2-amino-5-methoxyphenol

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

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

Procedure: Hill and Ramage reported at J. Chem. Soc., 3709 (1964) a convenient synthesis of 7-methoxy-1,4-benzoxazine from 2-amino-5-methoxyphenol 9a. Compound 9a reacted with chloroacetyl chloride in acetone to give 2-chloroacetamido-5-methoxy phenol 10a. An intramolecular cyclization of 10a with aqueous sodium hydroxide produced 7-methoxy-3-oxo-1,4-benzoxazine 11a, which upon reduction with lithium aluminum hydride in THF resulted in the formation of 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine 12a. ##STR4##

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

Procedure: Hill and Ramage reported at J. Chem. Soc., 3709 (1964) a convenient synthesis of 7-methoxy-1,4-benzoxazine from 2-amino-5-methoxyphenol 9a. Compound 9a reacted with chloroacetyl chloride in acetone to give 2-chloroacetamido-5-methoxy phenol 10a. An intramolecular cyclization of 10a with aqueous sodium hydroxide produced 7-methoxy-3-oxo-1,4-benzoxazine 11a, which upon reduction with lithium aluminum hydride in THF resulted in the formation of 7-methoxy-3,4-dihydro-2H-1,4-benzoxazine 12a. ##STR4##

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

Procedure: 2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene (20 ml). This toluene solution was added dropwise to a solution of 2-amino-5-methoxyphenol (2.0 g) in pyridine (50 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diluted hydrochloric acid and diisopropyl ether to give N-(2-hydroxy-4-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g). the solvent was evaporated under reduced pressure The precipitated crystals were collected by filtration washed with diluted hydrochloric acid and diisopropyl ether

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

Procedure: 2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene (20 ml). This toluene solution was added dropwise to a solution of 2-amino-5-methoxyphenol (2.0 g) in pyridine (50 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diluted hydrochloric acid and diisopropyl ether to give N-(2-hydroxy-4-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g). the solvent was evaporated under reduced pressure The precipitated crystals were collected by filtration washed with diluted hydrochloric acid and diisopropyl ether

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

Procedure: 2-Hydroxy-4-methoxyaniline (1.00 g, 7.19 mmol) and potassium O-ethyl xanthate (1.27 g, 7.91 mmol) were heated to reflux in pyridine (20 mL). After 2 h, the reaction mixture was allowed to cool to rt and was poured into a solution of conc. HCl (10 mL) in ice water (80 mL). The resulting white solid was collected by filtration, washed with water (3×), and dried in a vacuum oven. This gave 0.733 g (56%) of the desired product. LC-MS: RT=6.67 min., [M+H]+=182.1. The resulting white solid was collected by filtration washed with water (3×) dried in a vacuum oven

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

Procedure: 2-Hydroxy-4-methoxyaniline (1.00 g, 7.19 mmol) and potassium O-ethyl xanthate (1.27 g, 7.91 mmol) were heated to reflux in pyridine (20 mL). After 2 h, the reaction mixture was allowed to cool to rt and was poured into a solution of conc. HCl (10 mL) in ice water (80 mL). The resulting white solid was collected by filtration, washed with water (3×), and dried in a vacuum oven. This gave 0.733 g (56%) of the desired product. LC-MS: RT=6.67 min., [M+H]+=182.1. The resulting white solid was collected by filtration washed with water (3×) dried in a vacuum oven

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 7-methoxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (prepared from 2-amino-5-methoxyphenol using the similar procedure detailed in Example #56, Step A-D and Example #106, Step A, 1 g, 3.42 mmol) and lithium chloride (0.44 g, 10.27 mmol) in DMF (10 mL) was heated at 150° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give 7-hydroxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.65 g, 68%) as a red solid. TLC (eluting with 50% EtOAc in petroleum ether) Rf=0.5. The reaction mixture was cooled to ambient temperature the solvent was removed in vacuo The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 7-methoxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (prepared from 2-amino-5-methoxyphenol using the similar procedure detailed in Example #56, Step A-D and Example #106, Step A, 1 g, 3.42 mmol) and lithium chloride (0.44 g, 10.27 mmol) in DMF (10 mL) was heated at 150° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether) to give 7-hydroxy-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.65 g, 68%) as a red solid. TLC (eluting with 50% EtOAc in petroleum ether) Rf=0.5. The reaction mixture was cooled to ambient temperature the solvent was removed in vacuo The residue was purified by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Next, a mixture of potassium ethyl xanthate (4.6 g, 28.8 mmol) and crude 2-amino-5-methoxyphenol (4.0 g, 28.8 mmol) was dissolved in ethanol (150 mL). The mixture was heated at 80° C. overnight. After cooling, the solvent was evaporated under reduced pressure. The resultant residue was dissolved in water and treated with 1N HCl to pH 5, resulting in a precipitate, which was collected. The solid thus collected was purified by chromatography with petroleum ether/ethyl acetate (3:1 v/v) to afford 2-mercapto-6-methoxybenzoxazole (4.0 g, yield 77%). After cooling the solvent was evaporated under reduced pressure The resultant residue was dissolved in water treated with 1N HCl to pH 5 resulting in a precipitate, which was collected The solid thus collected was purified by chromatography with petroleum ether/ethyl acetate (3:1 v/v)

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

Procedure: Next, a mixture of 2-amino-5-methoxyphenol (3c) (6.03 g, 43.33 mmol) and potassium ethyl xanthate (6.95 g, 73.33 mmol) in ethanol (80 mL) was heated at reflux for 18 h. The reaction was subsequently cooled and the solvent was removed in vacuo. The residue was taken up in ethyl acetate (150 mL), washed successively with 4N HCl, water, and brine. The organic solution was subsequently dried over Na2SO4. After filtration to remove the drying aid, the solvent was evaporated to give 6.23 g (79%) of 6-methoxybenzoxazole-2-thiol. was heated at reflux for 18 h The reaction was subsequently cooled the solvent was removed in vacuo washed successively with 4N HCl, water, and brine The organic solution was subsequently dried over Na2SO4 After filtration to remove the drying aid the solvent was evaporated

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

Procedure: Subsequently, a mixture of 5-methoxy-2-nitrophenol (7.47 g) and 10% Pd/C (1.87 g) was prepared in an ethyl acetate/ethanol (100 mL, 1:1 v/v) mixture. The resulting slurry was stirred under an H2 atmosphere for 3.5 h at room temperature. Hydrogen was subsequently purged from the reaction flask and the reaction mixture was filtered through Celite. After washing the celite pad with additional solvent, volatiles in the resultant filtrate were removed in vacuo to give 2-amino-5-methoxyphenol (6.03 g, 98%). Hydrogen was subsequently purged from the reaction flask the reaction mixture was filtered through Celite After washing the celite pad with additional solvent, volatiles in the resultant filtrate were removed in vacuo