Deoxyfluorination of Electron-Deficient Phenols

In this study, we report a facile synthesis of 2-chloro-1,3-bis(2,6-diisopropylphenyl)imidazolium salts in aqueous media under ambient conditions using hypochlorite as a chlorinating agent. In addition, an air-stable and moisture-insensitive deoxyfluorination reagent based on poly[hydrogen fluoride] salt is presented, which is capable of converting electron-deficient phenols or aryl silyl ethers into the corresponding aryl fluorides in the presence of DBU as a base, with good to excellent yields and high tolerance to functional groups.


General Information
All reactions where not stated otherwise were carried out under an ambient atmosphere. All chemicals and solvents were used as received without further purification unless otherwise specified. Synthesis that required inert conditions were carried out using standard Schlenk techniques under dry argon atmosphere. Acetonitrile, toluene, 1,4-dioxane, THF and DME were dried by distillation from deep purple sodium benzophenone ketyl and stored over molecular sieves (3Å or 4Å) for at least 48 h before use.
Other solvents were dried with molecular sieves for at least 72h before use. Glassware was oven-dried overnight at 150°C before use. Reactions involving aqueous hydrofluoric acid were carried out using polypropylene plastic equipment. All deoxyfluorination reaction involving reagent (2b) were carried out in capped 7 mL glass vials. Reagent (2b) was dried overnight at 70°C under vacuum in Teflon tube inserted into 500 mL Schlenk flask.

TLC and Column Chromatography
TLC analysis was performed on analytical TLC chromatographic plates (Merc Silica gel 60 F254). Spots were visualized under UV light (254 nm) or by iodine vapours. Column chromatography was performed using LiChroprep Silica gel 60 (15-25 μm particle size) and forced flow of eluent.

NMR Spectroscopy
NMR samples were prepared under ambient atmosphere. All deuterated solvents were stored over 3 Å molecular sieves. NMR spectra were recorded at the Slovenian NMR Centre (National Institute of Chemistry) using a Bruker AVANCE NEO 600 or 400 MHz NMR Spectrometer. Spectra were recorded at 298 K. Chemical shifts of 1 H and 13 C were referenced to residual signals of deuterated solvents and are given relative to tetramethylsilane (TMS). The 19 F references were calculated according to IUPAC guidelines and are given relative to CFCl3. Spectra were analysed using MestReNova 12 (Mestrelab Research S.L.) or Topspin 4.1.4. (Bruker BioSpin GmbH) program packages. Quantitative 19 F NMR spectroscopy was performed by peak integration of analyte and 2-nitrobenzotrifluoride as internal standard (-60 ppm in C6D6).

Raman Spectroscopy
Samples were loaded onto microscope slide glass under ambient atmosphere. Raman spectra were recorded using a Horiba Jobin Yvon Labram-HR spectrometer coupled with an Olympus BXFM-ILHS microscope at room temperature. Samples were excited with the 633 nm (red) emission line of He-Ne laser. Data was processed with Microsoft Excel.

Crystal Structure Determination
Crystal data were collected on a Gemini A diffractometer equipped with an Atlas CCD detector using graphite-monochromated Cu Kα radiation. All crystal data were collected at 150 K unless otherwise stated. Data were processed using the CrysAlisPro software package. An analytical absorption correction was applied to all data sets. Structures were solved using the SHELXT program. Structure refinement was performed using the SHELXL software implemented in the Olex2 program package.
Figures were prepared using Diamond 4.0. Ellipsoids are drawn at 50% probability.
Reaction mixture was left stirring overnight and then filtered off. The filter cake was washed with icecooled EtOH (100 mL) and then left to dry in an oven (60°C) to afford 169 g of (S1) as a yellow crystalline solid (90% yield). Spectroscopic data corresponds with that previously reported. 1
Reaction mixture was left stirring overnight at room temperature and then vacuum filtered off. The remaining solid was washed with deionized water (2× 5 mL), dried at 70°C and analyzed by NMR spectroscopy (MeCN-d3 solvent).  Crystal Structure: Full data available on page S47.

Optimization of method 1 (sodium hypochlorite)
Reactions were carried out in 80 mL beaker. To a solution of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (1a) (420 mg, 0.99 mmol, 1.0 equiv.) in deionized water (15 mL) was added a solution of NaClO3 (110 mg, 1.03 mmol, 1.05 equiv.) in deionized water (15 mL) at room temperature forming a white precipitate. To a suspension was added a diluted solution of sodium hypochlorite (varied amount) in deionized water (5 mL) at once. Reaction mixture was left stirring for various amount of time and then vacuum filtered off. The remaining solid was washed with deionized water (2× 5 mL), dried at 70°C and analyzed by NMR spectroscopy (MeCN-d3 solvent).

Optimization of method 2 (calcium hypochlorite)
Reaction was carried out in 80 mL beaker. To a solution of 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride (1a) (420 mg, 0.99 mmol, 1.0 equiv.) in deionized water (15 mL) was added previously prepared Ca(ClO)2 reagent solution (varied amount) diluted with deionized water to total volume of 3 mL. The resulting reaction mixture was stirred for various amount of time at room temperature and then quenched with addition of NaClO3 (110 mg, 1.03 mmol, 1.05 equiv.) in deionized water (5 mL) to form a white precipitate. Suspension was vacuum filtered off and the remaining solid washed with deionized water (2× 5 mL), dried at 70°C and analyzed by NMR spectroscopy (MeCN-d3 solvent).

S5 Synthesis of trimethylsilyl (TMS) protected phenols
Synthesis of trimethylsilyl (TMS) protected phenols (6) was performed according to the modified literature procedure from corresponding phenol (4) and HMDS 5 .
Reaction completion was monitored by TLC. During the reaction liquid product formed. Reaction mixture was then extracted with Et2O (2× 3 mL) and volatiles removed under vacuum to afford spectroscopically pure TMS protected phenols (6) as viscous oils in high yields.

Ethyl 4-trimethylsilyloxybenzoate (6f):
Following general procedure from (4f), colorless oil, 87% yield. given below). Once cooled to room temperature, the reaction mixture is purified by flash silica gel column chromatography to afford fluorinated product (5) and recyclable imidazolone (3) side product. Spectroscopic data are consistent with previously reported data. 7

4-Fluorobenzonitrile (5d)
Compound (5d) was too volatile to isolate! Reaction was performed according to general procedure for determination of reaction conversions (page S34).  Spectroscopic data are consistent with previously reported data. 12

1-Fluoro-3,5-dichlorobenzene (5l)
Compound (5l) was too volatile to isolate! Reaction was performed according to general procedure for determination of reaction conversions (page S34). Spectroscopic data are consistent with previously reported data. 7
Vial is then sealed, submerged in an oil bath and reaction mixture stirred at specified conditions. Once cooled down to room temperature, internal standard (2-nitrobenzotrifluoride in toluene, 0.083 M, 1.0 mL, 0.25 mmol of fluorine) is added and the reaction mixture analyzed with quantitative 19 F NMR spectroscopy by comparing peak integrals to determine reaction conversion to product (8).

S13 Deoxyfluorination of silyl protected phenols
Trimethylsilyl protected phenols were synthesized according to modified literature procedure 5 (page S17).

Molecular formula C27H36N2O
Molar mass 404.58 Crystal system / space group

Molecular formula C21H13O4F
Molar mass 348.31 Crystal system / space group