1-fluoro-2-methoxybenzene

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

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

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

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

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

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

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

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: Pentamethylenediethylenetetramine (31.2 ml) was added to a solution of 2-fluoroanisole (15.0 g) in THF (450 ml). The reaction mixture was cooled to −78° C. and n-butyllithium (59.6 ml, 2.5M solution in hexanes) was added dropwise. Stirring was maintained for 2 h before the solution was added in a dropwise fashion to a flask containing solid carbon dioxide pellets. Upon complete addition (30 min) the mixture was allowed to warm to room temperature before removal of the volatiles in vacuo. The residue was dissolved in 10% sodium hydroxide solution (300 ml) and extracted with Et2O (3×). The aqueous was acidified to pH 1 with concentrated hydrochloric acid before extracting with DCM. The organics were washed with H2O, dried (MgSO4) and concentrated in vacuo to afford the subtitle compound as a yellow solid. Yield: 7.1 g. was maintained for 2 h before the solution was added in a dropwise fashion to a flask Upon complete addition (30 min) the mixture to warm to room temperature before removal of the volatiles in vacuo extracted with Et2O (3×) before extracting with DCM The organics were washed with H2O dried (MgSO4) concentrated in vacuo

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

Procedure: A solution of titanium tetrachloride (182 g, 0.96 mol, 1.2 equiv.) and α,α, -dichloromethylmethyl ether (110 g, 0.96 mol) in an equal volume of methylene chloride is slowly added (30 minutes) to a solution of o-fluoroanisole (101 g, 0.80 mol) in dry methylene chloride (50 ml) at 10-20° C. The mixture is stirred at room temperature for one hour, is poured over crushed ice water and ether (1 l ) with stirring. This mixture is stirred under nitrogen until solution occurs. The organic layer is extracted with water, aqueous sodium bicarbonate, and is dried (MgSO4). The solvent is evaporated at 30° C. The residual oil is vacuum-distilled through a jacketed Vigreux column to give 3-fluoro-4-methoxybenzaldehyde, B.P. 120-121° C. (10 mm Hg) Rf 0.6 on a silica-gel G plate with methylene chloride. is poured with stirring This mixture is stirred under nitrogen until solution The organic layer is extracted with water, aqueous sodium bicarbonate is dried (MgSO4) The solvent is evaporated at 30° C The residual oil is vacuum-distilled through a jacketed Vigreux column

Conditions: temp:7.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetyl chloride (51.0 g, 0.65 mol) was added dropwise to a stirred solution of aluminum chloride (80.0 g, 0.6 mol) and chloroform (750 mL), maintaining the temperature between 5-10° C. The mixture was stirred for 10 minutes at 5° C. before the dropwise addition of 2-fluoroanisole (62.6 g, 0.5 mol). The mixture was stirred at 0-10° C. for 1 hour and poured into ice (1 L). The resultant layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The combined organic layers were washed with water (2×150 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 mL. Hexanes were added and a white solid formed which was isolated by filtration and air dried. This material was recrystallized from a mixture of dichloromethane and hexanes to afford (77.2 g, 92%) of material suitable for use in the next step: mp 92-94° C. The resultant layers were separated the aqueous layer was extracted with dichloromethane (2×250 mL) The combined organic layers were washed with water (2×150 mL) dried over anhydrous MgSO4 filtered concentrated in vacuo to a volume of 300 mL Hexanes were added a white solid formed which was isolated by filtration and air dried This material was recrystallized from a mixture of dichloromethane and hexanes