Overcoming the limitations of directed c–h functionalizations of heterocycles

ABSTRACT 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. Access through your institution Buy or subscribe This is a preview of

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DIRECTED C–H FUNCTIONALIZATION WITH NUCLEOPHILES Article 27 October 2022 REMOTE SITE-SELECTIVE ARENE C–H FUNCTIONALIZATION ENABLED BY N-HETEROCYCLIC CARBENE ORGANOCATALYSIS Article 11 July

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Download references ACKNOWLEDGEMENTS 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 Author notes * Yue-Jin Liu and Hui Xu: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * State Key

Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China , Yue-Jin Liu, Hui Xu, Wei-Jun Kong, 

Ming Shang, Hui-Xiong Dai & Jin-Quan Yu * Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA, Jin-Quan Yu Authors *

Yue-Jin Liu View author publications You can also search for this author inPubMed Google Scholar * Hui Xu View author publications You can also search for this author inPubMed Google Scholar

* Wei-Jun Kong View author publications You can also search for this author inPubMed Google Scholar * Ming Shang View author publications You can also search for this author inPubMed Google

Scholar * Hui-Xiong Dai View author publications You can also search for this author inPubMed Google Scholar * Jin-Quan Yu View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS 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. CORRESPONDING AUTHORS Correspondence to Hui-Xiong Dai or Jin-Quan Yu.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION 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) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3

POWERPOINT SLIDE FOR FIG. 4 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Liu, YJ., Xu, H., Kong, WJ. _et al._ Overcoming the limitations of directed

C–H functionalizations of heterocycles. _Nature_ 515, 389–393 (2014). https://doi.org/10.1038/nature13885 Download citation * Received: 18 February 2014 * Accepted: 16 September 2014 *

Published: 10 November 2014 * Issue Date: 20 November 2014 * DOI: https://doi.org/10.1038/nature13885 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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