4-Fluoro-1,2-dimethoxybenzene

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

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

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sulfur trioxide N,N-dimethylformamide complex (4.108 g, 27 mmol) in 1,2-dichloroethane was added 4-fluoroveratrole (3.49 g, 22 mmol) dropwise. The mixture was slowly heated to 85° C. in an oil bath. After 2.5 h, the solids had dissolved to afford a golden yellow solution. A trace of starting material was still present and heating was continued for a further 4.5 h. The oil bath was removed and thionyl chloride (1.95 ml, 27 mmol) added dropwise. The mixture was heated 4 h at 85° C. and allowed to cool to room temperature. The solution was poured into water and extracted with dichloromethane (3×50 ml), the combined organics washed with water, dried over magnesium sulfate and evaporated. Remaining traces of N,N-dimethylformamide were removed azeotropically with toluene to afford the product as an off-white solid that was used without further purification. the solids had dissolved to afford a golden yellow solution heating was continued for a further 4.5 h The oil bath was removed The mixture was heated 4 h at 85° C. to cool to room temperature extracted with dichloromethane (3×50 ml) the combined organics washed with water dried over magnesium sulfate evaporated Remaining traces of N,N-dimethylformamide were removed azeotropically with toluene

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of sulfur trioxide N,N-dimethylformamide complex (4.108 g, 27 mmol) in 1,2-dichloroethane was added 4-fluoroveratrole (3.49 g, 22 mmol) dropwise. The mixture was slowly heated to 85° C. in an oil bath. After 2.5 h, the solids had dissolved to afford a golden yellow solution. A trace of starting material was still present and heating was continued for a further 4.5 h. The oil bath was removed and thionyl chloride (1.95 ml, 27 mmol) added dropwise. The mixture was heated 4 h at 85° C. and allowed to cool to room temperature. The solution was poured into water and extracted with dichloromethane (3×50 ml), the combined organics washed with water, dried over magnesium sulfate and evaporated. Remaining traces of N,N-dimethylformamide were removed azeotropically with toluene to afford the product as an off-white solid that was used without further purification. the solids had dissolved to afford a golden yellow solution heating was continued for a further 4.5 h The oil bath was removed The mixture was heated 4 h at 85° C. to cool to room temperature extracted with dichloromethane (3×50 ml) the combined organics washed with water dried over magnesium sulfate evaporated Remaining traces of N,N-dimethylformamide were removed azeotropically with toluene

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

Procedure: 12.7 g (95 mmol) of aluminium trichloride in 80 ml of 1,2-dichloroethane are stirred under nitrogen and cooled to 3°. 13.35 g (95 mmol) of benzoyl chloride are added. At 30°, this red solution is added dropwise over a period of 25 minutes to a solution of 12.55 g (80.3 mmol) of 1,2-dimethoxy-4-fluorobenzene (4-fluoroveratrole) in 80 ml of 1,2-dichloroethane. The reaction mixture is stirred for a further 3 hours at 3°, then for 31/2 hours at room temperature and then poured onto a mixture of 250 ml of ice and 20 ml of concentrated hydrochloric acid. The organic phase is separated off and the aqueous phase is extracted several times with ether. Organic phase and ether solutions are combined, washed with 1N sodium hydroxide solution, water and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The resulting yellow oil is stirred with 50 ml of ether in an ice bath until crystallisation takes place, yielding the desired (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone in the form of white crystals having a melting point of 102°-103°. cooled to 3° The organic phase is separated off the aqueous phase is extracted several times with ether washed with 1N sodium hydroxide solution, water and with saturated sodium chloride solution dried over magnesium sulphate concentrated by evaporation The resulting yellow oil is stirred with 50 ml of ether in an ice bath until crystallisation

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

Procedure: Six bomb tubes, each containing 4.8 g (30.0 mmol) of 4-fluoro-1,2-dimethoxybenzene (obtained from 3,4-dimethoxyaniline by a Balz-Schiemann reaction), 7.5 g (37.5 mmol) of (2-pyridinyl)-benzoate and 300 ml of trifluoroacetic acid, are heated at 100° for 41/2 hours while stirring magnetically. The contents of all six bomb tubes is poured into 600 ml of water while stirring vigorously and the solid substance that separates out is filtered with suction. The filtrate is extracted several times with toluene. The solid substance is dissolved in the combined toluene extracts. The toluene solution is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation. The resulting semi-solid oil is dissolved in 500 ml of warm isopropanol and treated with carbon. The filtered solution is concentrated in vacuo until crystallisation begins. After complete crystallisation, the (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone is filtered with suction and washed with cold isopropanol, yielding white crystals having a melting point of 102°-104°.

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

Procedure: Six bomb tubes, each containing 4.8 g (30.0 mmol) of 4-fluoro-1,2-dimethoxybenzene (obtained from 3,4-dimethoxyaniline by a Balz-Schiemann reaction), 7.5 g (37.5 mmol) of (2-pyridinyl)-benzoate and 300 ml of trifluoroacetic acid, are heated at 100° for 41/2 hours while stirring magnetically. The contents of all six bomb tubes is poured into 600 ml of water while stirring vigorously and the solid substance that separates out is filtered with suction. The filtrate is extracted several times with toluene. The solid substance is dissolved in the combined toluene extracts. The toluene solution is washed with water and saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness by evaporation. The resulting semi-solid oil is dissolved in 500 ml of warm isopropanol and treated with carbon. The filtered solution is concentrated in vacuo until crystallisation begins. After complete crystallisation, the (4,5-dimethoxy-2-fluorophenyl)-phenylmethanone is filtered with suction and washed with cold isopropanol, yielding white crystals having a melting point of 102°-104°.

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

Procedure: In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N2 inlet was placed 4-fluoroveratrole (0.78 g, 5.0 mmol, Aldrich Chemical Co.) in 20 ml of anhydrous CH2Cl2. After cooling to 0° C., titanium (IV) chloride (0.91 ml, 1.57 g, 8.3 mmol) was added, followed after 10 min. by a,a-dichloromethyl methyl ether (0.45 ml, 0.575 g, 5.0 mmol). The mixture was allowed to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHCO3. The suspension was filtered through a pad of d.e. (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH2Cl2 and the organic phases were combined and washed with water followed by saturated aqueous NaCl. After drying with MgSO4, the organic solvent was removed in vacuo to give the title compound as a white solid, 910 mg. In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N2 inlet to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHCO3 The suspension was filtered through a pad of d.e (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH2Cl2 washed with water After drying with MgSO4 the organic solvent was removed in vacuo

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

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

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

Procedure: In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N2 inlet was placed 4-fluoroveratrole (0.78 g, 5.0 mmol, Aldrich Chemical Co.) in 20 ml of anhydrous CH2Cl2. After cooling to 0° C., titanium (IV) chloride (0.91 ml, 1.57 g, 8.3 mmol) was added, followed after 10 min. by a,a-dichloromethyl methyl ether (0.45 ml, 0.575 g, 5.0 mmol). The mixture was allowed to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHCO3. The suspension was filtered through a pad of d.e. (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH2Cl2 and the organic phases were combined and washed with water followed by saturated aqueous NaCl. After drying with MgSO4, the organic solvent was removed in vacuo to give the title compound as a white solid, 910 mg. In a flame-dried, round-bottomed flask fitted with a magnetic stirrer and N2 inlet to warm to room temperature and after 2 hr it was quenched with an excess of aqueous saturated NaHCO3 The suspension was filtered through a pad of d.e (diatomaceous earth), the aqueous phase was extracted with additional amounts of CH2Cl2 washed with water After drying with MgSO4 the organic solvent was removed in vacuo

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

Procedure: To a cold (−78° C.) solution of 4-fluoro-1,2-dimethoxybenzene (15.00 g, 96.05 mmol) in anhydrous THF (150 mL) was added n-BuLi (84.5 mL, 211.32 mmol, 2.5 M solution in hexanes) under nitrogen and stirred it for 3 h at −78° C. Quenched the reaction with DMF (75 mL) at −65° C., added 2N HCl (300 mL) dropwise and further stirred for 30 min. Two layers separation was observed. Aqueous layer was extracted with EtOAc. Combined organic layers were washed with water, brine and dried over MgSO4. Filtered the ethyl acetate layer and concentrated it in vacuo. The title compound was purified by flash column chromatography using pure hexanes then 10 and 20% EtOAc in hexanes which provided 14.40 g (78.19 mmol, 82%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 7.36 (dd, J=9.0, 5.1 Hz, 1H), 7.03 (t, J=9.6 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ ppm −131.68-−131.66 (m, 1F). Quenched the reaction with DMF (75 mL) at −65° C. further stirred for 30 min Two layers separation Aqueous layer was extracted with EtOAc Combined organic layers were washed with water, brine dried over MgSO4 Filtered the ethyl acetate layer concentrated it in vacuo The title compound was purified by flash column chromatography