1-(4-bromo-3-fluorophenyl)ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (from Step 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82 mmol). The mixture was stirred overnight at room temperature. To the mixture was added celite, the reaction mixture was filtered through a celite pad and rinsed several times with DCM. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid. To the mixture was added celite the reaction mixture was filtered through a celite pad rinsed several times with DCM The filtrate was concentrated under reduced pressure The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification. The ice bath was removed The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) further diluted with water (10 mL) The separated aqueous layer was extracted with ethyl acetate (2×40 mL) The combined organic layers were washed with brine (60 mL) dried over sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (from Step 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82 mmol). The mixture was stirred overnight at room temperature. To the mixture was added celite, the reaction mixture was filtered through a celite pad and rinsed several times with DCM. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid. To the mixture was added celite the reaction mixture was filtered through a celite pad rinsed several times with DCM The filtrate was concentrated under reduced pressure The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification. The ice bath was removed The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) further diluted with water (10 mL) The separated aqueous layer was extracted with ethyl acetate (2×40 mL) The combined organic layers were washed with brine (60 mL) dried over sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(4-bromo-3-fluorophenyl)ethanol (1 g, 4.58 mmol), phenol (474 mg, 4.58 mmol), and triphenyl phosphine (2.4 g, 6.88 mmol) was stirred in dry tetrahydrofuran (40 mL) under nitrogen atmosphere. After 1 h, the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (2.3 g, 6.88 mmol) was added with drop-wise method and the reaction was stirred at room temperature for 18 hours. The solvent was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether) to get 1-bromo-2-fluoro-4-(1-phenoxyethyl)benzene (900 mg, 89%). The solvent was evaporated the residue was purified by column chromatography (silica gel, petroleum ether)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-3-fluorobenzaldehyde (5 g, 24.75 mmol) in anhydrous tetrahydrofuran (100 mL) was added methyl magnesium bromide (3 M solution in tetrahydrofuran, 8.21 mL) at −45° C. under the atmosphere of nitrogen then stirred at room temperature. After 2 hours, LC-MS showed the desired product has received. The aqueous of ammonium chloride (15 mL) was added to quench the reaction, and extracted with ethyl acetate (50 mL), combined and concentrated the organic layers. The crude product was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to give 1-(4-bromo-3-fluorophenyl)ethanol (4 g, 78%). LCMS (M+H+) m/z: calcd 217.97. found 218. 1H NMR (300 MHz, CD3OD): δ 7.92-7.87 (m, 1H), 7.23-7.19 (m, 1H), 7.07-7.10 (m, 1H), 4.80 (d, J=6.3 Hz, 1H), 1.41 (t, J=2.7 Hz, 3H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of crude 1-(4-bromo-3-fluorophenyl)ethanol oil (from Step 1) in DCM (100 mL) was added pyridinium dichromate (8.96 g, 23.82 mmol). The mixture was stirred overnight at room temperature. To the mixture was added celite, the reaction mixture was filtered through a celite pad and rinsed several times with DCM. The filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 1-(4-bromo-3-fluorophenyl)ethanone (3.08 g) as a white solid. To the mixture was added celite the reaction mixture was filtered through a celite pad rinsed several times with DCM The filtrate was concentrated under reduced pressure The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate]

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methylmagnesium bromide (3M in diethylether, 6.77 mL, 20.31 mmol) was added dropwise over ˜15 min to a solution of 4-bromo-3-fluorobenzaldehyde (3.1 g, 15.27 mmol) in THF (50 mL) under argon at a temperature of −60° C. to −50° C. The ice bath was removed and the reaction mixture was allowed to warm to room temperature and stirred ˜20 hr. The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) and further diluted with water (10 mL). The separated aqueous layer was extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to provide crude 1-(4-bromo-3-fluorophenyl)ethanol as a pale yellow oil, which was directly used without further purification. The ice bath was removed The reaction mixture was slowly diluted/quenched with saturated aqueous ammonium chloride solution (20 mL) further diluted with water (10 mL) The separated aqueous layer was extracted with ethyl acetate (2×40 mL) The combined organic layers were washed with brine (60 mL) dried over sodium sulfate filtered concentrated under reduced pressure