Palladium-catalysed electrophilic aromatic C-H fluorination

被引:126
作者
Yamamoto, Kumiko [1 ,2 ]
Li, Jiakun [1 ]
Garber, Jeffrey A. O. [1 ,2 ]
Rolfes, Julian D. [1 ,2 ]
Boursalian, Gregory B. [1 ,2 ]
Borghs, Jannik C. [2 ]
Genicot, Christophe [3 ]
Jacq, Jerome [3 ]
van Gastel, Maurice
Neese, Frank [1 ]
Ritter, Tobias [1 ,2 ]
机构
[1] Max Planck Inst Kohlenforsch, Kaiser Wilhelm Pl 1, D-45470 Mulheim, Germany
[2] Harvard Univ, Dept Chem & Chem Biol, 12 Oxford St, Cambridge, MA 02138 USA
[3] UCB Biopharma, UCB NewMed, Global Chem, B-1420 Braine Lalleud, Belgium
基金
日本学术振兴会;
关键词
OXIDATIONS; CHEMISTRY; PHARMACEUTICALS; CHLORINATIONS; SEPARATION; MECHANISM; ARENES; BONDS;
D O I
10.1038/nature25749
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:511 / 514
页数:4
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