Palladium-catalysed electrophilic aromatic C–H fluorination

Abstract

Aryl fluorides are widely used in the pharmaceutical and agrochemical industries, 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. 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.

Radikalische Trifluormethoxylierung aromatischer Verbindungen durch photochemische N‐O‐Bindungsaktivierung

“…Benzylderivate und Aldehyde werden auch toleriert, dies im Gegensatz zu ungeschützten Aminen oder Allylpositionen mit tiefen homolytischen Bindungsspaltungenergien, die im Kontakt mit Reagenz 3a dimerisieren oder direkt oxidiert werden. ¾hnlich wie bei Arylfluoriden erwies sich die Trennung der einzelnen Trifluormethoxyisomere voneinander sowie vom Ausgangsmaterial als schwierige Aufgabe [26]. Dennoch waren wir in fast allen Fällen in der Lage,die einzelnen Isomere der neuen Verbindungen durch präparative HPLC oder Säulenchromatographie zu reinigen, mit der Ausnahme von hochflüchtigen Produkten, fürw elche authentische Proben den-noch erhältlich sind (siehe SI).…”

Metal‐Terpyridine Complexes in Catalytic Application – A Spotlight on the Last Decade

“…More recently, the Ritter et al . also introduced a direct C−H fluorination protocol In which the heteroleptic Pd(II) catalyst 22 was used . A broad range of substrates, including some pharmaceutically important compounds, was fluorinated in moderate to high yields under remarkably mild conditions (Scheme ).…”

meta-C–H arylation of fluoroarenes via traceless directing group relay strategy

“…Very recently, Ritter and co-workers have developed a general method for aromatic C–H fluorination, however restricted to the ortho and para positions of arene rings. 7 …”