Direct β‐ and γ‐C(sp3)−H Alkynylation of Free Carboxylic Acids

• Published in: Angewandte Chemie International Edition Vol. 59; no. 51; pp. 23127 - 23131
• Main Authors: Ghiringhelli, Francesca, Uttry, Alexander, Ghosh, Kiron Kumar, Gemmeren, Manuel
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 14.12.2020; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Alkynylation; Carboxylic acids; Chemistry; Chemistry, Multidisciplinary; Communication; Communications; C−H activation; Enantiomers; Ligand-enabled catalysis; Palladium; Physical Sciences; Science & Technology; Substrates; Alkynylation; C(SP)-H BONDS; ACTIVATION; BETA-C(SP)-H ARYLATION; FUNCTIONALIZATIONS; ALPHA-AMINO-ACIDS; Palladium; Carboxylic acids; C-H BONDS; C-H activation; CATALYZED DIRECT ETHYNYLATION; DERIVATIVES; SP; Ligand-enabled catalysis; C−H activation
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202010784

In this study we report the identification of a novel class of ligands for palladium‐catalyzed C(sp3)−H activation that enables the direct alkynylation of free carboxylic acid substrates. In contrast to previous synthetic methods, no introduction/removal of an exogenous directing group is required. A broad scope of acids including both α‐quaternary and challenging α‐non‐quaternary can be used as substrates. Additionally, the alkynylation in the distal γ‐position is reported. Finally, this study encompasses preliminary findings on an enantioselective variant of the title transformation as well as synthetic applications of the products obtained. No detours—The direct C(sp3)−H alkynylation of free carboxylic acids in the β‐ and γ‐position is achieved using a Pd‐catalyst with a newly discovered ligand class. The synthetic method features a broad scope including preliminary findings on an enantioselective variant and can be conducted on a preparatively useful scale.