Palladium-catalysed electrophilic aromatic C–H fluorination

• Published in: Nature (London) Vol. 554; no. 7693; pp. 511 - 514
• Main Authors: Yamamoto, Kumiko, Li, Jiakun, Garber, Jeffrey A. O., Rolfes, Julian D., Boursalian, Gregory B., Borghs, Jannik C., Genicot, Christophe, Jacq, Jérôme, van Gastel, Maurice, Neese, Frank, Ritter, Tobias
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.02.2018; Nature Publishing Group
• Subjects: 119/118; 140/131; 639/638/403/933; 639/638/77/888; Agrochemicals; Aromatic compounds; Brain; Catalysis; Chemical bonds; Drug development; Fluorides; Fluorination; Fluorine; Functional groups; Humanities and Social Sciences; Hydrogen; letter; Ligands; Methods; multidisciplinary; Palladium; Pharmaceutical industry; Pharmaceuticals; Reagents; Science; Substrates
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature25749

An approach for the direct electrophilic C–H fluorination of arenes is reported, using a palladium catalyst and mild fluorinating reagents. Palladium-propelled C–H fluorination In the pharmaceutical industry, fluorine has long been added to organic molecules to improve the bioavailability of drugs. These molecules are also important in positron-emission tomography (PET) imaging and in the agrochemical industry. Although aryl fluorides are an important class of such molecules, general methods for the direct C–H fluorination of aromatic compounds are lacking. Here, Tobias Ritter and colleagues report that electrophilic fluorinating agents react with palladium( II ) to generate a more active catalytic fluorinating agent. This agent can react with a range of unfunctionalized aromatic compounds directly, including several pharmaceuticals, and so provides access to a range of fluorinated compounds that were otherwise not readily accessible. Aryl fluorides are widely used in the pharmaceutical and agrochemical industries 1 , 2 , and recent advances have enabled their synthesis through the conversion of various functional groups. However, there is a lack of general methods for direct aromatic carbon–hydrogen (C–H) fluorination 3 . Conventional methods require the use of either strong fluorinating reagents, which are often unselective and difficult to handle, such as elemental fluorine, or less reactive reagents that attack only the most activated arenes, which reduces the substrate scope. A method for the direct fluorination of aromatic C–H bonds could facilitate access to fluorinated derivatives of functional molecules that would otherwise be difficult to produce. For example, drug candidates with improved properties, such as increased metabolic stability or better blood–brain-barrier penetration, may become available. Here we describe an approach to catalysis and the resulting development of an undirected, palladium-catalysed method for aromatic C–H fluorination using mild electrophilic fluorinating reagents. The reaction involves a mode of catalysis that is unusual in aromatic C–H functionalization because no organometallic intermediate is formed; instead, a reactive transition-metal-fluoride electrophile is generated catalytically for the fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional-group tolerance of this reaction could provide access to functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible.