Carbon-Fluorine Bond Formation for the Synthesis of Aryl Fluorides

Abstract

A selection of carbon-fluorine bond-forming reactions is presented with particular focus on transition metal-mediated fluorination. A brief summary of conventional fluorination reactions is followed by a discussion of fluorination reactions mediated by palladium and silver. Investigations into the mechanism as well as the conceptual difficulty associated with transition metal-mediated carbonfluorine bond formation are presented.

Catalysis for fluorination and trifluoromethylation

“…For reductive elimination of two ligands to occur, there must be sufficient orbital overlap between both metal–ligand σ bonds 12 . In general, because metal–fluorine bonds are significantly polarized towards fluorine due to fluorine’s high electronegativity and small size, electron density is lacking in the region where it is required for carbon–fluorine bond formation.…”

“…Yet, despite fluorine’s importance and over 100 years of organofluorine chemistry, carbon–fluorine bond formation is still challenging 9–12 . Conventional fluorination reactions that have been developed in the early 20 th century are generally limited to very simple molecules 13 .…”

Fluorine-18 Radiochemistry, Labeling Strategies and Synthetic Routes

“…Electrophilic 18 F–F 2 and its derivatives allow labeling of electron rich aromatic rings and alkenes, but because the regioselectivity is low, a mixture of fluoro isomers is obtained that presents challenging purification needs (Figure 9 A). 9 , 60 , 61 The regioselectivity of the 18 F-fluorine can be increased by using organometallic precursors (Figure 9 B); aryltrimethyltin is superior to arylmercury, aryltrimethylsilane, and aryltrimethylgermanium. 9 , 62 As a direct outcome of improving the selectivity of 18 F-fluorine, fewer byproducts form and higher RCY of the desired 18 F product is realized.…”

Deoxyfluorination of Phenols

“…3 Simple aryl fluorides can be accessed by conventional fluorination reactions such as the Balz-Schiemann reaction, 4 but currently, only two fluorination reactions are available to make functionalized fluoroarenes with a large variety of substitution patterns: Buchwald’s palladium-catalyzed nucleophilic fluorination of aryl triflates, 1j and a silver-catalyzed electrophilic fluorination of aryl stannanes reported by our group. 1l Both reactions currently lack practicality: The palladium-catalyzed reaction requires anhydrous conditions and can give mixtures of constitutional isomers, and the silver-catalyzed reaction requires the stepwise synthesis of toxic aryl stannanes.…”