2-(5-fluoro-2-methoxyphenyl)propan-2-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added to a stirred solution of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol (2.85 g, 15.5 mmol) and 2-trimethylsilanyloxy-acrylic acid ethyl ester (23.3 mmol, 4.37 g) in anhydrous methylene chloride (45 mL) cooled to −78° C. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) indicated that a significant amount of starting material remained. More stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added with the temperature around −50° C. After 2 hours, all the starting material had been consumed. The reaction mixture was treated with water (100 mL), stirred for 15 minutes and diluted with methylene chloride. The methylene chloride layer was separated, washed with two 50 mL portions of the water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown oil. The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes and a fraction corresponding to Rf=0.28 was collected to give the title compound (35%) as a light brown oil. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) all the starting material had been consumed The reaction mixture was treated with water (100 mL) diluted with methylene chloride The methylene chloride layer was separated washed with two 50 mL portions of the water dried over anhydrous sodium sulfate concentrated in vacuo to give a light brown oil The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes a fraction corresponding to Rf=0.28 was collected

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-bromo-4-fluoro anisole (4.1 g, 20 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under an atmosphere of argon was added n-butyl lithium (8.8 mL of 2.5 M solution in hexanes, 22 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with anhydrous acetone (5 mL). After 15 minutes, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. Combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-(5-fluoro-2-methoxyphenyl)propan-2-ol as a light brown thick oil (85% yield) which solidified on standing. The crude product was used for the next reaction without further purification. maintained under an atmosphere of argon After 15 minutes the reaction mixture was quenched with a saturated solution of ammonium chloride extracted with three 50 mL portions of methylene chloride Combined extracts were washed with three 25 mL portions of water dried over anhydrous sodium sulfate the solvent was evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added to a stirred solution of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol (2.85 g, 15.5 mmol) and 2-trimethylsilanyloxy-acrylic acid ethyl ester (23.3 mmol, 4.37 g) in anhydrous methylene chloride (45 mL) cooled to −78° C. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) indicated that a significant amount of starting material remained. More stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added with the temperature around −50° C. After 2 hours, all the starting material had been consumed. The reaction mixture was treated with water (100 mL), stirred for 15 minutes and diluted with methylene chloride. The methylene chloride layer was separated, washed with two 50 mL portions of the water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown oil. The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes and a fraction corresponding to Rf=0.28 was collected to give the title compound (35%) as a light brown oil. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) all the starting material had been consumed The reaction mixture was treated with water (100 mL) diluted with methylene chloride The methylene chloride layer was separated washed with two 50 mL portions of the water dried over anhydrous sodium sulfate concentrated in vacuo to give a light brown oil The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes a fraction corresponding to Rf=0.28 was collected

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-bromo-4-fluoro anisole (4.1 g, 20 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under an atmosphere of argon was added n-butyl lithium (8.8 mL of 2.5 M solution in hexanes, 22 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with anhydrous acetone (5 mL). After 15 minutes, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. Combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-(5-fluoro-2-methoxyphenyl)propan-2-ol as a light brown thick oil (85% yield) which solidified on standing. The crude product was used for the next reaction without further purification. maintained under an atmosphere of argon After 15 minutes the reaction mixture was quenched with a saturated solution of ammonium chloride extracted with three 50 mL portions of methylene chloride Combined extracts were washed with three 25 mL portions of water dried over anhydrous sodium sulfate the solvent was evaporated

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 2-(5-chloro-2-methoxyphenyl)propan-2-ol (m.p. 56° C.) was prepared from 5-chloro-2-methoxyacetophenone following the method described in Example 3 for the preparation of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol.

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

Procedure: 2-(5-chloro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane (m.p. 97° C.) was prepared from 2-(5-fluoro-2-methoxyphenyl)propan-2-ol and 4-chlorophenol following the method described in Example 3 for the preparation of 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane.

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

Procedure: 2-(5-fluoro-2-methoxyphenyl)propan-2-ol (6 g) was added in small portions to a melt of 4-fluorophenol (12 g) and concentrated hydrochloric acid (10 days) at 90° C. The mixture was stirred at this temperature overnight and was then cooled and dissolved in ether. The excess of p-fluorophenol was removed by extraction with 5% aqueous sodium hydroxide solution. The alkali insoluble material crystallised from hexane to give 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl) propane (3.9 g) as colourless prisms; m.p. 90° C. was then cooled The excess of p-fluorophenol was removed by extraction with 5% aqueous sodium hydroxide solution The alkali insoluble material crystallised from hexane

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added to a stirred solution of 2-(5-fluoro-2-methoxyphenyl)propan-2-ol (2.85 g, 15.5 mmol) and 2-trimethylsilanyloxy-acrylic acid ethyl ester (23.3 mmol, 4.37 g) in anhydrous methylene chloride (45 mL) cooled to −78° C. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) indicated that a significant amount of starting material remained. More stannic chloride (5 mL of 1 M solution in methylene chloride, 5 mmol) was added with the temperature around −50° C. After 2 hours, all the starting material had been consumed. The reaction mixture was treated with water (100 mL), stirred for 15 minutes and diluted with methylene chloride. The methylene chloride layer was separated, washed with two 50 mL portions of the water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a light brown oil. The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes and a fraction corresponding to Rf=0.28 was collected to give the title compound (35%) as a light brown oil. After 7 hours with the temperature maintained in the range of −78° C. to −50° C., TLC in hexanes-EtOAc (9:1) all the starting material had been consumed The reaction mixture was treated with water (100 mL) diluted with methylene chloride The methylene chloride layer was separated washed with two 50 mL portions of the water dried over anhydrous sodium sulfate concentrated in vacuo to give a light brown oil The crude product was purified by flash column chromatography over silica gel eluting with 10% EtOAc in hexanes a fraction corresponding to Rf=0.28 was collected

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 2-bromo-4-fluoro anisole (4.1 g, 20 mmol) in anhydrous THF (40 mL) cooled to −78° C. and maintained under an atmosphere of argon was added n-butyl lithium (8.8 mL of 2.5 M solution in hexanes, 22 mmol). After stirring at −78° C. for 45 minutes, the reaction mixture was treated with anhydrous acetone (5 mL). After 15 minutes, the reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with three 50 mL portions of methylene chloride. Combined extracts were washed with three 25 mL portions of water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-(5-fluoro-2-methoxyphenyl)propan-2-ol as a light brown thick oil (85% yield) which solidified on standing. The crude product was used for the next reaction without further purification. maintained under an atmosphere of argon After 15 minutes the reaction mixture was quenched with a saturated solution of ammonium chloride extracted with three 50 mL portions of methylene chloride Combined extracts were washed with three 25 mL portions of water dried over anhydrous sodium sulfate the solvent was evaporated