ArticleNature2014
Overcoming the limitations of directed C-H functionalizations of heterocycles.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
- Enantioselective Rh-catalyzed addition of indoles to enones and the key role of the free N-H group with acyclic enones.Chemical science · 2026Article
- Enantioselective Pyrazole Alkylation via Iridium and Squaramide Catalyzed N-H Insertion.Journal of the American Chemical Society · 2026Article
- Precise borylation of targeted methyl group via an orderly chain-walking strategy.Science advances · 2026Article
- Synthetic Applications of Hydroxamic Acids and Their Derivatives in Organic Chemistry.ACS organic & inorganic Au · 2026Review
- Article
- Design, Synthesis, and Structural Evolution of Pseudo-Natural Product IDO1 Inhibitors and Degraders.Angewandte Chemie (International ed. in English) · 2026Article
- Design of a Recyclable Photoresponsive Adsorbent via Green Synthesis of Ag Nanoparticles in Porous Aromatic Frameworks for Low-Energy Desulfurization.Molecules (Basel, Switzerland) · 2026Article
- Synergistic solvent-catalyst paradigm for sustainable aerobic allylic C-H functionalization.National science review · 2025Article
- α-Amido Sulfonium Salts Provide a Platform for Photocatalytic Metal-Free Carbon-Carbon Bond Formation in Amides.ACS catalysis · 2025Article
- The Importance of Atomic Charges for Predicting Site-Selective Ir-, Ru-, and Rh-Catalyzed C-H Borylations.The Journal of organic chemistry · 2025Article
- Oxidant-free cross-dehydrogenative oxyalkylation enables late-stage functionalization of drugs.Innovation (Cambridge (Mass.)) · 2025Article
- Access to Carbonyl Azides via Iodine(III)-Mediated Cross-Coupling.Organic letters · 2024Article
- Ring Transformation of Cyclopropenes to Benzo-Fused Five-Membered Oxa- and Aza-Heterocycles via a Formal [4+1] Cyclization.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- An osmium(II) methane complex: Elucidation of the methane coordination mode.Science advances · 2023Article
- Dual-Ligand Catalyst for the Nondirected C-H Olefination of Heteroarenes.Journal of the American Chemical Society · 2023Article
- Dual ligand approach increases functional group tolerance in the Pd-catalysed C-H arylation ofChemical science · 2023Article
- Excited-state palladium-catalysed reductive alkylation of imines: scope and mechanism.Chemical science · 2022Article
- Expanding chemical space by para-C-H arylation of arenes.Nature communications · 2022Article
- Article
- Late-stage C-H functionalization offers new opportunities in drug discovery.Nature reviews. Chemistry · 2021Review
Corrections and comments
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Authors and funding
6 authors.
Funding
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 discovery, in which regard they have attracted much interest from pharmaceutical companies. 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.