Recent Advances in Electrochemical Systems for Selective Fluorination of Organic Compounds.

Abstract

Organofluorine compounds are key materials applied in daily life because of their versatile utility as functional materials, pharmaceuticals, and agrochemicals. Development of the selective fluorination of organic molecules under safe conditions is therefore one of the most important subjects in modern synthetic organofluorine chemistry. Thus, various electrophilic fluorination reagents such as XeF2, (PhSO2)2NF (NFSI), Et2NSF3 (DAST), (MeOCH2CH2)2NSF3 (Deoxofluor), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-fluoropyridinium salts, and 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead) have been developed for chemical fluorination to date and the development of new fluorinating reagents is still ongoing. Electrochemical synthesis has recently attracted much attention from the perspective of green sustainable chemistry because no hazardous reagents are required and scale-up is generally easy. Although electrochemical perfluorination of organic compounds using a nickel anode in anhydrous HF has been well-established to manufacture perfluoro-functional materials, electrochemical partial fluorination (selective electrochemical fluorination) has been underdeveloped due to the low nucleophilicity of fluoride ions and anode passivation, which interferes with electrolysis. Selective electrochemical fluorination can be commonly achieved in aprotic solvents containing fluoride ions to provide mostly mono- and difluorinated products. Electrolysis is conducted at constant potentials slightly higher than the first oxidation potential of a substrate. Constant current electrolysis is also effective for selective fluorination in many cases. Choice of the combination of a supporting fluoride salt and an electrolytic solvent is most important to accomplish efficient selective fluorination. In this Account, we focus on our recent work on the electrochemical mono- and difluorination of various organic compounds and their synthetic application. We first briefly explain our research background of electrochemical fluorination. Main factors such as the effects of fluoride salts as supporting electrolytes, electrolytic solvents, and anode materials on the selectivity and efficiency of fluorination are discussed. Next, effects of PEG oligomer additives enhancing the nucleophilicity of fluoride ions and organic solvent-free systems using poly(HF) salt ionic liquids as well as recyclable mediatory systems for electrochemical fluorination are described. The desulfurizative monofluorination of xanthate and gem-difluorination of benzothioate and dithioacetals are briefly mentioned. Regioselective anodic fluorination of various heterocyclic compounds having a phenylthio group as electroauxiliary and heterocycles containing sulfur and other heteroatoms are also described. In addition, a boryl group is shown to be a good leaving group for anodic fluorination. Moreover, electrochemically α,α-difluorinated phenylsulfides and phenylselenides are illustrated to be useful for photochemical C-H difluoromethylation of aromatic and heteroaromatic compounds. Finally, this Account also highlights highly diastereoselective fluorination of aliphatic heterocyclic and open-chain compounds, as well as new electrolytic fluorination methods using inorganic fluoride salts such as KF and CsF.