3,5-dibromo-4-methoxyaniline

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

Procedure: 3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+. The column was eluted further to give recovered The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9 the layers separated the aqueous layer extracted into DCM (3×50 mL) The combined organic phase was dried over Na2SO4 concentrated to dryness under reduced pressure purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane

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

Procedure: 3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+. The column was eluted further to give recovered The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9 the layers separated the aqueous layer extracted into DCM (3×50 mL) The combined organic phase was dried over Na2SO4 concentrated to dryness under reduced pressure purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane

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

Procedure: 3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+. A thick, beige precipitate formed the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9 the layers separated the aqueous layer extracted into DCM (3×50 mL) The combined organic phase was washed with brine dried over Na2SO4 concentrated to dryness under reduced pressure to give a brown solid The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane

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

Procedure: 4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+. to give a dark brown solution The acetone was removed under reduced pressure the residue partitioned between EtOAc and water Sodium metabisulphite and brine were added separation of the layers The mixture was extracted into EtOAc (4×150 mL) The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) brine, dried over Na2SO4 concentrated under reduced pressure A dark brown oil was obtained which crystallised The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane

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

Procedure: 4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+. to give a dark brown solution The acetone was removed under reduced pressure the residue partitioned between EtOAc and water Sodium metabisulphite and brine were added separation of the layers The mixture was extracted into EtOAc (4×150 mL) The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) brine, dried over Na2SO4 concentrated under reduced pressure A dark brown oil was obtained which crystallised The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane

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

Procedure: 3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+. The column was eluted further to give recovered The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9 the layers separated the aqueous layer extracted into DCM (3×50 mL) The combined organic phase was dried over Na2SO4 concentrated to dryness under reduced pressure purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane

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

Procedure: 3,5-Dibromo-4-methoxy-aniline (13.04 g, 46.42 mmol) was dissolved in DCM (500 mL) and a solution of bromine (2.38 mL, 46.42 mmol) in DCM (80 mL) was added dropwise. A thick, beige precipitate formed. After 45 minutes, the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to dryness under reduced pressure to give a brown solid. The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane. The relevant fractions were combined to give 2,3,5-tribromo-4-methoxy-aniline which was contaminated with some 2,3,5,6-tetrabromo-4-methoxy-aniline (12.64 g). The column was eluted further to give recovered starting material 3,5-dibromo-4-methoxy-aniline (2.84 g). The recovered starting material, 3,5-dibromo-4-methoxy-aniline (2.84 g, 10.11 mmol) was dissolved in DCM (100 mL) and a solution of bromine (0.52 mL, 10.11 mmol) in DCM (5 mL) was added dropwise. The mixture was stirred at rt for 2.5 h. The mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9, the layers separated and the aqueous layer extracted into DCM (3×50 mL). The combined organic phase was dried over Na2SO4 and concentrated to dryness under reduced pressure. This material was combined with the impure 2,3,5-tribromo-4-methoxy-aniline and purified by chromatography, Biotage SP4, 330 g Si cartridge, 10% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as an orange oil, 9.95 g (60%). m/z: 357.93/359.89/361.90/363.84 [M+H]+. A thick, beige precipitate formed the mixture was quenched with NaHCO3 solution (saturated, aq) to pH 9 the layers separated the aqueous layer extracted into DCM (3×50 mL) The combined organic phase was washed with brine dried over Na2SO4 concentrated to dryness under reduced pressure to give a brown solid The mixture was purified by chromatography, Biotage SP4, 2×120 g Si cartridges in series, 10-50% EtOAc in cyclohexane