2-Chloro-5-fluoroanisole

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

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%). The reaction solution was cooled to room temperature extracted with MTBE The organic layer was washed with saturated brine dried over magnesium sulfate The drying agent was removed by filtration the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate)

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

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%). The reaction solution was cooled to room temperature extracted with MTBE The organic layer was washed with saturated brine dried over magnesium sulfate The drying agent was removed by filtration the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%). The reaction solution was cooled to room temperature extracted with MTBE The organic layer was washed with saturated brine dried over magnesium sulfate The drying agent was removed by filtration the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%). The reaction solution was cooled to room temperature extracted with MTBE The organic layer was washed with saturated brine dried over magnesium sulfate The drying agent was removed by filtration the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%). The reaction solution was cooled to room temperature extracted with MTBE The organic layer was washed with saturated brine dried over magnesium sulfate The drying agent was removed by filtration the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate)

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

Procedure: Under ice-cooling, monoethyl oxalate monochloride (10.5 g) is added dropwise to a solution of aluminum chloride (10.5 g) in nitrobenzene (30 ml). To the solution is added dropwise 2-chloro-5-fluoroanisole (84 g). After 30 minutes, the mixture is poured into ice-water and extracted with ether. The extract is washed with dilute hydrochloric acid and dilute aqueous sodium bicarbonate, dried and evaporated to remove the solvent. Recrystallization from a mixture of ether and n-hexane gives ethyl 4-methyl-3-chloro-6-fluorophenylglyoxalate (mp. 84°-85° C.). A mixture of the glyoxalate (5.21 g), ethylene glycol (28 ml), potassium hydroxide (4.5 g) and hydrazine monohydrate (2.85 ml) is heated at 155°-158° C. for 1.5 hours and then at 220° C. for 2 hours and poured into water. The mixture is washed with ether, acidified with hydrochloric acid and extracted with ether. The extract is evaporated. The obtained residue is recrystallized from dichloromethane to give 3-chloro-4-hydroxy-6-fluorophenylacetic acid (mp. 137°-138° C.). A part of the acid (0.615 g) is suspended in dichloromethane (15 m) and esterified with diphenyldiazomethane to give crystals of the corresponding diphenylmethyl ester (mp. 121°-122° C.). Under ice-cooling extracted with ether The extract is washed with dilute hydrochloric acid and dilute aqueous sodium bicarbonate dried evaporated to remove the solvent Recrystallization from a mixture of ether and n-hexane

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-5-fluoroanisole (0.52 ml, 4.10 mmol), benzophenone hydrazone (0.98 g, 5.00 mmol), sodium-tert-butoxide (561 mg, 5.80 mmol), in toluene (8.0 ml) was charged with Pd2(dba)3 (77.0 mg, 0.08 mmol) and 2-(di-t-butylphosphino)biphenyl (50.0 mg, 0.17 mmol) and heated to 80° C. under argon. The mixture was stirred overnight and checked with LCMS and TLC. The mixture was allowed to cool to room temperature and the reaction mixture was diluted with EtOAc (20 ml) and filtered. Material was used crude in the next step. to cool to room temperature filtered

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Chloro-4-fluoro-2-methoxy-benzene (4.3 g, 26.78 mmol) and isobutyronitrile (9.61 mL, 4.0 eq.) were dissolved in toluene (9.0 mL), added with KHMDS (80 mL, 0.5 M toluene solution) and stirred at 65° C. for 2 hr. The reaction solution was cooled to room temperature, added with aqueous solution of 1 N hydrochloric acid and then extracted with MTBE. The organic layer was washed with saturated brine and dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.72 g, 31%). The reaction solution was cooled to room temperature extracted with MTBE The organic layer was washed with saturated brine dried over magnesium sulfate The drying agent was removed by filtration the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (hexane/ethyl acetate)