Synthesis of Fluorinated Alkyl Aryl Ethers by Palladium-Catalyzed C–O Cross-Coupling

Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and -poor (hetero)arenes. The method provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.


General Information
All reagents were purchased from commercial suppliers (Sigma-Aldrich, Alfa Aesar, Fluorochem and Apollo Scientific) and used without further purification. Moisture sensitive reactions were carried out using solvents obtained from the MBRAUN-SPS solvent purification system (CH2Cl2, THF, pentane, toluene, DMF, Et2O). Toluene used for cross-coupling was obtained from the MBRAUN-SPS solvent purification system and stored under N2 over 3Å molecular sieves. However, when toluene was used directly from the MBRAUN-SPS solvent purification system without storage over sieves, the same yields were observed. Reactions were monitored by thin layer chromatography (TLC) on silica gel precoated aluminium sheets (Merck Kieselgel 60 F254 plates). Visualization was accomplished by irradiation with UV light at 254 nm. Flash column chromatography (FCC) was performed on Merck silica gel (60, particle size 0.040-0.063 mm). All NMR spectra were recorded on Bruker AVIIIHD 400, AVIIIHD 500 or VII 500. 1 H and 13 CNMR spectral data are reported as chemical shifts (δ) in parts per million (ppm) relative to the solvent peak using the Bruker internal referencing procedure (edlock). 19 F NMR spectra are referenced relative to CFCl3. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t= triplet, q = quartet, pent=pentet, sept=septet, br=broad,m = multiplet), coupling constants (Hz) and integration. NMR spectra were processed with MestReNova 11.0 or higher. High resolution mass spectra (HRMS, m/z) were recorded on a Thermo Exactive High-Resolution Orbitrap FTMS instrument equipped with Waters Acquity liquid chromatography system using either the heated electrospray (HESI-II) probe for positive electrospray ionization (ESI+) or the atmospheric pressure chemical ionization (APCI) probe. Infrared spectra were recorded as the neat compound or in solution using a Bruker tensor 27 FT-IR spectrometer. Absorptions are reported in wavenumber (cm -1 ). Melting points of solids were measured on a Griffin apparatus and are uncorrected.

General procedure
To an oven dried Schlenk tube was added Cs2CO3 (488 mg, 1.50 mmol). The Schlenk tube was placed under vacuum and heated at 450 °C with a heat gun for around 3 minutes, or until the Cs2CO3 stopped 'jumping'. After the tube had cooled to room temperature it was placed under an N2 atmosphere, and aryl bromide (1.00 mmol) and t BuBrettPhos Pd G3 (8.5 mg, 0.01 mmol) were added. Dry, degassed toluene (3 mL) was added, followed by the fluorinated alcohol (1.50 mmol). The Schlenk tube was sealed and heated at 80 °C or 100 °C in a preheated oil bath for the specified time. After completion, the reaction mixture was cooled to room temperature, and then diluted with CH2Cl2 (5 mL). The mixture was filtered through a Celite pad. The Schlenk tube was washed out through the Celite pad with additional CH2Cl2 (2 x 5 mL). The filtrate was concentrated in vacuo and purified by flash column chromatography.

and a ligand
To an oven dried Schlenk tube was added Cs2CO3 (244 mg, 0.75 mmol). The Schlenk tube was placed under vacuum and heated at 450 °C with a heat gun for around 3 minutes, or until the Cs2CO3 stopped 'jumping'. After the tube had cooled to room temperature, it was placed under an N2 atmosphere, and then ligand (6.25 μmol) was added followed by a solution of Pd2(dba)3 (2.3 mg, 2.5 μmol) in dry toluene (1.5 mL), prepared under N2. The mixture was stirred at room temperature for 20 minutes. Then 1-(4-bromophenyl)propan-2-one (107 mg, 0.502 mmol) was added, followed by trifluoroethanol (54 μL, 0.75 mmol). The Schlenk tube was sealed under N2, and heated in a preheated oil bath at the specified temperature for the specified duration. The reaction mixture was allowed to cool, diluted with CH2Cl2, and filtered through Celite. The filter cake was washed with additional CH2Cl2, and then PhCF3 (25 μL, 0.204 mmol) was added to the filtrate. A sample of the filtrate was taken, diluted with CDCl3, and analysed by quantitative fluorine NMR.

Procedure for screening coupling reaction using t BuBrettPhos Pd G3
The base (0.75 mmol) was added to an oven dried Schlenk tube. The Schlenk tube was placed under vacuum and heated with a heat gun for around 3 minutes. Note that NaO t Bu was weighed into a pre-dried Schlenk tube in a N2 filled glove box, and used directly without heating with a heat gun. After the tube had cooled to room temperature, it was placed under an N2 atmosphere, and t BuBrettPhos Pd G3 (4.2 mg, 4.9 μmol) was added, followed by 1-(4bromophenyl)propan-2-one (107 mg, 0.502 mmol), trifluoroethanol (54 μL, 0.75 mmol), and finally dry solvent (1.5 mL). The Schlenk tube was sealed under N2, and heated in a preheated oil bath at the specified temperature for the specified duration. The reaction mixture was allowed to cool, diluted with CH2Cl2, and filtered through Celite. The filter cake was washed with additional CH2Cl2, and then PhCF3 (25 μL, 0.204 mmol) was added to the filtrate. A sample of the filtrate was taken, diluted with CDCl3, and analysed by quantitative fluorine NMR.

Scale-up of 3-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (2u)
Cs2CO3 (10.5 mmol) was added to a 2-neck 100 mL round-bottom flask equipped with a stirring bar. The flask was placed under vacuum and heated at 550 °C for 5 -10 minutes to dry the caesium carbonate. After cooling to room temperature, the flask was placed under an N2 atmosphere, and then equipped with an air condenser. The flask was placed under vacuum again, and all the glassware was dried again at 450 °C. After cooling to room temperature, the setup was placed under an N2 atmosphere, and 3-bromobenzaldehyde (7.00 mmol) and t BuBrettPhos Pd G3 (0.035 mmol) were added. Dry, degassed toluene (20 mL) was added, followed by 2,2,3,3-tetrafluoropropan-1-ol (10.5 mmol). The reaction mixture was heated at 80 °C for 2 hours, stirring at 700 RPM. The reaction progress was monitored by 19 F NMR. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The Celite was washed with CH2Cl2 (100 mL). The filtrate was washed with water (100 mL), brine (100 mL), dried over MgSO4, and then concentrated in vacuo. The crude product was purified by flash column chromatography (10% ethyl acetate in pentane) to afford to the desired compound as a pale-yellow oil (1.53g, 92%).

NMR spectra
2a. 1-(4-(2,2,2-trifluoroethoxy)phenyl)propan-2-one 2b. 1-methoxy-4-(2,2,2-trifluoroethoxy)benzene 2c. 1,3-dimethoxy-5-(2,2,2-trifluoroethoxy)benzene 3d. 4-(4-(2,2-difluoroethoxy) An aliquot of 20-30 MBq of [ 18 F]fluoride was dispensed into a 3.5 mL v-vial equipped with a lid and septum. Then a solution of (1R,2S,5R)-menthol bromodifluoroacetate (8) and 1, in dry solvent (300 µL) was added, and the reaction mixture was heated at the specified temperature for 10 minutes. The reaction was mixture was diluted with EtOH (200 µL) and then analysed by radio-HPLC. After trapping, the cartridge was washed with H2O (2 mL), and then blow dried under a flow N2 (1.6 -1.8 L min -1 ) for around 20 minutes. The radioactivity of the cartridge was monitored using a radiodetector strapped to the cartridge. At the point at which the activity started to drop, the N2 flow was stopped. The cartridge was then eluted with anhydrous dioxane (2 mL) into a 5 mL v-vial containing NaBH4 (10 mg, 0.265 mmol). Residual solvent on the cartridge was blown into the reaction vial using a flow of N2 for around 5 seconds. The reaction mixture was heated at 60 °C for 10 minutes without a vent needle. The mixture was then taken up in a syringe and passed over a Sep-Pak silica light cartridge, pre-activated with anhydrous dioxane (5 mL), into a dry 5 mL v-vial. Remaining solvent on the cartridge was blown into the vial using a flow of N2 for around 5 seconds.

Activity yield:
The non-decay corrected activity yield for [ 18 F]trifluoroethanol was 2 ± 1% (n = 4), calculated from the activity of dry [ 18 ]TBAF used at the start of the synthesis. The major loss of activity was in the 18 F-fluorination of 8 to prepare [ 18 F]9. While this reaction gave good radiochemical yields on the screening scale, on full-batch scale, activity yields were poor; 5 ± 2% (n = 4).

Notes on drying [ 18 F]9:
If drying of intermediate [ 18 F]9 was omitted, the subsequent reduction with NaBH4 still worked affording [ 18 F]trifluoroethanol almost quantitatively. However, the obtained solution of [ 18 F]trifluoroethanol was unreactive in subsequent cross-coupling reactions. It was determined that this was due to the presence of large amounts of water in the final solution.
The reformulation post-HPLC doesn't remove all the water, as some water is trapped on C18 cartridge and elutes along with the [ 18 F]9 when dioxane is passed over the cartridge. The easiest and most efficient way to remove this water was to dry the cartridge under a flow of N2. The activity on the cartridge was monitored during the drying process, as drying for an extended duration with a flow of N2 led to a loss of radioactivity. Drying with N2 was stopped as soon as the activity on the cartridge began to drop faster than what is normal due to decay. This was typically around 20 minutes. Drying for shorter durations resulted in no reaction in the final cross-coupling reaction. Another method to remove the water was elution of the C18 cartridge with pentane, and then passing the biphasic pentane/water mixture directly over a Sep-Pak Alumina N Plus Long Cartridge (WAT020510). While this works very well to remove water, a large amount of radioactivity is lost in the process. Drying of [ 18 F]9 via heating to 60 °C under a flow of N2 led to a loss of radioactivity.

Notes on molar activity:
This method for 18 F-labelling is based on the work of Szabó and Schou. 6 Under similar labelling conditions, Szabó and Schou obtained a molar activity of 0.1 GBq µmol -1 for labelling of 18 Ftrifluoroacetamides from bromodifluoroacetamides. We expect the molar activity obtained with this procedure to be in a similar range. This low value is believed to originate from intramolecular 19 F-fluoride transfer from the starting material. Indeed, in our control experiments, simply heating up 8 under the reaction conditions in the absence of a fluoride source led to formation of non-radioactive 9.

Procedure for Cross-Coupling [ 18 F]trifluoroethanol with Aryl Bromides
To a 3.5mL v-vial was added first t BuBrettPhos Pd G3 (2-3 mg, ~0.003 mmol), then aryl bromide (0.03 mmol), then dry Cs2CO3 (13 mg, 0.04 mmol, pre-dried at 450 °C under vacuum in a Schlenk tube). The vial sealed with a stir bar and septum. A vent needle was added the and the vial was flushed with N2 for ~ 1 minute. Then, [ 18 F]trifluoroethanol solution in dioxane was added (15-20 MBq). The reaction was heated at the specified temperature for 20 minutes. The reaction was diluted with 100 uL MeCN and analysed by radio-HPLC. NOTE: no significant loss in activity, beyond that due to decay, was observed after 20 minutes. This indicates that loss of [ 18 F]trifluoroethanol due to evaporation was insignificant.