4-bromo-2-methoxybenzamide

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

Procedure: A solution of 4-bromo-2-methoxybenzamide (508 mg, 2.21 mmol) in anhydrous DCM (10 mL) was cooled to 0° C. and then treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (0.991 mL, 6.62 mmol). The mixture was stirred at 0° C. for 15 min, and then treated with phenyl dichlorophosphate (0.660 mL, 4.42 mmol) over 2 min. The reaction was stirred at 0° C. for 10 min, and then warmed to RT where it stirred for 1 h. After this time, the mixture was partitioned between DCM (10 mL) and saturated NH4Cl (20 mL). The aqueous phase was extracted with DCM. The combined extracts were dried (MgSO4) and concentrated to give the crude product, which was purified by flash chromatography (12 g SiO2 column; 0-30% EtOAc/Hex gradient) to give 4-bromo-2-methoxybenzonitrile (250 mg, 1.18 mmol, 53% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.40 (1H, s), 7.16 (1H, s), 7.12 (1H, s), 3.91 (3H, s). The reaction was stirred at 0° C. for 10 min warmed to RT where it stirred for 1 h After this time, the mixture was partitioned between DCM (10 mL) and saturated NH4Cl (20 mL) The aqueous phase was extracted with DCM The combined extracts were dried (MgSO4) concentrated to give the crude product, which was purified by flash chromatography (12 g SiO2 column; 0-30% EtOAc/Hex gradient)

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

Procedure: A mixture of methyl 4-bromo-2-methoxybenzoate (2.66 g, 10.85 mmol), 28% ammonium hydroxide (25 mL, 642 mmol) and ammonium chloride (2.0 g, 37.4 mmol) was stirred at RT for 20 min and then at 50° C. Once the material converted forms to an oil (ca. 20 min), the mixture was cooled to RT and more ammonium hydroxide (25 mL, 642 mmol) and ammonium chloride (2.0 g, 37.4 mmol) were added. Upon completion of addition, the reaction mixture was stirred at RT overnight. After this time, the mixture was heated to reflux in an open flask to drive off the excess ammonia and then cooled to RT. The mixture was neutralized with conc. HCl and then extracted with ethyl acetate. The extract was dried (Na2SO4) and then concentrated to give a residue. The residue was purified by flash chromatography (40 g silica gel cartridge; EtOAc/Hex) to give 4-bromo-2-methoxybenzamide (510 mg, 2.22 mmol, 20% yield) as a white solid. at 50° C to an oil (ca. 20 min) the mixture was cooled to RT Upon completion of addition the reaction mixture was stirred at RT overnight After this time, the mixture was heated to reflux in an open flask cooled to RT extracted with ethyl acetate The extract was dried (Na2SO4) concentrated to give a residue The residue was purified by flash chromatography (40 g silica gel cartridge; EtOAc/Hex)