2-(Methylamino)phenol

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

Procedure: To a mixture of 104A (2.33 g, 18.9 mmol) and dibromoethane (6.5 mL, 75.7 mmol) in a mixture of acetone (80 mL) and water (20 mL) at room temperature was added potassium carbonate (10.46 g, 75.7 mmol). The mixture was heated at reflux for 3 days. HPLC indicated that the reaction was complete, and the acetone was removed under reduced pressure. The aqueous residue was extracted with DCM, washed with water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by silica gel chromatography afforded 104B (2.22 g, 79%). HPLC retention time=2.07 min. (Condition B) and LC/MS M+1=150.08. 1H-NMR (500 MHz, CDCl3) δ 2.91 (s, 3H), 3.28 (t, 2H), 4.33 (t, 2H), 6.70 (t, 1H, J=7.5 Hz), 6.72 (d, 1H, J=7.5 Hz), 6.82 (d, 1H, J=7.5 Hz), and 6.89 (t, 1H, J=7.5 Hz). The mixture was heated at reflux for 3 days the acetone was removed under reduced pressure The aqueous residue was extracted with DCM washed with water dried over anhydrous sodium sulfate Concentration under reduced pressure followed by purification by silica gel chromatography

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

Procedure: To a stirred suspension of sodium borohydride (4.77 g, 126.0 mmol) and benzoxazole (5.00 g, 42.0 mmol) in THF (150 mL) was added ˜1 mL of acetic acid. The reaction mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The excess sodium borohydride was decomposed with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was collected, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 104A in near quantitative yield. HPLC retention time=0.34 min. (Condition B). 1H-NMR (500 MHz, d6-DMSO) δ 2.69 (s, 3H), 4.70 (brs, 1H), 6.40-6.42 (m, 2H), 6.63-6.66 (m, 2H), and 9.12 (brs, 1H). concentrated to dryness under reduced pressure extracted with EtOAc The organic layer was collected washed with water washed with brine dried over anhydrous sodium sulfate Concentration under reduced pressure

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

Procedure: To a stirred suspension of sodium borohydride (4.77 g, 126.0 mmol) and benzoxazole (5.00 g, 42.0 mmol) in THF (150 mL) was added ˜1 mL of acetic acid. The reaction mixture was stirred overnight at room temperature and concentrated to dryness under reduced pressure. The excess sodium borohydride was decomposed with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was collected, washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 104A in near quantitative yield. HPLC retention time=0.34 min. (Condition B). 1H-NMR (500 MHz, d6-DMSO) δ 2.69 (s, 3H), 4.70 (brs, 1H), 6.40-6.42 (m, 2H), 6.63-6.66 (m, 2H), and 9.12 (brs, 1H). concentrated to dryness under reduced pressure extracted with EtOAc The organic layer was collected washed with water washed with brine dried over anhydrous sodium sulfate Concentration under reduced pressure

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

Procedure: A solution of 2-methylaminophenol (0.74 g, 6.0 mmol), Triton B (60 μL, 40% in water) and acrylonitrile (4.0 mL, 60 mmol) was refluxed for 16 hrs. The mixture was diluted with ethyl acetate. The organic layer was then washed with water and brine, and was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to give 3-(2-methylamino-phenoxy)-propionitrile (4.0 g) as a brown oil. [M+H]+ 177.1; tR=0.715 min (method 1). The organic layer was then washed with water and brine was dried over MgSO4 After filtration and concentration the residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane

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

Procedure: 3-Bromo-4-chloro-benzoyl chloride (Step 2A, 106.9 mmol) in acetonitrile (300 mL) was added dropwise over 30 minutes to a vigorously stirring solution of 2-methylamino-phenol (15.1 g, 122.9 mmol) and NaHCO3 (18.0 g, 213.7 mmol) in acetonitrile (200 mL) and water (200 mL). The mixture was stirred for additional 1 h and then concentrated to remove acetonitrile. The solid was filtered, washed with HCl (1N, 600 mL) and water (500 mL), and dried. The solid was dissolved in dichloromethane (500 mL) and n-butylamine (20 mL) was added. The mixture was stirred at rt for 16 hrs and concentrated. The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) and then crystallized from hexane/ethyl acetate (75/25) to give 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (20.5 g) as a white solid. MS [M+H]+: 339.7/341.8; tR=2.19 min. (method 1) concentrated to remove acetonitrile The solid was filtered washed with HCl (1N, 600 mL) and water (500 mL) dried The solid was dissolved in dichloromethane (500 mL) n-butylamine (20 mL) was added The mixture was stirred at rt for 16 hrs concentrated The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) crystallized from hexane/ethyl acetate (75/25)

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

Procedure: A solution of 2-methylaminophenol (0.74 g, 6.0 mmol), Triton B (60 μL, 40% in water) and acrylonitrile (4.0 mL, 60 mmol) was refluxed for 16 hrs. The mixture was diluted with ethyl acetate. The organic layer was then washed with water and brine, and was dried over MgSO4. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane to give 3-(2-methylamino-phenoxy)-propionitrile (4.0 g) as a brown oil. [M+H]+177.1; tR=0.715 min (method 1). The organic layer was then washed with water and brine was dried over MgSO4 After filtration and concentration the residue was purified via silica gel flash column chromatography eluting with 20% ethyl acetate in hexane

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

Procedure: 3-Bromo-4-chloro-benzoyl chloride (Step 2A, 106.9 mmol) in acetonitrile (300 mL) was added dropwise over 30 minutes to a vigorously stirring solution of 2-methylamino-phenol (15.1 g, 122.9 mmol) and NaHCO3 (18.0 g, 213.7 mmol) in acetonitrile (200 mL) and water (200 mL). The mixture was stirred for additional 1 h and then concentrated to remove acetonitrile. The solid was filtered, washed with HCl (1N, 600 mL) and water (500 mL), and dried. The solid was dissolved in dichloromethane (500 mL) and n-butylamine (20 mL) was added. The mixture was stirred at rt for 16 hrs and concentrated. The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) and then crystallized from hexane/ethyl acetate (75/25) to give 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (20.5 g) as a white solid. MS [M+H]+: 339.7/341.8; tR=2.19 min. (method 1) concentrated to remove acetonitrile The solid was filtered washed with HCl (1N, 600 mL) and water (500 mL) dried The solid was dissolved in dichloromethane (500 mL) n-butylamine (20 mL) was added The mixture was stirred at rt for 16 hrs concentrated The residue was partially purified via silica gel flash chromatography (eluting with 20% to 35% ethyl acetate in hexane) crystallized from hexane/ethyl acetate (75/25)

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

Procedure: 0.97 g of 2-(N-methylamino)-phenol were dissolved in 50 ml acetone, followed by the addition of 2 g of K2CO3 dissolved in water. To this suspension was added slowly a solution of 2.66 g of dibromoethane in acetone. The reaction mixture was stirred for 22 hours under reflux. Acetone was evaporated and 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 3× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1 g of pure 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine. under reflux Acetone was evaporated 200 ml of EtOAc were added the organic layer was washed 3× with 0.1N HCl and 3× with brine The remaining organic layer was dried over MgSO4 filtrated EtOAc was removed under reduced pressure

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

Procedure: 0.97 g of 2-(N-methylamino)-phenol were dissolved in 50 ml acetone, followed by the addition of 2 g of K2CO3 dissolved in water. To this suspension was added slowly a solution of 2.66 g of dibromoethane in acetone. The reaction mixture was stirred for 22 hours under reflux. Acetone was evaporated and 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 3× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1 g of pure 4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine. under reflux Acetone was evaporated 200 ml of EtOAc were added the organic layer was washed 3× with 0.1N HCl and 3× with brine The remaining organic layer was dried over MgSO4 filtrated EtOAc was removed under reduced pressure

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

Procedure: 1 g of 2-(N-methylamino)-phenol were dissolved in chloroform, followed by the addition of 10 ml of sat. NaHCO3 in water. To this suspension was added slowly under vigorous stirring a solution of 1 g of 2-chloroacetylchloride in acetone. The reaction mixture was stirred for 2 hours at room temperature. The layers were separated. The organic layer was washed with water and dried over Na2SO4. After evaporating the solvent, the red oil was taken up in 30 ml DMF and 1 g of K2CO3 were added and the slurry was heated at 70° C. for additional 2 hours. The cyclization was followed by TLC. 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 5× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1.45 g of pure 4-methyl-4H-benzo[1,4]oxazin-3-one. To this suspension was added slowly The layers were separated The organic layer was washed with water dried over Na2SO4 After evaporating the solvent 1 g of K2CO3 were added the slurry was heated at 70° C. for additional 2 hours 200 ml of EtOAc were added the organic layer was washed 3× with 0.1N HCl and 5× with brine The remaining organic layer was dried over MgSO4 filtrated EtOAc was removed under reduced pressure

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

Procedure: 1 g of 2-(N-methylamino)-phenol were dissolved in chloroform, followed by the addition of 10 ml of sat. NaHCO3 in water. To this suspension was added slowly under vigorous stirring a solution of 1 g of 2-chloroacetylchloride in acetone. The reaction mixture was stirred for 2 hours at room temperature. The layers were separated. The organic layer was washed with water and dried over Na2SO4. After evaporating the solvent, the red oil was taken up in 30 ml DMF and 1 g of K2CO3 were added and the slurry was heated at 70° C. for additional 2 hours. The cyclization was followed by TLC. 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 5× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1.45 g of pure 4-methyl-4H-benzo[1,4]oxazin-3-one. To this suspension was added slowly The layers were separated The organic layer was washed with water dried over Na2SO4 After evaporating the solvent 1 g of K2CO3 were added the slurry was heated at 70° C. for additional 2 hours 200 ml of EtOAc were added the organic layer was washed 3× with 0.1N HCl and 5× with brine The remaining organic layer was dried over MgSO4 filtrated EtOAc was removed under reduced pressure

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

Procedure: 1 g of 2-(N-methylamino)-phenol were dissolved in chloroform, followed by the addition of 10 ml of sat. NaHCO3 in water. To this suspension was added slowly under vigorous stirring a solution of 1 g of 2-chloroacetylchloride in acetone. The reaction mixture was stirred for 2 hours at room temperature. The layers were separated. The organic layer was washed with water and dried over Na2SO4. After evaporating the solvent, the red oil was taken up in 30 ml DMF and 1 g of K2CO3 were added and the slurry was heated at 70° C. for additional 2 hours. The cyclization was followed by TLC. 200 ml of EtOAc were added and the organic layer was washed 3× with 0.1N HCl and 5× with brine. The remaining organic layer was dried over MgSO4 and filtrated. EtOAc was removed under reduced pressure affording 1.45 g of pure 4-methyl-4H-benzo[1,4]oxazin-3-one. To this suspension was added slowly The layers were separated The organic layer was washed with water dried over Na2SO4 After evaporating the solvent 1 g of K2CO3 were added the slurry was heated at 70° C. for additional 2 hours 200 ml of EtOAc were added the organic layer was washed 3× with 0.1N HCl and 5× with brine The remaining organic layer was dried over MgSO4 filtrated EtOAc was removed under reduced pressure