Overcoming the limitations of directed C–H functionalizations of heterocycles


In directed C–H activation reactions, any nitrogen or sulphur atoms present in heterocyclic substrates will coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C–H functionalization at an undesired position, limits the application of C–H activation reactions in heterocycle-based drug discovery1,2,3,4,5, in which regard they have attracted much interest from pharmaceutical companies3,4,5. Here we report a robust and synthetically useful method that overcomes the complications associated with performing C–H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand that promotes the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is localized near the target C–H bond, avoiding interference from any nitrogen or sulphur atoms present in the heterocyclic substrates. This reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulphur and phosphorus. Thus, this operationally simple aerobic reaction demonstrates that it is possible to bypass a fundamental limitation that has long plagued applications of directed C–H activation in medicinal chemistry.

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Figure 1: Development of a catalytic system to overcome fundamental limitations of heterocyclic C–H bond functionalizations.
Figure 2: Discovery of an efficient aerobic C–H activation reaction.
Figure 3: Scope of the reaction.
Figure 4: Overriding the conventional positional selectivity dictated by heterocycles.


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We thank the following for financial support: the Shanghai Institute of Organic Chemistry, the Chinese Academy of Sciences, the CAS/SAFEA International Partnership Program for Creative Research Teams, the National Natural Science Foundation of China (grant NSFC-21121062), the Recruitment Program of Global Experts, the Scripps Research Institute and the NIH (NIGMS, 1R01 GM102265).

Author information

Y.-J.L. and H.X. performed the reaction discovery experiments and contributed equally. W.-J.K., H.X. and M.S. performed the reactions with the heterocyclic substrates. H.-X.D. and J.-Q.Y. conceived the concept, directed the project and prepared this manuscript.

Correspondence to Hui-Xiong Dai or Jin-Quan Yu.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Text, Supplementary Methods, Supplementary Data and additional references - see Contents for details. (PDF 36081 kb)

Supplementary Data

This zipped file contains the 'cif' files for the X-ray crystallographic data for compounds: complex E, complex F, 3a, and 5i. (ZIP 98 kb)

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Liu, Y., Xu, H., Kong, W. et al. Overcoming the limitations of directed C–H functionalizations of heterocycles. Nature 515, 389–393 (2014). https://doi.org/10.1038/nature13885

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