2,4-Difluoro-3-methoxybenzaldehyde

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system)

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

Procedure: Lithium diisopropyl amide (1.5M cyclohexane solution, 5.6 mL) was added dropwise to a THF (10 mL) solution of 2,6-difluoroanisole (1.00 g) at −72° C. under nitrogen atmosphere, and the reaction solution was agitated for 30 minutes. DMF (2.7 mL) was added to the reaction mixture, the reaction solution was agitated for 30 minutes at −78° C., and then agitated at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system) and 433 mg of the title compound was obtained. the reaction solution was agitated for 30 minutes at −78° C. agitated at room temperature for 1 hour the organic layer was partitioned The organic layer was washed with a saturated saline solution dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate system)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1M BBr3 in DCM (2.179 ml) was added dropwise in about 30 min. to a stirred solution of 2,4-difluoro-3-methoxybenzaldehyde (0.25 g, 1.452 mmol) in DCM, cooled at −10° C. and under nitrogen atmosphere The solution was stirred for 4 hrs at RT and then diluted with a mixture of THF/H2O (9/1) and heated for 30 min. at 80° C. The solvent was removed and the residue was partitioned between 10N NaOH and Et2O. The aqueous layer was acidified with 10 N HCl and extracted with Et2O/EtOAc (2/1). Organic layers were dried over sodium sulphate and evaporated to give 2,4-difluoro-3-hydroxybenzaldehyde (225 mg) as pale brown powder. heated for 30 min. at 80° C The solvent was removed the residue was partitioned between 10N NaOH and Et2O extracted with Et2O/EtOAc (2/1) Organic layers were dried over sodium sulphate evaporated

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1M BBr3 in DCM (2.179 ml) was added dropwise in about 30 min. to a stirred solution of 2,4-difluoro-3-methoxybenzaldehyde (0.25 g, 1.452 mmol) in DCM, cooled at −10° C. and under nitrogen atmosphere The solution was stirred for 4 hrs at RT and then diluted with a mixture of THF/H2O (9/1) and heated for 30 min. at 80° C. The solvent was removed and the residue was partitioned between 10N NaOH and Et2O. The aqueous layer was acidified with 10 N HCl and extracted with Et2O/EtOAc (2/1). Organic layers were dried over sodium sulphate and evaporated to give 2,4-difluoro-3-hydroxybenzaldehyde (225 mg) as pale brown powder. heated for 30 min. at 80° C The solvent was removed the residue was partitioned between 10N NaOH and Et2O extracted with Et2O/EtOAc (2/1) Organic layers were dried over sodium sulphate evaporated