N-[(2,6-dichlorophenyl)methylidene]hydroxylamine

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (2.2 g, 11.6 mmol) in N,N,-dimethylformamide (7 mL) cooled in a water bath was added solid N-chlorosuccinimide (1.5 g, 11.6 mmol). The solution was stirred with the flask in the water bath for approximately 20 minutes and then with the flask out of the bath for approximately 1 hour. The solution was poured into water and then extracted twice with ether. The combined organic phases were dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.4 g, 13.9 mmol) in tetrahydrofuran (3 mL) at 0° C. was added a 3.16 M solution of sodium ethoxide in ethanol (4.4 mL, 13.9 mmol) quickly. The solution was stirred for a few minutes. To that solution was added the isolated imidoyl chloride in tetrahydrofuran (5 mL) dropwise. The solution was stirred at 0° C. for approximately 1 h and then allowed to stir at ambient temperature overnight. The solution was poured into water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford a white solid (1.5 g, 38%). 1H-NMR (DMSO-d6) δ 7.63-7.53 (m, 3H), 4.25 (quintet, J=9 Hz, 1H), 4.02 (q, J=7 Hz, 2H), 2.43-2.36 (m, 4H), 2.15-1.89 (m, 2H), 0.94 (t, J=7 Hz, 3H). extracted twice with ether The combined organic phases were dried over magnesium sulfate concentrated The solution was stirred at 0° C. for approximately 1 h to stir at ambient temperature overnight extracted with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (2.2 g, 11.6 mmol) in N,N,-dimethylformamide (7 mL) cooled in a water bath was added solid N-chlorosuccinimide (1.5 g, 11.6 mmol). The solution was stirred with the flask in the water bath for approximately 20 minutes and then with the flask out of the bath for approximately 1 hour. The solution was poured into water and then extracted twice with ether. The combined organic phases were dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.4 g, 13.9 mmol) in tetrahydrofuran (3 mL) at 0° C. was added a 3.16 M solution of sodium ethoxide in ethanol (4.4 mL, 13.9 mmol) quickly. The solution was stirred for a few minutes. To that solution was added the isolated imidoyl chloride in tetrahydrofuran (5 mL) dropwise. The solution was stirred at 0° C. for approximately 1 h and then allowed to stir at ambient temperature overnight. The solution was poured into water and extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford a white solid (1.5 g, 38%). 1H-NMR (DMSO-d6) δ 7.63-7.53 (m, 3H), 4.25 (quintet, J=9 Hz, 1H), 4.02 (q, J=7 Hz, 2H), 2.43-2.36 (m, 4H), 2.15-1.89 (m, 2H), 0.94 (t, J=7 Hz, 3H). extracted twice with ether The combined organic phases were dried over magnesium sulfate concentrated The solution was stirred at 0° C. for approximately 1 h to stir at ambient temperature overnight extracted with ethyl acetate The combined organic phases were dried over magnesium sulfate concentrated purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (26.4 g, 139 mmol) in DMF (70 mL) at 5° C. was added solid N-chlorosuccinimide (18.6 g, 139 mmol) in portions. The mixture was allowed to stir and warm to ambient temperature (with occasional cooling when warming was noted) over approximately 1.5 hour and then poured into ether. The organic layer containing the crude imidoyl chloride was washed twice with water followed by brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 4-methyl-3-oxohexanoate (28.8 g, 167 mmol) in tetrahydrofuran (50 mL) at 0° C. was added a 21 wt % solution of sodium ethoxide in ethanol (62.3 mL, 167 mmol) quickly. The above imidoyl chloride was added dropwise in tetrahydrofuran (100 mL). The solution was allowed to stir while warming to ambient temperature overnight. The mixture was then poured into ether, washed twice with water followed by brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which was dissolved in tetrahydrofuran (75 mL) at 0° C. Then a 1.5 M solution of diisobutylaluminum hydride in toluene (100 mL, 150 mmol) was added slowly. The solution was allowed to warm slightly while stirring for approximately 2.5 hours and then was re-cooled to 0° C. and stirred for 1.5 hours. Then approximately 20 mL of Rochelle's salt was added carefully followed by ethyl acetate and the mixture was stirred overnight. Then the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid. The enantiomers were resolved by supercritical fluid chromatography (Chiralpak AD, 10% methanol in supercritical carbon dioxide) and the resulting solid was taken up with dichloromethane, dried over magnesium sulfate and concentrated to afford {3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methanol (1.35 g, 6%) 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.20-4.06 (m, 2H), 3.15-3.10 (m, 1H), 1.69-1.62 (m, 2H), 1.29 (d, J=7 Hz, 3H), 0.79 (t, J=7 Hz, 3H). (with occasional cooling when warming was noted) over approximately 1.5 hour was washed twice with water dried over magnesium sulfate concentrated to stir while warming to ambient temperature overnight washed twice with water dried over magnesium sulfate concentrated purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which to warm slightly while stirring for approximately 2.5 hours was re-cooled to 0° C. stirred for 1.5 hours the mixture was stirred overnight Then the layers were separated the aqueous layer was extracted two more times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate concentrated purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid dried over magnesium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (26.4 g, 139 mmol) in DMF (70 mL) at 5° C. was added solid N-chlorosuccinimide (18.6 g, 139 mmol) in portions. The mixture was allowed to stir and warm to ambient temperature (with occasional cooling when warming was noted) over approximately 1.5 hour and then poured into ether. The organic layer containing the crude imidoyl chloride was washed twice with water followed by brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 4-methyl-3-oxohexanoate (28.8 g, 167 mmol) in tetrahydrofuran (50 mL) at 0° C. was added a 21 wt % solution of sodium ethoxide in ethanol (62.3 mL, 167 mmol) quickly. The above imidoyl chloride was added dropwise in tetrahydrofuran (100 mL). The solution was allowed to stir while warming to ambient temperature overnight. The mixture was then poured into ether, washed twice with water followed by brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which was dissolved in tetrahydrofuran (75 mL) at 0° C. Then a 1.5 M solution of diisobutylaluminum hydride in toluene (100 mL, 150 mmol) was added slowly. The solution was allowed to warm slightly while stirring for approximately 2.5 hours and then was re-cooled to 0° C. and stirred for 1.5 hours. Then approximately 20 mL of Rochelle's salt was added carefully followed by ethyl acetate and the mixture was stirred overnight. Then the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid. The enantiomers were resolved by supercritical fluid chromatography (Chiralpak AD, 10% methanol in supercritical carbon dioxide) and the resulting solid was taken up with dichloromethane, dried over magnesium sulfate and concentrated to afford {3-(2,6-dichlorophenyl)-5-[(1R)-1-methylpropyl]-4-isoxazolyl}methanol (1.35 g, 6%) 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.20-4.06 (m, 2H), 3.15-3.10 (m, 1H), 1.69-1.62 (m, 2H), 1.29 (d, J=7 Hz, 3H), 0.79 (t, J=7 Hz, 3H). (with occasional cooling when warming was noted) over approximately 1.5 hour was washed twice with water dried over magnesium sulfate concentrated to stir while warming to ambient temperature overnight washed twice with water dried over magnesium sulfate concentrated purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which to warm slightly while stirring for approximately 2.5 hours was re-cooled to 0° C. stirred for 1.5 hours the mixture was stirred overnight Then the layers were separated the aqueous layer was extracted two more times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate concentrated purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid dried over magnesium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (26.4 g, 139 mmol) in N,N-dimethylformamide (70 mL) at 5° C. was added solid N-chlorosuccinimide (18.6 g, 139 mmol) in portions. The mixture was allowed to stir and warm to ambient temperature (with occasional cooling when warming was noted) over approximately 1.5 hour and then poured into ether. The ether layer containing the crude imidoyl chloride was washed twice with water followed by brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 4-methyl-3-oxohexanoate (28.8 g, 167 mmol) in tetrahydrofuran (50 mL) at 0° C. was added sodium ethoxide (21 wt % in ethanol, 62.3 mL, 167 mmol) quickly. Then the above imidoyl chloride was added dropwise in tetrahydrofuran (100 mL). The solution was allowed to stir while warming to ambient temperature overnight. The mixture was then poured into ether, washed twice with water followed by brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which was dissolved in tetrahydrofuran (75 mL) at 0° C. Then a 1.5 M solution of diisobutylaluminum hydride in toluene (100 mL, 150 mmol) was added slowly. The solution was allowed to warm slightly while stirring for approximately 2.5 hours and then was re-cooled to 0° C. and stirred for 1.5 hours. Then aqueous Rochelle's salt (20 mL) was added carefully followed by ethyl acetate and the mixture was stirred overnight. Then the layers were separated and the aqueous layer was extracted two more times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid. The enantiomers were resolved by supercritical fluid chromatography (Chiralpak AD, 10% methanol in supercritical carbon dioxide) and the resulting solid was taken up with dichloromethane, dried over magnesium sulfate and concentrated to afford {3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methanol (1.53 g, 7%) 1H-NMR (400 MHz, DMSO-d6) δ 7.61-7.51 (m, 3H), 4.85 (t, J=5 Hz, 1H), 4.20-4.06 (m, 2H), 3.15-3.10 (m, 1H), 1.69-1.62 (m, 2H), 1.29 (d, J=7 Hz, 3H), 0.79 (t, J=7 Hz, 3H). (with occasional cooling when warming was noted) over approximately 1.5 hour was washed twice with water dried over magnesium sulfate concentrated to stir while warming to ambient temperature overnight washed twice with water dried over magnesium sulfate concentrated purified by chromatography (silica gel, 1.25% acetone in hexanes) to afford an oil which to warm slightly while stirring for approximately 2.5 hours was re-cooled to 0° C. stirred for 1.5 hours the mixture was stirred overnight Then the layers were separated the aqueous layer was extracted two more times with ethyl acetate The combined organic layers were washed with brine dried over magnesium sulfate concentrated purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford a white solid dried over magnesium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solutions were stirred while in the water bath for approximately 20 min and the outside the bath for approximately 1 hour. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclopropyl-3-oxopropanoate (2.17 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (289 mg, 8%). 1H-NMR (400 MHz, DMSO-d6) δ 7.62-7.53 (m, 3H), 4.04 (q, J=7 Hz, 2H), 2.84-2.82 (m, 1H), 1.35-1.25 (m, 4H), 0.93 (t, J=7 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated The solution was stirred at 0° C. for 10 minutes at ambient temperature overnight extracted three times with ethyl acetate The combined organic layers were dried over magnesium sulfate concentrated purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solution was stirred while in the water bath for approximately 20 min and outside the bath for approximately 1 hr. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.37 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.52 g, 38%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.29-4.20 (m, 1H), 4.02 (q, J=7 Hz, 2H), 2.43-2.36 (m, 4H), 2.15-2.06 (m, 1H), 1.97-1.89 (m, 1H), 0.94 (t, J=7 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated The solution was stirred at 0° C. for 10 minutes at ambient temperature overnight extracted three times with ethyl acetate The combined organic layers were dried over magnesium sulfate concentrated purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a water bath-cooled solution of 2,6-dichlorobenzaldehyde oxime (2.20 g, 11.6 mmol) in N,N-dimethylformamide (7 mL) was added solid N-chlorosuccinimide (1.55 g, 11.6 mmol). The solution was stirred while in the water bath for approximately 20 min and outside the bath for approximately 1 hr. The solution was poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and then concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (2.37 g, 13.9 mmol) in THF (3 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 4.36 mL, 13.9 mmol). The solution was stirred for a few minutes and then the above imidoyl chloride was added. The solution was stirred at 0° C. for 10 minutes and then at ambient temperature overnight. The solution was poured into water and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, concentrated and purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (1.52 g, 38%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.29-4.20 (m, 1H), 4.02 (q, J=7 Hz, 2H), 2.43-2.36 (m, 4H), 2.15-2.06 (m, 1H), 1.97-1.89 (m, 1H), 0.94 (t, J=7 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated The solution was stirred at 0° C. for 10 minutes at ambient temperature overnight extracted three times with ethyl acetate The combined organic layers were dried over magnesium sulfate concentrated purified by chromatography (silica gel, 0-5% ethyl acetate in hexanes gradient elution)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (3.73 g, 19.6 mmol) in N,N-dimethylformamide (12 mL) was added solid N-chlorosuccinimide (2.62 g, 19.6 mmol). The solution was stirred for approximately 1 hour and the poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and concentrated. To a solution of ethyl 3-cyclopentyl-3-oxopropanoate (4.34 g, 23.6 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 25 wt % solution of sodium ethoxide in ethanol (7.4 mL, 24 mmol) quickly. The above imidoyl chloride was added. A solid was seen to precipitate. The mixture was allowed to warm to ambient temperature and stir overnight. The mixture was then poured into water and extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes) to afford ethyl 5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (3.04 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.02 (q, J=7 Hz, 2H), 3.92-3.84 (m, 1H), 2.14-2.06 (m, 2H), 1.84-1.64 (m, 6H), 0.91 (t, J=5 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated to precipitate stir overnight The mixture was then poured into water extracted three times with ethyl acetate the combined organic layers were dried over magnesium sulfate concentrated the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2,6-dichlorobenzaldehyde oxime (3.73 g, 19.6 mmol) in N,N-dimethylformamide (12 mL) was added solid N-chlorosuccinimide (2.62 g, 19.6 mmol). The solution was stirred for approximately 1 hour and the poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and concentrated. To a solution of ethyl 3-cyclopentyl-3-oxopropanoate (4.34 g, 23.6 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 25 wt % solution of sodium ethoxide in ethanol (7.4 mL, 24 mmol) quickly. The above imidoyl chloride was added. A solid was seen to precipitate. The mixture was allowed to warm to ambient temperature and stir overnight. The mixture was then poured into water and extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes) to afford ethyl 5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (3.04 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.02 (q, J=7 Hz, 2H), 3.92-3.84 (m, 1H), 2.14-2.06 (m, 2H), 1.84-1.64 (m, 6H), 0.91 (t, J=5 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated to precipitate stir overnight The mixture was then poured into water extracted three times with ethyl acetate the combined organic layers were dried over magnesium sulfate concentrated the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes)