N-[(2-methylphenyl)methylidene]hydroxylamine

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

Procedure: A mixture of 2-methylbenzaldehyde (10.8 g, 90 mmol), hydroxylammonium chloride (9.4 g, 135 mmol), sodium hydroxide (18.0,0.45 mol), ethanol (80 ml) and water (20 ml) was heated at reflux for 1 h. A solution of citric acid (20 g) in water (700 ml) was added and the mixture was left for crystallisation. The precipitate was collected and recrystallised from water to give 8.6 g of 2-methylbenzaldehyde oxime. M.p. 49.0-49.4° C. was heated at reflux for 1 h the mixture was left for crystallisation The precipitate was collected recrystallised from water

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

Procedure: N-Chlorosuccinimide (2.22 g, 16.6 mmol, 1.0 equiv) was added to a stirred solution of 2-methyl-benzaldehyde oxime (2.25 g, 16.6 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) at ambient temperature. Stirring was continued for 2 hours and the reaction quenched (ice-water). The resultant mixture was extracted with ethyl acetate. The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×). The organic was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 2.07 g (74%) of N-hydroxy-2-methylbenzenecarboximidoyl chloride as a green oil. 1H NMR (300 MHz, CDCl3) δ: 8.14 (s, 1H), 7.48-7.44 (m, 1H), 7.37-7.20 (m, 3H), 2.43 (s, 3H). the reaction quenched (ice-water) The resultant mixture was extracted with ethyl acetate The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×) The organic was then dried over anhydrous sodium sulfate filtered concentrated under vacuum

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

Procedure: N-Chlorosuccinimide (2.22 g, 16.6 mmol, 1.0 equiv) was added to a stirred solution of 2-methyl-benzaldehyde oxime (2.25 g, 16.6 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) at ambient temperature. Stirring was continued for 2 hours and the reaction quenched (ice-water). The resultant mixture was extracted with ethyl acetate. The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×). The organic was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 2.07 g (74%) of N-hydroxy-2-methylbenzenecarboximidoyl chloride as a green oil. 1H NMR (300 MHz, CDCl3) δ: 8.14 (s, 1H), 7.48-7.44 (m, 1H), 7.37-7.20 (m, 3H), 2.43 (s, 3H). the reaction quenched (ice-water) The resultant mixture was extracted with ethyl acetate The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×) The organic was then dried over anhydrous sodium sulfate filtered concentrated under vacuum

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

Procedure: 60 g of 2-methylbenzaldehyde oxime was dissolved in 1 L of dichloroethane, and then, 65 g of N-chlorosuccinimide and 100 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by thin layer chromatography (TLC). When 2-methylbenzaldehyde oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature of 0° C., and then 56 g of NaHCO3 and 41 mL of 2-methyl-2-propene-1-ol were sequentially added thereto. The reaction mixture was stirred at room temperature overnight, and then washed with water, and then, an separated organic layer was dried and concentrated by using magnesium sulfate, and then, purified by column chromatography to obtain 70 g of (5-methyl-3-o-tolyl-4,5-dihydroisoxazole-5-yl)methanol. The obtained compound was dissolved in 1 L of toluene, and then, 1 L of water, 90 g of NaOH, and 4.5 g of tetrabutylammonium hydrogensulfate were added thereto. After the reaction mixture was stirred for 30 minutes at room temperature, 77 g of 2,6-difluorobenzyl chloride was slowly dropped thereto. The reaction mixture was stirred at a temperature of 60° C. for 5 hours and cooled, and then, a separated organic layer was washed with water and then dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 88 g of 5-((2,6-difluorobenzyloxy)methyl)-5-methyl-3-o-tolyl-4,5-dihydroisoxazole. at a temperature of 0° C the reaction mixture was cooled to a temperature of 0° C. The reaction mixture was stirred at room temperature overnight washed with water an separated organic layer was dried concentrated purified by column chromatography

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

Procedure: 60 g of 2-methylbenzaldehyde oxime was dissolved in 1 L of dichloroethane, and then, 65 g of N-chlorosuccinimide and 100 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by thin layer chromatography (TLC). When 2-methylbenzaldehyde oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature of 0° C., and then 56 g of NaHCO3 and 41 mL of 2-methyl-2-propene-1-ol were sequentially added thereto. The reaction mixture was stirred at room temperature overnight, and then washed with water, and then, an separated organic layer was dried and concentrated by using magnesium sulfate, and then, purified by column chromatography to obtain 70 g of (5-methyl-3-o-tolyl-4,5-dihydroisoxazole-5-yl)methanol. The obtained compound was dissolved in 1 L of toluene, and then, 1 L of water, 90 g of NaOH, and 4.5 g of tetrabutylammonium hydrogensulfate were added thereto. After the reaction mixture was stirred for 30 minutes at room temperature, 77 g of 2,6-difluorobenzyl chloride was slowly dropped thereto. The reaction mixture was stirred at a temperature of 60° C. for 5 hours and cooled, and then, a separated organic layer was washed with water and then dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 88 g of 5-((2,6-difluorobenzyloxy)methyl)-5-methyl-3-o-tolyl-4,5-dihydroisoxazole. at a temperature of 0° C the reaction mixture was cooled to a temperature of 0° C. The reaction mixture was stirred at room temperature overnight washed with water an separated organic layer was dried concentrated purified by column chromatography

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

Procedure: A mixture of 2-methylbenzaldehyde (10.8 g, 90 mmol), hydroxylammonium chloride (9.4 g, 135 mmol), sodium hydroxide (18.0,0.45 mol), ethanol (80 ml) and water (20 ml) was heated at reflux for 1 h. A solution of citric acid (20 g) in water (700 ml) was added and the mixture was left for crystallisation. The precipitate was collected and recrystallised from water to give 8.6 g of 2-methylbenzaldehyde oxime. M.p. 49.0-49.4° C. was heated at reflux for 1 h the mixture was left for crystallisation The precipitate was collected recrystallised from water

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

Procedure: N-Chlorosuccinimide (2.22 g, 16.6 mmol, 1.0 equiv) was added to a stirred solution of 2-methyl-benzaldehyde oxime (2.25 g, 16.6 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) at ambient temperature. Stirring was continued for 2 hours and the reaction quenched (ice-water). The resultant mixture was extracted with ethyl acetate. The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×). The organic was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 2.07 g (74%) of N-hydroxy-2-methylbenzenecarboximidoyl chloride as a green oil. 1H NMR (300 MHz, CDCl3) δ: 8.14 (s, 1H), 7.48-7.44 (m, 1H), 7.37-7.20 (m, 3H), 2.43 (s, 3H). the reaction quenched (ice-water) The resultant mixture was extracted with ethyl acetate The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×) The organic was then dried over anhydrous sodium sulfate filtered concentrated under vacuum

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

Procedure: 60 g of 2-methylbenzaldehyde oxime was dissolved in 1 L of dichloroethane, and then, 65 g of N-chlorosuccinimide and 100 mL of dimethylformamide were slowly added thereto at a temperature of 0° C. The reaction mixture was stirred at room temperature for 1 hour, and then, the reaction state was confirmed by thin layer chromatography (TLC). When 2-methylbenzaldehyde oxime, which was a starting material, disappeared, the reaction mixture was cooled to a temperature of 0° C., and then 56 g of NaHCO3 and 41 mL of 2-methyl-2-propene-1-ol were sequentially added thereto. The reaction mixture was stirred at room temperature overnight, and then washed with water, and then, an separated organic layer was dried and concentrated by using magnesium sulfate, and then, purified by column chromatography to obtain 70 g of (5-methyl-3-o-tolyl-4,5-dihydroisoxazole-5-yl)methanol. The obtained compound was dissolved in 1 L of toluene, and then, 1 L of water, 90 g of NaOH, and 4.5 g of tetrabutylammonium hydrogensulfate were added thereto. After the reaction mixture was stirred for 30 minutes at room temperature, 77 g of 2,6-difluorobenzyl chloride was slowly dropped thereto. The reaction mixture was stirred at a temperature of 60° C. for 5 hours and cooled, and then, a separated organic layer was washed with water and then dried by using magnesium sulfate and concentrated, and the concentrate was separated by silicagel column chromatography to obtain 88 g of 5-((2,6-difluorobenzyloxy)methyl)-5-methyl-3-o-tolyl-4,5-dihydroisoxazole. at a temperature of 0° C the reaction mixture was cooled to a temperature of 0° C. The reaction mixture was stirred at room temperature overnight washed with water an separated organic layer was dried concentrated purified by column chromatography