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid-derived directing group and a 2-pyridone ligand that enables the preferential activation of the distal γ-C(sp3)–H bond over the proximate β-C(sp3)–H bonds for a wide range of alcohol-derived substrates. A competition experiment between the five- and six-membered cyclopalladation step, as well as kinetic experiments, demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp3)–H activation.

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Fig. 1: Reversing the site-selectivity for C(sp3)–H activation of aliphatic alcohols.
Fig. 2: Mechanistic study and removal of directing group.

Data availability

The data supporting the findings of this study are available in the article and its Supplementary Information. Metrical parameters for the structure of 7 (see Supplementary Information) are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference no. CCDC-1872396.

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Acknowledgements

We gratefully acknowledge Scripps Research, the NIH (National Institute of General Medical Sciences grant no. 2R01GM084019) for their financial support.

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Authors

Contributions

J.-Q.Y. and G.X. conceived the concept. G.X. developed the distal C(sp3)–H arylation for aliphatic alcohols. G.X. and J.W. synthesized the alcohol substrates and investigated the scope. G.X., Z.L. and L.L. conducted the experiments for aryl iodide scope. G.X. and P.V. conducted the mechanistic studies. J.-Q.Y. supervised the project.

Corresponding author

Correspondence to Jin-Quan Yu.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary experimental details and compound characterization data, kinetic experiments, tables for ligands and directing-group screening.

Crystallographic data

CIF for palladacycle 7; CCDC reference: 1872396

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Xia, G., Weng, J., Liu, L. et al. Reversing conventional site-selectivity in C(sp3)–H bond activation. Nat. Chem. 11, 571–577 (2019). https://doi.org/10.1038/s41557-019-0245-6

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