2,2-dimethyl-3H-1,3-benzoxazin-4-one

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: A solution of 2,2-dimethyl-4-keto-1,3-benzoxazine (1.77 g, 10.0 mmol) and PCl5 (2.09 g, 10.0 mmol) in POCl3 (3.0 mL) was stirred at RT for 1 h then at 50-60° C. for 2 h. The reaction was concentrated and the product distilled (90-95° C./2-3 mm Hg) to afford 4-chloro-2,2-dimethyl-3H-1,3-benzoxazine. (0.496 g, 25%) as a clear oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.58 (d, 1H), 7.48 (m, 1H), 6.97 (m, 1H), 6.94 (d, 1H), 1.63 (s, 6H). The reaction was concentrated the product distilled (90-95° C./2-3 mm Hg)

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

Procedure: A solution of salicylamide (4.14 g, 30.2 mmol) and conc. sulfuric acid (3 drops) in acetone (40 mL) was refluxed for 5 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O, then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2,2-dimethyl-4-keto-1,3-benzoxazine (2.50 g, 47%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.92 (d, 1H), 7.60 (bs, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.92 (d, 1H), 1.65 (s, 6H). The reaction was concentrated The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O sat. aq. NaCl, dried (MgSO4) concentrated

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

Procedure: To a stirred solution of 2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazine (0.3 g, 1.69 mmol) in DMF (3 mL) was added potassium carbonate (0.47 g, 3.39 mmol) and stirred for 30 min. To this reaction mixture was added a solution of ethyl 2-ethoxy-3-[4-(2-bromoethoxy) phenyl]propanoate (0.70 g, 2.03 mmol) (disclosed in U.S. patent application Ser. No. 09/012,585) in DMF (1 mL) and stirred for 24 h at 60-70° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% of ethyl acetate in pet ether as eluent to afford the title compound (0.34 g, 45%) as a liquid. extracted with ethyl acetate (3×10 mL) The combined organic extracts were washed with brine dried over anhydrous Na2SO4 concentrated The residue was chromatographed on silica gel using a gradient of 5-15% of ethyl acetate in pet ether as eluent

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

Procedure: A 250-ml flask equipped with condenser, stirrer and thermometer and immersed in an ice bath was charged with 150 ml of dichloromethane, 8.3 g (0.047 mol) of 2,2-dimethyl-1,3-benzoxazin-4-one and 10.9 g (0.047 mol) of 1,1,2,2-tetrachloroethylsulfenyl chloride. Then 4.75 g (0.047 mol) of triethylamine dissolved in 10 ml of dichloromethane was added dropwise over a period of 15 minutes. The resulting solution was stirred at 0° C. for 45 more minutes. The crude reaction mixture was washed three times with equal quantities of water. The organic phase was dried and then stripped of solvent. The resulting residue was washed with 200 ml of hexane and filtered. The dried filter cake, 5.1 g, was unreacted 2,2-dimethyl-1,3-benzoxazin-4-one. The filtrate was stripped of hexane and the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane to give 2.8 g of 2,2-dimethyl-3-(1',1',2',2'-tetrachloroethylthio)-1,3-benzoxazin-4-one. Analysis, calculated for C12H11Cl4NO2S: %C, 37.81; %S, 8.55. Found: %Cl, 40.0; %S, 8.8. NMR spectra confirmed the assigned structure. The infrared spectra had strong adsorption at 1785, 1600, 1460, 1300, 1240 and 740 cm-1. These spectra also had many distinct, medium-strength adsorption bands in the 800-1700 cm-1 region. A 250-ml flask equipped with condenser, stirrer thermometer and immersed in an ice bath was added dropwise over a period of 15 minutes The crude reaction mixture was washed three times with equal quantities of water The organic phase was dried The resulting residue was washed with 200 ml of hexane filtered The dried filter cake, 5.1 g the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane

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

Procedure: A 250-ml flask equipped with condenser, stirrer and thermometer and immersed in an ice bath was charged with 150 ml of dichloromethane, 8.3 g (0.047 mol) of 2,2-dimethyl-1,3-benzoxazin-4-one and 10.9 g (0.047 mol) of 1,1,2,2-tetrachloroethylsulfenyl chloride. Then 4.75 g (0.047 mol) of triethylamine dissolved in 10 ml of dichloromethane was added dropwise over a period of 15 minutes. The resulting solution was stirred at 0° C. for 45 more minutes. The crude reaction mixture was washed three times with equal quantities of water. The organic phase was dried and then stripped of solvent. The resulting residue was washed with 200 ml of hexane and filtered. The dried filter cake, 5.1 g, was unreacted 2,2-dimethyl-1,3-benzoxazin-4-one. The filtrate was stripped of hexane and the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane to give 2.8 g of 2,2-dimethyl-3-(1',1',2',2'-tetrachloroethylthio)-1,3-benzoxazin-4-one. Analysis, calculated for C12H11Cl4NO2S: %C, 37.81; %S, 8.55. Found: %Cl, 40.0; %S, 8.8. NMR spectra confirmed the assigned structure. The infrared spectra had strong adsorption at 1785, 1600, 1460, 1300, 1240 and 740 cm-1. These spectra also had many distinct, medium-strength adsorption bands in the 800-1700 cm-1 region. A 250-ml flask equipped with condenser, stirrer thermometer and immersed in an ice bath was added dropwise over a period of 15 minutes The crude reaction mixture was washed three times with equal quantities of water The organic phase was dried The resulting residue was washed with 200 ml of hexane filtered The dried filter cake, 5.1 g the resulting residue was chromatographed through 300 g of silica gel using 1 liter of hexane, 1 liter of 3% ether-hexane and 3 liters of 5% ether-hexane

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

Procedure: A 500-ml flask was charged with 250 ml of chloroform, 27.4 g (0.2 mol) of salicylamide, 23.2 g (0.4 mol) of acetone and 2.7 g of toluene sulfonic acid monohydrate. The flask was equipped with a Soxhlet extraction vessel containing 36.7 g of molecular sieves (Linde Type 3A, 1/16 inch) in the thimble. The reaction mixture was refluxed for 24 hours. Then fresh sieves were placed in the Soxhlet and 10 g of acetone was added to the reaction mixture. Reflux was continued for 24 hours. The flask was equipped with a Soxhlet extraction vessel The reaction mixture was refluxed for 24 hours was added to the reaction mixture Reflux

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

Procedure: A 500-ml flask was charged with 250 ml of chloroform, 27.4 g (0.2 mol) of salicylamide, 23.2 g (0.4 mol) of acetone and 2.7 g of toluene sulfonic acid monohydrate. The flask was equipped with a Soxhlet extraction vessel containing 36.7 g of molecular sieves (Linde Type 3A, 1/16 inch) in the thimble. The reaction mixture was refluxed for 24 hours. Then fresh sieves were placed in the Soxhlet and 10 g of acetone was added to the reaction mixture. Reflux was continued for 24 hours. The flask was equipped with a Soxhlet extraction vessel The reaction mixture was refluxed for 24 hours was added to the reaction mixture Reflux

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

Procedure: To a solution of salicylamide (20.0 g, 0.146 mol; Aldrich Chemical Company, Inc., Milwaukee, Wis.) in 2,2-dimethoxypropane (300 mL) was added pyridinium p-toluenesulfonate (11.0 g, 0.044 mol) and then heated to reflux for 2 h. TLC (dichloromethane: methanol=20:1) indicated the reaction was complete. The solvent was removed and then the residue was taken up in ethyl acetate (150 mL). The solution was washed twice with sodium bicarbonate and once with brine. The organic layer was dried and concentrated under reduced pressure to afford (I-30a) (26.0 g, yield: 93.4%) as a yellow solid, which was used to next step without any purification. heated to reflux for 2 h The solvent was removed The solution was washed twice with sodium bicarbonate and once with brine The organic layer was dried concentrated under reduced pressure to afford (I-30a) (26.0 g, yield: 93.4%) as a yellow solid, which was used to next step without any purification

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

Procedure: A solution of 2,2-dimethyl-4-keto-1,3-benzoxazine (1.77 g, 10.0 mmol) and PCl5 (2.09 g, 10.0 mmol) in POCl3 (3.0 mL) was stirred at RT for 1 h then at 50-60° C. for 2 h. The reaction was concentrated and the product distilled (90-95° C./2-3 mm Hg) to afford 4-chloro-2,2-dimethyl-3H-1,3-benzoxazine. (0.496 g, 25%) as a clear oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.58 (d, 1H), 7.48 (m, 1H), 6.97 (m, 1H), 6.94 (d, 1H), 1.63 (s, 6H). The reaction was concentrated the product distilled (90-95° C./2-3 mm Hg)

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

Procedure: A solution of salicylamide (4.14 g, 30.2 mmol) and conc. sulfuric acid (3 drops) in acetone (40 mL) was refluxed for 5 h. The reaction was concentrated and the residue taken up in ethyl acetate. The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O , then sat. aq. NaCl, dried (MgSO4) and concentrated to afford 2,2-dimethyl-4-keto-1,3-benzoxazine (2.50 g, 47%) as a white solid: 1H NMR (CDCl3, 300 MHz, ppm) 7.92 (d, 1H), 7.60 (bs, 1H), 7.47 (m, 1H), 7.06 (m, 1H), 6.92 (d, 1H), 1.65 (s, 6H). The reaction was concentrated The organic solution was washed with 1 N NaOH (2×), 1 N HCl (2×), H2O sat. aq. NaCl, dried (MgSO4) concentrated