2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride

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

Procedure: 2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.72 g, 95.6 mmol) and 2,2-dichloro-N-(3-ethynylphenyl) acetamide (2.5 g, 110 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.8 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 5 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(3-ethynylphenyl) acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined and then crystallized from hexanes-ethyl acetate to give 2,2-dichloro-N-[3-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl] acetamide as a white crystalline solid, 1.80 g (m.p. 167° C.). NMR (300 MHz, CDCl3): 8.21 (broad s, 1H, NH), 8.08 (m, 1H), 7.71 (m, 2H), 7.52 (t, 1H), 7.42–7.46 (m, 2H), 7.32–7.38 (m, 1H), 6.69 (s, 1H), 6.07 ppm (s, 1H). MW=416 confirmed by LC-MS, tr=36.9 min (Method W) MH+=415–419. then heated at reflux for 5 h The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate washed successively with water and brine The ethyl acetate solution was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting solid was purified by column chromatography on silica gel eluting with 8:2 hexanes-ethyl acetate crystallized from hexanes-ethyl acetate

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

Procedure: 2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.72 g, 95.6 mmol) and 2,2-dichloro-N-(3-ethynylphenyl) acetamide (2.5 g, 110 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.8 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 5 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(3-ethynylphenyl) acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined and then crystallized from hexanes-ethyl acetate to give 2,2-dichloro-N-[3-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl] acetamide as a white crystalline solid, 1.80 g (m.p. 167° C.). NMR (300 MHz, CDCl3): 8.21 (broad s, 1H, NH), 8.08 (m, 1H), 7.71 (m, 2H), 7.52 (t, 1H), 7.42–7.46 (m, 2H), 7.32–7.38 (m, 1H), 6.69 (s, 1H), 6.07 ppm (s, 1H). MW=416 confirmed by LC-MS, tr=36.9 min (Method W) MH+=415–419. then heated at reflux for 5 h The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate washed successively with water and brine The ethyl acetate solution was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting solid was purified by column chromatography on silica gel eluting with 8:2 hexanes-ethyl acetate crystallized from hexanes-ethyl acetate

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

Procedure: A solution of 2,6-dichlorobenzaldehyde oxime (19.8 g, 0.104 mol) in N,N-dimethyl formamide (80 mL) was placed in an ambient temperature water bath and was treated with N-chlorosuccinimide (13.9 g, 0.104 mole). Following dissolution, an exotherm was observed along with a color change to dark yellow. The reaction was stirred an additional hour then the contents were then poured into water (200 mL) and the product extracted with diethyl ether (300 mL). The ethereal layer was washed with water (3×100 mL) and brine (50 mL), then dried over anhydrous magnesium sulfate. After filtering, the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification. Separately, a solution of methyl isobutyryl acetate (18 g, 0.125 mol) in tetrahydrofuran (25 mL) at 0° C. was treated with a solution of sodium methoxide (250 mL, 0.5 M in methanol). A solution of the above crude 2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride in tetrahydrofuran (80 mL) was then added dropwise. After stirring at ambient temperature for 16 h the solvent was removed in vacuo. The residue was triturated with water (250 mL) and the resulting solids filtered and washed with water. Yield=22.7 g. (69%) of methyl 3-(2,6-dichlorophenyl)-5-isopropylisoxazole-4-carboxylate. was placed in an ambient temperature dissolution the product extracted with diethyl ether (300 mL) The ethereal layer was washed with water (3×100 mL) and brine (50 mL) dried over anhydrous magnesium sulfate After filtering the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification After stirring at ambient temperature for 16 h the solvent was removed in vacuo The residue was triturated with water (250 mL) the resulting solids filtered washed with water

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

Procedure: A solution of 2,6-dichlorobenzaldehyde oxime (19.8 g, 0.104 mol) in N,N-dimethyl formamide (80 mL) was placed in an ambient temperature water bath and was treated with N-chlorosuccinimide (13.9 g, 0.104 mole). Following dissolution, an exotherm was observed along with a color change to dark yellow. The reaction was stirred an additional hour then the contents were then poured into water (200 mL) and the product extracted with diethyl ether (300 mL). The ethereal layer was washed with water (3×100 mL) and brine (50 mL), then dried over anhydrous magnesium sulfate. After filtering, the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification. Separately, a solution of methyl isobutyryl acetate (18 g, 0.125 mol) in tetrahydrofuran (25 mL) at 0° C. was treated with a solution of sodium methoxide (250 mL, 0.5 M in methanol). A solution of the above crude 2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride in tetrahydrofuran (80 mL) was then added dropwise. After stirring at ambient temperature for 16 h the solvent was removed in vacuo. The residue was triturated with water (250 mL) and the resulting solids filtered and washed with water. Yield=22.7 g. (69%) of methyl 3-(2,6-dichlorophenyl)-5-isopropylisoxazole-4-carboxylate. was placed in an ambient temperature dissolution the product extracted with diethyl ether (300 mL) The ethereal layer was washed with water (3×100 mL) and brine (50 mL) dried over anhydrous magnesium sulfate After filtering the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification After stirring at ambient temperature for 16 h the solvent was removed in vacuo The residue was triturated with water (250 mL) the resulting solids filtered washed with water

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

Procedure: A solution of 2,6-dichlorobenzaldehyde oxime (19.8 g, 0.104 mol) in N,N-dimethyl formamide (80 mL) was placed in an ambient temperature water bath and was treated with N-chlorosuccinimide (13.9 g, 0.104 mole). Following dissolution, an exotherm was observed along with a color change to dark yellow. The reaction was stirred an additional hour then the contents were then poured into water (200 mL) and the product extracted with diethyl ether (300 mL). The ethereal layer was washed with water (3×100 mL) and brine (50 mL), then dried over anhydrous magnesium sulfate. After filtering, the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification. Separately, a solution of methyl isobutyryl acetate (18 g, 0.125 mol) in tetrahydrofuran (25 mL) at 0° C. was treated with a solution of sodium methoxide (250 mL, 0.5 M in methanol). A solution of the above crude 2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride in tetrahydrofuran (80 mL) was then added dropwise. After stirring at ambient temperature for 16 h the solvent was removed in vacuo. The residue was triturated with water (250 mL) and the resulting solids filtered and washed with water. Yield=22.7 g. (69%) of methyl 3-(2,6-dichlorophenyl)-5-isopropylisoxazole-4-carboxylate. was placed in an ambient temperature dissolution the product extracted with diethyl ether (300 mL) The ethereal layer was washed with water (3×100 mL) and brine (50 mL) dried over anhydrous magnesium sulfate After filtering the solvent was removed in vacuo to yield a yellow oil which was used in the next step without further purification After stirring at ambient temperature for 16 h the solvent was removed in vacuo The residue was triturated with water (250 mL) the resulting solids filtered washed with water

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

Procedure: 2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.67 g, 11.9 mmol) and 4-ethynylbenzonitrile (1.50 g, 11.9 mmol) were dissolved in anhydrous tetrahydrofuran (150 mL) and triethylamine (2.15 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 6 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 4-ethynylbenzonitrile. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 7:3 hexanes-ethyl acetate. The appropriate fractions were combined to give 3-(2,6-dichlorophenyl)-5-(4-cyanophenyl) isoxazole as a white solid, 0.58 g. then heated at reflux for 6 h The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate washed successively with water and brine The ethyl acetate solution was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting solid was purified by column chromatography on silica gel eluting with 7:3 hexanes-ethyl acetate

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

Procedure: 2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.01 g, 4.5 mmol) and 2,2-dichloro-N-(4-ethynylphenyl)acetamide (1.01 g, 4.42 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(4-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[4-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a tan solid. then heated at reflux for 4 h The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate washed successively with water and brine The ethyl acetate solution was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting solid was purified by column chromatography on silica gel eluting with 8:2 hexanes-ethyl acetate

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

Procedure: 2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.25 g, 5.6 mmol) and 2,2-dichloro-N-(2-ethynylphenyl)acetamide (1.93 g, 8.5 mmol) were dissolved in anhydrous tetrahydrofuran (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(2-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[2-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a light brown solid, 1.24 g. then heated at reflux for 4 h The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate washed successively with water and brine The ethyl acetate solution was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting solid was purified by column chromatography on silica gel eluting with 8:2 hexanes-ethyl acetate

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

Procedure: To a solution of 0.1 g (0.4455 mmol) alpha-Chloro-2,6-dichlorobenzaldoxime in 5 mL methyl 3-oxobutanoate, 0.11 mL (1.5 eq) diisopropylethlamine were added. The mixture was stirred for 24 h then ethylacetate was removed in the vacuo. The residue was dried under high vacuo and the crude product was triturated in water until it became solid. The solid was filtered off and further purified by recrystallization from a water-methanol mixture. The crystals were filtered off, washed with water and dried under reduced pressure to afford 248 mg (87%) of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate. Result of LC/MS [M+H]+: 286.12; 1H NMR (DMSO-d6; CCl4): 2.77 (3H, s, CH3-isooxazole), 3.28 (3H, s, CH3-methoxy), 7.54-7.65 (3H, m, aromatic) ethylacetate was removed in the vacuo The residue was dried under high vacuo the crude product was triturated in water until it The solid was filtered off further purified by recrystallization from a water-methanol mixture The crystals were filtered off washed with water dried under reduced pressure

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

Procedure: 2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (2.72 g, 95.6 mmol) and 2,2-dichloro-N-(3-ethynylphenyl) acetamide (2.5 g, 110 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.8 mL). The mixture was stirred at room temperature for 1h then heated at reflux for 5 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(3-ethynylphenyl) acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined and then crystallized from hexanes-ethyl acetate to give 2,2-dichloro-N-[3-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl] acetamide as a white crystalline solid, 1.80 g (m.p. 167° C.). NMR (300 MHz, CDCl3): 8.21 (broad s, 1H, NH), 8.08 (m, 1H), 7.71 (m, 2H), 7.52 (t, 1H), 7.42-7.46 (m, 2H), 7.32-7.38 (m, 1H), 6.69 (s, 1H), 6.07 ppm (s, 1H). MW=416 confirmed by LC-MS, tr=36.9 min (Method W) MH+=415-419. then heated at reflux for 5 h The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate washed successively with water and brine The ethyl acetate solution was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The resulting solid was purified by column chromatography on silica gel eluting with 8:2 hexanes-ethyl acetate crystallized from hexanes-ethyl acetate

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

Procedure: To a solution of 0.1 g (0.4455 mmol) alpha-Chloro-2,6-dichlorobenzaldoxime in 5 mL methyl 3-oxobutanoate, 0.11 mL (1.5 eq) diisopropylethlamine were added. The mixture was stirred for 24 h then ethylacetate was removed in the vacuo. The residue was dried under high vacuo and the crude product was triturated in water until it became solid. The solid was filtered off and further purified by recrystallization from a water-methanol mixture. The crystals were filtered off, washed with water and dried under reduced pressure to afford 248 mg (87%) of methyl 3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate. Result of LC/MS [M+H]+: 286.12; 1H NMR (DMSO-d6; CCl4): 2.77 (3H, s, CH3-isooxazole), 3.28 (3H, s, CH3-methoxy), 7.54-7.65 (3H, m, aromatic) ethylacetate was removed in the vacuo The residue was dried under high vacuo the crude product was triturated in water until it The solid was filtered off further purified by recrystallization from a water-methanol mixture The crystals were filtered off washed with water dried under reduced pressure

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

Procedure: tert-Butyl 2-(3-ethynylphenylamino)-2-oxoethylcarbamate (1.6 g, 5.83 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) and treated with triethylamine (0.82 g, 8.1 mmol) and then 2,6-dichloro-N-hydroxybenzimidoyl chloride (1.4 g, 6.3 mmol). After stirring 15 min at room temperature the mixture was heated at reflux for 4 h. The mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)-2-oxoethylcarbamate. 1H NMR (CDCl3): 8.51 (br s, 1H), 8.01 (s, 1H), 7.51-7.45 (m, 2H), 7.40-7.28 (m, 4H), 6.63 (m, 1H), 5.28 (br s, 2H), 3.95 (d, 2H), 1.45 ppm (s, 9H). was heated at reflux for 4 h washed with brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure