4-BROMO-2-FLUOROBENZALDEHYDE DIMETHYL ACETAL

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (111 mg, 0.49 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (469 mg, 0.98 mmol) and sodium tert-butoxide (4.88 g, 49.2 mmol) were combined and the flask was purged with nitrogen. A solution of 1-piperazin-1-ylethanone (4.1 g, 32 mmol) and 4-bromo-1-(dimethoxymethyl)-2-fluoro-benzene (6.13 g, 24.6 mmol) in 1,4-dioxane (82 mL) was then added and the reaction was stirred at 100° C. for 16 hours. The reaction was then filtered through diatomaceous earth and concentrated. The resulting residue was dissolved in 50 mL of THF and 50 mL of 1 N aqueous HCl was added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then neutralized with saturated aqueous Na2CO3 and extracted with dichloromethane (×3), dried with MgSO4, concentrated and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 60% yield). LCMS (m/z) ES+ 251 [M+1]+. the flask was purged with nitrogen The reaction was then filtered through diatomaceous earth concentrated The resulting residue was dissolved in 50 mL of THF 50 mL of 1 N aqueous HCl was added the reaction was stirred at ambient temperature for 16 hours extracted with dichloromethane (×3) dried with MgSO4 concentrated purified by silica gel column chromatography (0-10% methanol in dichloromethane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Palladium(II) acetate (111 mg, 0.49 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (469 mg, 0.98 mmol) and sodium tert-butoxide (4.88 g, 49.2 mmol) were combined and the flask was purged with nitrogen. A solution of 1-piperazin-1-ylethanone (4.1 g, 32 mmol) and 4-bromo-1-(dimethoxymethyl)-2-fluoro-benzene (6.13 g, 24.6 mmol) in 1,4-dioxane (82 mL) was then added and the reaction was stirred at 100° C. for 16 hours. The reaction was then filtered through diatomaceous earth and concentrated. The resulting residue was dissolved in 50 mL of THF and 50 mL of 1 N aqueous HCl was added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then neutralized with saturated aqueous Na2CO3 and extracted with dichloromethane (x3), dried with MgSO4, concentrated and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(4-acetylpiperazin-1-yl)-2-fluoro-benzaldehyde (3.68 g, 60% yield). LCMS (m/z) ES+ 251 [M+1]+. the flask was purged with nitrogen The reaction was then filtered through diatomaceous earth concentrated The resulting residue was dissolved in 50 mL of THF 50 mL of 1 N aqueous HCl was added the reaction was stirred at ambient temperature for 16 hours extracted with dichloromethane (x3) dried with MgSO4 concentrated purified by silica gel column chromatography (0-10% methanol in dichloromethane)

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

Procedure: To a solution of 4-bromo-1-dimethoxymethyl-2-fluorobenzene (4.53 g, 18.2 mmol) in 1 tetrahydrofuran (50 mL) were added n-butyllithium (1.6 mol/L in hexanes; 15 mL) and dimethylformamide (2.1 mL, 27 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted twice with ether. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (6:1 Hexane/ethyl acetate) to afford 4-dimethoxymethyl-3-fluorobenzaldehyde (2.26 g, 63%). the mixture was extracted twice with ether washed with brine dried on anhydrous sodium sulfate The solvent was removed under reduced pressure the residue was purified by column chromatography (6:1 Hexane/ethyl acetate)

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

Procedure: To a solution of 4-bromo-2-fluorobenzaldehyde (3.97 g, 18.8 mmol) in methanol (200 mL) was added p-toluenesulfonic acid monohydrate (357 mg, 1.88 mmol), and the mixture was heated to reflux for 4 h. Aqueous sodium carbonate (1 mol/L; 2 mL) was added, and the mixture was concentrated to a volume of ca. 50 mL and extracted with ether. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 4-bromo-1-dimethoxymethyl-2-fluorobenzene (4.56 g, 97%). the mixture was heated to reflux for 4 h the mixture was concentrated to a volume of ca. 50 mL extracted with ether The organic layer was washed with brine dried on anhydrous sodium sulfate The solvent was removed under reduced pressure