Renewable Reagent for Nucleophilic Fluorination
Blaž Alič*, Jan Petrovčič, Jan Jelen, Gašper Tavčar* and Jernej Iskra*
*Jožef Stefan Institute, Jamova 39, 1000 Ljubljana;
University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia, Email:
blaz.alic
ijs.si, gasper.tavcarijs.si,
jernej.iskrafkkt.uni-lj.si
B. Alič, J. Petrovčič, J. Jelen, G. Tavčar, J. Iskra, J. Org. Chem., 2022, 87, 5987-5993.
DOI: 10.1021/acs.joc.2c00247
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Abstract
[IPrH][F(HF)2] is a highly selective and soluble reagent for a microwave-assisted fluorination of various organic substrates. The scope of substrates includes benzyl bromides, iodides, chlorides, aliphatic halides, tosylates, mesylates, α-haloketones, a silyl chloride, acyl and sulfuryl chlorides, and a nitroarene. The reagent can be regenerated using hydrofluoric acid without organic solvents.
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Details
The article discusses the development and application of three 1,3-diarylimidazolium-based fluoride reagents, specifically [IPrH][F(HF)n] (n = 0, 1, or 2), for nucleophilic fluorination. These reagents address issues of solubility, hygroscopicity, instability, and complex preparation associated with traditional nucleophilic fluoride reagents. Among them, [IPrH][F(HF)2] (reagent 3) is highlighted for its selectivity and stability. The study demonstrates that microwave-assisted activation and the addition of sterically hindered amine DIPEA or alkali metal fluorides significantly enhance the fluorination rate. The reagents effectively fluorinate a variety of substrates, including benzyl halides, aliphatic halides, and other functional groups, with reagent 3 showing the highest chemoselectivity. The synthesis of reagent 3 is simplified, avoiding anhydrous conditions, and a recycling protocol using hydrofluoric acid is developed, promoting a greener and more sustainable fluorination process. The research underscores the potential of imidazole-based fluoride reagents for industrial-scale applications, with future work aimed at further optimizing their use and regeneration.
Fluorination of benzyl bromides on preparative scale
0.5 mmol of benzylic substrate was dissolved in 1 ml of acetonitrile. 0.6 equivalents of [IPrH][F(HF)2] and 1.8 equiv. of DIPEA were added. Reaction mixture was transferred into a microwave reactor vial using an additional 1 ml of acetonitrile. Reactions were carried out under microwave irradiation at 120 °C for 1 h. After the reaction, 5 drops of diethylamine were added and reaction mixture was reheated to 80 °C for 5 minutes. Acetonitrile was removed under reduced pressure. A few milliliters of mobile phase was poured over the obtained residue causing imidazolium salts to precipitate. Resulting solution of crude fluorinated product was purified using flash column chromatography to yield corresponding benzyl fluoride.
Deoxyfluorination of Electron-Deficient Phenols
J. Jelen, G. Tavčar, Org. Lett., 2023, 25, 3649-3653.
Key Words
benzyl fluorides, microwave synthesis
ID: J42-Y2022
