2-propan-2-yloxyisoindole-1,3-dione

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: N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H; 7.61, d, J=8.8 Hz, 1H; 7.49, d, J=8.8 Hz, 1H; 7.46, d, J=2.4 Hz, 1H; 7.42, dd, J=2.4 and 8.8 Hz, 1H; 7.30, dd, J=2.4 and 8.8 Hz, 1H; 7.24, d, J=2.4 Hz, 1H; 4.49, m, 1H; 4.39, m, 1H; 2.97, m, 1H; 2.45, m, 1H; 1.97-1.71, m, 14H; 1.34-1.24, m, 18H. HRMS (M+) 426.0983. the reaction stirred for 15 hours at RT The reaction mixture was concentrated under vacuum the residue dissolved in Et2O (50 mL) washed with water, brine dried over MgSO4 the solvent removed under reduced pressure The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1)

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

Procedure: N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H, 7.61, d, J=8.8 Hz, 1H, 7.49, d, J=8.8 Hz, 1H, 7.46, d, J=2.4 Hz, 1H, 7.42, dd, J=2.4 and 8.8 Hz, 1H, 7.30, dd, J=2.4 and 8.8 Hz, 1H, 7.24, d, J=2.4 Hz, 1H, 4.49, m, 1H, 4.39, m, 1H, 2.97, m, 1H, 2.45, m, 1H, 1.97-1.71, m, 14H, 1.34-1.24, m, 18H. HRMS (M+) 426.0983. the reaction stirred for 15 hours at RT The reaction mixture was concentrated under vacuum the residue dissolved in Et2O (50 mL) washed with water, brine dried over MgSO4 the solvent removed under reduced pressure The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1)

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

Procedure: N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H, 7.61, d, J=8.8 Hz, 1H, 7.49, d, J=8.8 Hz, 1H, 7.46, d, J=2.4 Hz, 1H, 7.42, dd, J=2.4 and 8.8 Hz, 1H, 7.30, dd, J=2.4 and 8.8 Hz, 1H, 7.24, d, J=2.4 Hz, 1H, 4.49, m, 1H, 4.39, m, 1H, 2.97, m, 1H, 2.45, m, 1H, 1.97-1.71, m, 14H, 1.34-1.24, m, 18H. HRMS (M+) 426.0983. the reaction stirred for 15 hours at RT The reaction mixture was concentrated under vacuum the residue dissolved in Et2O (50 mL) washed with water, brine dried over MgSO4 the solvent removed under reduced pressure The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Solid potassium carbonate (8.64 g, 62.5 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) in dimethyl sulfoxide (37 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture, isopropyl bromide (3.41 mL, 37.5 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-isopropyloxy-isoindole-1,3-dione (4.44 g, 86.6%) as a white solid which was used in the next step without further purification. the mixture stirred at 80° C. for 3 h After ice-cooling the resulting precipitate was collected by filtration in vacuo washed with water (25 mL) and hexanes (15 mL) dried in vacuo

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

Procedure: Diethyl azodicarboxylate (14.5 mL, 73.56 mmol) was added dropwise at 0° C. to a stirred suspension of propan-2-ol (4.7 mL, 61.30 mmol), triphenylphosphine (19.30 g, 73.56 mmol), and N-hydroxyphthalimide (10.00 g, 61.30 mmol) in THF (50 mL). The mixture was stirred at room temperature for 20 h and evaporated to dryness. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1) to yield 2-isopropoxy-isoindole-1,3-dione (LIX, 10.92 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm): 7.86 (4H, s), 4.44 (1H, septet, J=6.2 Hz), 1.28 (6H, d, J=6.2 Hz). evaporated to dryness The product was purified by flash column chromatography elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1)

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

Procedure: Diethyl azodicarboxylate (14.5 mL, 73.56 mmol) was added dropwise at 0° C. to a stirred suspension of propan-2-ol (4.7 mL, 61.30 mmol), triphenylphosphine (19.30 g, 73.56 mmol), and N-hydroxyphthalimide (10.00 g, 61.30 mmol) in THF (50 mL). The mixture was stirred at room temperature for 20 h and evaporated to dryness. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1) to yield 2-isopropoxy-isoindole-1,3-dione (LIX, 10.92 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm): 7.86 (4H, s), 4.44 (1H, septet, J=6.2 Hz), 1.28 (6H, d, J=6.2 Hz). evaporated to dryness The product was purified by flash column chromatography elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1)

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

Procedure: A vigorously stirred solution of 2-isopropoxy-1H-isoindole-1,3(2H)-dione [2.50 g, 12.2 mmol, Synth. Comm., 22(10), 1427-1432 (1992)] in 35 mL of tetrahydrofuran under an Argon atmosphere at ambient temperature was treated with anhydrous hydrazine (0.421 mL, 13.41 mmol). After 1.5 hours, 4-methoxybenzenesulphonyl chloride (3.024 g, 14.63 mmol), dichloromethane (20 mL) and N,N-diisopropylethylamine (6.38 mL, 36.6 mmol) was added with continued stirring. After an additional 2 hours at ambient temperature, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on Flash grade silica gel eluting with 30% ethyl acetate in hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(isopropoxy)-4-methoxy-1-benzenesulfonamide (2.061 g, 69%) as a white solid. H1-NMR (chloroform-D3): 1.22 (d, 6H), 3.92 (s, 3H), 4.27 (m, 1H), 6.70 (s, 1H), 7.05 (d, 2H), 7.90 (d, 2H). MS(ESI): 268 (M+Na). After an additional 2 hours at ambient temperature the reaction mixture was evaporated in vacuo to a residue partitioned between ethyl acetate and 1N hydrochloric acid The layers were separated the aqueous layer was extracted again with ethyl acetate The combined organic layers were washed with 5% w/v potassium carbonate and brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo to a residue The crude material was purified on Flash grade silica gel eluting with 30% ethyl acetate in hexane Fractions containing the product evaporated in vacuo dried under high vacuum

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

Procedure: A vigorously stirred solution of 2-isopropoxy-1H-isoindole-1,3(2H)-dione [2.50 g, 12.2 mmol, Synth. Comm., 22(10), 1427-1432 (1992)] in 35 mL of tetrahydrofuran under an Argon atmosphere at ambient temperature was treated with anhydrous hydrazine (0.421 mL, 13.41 mmol). After 1.5 hours, 4-methoxybenzenesulphonyl chloride (3.024 g, 14.63 mmol), dichloromethane (20 mL) and N,N-diisopropylethylamine (6.38 mL, 36.6 mmol) was added with continued stirring. After an additional 2 hours at ambient temperature, the reaction mixture was evaporated in vacuo to a residue and partitioned between ethyl acetate and 1N hydrochloric acid. The layers were separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with 5% w/v potassium carbonate and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue. The crude material was purified on Flash grade silica gel eluting with 30% ethyl acetate in hexane. Fractions containing the product were combined, evaporated in vacuo, and dried under high vacuum to provide N1-(isopropoxy)-4-methoxy-1-benzenesulfonamide (2.061 g, 69%) as a white solid. H1-NMR (chloroform-D3): 1.22 (d, 6H), 3.92 (s, 3H), 4.27 (m, 1H), 6.70 (s, 1H), 7.05 (d, 2H), 7.90 (d, 2H). MS(ESI): 268 (M+Na). After an additional 2 hours at ambient temperature the reaction mixture was evaporated in vacuo to a residue partitioned between ethyl acetate and 1N hydrochloric acid The layers were separated the aqueous layer was extracted again with ethyl acetate The combined organic layers were washed with 5% w/v potassium carbonate and brine dried over anhydrous magnesium sulfate filtered evaporated in vacuo to a residue The crude material was purified on Flash grade silica gel eluting with 30% ethyl acetate in hexane Fractions containing the product evaporated in vacuo dried under high vacuum

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

Procedure: N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-isopropoxyphthalimide (308 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(4-chloro-2-cyclohexanecarbonylphenyl)-trifluoromethanesulfonamide 29E (370 mg, 1.0 mmol), and the reaction stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum, and the residue dissolved in Et2O (50 mL) and washed with water, brine, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1) to afford N-[4-chloro-2-(cyclohexylisopropoxyiminomethyl)phenyl]trifluoromethanesulfonamide 210 (390 mg, 91%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (1:1 mixture of E- and Z-isomers) δ 10.59, br s, 1H; 8.11, br s, 1H; 7.61, d, J=8.8 Hz, 1H; 7.49, d, J=8.8 Hz, 1H; 7.46, d, J=2.4 Hz, 1H; 7.42, dd, J=2.4 and 8.8 Hz, 1H; 7.30, dd, J=2.4 and 8.8 Hz, 1H; 7.24, d, J=2.4 Hz, 1H; 4.49, m, 1H; 4.39, m, 1H; 2.97, m, 1H; 2.45, m, 1H; 1.97-1.71, m, 14H; 1.34-1.24, m, 18H. HRMS (M+) 426.0983. the reaction stirred for 15 hours at RT The reaction mixture was concentrated under vacuum the residue dissolved in Et2O (50 mL) washed with water, brine dried over MgSO4 the solvent removed under reduced pressure The residue was purified by column chromatography (eluting with CH2Cl2/PE, 1:1)

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

Procedure: Diethyl azodicarboxylate (14.5 mL, 73.56 mmol) was added dropwise at 0° C. to a stirred suspension of propan-2-ol (4.7 mL, 61.30 mmol), triphenylphosphine (19.30 g, 73.56 mmol), and N-hydroxyphthalimide (10.00 g, 61.30 mmol) in THF (50 mL). The mixture was stirred at room temperature for 20 h and evaporated to dryness. The product was purified by flash column chromatography using gradient elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1) to yield 2-isopropoxy-isoindole-1,3-dione (LIX, 10.92 g, 87%). 400 MHz 1H NMR (DMSO-d6, ppm): 7.86 (4H, s), 4.44 (1H, septet, J=6.2 Hz), 1.28 (6H, d, J=6.2 Hz). evaporated to dryness The product was purified by flash column chromatography elution from petroleum ether/EtOAc (9:1) to petroleum ether/EtOAc (5:1)