N-hydroxy-2-methylbenzenecarboximidoyl chloride

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

Procedure: To a stirred solution of N-hydroxy-2-methylbenzenecarboximidoyl chloride (2.07 g, 12.2 mmol, 1.0 equiv) in diethyl ether (15 mL) was added a solution of 3-pyrrolidin-1-yl-acrylic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 4,187,099) (2.06 g, 12.2 mmol, 1.0 equiv) and triethylamine (1.48 g, 12.2 mmol, 1.0 equiv) in diethyl ether (30 mL) dropwise over 15 minutes. The resultant mixture was stirred at ambient temperature for 16 hours, partitioned between water and diethyl ether and separated. The aqueous phase was extracted with diethyl ether (2×), and the combined ethereal extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane) gave 1.32 g (47%) of 3-o-tolyl-isoxazole-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 9.02 (s, 1H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 3H), 4.19 (q, 2H), 2.23 (s, 3H), 1.17 (t, 3H). prepared partitioned between water and diethyl ether separated The aqueous phase was extracted with diethyl ether (2×) the combined ethereal extracts were dried over anhydrous sodium sulfate filtered concentrated under vacuum Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane)

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: To a stirred solution of N-hydroxy-2-methylbenzenecarboximidoyl chloride (2.07 g, 12.2 mmol, 1.0 equiv) in diethyl ether (15 mL) was added a solution of 3-pyrrolidin-1-yl-acrylic acid ethyl ester (prepared according to the procedure described in U.S. Pat. No. 4,187,099) (2.06 g, 12.2 mmol, 1.0 equiv) and triethylamine (1.48 g, 12.2 mmol, 1.0 equiv) in diethyl ether (30 mL) dropwise over 15 minutes. The resultant mixture was stirred at ambient temperature for 16 hours, partitioned between water and diethyl ether and separated. The aqueous phase was extracted with diethyl ether (2×), and the combined ethereal extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane) gave 1.32 g (47%) of 3-o-tolyl-isoxazole-4-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 9.02 (s, 1H), 7.39-7.34 (m, 1H), 7.32-7.24 (m, 3H), 4.19 (q, 2H), 2.23 (s, 3H), 1.17 (t, 3H). prepared partitioned between water and diethyl ether separated The aqueous phase was extracted with diethyl ether (2×) the combined ethereal extracts were dried over anhydrous sodium sulfate filtered concentrated under vacuum Purification by flash column chromatography on silica gel (gradient: 0 to 20% ethyl acetate in cyclohexane)

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