β- and γ-C(sp3)−H Heteroarylation of Free Carboxylic Acids: A Modular Synthetic Platform for Diverse Quaternary Carbon Centers

Guangrong Meng, Liang Hu, Martin Tomanik, Jin Quan Yu

Research output: Contribution to journalArticlepeer-review

Abstract

PdII-catalyzed C(sp3)−H activation of free carboxylic acids represents a significant advance from conventional cyclopalladation initiated reactions. However, developing a modular synthetic platform for diverse quaternary and tertiary carbon centers based on this reactivity, two challenges remain to be addressed: mono-selectivity in each consecutive C−H functionalization step; compatibility with heteroatoms. While the exclusive mono-selectivity was achieved by β-lactonization/nucleophilic attack, the latter limitation remains to be overcome. Herein, we report the PdII-catalyzed β- and γ-C(sp3)−H heteroarylation of free carboxylic acids using pyridine-pyridone ligands capable of overcoming these limitations. A sequence of three consecutive C(sp3)−H activation reactions of pivalic acid provides an unique platform for constructing diverse quaternary carbon centers containing heteroaryls which could serve as an enabling tool for escaping the flat land in medicinal chemistry.

Original languageEnglish (US)
Article numbere202214459
JournalAngewandte Chemie - International Edition
Volume62
Issue number9
DOIs
StatePublished - Feb 20 2023

Keywords

  • Carboxylic Acids
  • C−H Activation
  • Heteroarylation
  • Ligand Design
  • Palladium

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry

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