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