methyl 4-amino-2,6-dichlorobenzoate

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:0.00; pressure:0.00; stir:

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

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

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

Procedure: To a solution of 2,6-dichloro-4-aminobenzoic acid methyl ester (2.80 g) in CH2Cl2 (20 mL) at −10° C. was added a solution of tetrabutylammonium tribromide (6.94 g) in CH2Cl2 (30 mL) dropwise at −10° C. After 2 h, the mixture was warmed to room temperature, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1:4) to yield 2,6-dichloro-3-bromo-4-aminobenzoic acid methyl ester (2.99 g). ESMS: m/z 298 (MH+). washed with satd NaHCO3 and brine, dried (Na2SO4) filtered concentrated The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1:4)

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

Procedure: To a solution of 2,6-dichloro-4-aminobenzoic acid methyl ester (2.80 g) in CH2Cl2 (20 mL) at −10° C. was added a solution of tetrabutylammonium tribromide (6.94 g) in CH2Cl2 (30 mL) dropwise at −10° C. After 2 h, the mixture was warmed to room temperature, washed with satd. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1:4) to yield 2,6-dichloro-3-bromo-4-aminobenzoic acid methyl ester (2.99 g). ESMS: m/z 298 (MH+). washed with satd NaHCO3 and brine, dried (Na2SO4) filtered concentrated The residue was purified by column chromatography (silica gel; eluent: EtOAc/hexane 1:4)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 15% HCl (10 mL) and stirred for 30 min then cooled to 0-5° C. After addition of NaNO2 (188 mg) in small portions, the mixture was stirred for 30 min at that temperature. Precooled HBF4 (0.46 mL) was added and the mixture was stirred for 30 min. The resulting precipitate was collected and washed successively with cold water, MeOH and ether. The solid was then dried over conc. H2SO4 in a vacuum dessicator for a few days. The solid was heated with a bunsen burner until all the solid has melted. The resulting fumes were collected over water (distilling apparatus). The product was then recovered with Et2O. The solvent was evaporated and the crude product was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 50:1 to 20:1) to give 2,6-dichloro-4-fluorobenzoic acid methyl ester (241 mg). the mixture was stirred for 30 min at that temperature the mixture was stirred for 30 min The resulting precipitate was collected washed successively with cold water, MeOH and ether The solid was then dried over conc. H2SO4 in a vacuum dessicator for a few days The solid was heated with a bunsen burner until all the solid The resulting fumes were collected over water (distilling apparatus) The product was then recovered with Et2O The solvent was evaporated the crude product was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 50:1 to 20:1)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 20% HCl (25 mL) and stirred for 30 min then cooled to 0-5° C. After slow addition of NaNO2 (188 mg), the mixture was stirred for 30 min at that temperature and added to boiling water (50 mL) . The mixture was then refluxed for 2 h, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2) to give 2,6-dichloro-4-hydroxybenzoic acid methyl ester (275 mg). the mixture was stirred for 30 min at that temperature added The mixture was then refluxed for 2 h to cool to room temperature extracted with AcOEt dried (MgSO4) filtered evaporated The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Amino-2,6-dichlorobenzoic acid methyl ester (0.5 g) was suspended in 20% HCl (25 mL) and stirred for 30 min then cooled to 0-5° C. After slow addition of NaNO2 (188 mg), the mixture was stirred for 30 min at that temperature and added to boiling water (50 mL) . The mixture was then refluxed for 2 h, allowed to cool to room temperature and extracted with AcOEt, dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2) to give 2,6-dichloro-4-hydroxybenzoic acid methyl ester (275 mg). the mixture was stirred for 30 min at that temperature added The mixture was then refluxed for 2 h to cool to room temperature extracted with AcOEt dried (MgSO4) filtered evaporated The residue was purified by preparative TLC (silica gel; eluent: CH2Cl2)

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Amino-2,6-dichlorobenzoic acid methyl ester (1.00 g) was suspended in 40% aq. HBr and the mixture was cooled 1 to 0-5° C. After NaNO2 (376 mg) was added in small portions, the mixture was stirred for about 5 min. Copper (100 mg) was added and the mixture was warmed up to 100° C. The mixture was then stirred at 100° C. for 30 min, diluted with water and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane and AcOEt 50:1) to give 4-bromo-2,6-dichlorobenzoic acid methyl ester (1.07 g). the mixture was warmed up to 100° C The mixture was then stirred at 100° C. for 30 min extracted with AcOEt The extract was dried (MgSO4) filtered evaporated The residue was purified by column chromatography (silica gel; eluent: hexane and AcOEt 50:1)