{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Schellbach AV"],"funding":["EPSRC","Engineering and Physical Sciences Research Council"],"pagination":["e202512254"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12377440"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["64(35)"],"pubmed_abstract":["2,6-Di-tert-butyl substituted pyridines (<sup>t</sup>Bu<sub>2</sub>-py) are widely used non-nucleophilic Brønsted bases. Their ubiquity is due to their highly hindered basic site and chemically robust nature. Herein we report that simple M<sub>2</sub>X<sub>6</sub> Lewis acids (M═Al or Ga, X═Cl, Br or I) effect intermolecular sp<sup>3</sup>C─H metalation of <sup>t</sup>Bu<sub>2</sub>-py bases under mild conditions. The sp<sup>3</sup>C─H metalated products can be converted in situ into ─BPin, ─iodo, ─bromo and ─hydroxy derivatives for further elaboration. Mechanistic investigations indicate that: i) a frustrated Lewis pair effects sp<sup>3</sup>C─H heterolysis to form the C─M bond and a protonated pyridine; ii) C─H metalation requires singly halide-bridged super-electrophilic M<sub>2</sub>X<sub>6</sub> dimers for sufficiently low barriers. Finally, sp<sup>3</sup>C─H metalation using M<sub>2</sub>X<sub>6</sub> is not limited to <sup>t</sup>Bu<sub>2</sub>-py bases. Thus, it is important to be aware of this facile sp<sup>3</sup>C─H functionalisation when using a range of non-nucleophilic Brønsted bases."],"journal":["Angewandte Chemie (International ed. in English)"],"pubmed_title":["Intermolecular Sp&lt;sup&gt;3&lt;/sup&gt;C─H Metalation of Non-Nucleophilic Bronsted Bases Using Simple Lewis Acids."],"pmcid":["PMC12377440"],"funding_grant_id":["EP/X021858/1","EP/X035174/1","EP/W007517/1"],"pubmed_authors":["Fasano V","Ingleson MJ","Nichol GS","Schellbach AV","Willcox DR","Guarnaccia M"],"additional_accession":[]},"is_claimable":false,"name":"Intermolecular Sp&lt;sup&gt;3&lt;/sup&gt;C─H Metalation of Non-Nucleophilic Bronsted Bases Using Simple Lewis Acids.","description":"2,6-Di-tert-butyl substituted pyridines (<sup>t</sup>Bu<sub>2</sub>-py) are widely used non-nucleophilic Brønsted bases. Their ubiquity is due to their highly hindered basic site and chemically robust nature. Herein we report that simple M<sub>2</sub>X<sub>6</sub> Lewis acids (M═Al or Ga, X═Cl, Br or I) effect intermolecular sp<sup>3</sup>C─H metalation of <sup>t</sup>Bu<sub>2</sub>-py bases under mild conditions. The sp<sup>3</sup>C─H metalated products can be converted in situ into ─BPin, ─iodo, ─bromo and ─hydroxy derivatives for further elaboration. Mechanistic investigations indicate that: i) a frustrated Lewis pair effects sp<sup>3</sup>C─H heterolysis to form the C─M bond and a protonated pyridine; ii) C─H metalation requires singly halide-bridged super-electrophilic M<sub>2</sub>X<sub>6</sub> dimers for sufficiently low barriers. Finally, sp<sup>3</sup>C─H metalation using M<sub>2</sub>X<sub>6</sub> is not limited to <sup>t</sup>Bu<sub>2</sub>-py bases. Thus, it is important to be aware of this facile sp<sup>3</sup>C─H functionalisation when using a range of non-nucleophilic Brønsted bases.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Aug","modification":"2026-05-09T17:51:35.536Z","creation":"2026-04-08T01:07:03.563Z"},"accession":"S-EPMC12377440","cross_references":{"pubmed":["40567016"],"doi":["10.1002/anie.202512254"]}}