2-fluoro-3-methoxyphenol

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

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluoro-3-methoxyphenol (22.0 g) and triethylamine (93.9 g) in dichloroethane (250 mL) was added magnesium chloride (71.7 g), and the mixture was stirred at 40° C. for 1 hr. To this mixture was added paraformaldehyde (46.5 g), and the mixture was stirred for 16 hr. The reaction solution was allowed to be cooled to room temperature, 1N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (26.0 g). the mixture was stirred for 16 hr to be cooled to room temperature the mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by combi flash (petroleum ether/ethyl acetate)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-fluoro-3-methoxyphenol (22.0 g) and triethylamine (93.9 g) in dichloroethane (250 mL) was added magnesium chloride (71.7 g), and the mixture was stirred at 40° C. for 1 hr. To this mixture was added paraformaldehyde (46.5 g), and the mixture was stirred for 16 hr. The reaction solution was allowed to be cooled to room temperature, 1N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (26.0 g). the mixture was stirred for 16 hr to be cooled to room temperature the mixture was extracted with dichloromethane The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by combi flash (petroleum ether/ethyl acetate)

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

Procedure: To a solution of 2-fluoro-3-methoxyphenylboronic acid (30.4 g) in THF (300 mL) was added dropwise aqueous hydrogen peroxide (100 mL, 30% wt in water), and the mixture was heated with reflux for 1 hr. The reaction mixture was allowed to be cooled to room temperature, saturated aqueous sodium sulfite was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (24.8 g). the mixture was heated with reflux for 1 hr the mixture was extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by combi flash (petroleum ether/ethyl acetate)

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

Procedure: To a stirred mixture of 2-fluoro-3-methoxy-phenol (3.88 g, 0.027 mol) and methyl-2-butynoate (5.97 g, 0.061 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(2-fluoro-3-methoxy-phenoxy)-but-2-enoic acid methyl ester (4.37 g, 63%) as a colorless oil and used without further purification. After addition at reflux overnight was removed in vacuo the residue was diluted in diethyl ether washed first with 1N aqueous hydrochloric acid 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate The mixture was filtered evaporated the residue dried under high vacuum which

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

Procedure: To a solution of 2-fluoro-3-methoxy-phenylboronic acid (10.0 g, 0.059 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2-fluoro-3-methoxy-phenol (6.77 g, 81%) as a pale yellow oil. was added to come to room temperature The mixture was evaporated the residue was dissolved in ethyl acetate washed with hydrochloric acid (0.5N), water and brine The organic phase was dried filtered evaporated which

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

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

Procedure: To a stirred mixture of 2-fluoro-3-methoxy-phenol (3.88 g, 0.027 mol) and methyl-2-butynoate (5.97 g, 0.061 mol) in tetrahydrofuran (30 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (4.64 g, 0.030 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(2-fluoro-3-methoxy-phenoxy)-but-2-enoic acid methyl ester (4.37 g, 63%) as a colorless oil and used without further purification. After addition at reflux overnight was removed in vacuo the residue was diluted in diethyl ether washed first with 1N aqueous hydrochloric acid 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate The mixture was filtered evaporated the residue dried under high vacuum which

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

Procedure: To a solution of 2-fluoro-3-methoxy-phenylboronic acid (10.0 g, 0.059 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 65 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2-fluoro-3-methoxy-phenol (6.77 g, 81%) as a pale yellow oil. was added to come to room temperature The mixture was evaporated the residue was dissolved in ethyl acetate washed with hydrochloric acid (0.5N), water and brine The organic phase was dried filtered evaporated which

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

Procedure: A solution of 2-fluoro-3-methoxy-phenol (0.5 g, 3.53 mmol) and dichloromethane is stirred at −78° C. A 1M solution of boron tribromide in dichloromethane (3.9 mL, 3.9 mmol) is added slowly and the mixture is stirred 10 min cold, then warmed to 0° C. and stirred 1 hr. The reaction is quenched with ice and stirred at room temperature overnight. The product is extracted with ethyl acetate (2×50 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting residue is combined with boron trifluoride diethyl etherate (1.3 mL, 10.3 mmol) and acetic acid (0.2 mL, 3.28 mmol) and heated to reflux 8 hr. The mixture is cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is diluted with hexanes (50 mL), cooled to 0° C., and filtered to give the title compound (310 mg, 58%) as a tan solid. MS ES171 m+1. stirred 1 hr The reaction is quenched with ice stirred at room temperature overnight The product is extracted with ethyl acetate (2×50 mL) dried over magnesium sulfate filtered concentrated heated to reflux 8 hr The mixture is cooled to room temperature extracted with ethyl acetate (3×50 mL) The combined extracts are dried over magnesium sulfate filtered concentrated to about 10 mL volume The resulting mixture is diluted with hexanes (50 mL) cooled to 0° C. filtered

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

Procedure: A mixture of 2-fluoroanisole (1.8 ml, 15.85 mmol), pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran (10 mL) is stirred at −78° C. A 2.5 M solution of n-butyllithium in hexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solution is stirred at −78° C. 2 hr. Trimethylborate (2 mL, 17.45 mmol) is added and the reaction is warmed to room temperature and stirred 1 hr. Acetic acid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30% solution of hydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture is stirred rapidly 18 hr at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes:ethyl acetate to give the title compound (1.65 g, 73%) as a colorless oil. MS ES 141 m−1. the resulting solution is stirred at −78° C 2 hr the reaction is warmed to room temperature stirred 1 hr the resulting mixture is stirred rapidly 18 hr at room temperature extracted with ethyl acetate (3×50 mL) The combined extracts are dried over magnesium sulfate filtered concentrated to about 10 mL volume The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes

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

Procedure: A mixture of 2-fluoroanisole (1.8 ml, 15.85 mmol), pentamethyldiethyenetriamine (3.6 mL, 17.45 mmol) and tetrahydrofuran (10 mL) is stirred at −78° C. A 2.5 M solution of n-butyllithium in hexanes (7 ml, 17.45 mmol) is added dropwise and the resulting solution is stirred at −78° C. 2 hr. Trimethylborate (2 mL, 17.45 mmol) is added and the reaction is warmed to room temperature and stirred 1 hr. Acetic acid (1.4 ml, 23.8 mmol) is added followed by an aqueous 30% solution of hydrogen peroxide (1.8 mL, 17.45 mmol) and the resulting mixture is stirred rapidly 18 hr at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts are dried over magnesium sulfate, filtered and concentrated to about 10 mL volume. The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes:ethyl acetate to give the title compound (1.65 g, 73%) as a colorless oil. MS ES 141 m−1. the resulting solution is stirred at −78° C 2 hr the reaction is warmed to room temperature stirred 1 hr the resulting mixture is stirred rapidly 18 hr at room temperature extracted with ethyl acetate (3×50 mL) The combined extracts are dried over magnesium sulfate filtered concentrated to about 10 mL volume The resulting mixture is purified via silica chromatography eluting with hexanes to 8:1 hexanes