biostudies-literatureSchellbach AVEPSRCEngineering and Physical Sciences Research Councile202512254https://www.ebi.ac.uk/biostudies/studies/S-EPMC12377440biostudies-literatureUnknown64(35)2,6-Di-tert-butyl substituted pyridines (^tBu₂-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 M₂X₆ Lewis acids (M═Al or Ga, X═Cl, Br or I) effect intermolecular sp³C─H metalation of ^tBu₂-py bases under mild conditions. The sp³C─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 sp³C─H heterolysis to form the C─M bond and a protonated pyridine; ii) C─H metalation requires singly halide-bridged super-electrophilic M₂X₆ dimers for sufficiently low barriers. Finally, sp³C─H metalation using M₂X₆ is not limited to ^tBu₂-py bases. Thus, it is important to be aware of this facile sp³C─H functionalisation when using a range of non-nucleophilic Brønsted bases.Angewandte Chemie (International ed. in English)Intermolecular Sp<sup>3</sup>C─H Metalation of Non-Nucleophilic Bronsted Bases Using Simple Lewis Acids.PMC12377440EP/X021858/1EP/X035174/1EP/W007517/1Fasano VIngleson MJNichol GSSchellbach AVWillcox DRGuarnaccia MfalseIntermolecular Sp<sup>3</sup>C─H Metalation of Non-Nucleophilic Bronsted Bases Using Simple Lewis Acids.2,6-Di-tert-butyl substituted pyridines (^tBu₂-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 M₂X₆ Lewis acids (M═Al or Ga, X═Cl, Br or I) effect intermolecular sp³C─H metalation of ^tBu₂-py bases under mild conditions. The sp³C─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 sp³C─H heterolysis to form the C─M bond and a protonated pyridine; ii) C─H metalation requires singly halide-bridged super-electrophilic M₂X₆ dimers for sufficiently low barriers. Finally, sp³C─H metalation using M₂X₆ is not limited to ^tBu₂-py bases. Thus, it is important to be aware of this facile sp³C─H functionalisation when using a range of non-nucleophilic Brønsted bases.2025-01-01T00:00:00Z2025 Aug2026-05-09T17:51:35.536Z2026-04-08T01:07:03.563ZS-EPMC123774404056701610.1002/anie.202512254