2-(2-methoxyethoxy)isoindole-1,3-dione

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-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H; 8.87, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.54-7.31, m, 13H; 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H; 4.33, m, 4H; 3.67, m, 4H; 3.46, s, 3H; 3.38, s, 3H. HRMS (M+) 436.0465. the reaction stirred for 15 hours at 30° C 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19)

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-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H; 8.87, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.54-7.31, m, 13H; 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H; 4.33, m, 4H; 3.67, m, 4H; 3.46, s, 3H; 3.38, s, 3H. HRMS (M+) 436.0465. the reaction stirred for 15 hours at 30° C 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19)

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

Procedure: N,N-Dimethylethylenediamine (2.54 mL, 22.0 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (3.32 g, 15.0 mmol) in EtOH (50 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (20 mL) was then added to adjust the mixture to Ca. pH 4, followed by the addition of a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (3.02 g, 10.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1) afforded N-{4-chloro-2-[1-(2-methoxyethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 185 (3.0 g, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.40, br s, 1H; 7.65, d, J=8.8 Hz, 1H; 7.47, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 4.37, m, 2H; 3.71, m, 2H; 3.41, s, 3H; 2.32, s, 3H. HRMS (M+) 374.0308. the mixture stirred for 65 h at RT The reaction mixture was concentrated under vacuum the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1) Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1)

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

Procedure: 2E was deprotected as previously described in 2A, Step 2 to give tert-butyl 2-(aminooxy)ethylcarbamate (2F, 1.26 g, 58% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 3.37 (q, J=5.31 Hz, 2H) 3.62-3.85 (m, 2H) 4.90 (br. s., 1H) 5.47 (br. s., 2H).

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

Procedure: 2-methoxyethanol (2.00 g, 26.3 mmol), N-hydroxyphthalimide (4.72 g, 28.9 mmol, 1.1 eq., and triphenylphosphine (7.58 g, 28.9 mmol, 1.1 eq.) were dissolved in 85 mL of dry THF and then the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (6.91 g, 34.2 mmol, 1.3 eq.) was dissolved in 15 mL of dry THF and was added slowly to the above mixture. The reaction was stirred in the ice bath for 10 minutes and then the ice bath was removed. The reaction then was allowed to stir at room temperature under N2 overnight. The reaction was done by LC/MS and was concentrated to an oil. It was then purified by flash column chromatography using hexane/ethyl acetate 70/30 to give 2-(2-methoxyethoxy)isoindoline-1,3-dione (2A, 5.19 g, 89.2% yield). ESI-MS: m/z 222.3 (M+H)+. the mixture was cooled in an ice bath was added slowly to the above mixture the ice bath was removed The reaction was concentrated to an oil It was then purified by flash column chromatography

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-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil, 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H, 8.87, br s, 1H, 7.67, d, J=88 Hz, 1H, 7.54-7.31, m, 13H, 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H, 4.33, m, 4H, 3.67, m, 4H, 3.46, s, 3H, 3.38, s, 3H. HRMS (M+) 436.0465. the reaction stirred for 15 hours at 30° C 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19)

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

Procedure: N,N-Dimethylethylenediamine (2.54 mL, 22.0 mmol) was added to a solution of N-(2-methoxyethoxy)phthalimide (3.32 g, 15.0 mmol) in EtOH (50 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (20 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (3.02 g, 10.0 mmol) in EtOH (2 mL), and the mixture stirred for 65 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1) afforded N-{4-chloro-2-[1-(2-methoxyethoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 185 (3.0 g, 80%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) δ 11.40, br s, 1H, 7.65, d, J=8.8 Hz, 1H, 7.47, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H, 4.37, m, 2H, 3.71, m, 2H, 3.41, s, 3H, 2.32, s, 3H. HRMS (M+) 374.0308. the mixture stirred for 65 h at RT The reaction mixture was concentrated under vacuum the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 1:1) Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9 to 1:1)

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

Procedure: 2E was deprotected as previously described in 2A, Step 2 to give tert-butyl 2-(aminooxy)ethylcarbamate (2F, 1.26 g, 58% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 3.37 (q, J=5.31 Hz, 2H) 3.62-3.85 (m, 2H) 4.90 (br. s., 1H) 5.47 (br. s., 2H).

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

Procedure: 2-methoxyethanol (2.00 g, 26.3 mmol), N-hydroxyphthalimide (4.72 g, 28.9 mmol, 1.1 eq., and triphenylphosphine (7.58 g, 28.9 mmol, 1.1 eq.) were dissolved in 85 mL of dry THF and then the mixture was cooled in an ice bath. Diisopropyl azodicarboxylate (6.91 g, 34.2 mmol, 1.3 eq.) was dissolved in 15 mL of dry THF and was added slowly to the above mixture. The reaction was stirred in the ice bath for 10 minutes and then the ice bath was removed. The reaction then was allowed to stir at room temperature under N2 overnight. The reaction was done by LC/MS and was concentrated to an oil. It was then purified by flash column chromatography using hexane/ethyl acetate 70/30 to give 2-(2-methoxyethoxy)isoindoline-1,3-dione (2A, 5.19 g, 89.2% yield). ESI-MS: m/z 222.3 (M+H)+. the mixture was cooled in an ice bath was added slowly to the above mixture the ice bath was removed The reaction was concentrated to an oil It was then purified by flash column chromatography

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-hydroxyphthalimide (30.0 g, 184 mmol) and potassium carbonate (25.4 g, 138 mmol) in 300 mL NMP is heated to 50° C. Potassium iodide (0.15 g, 0.90 mmol) and 2-bromoethyl methyl ether (19.0 ml, 202 mmol) are added and the reaction mixture is stirred at 80° C. for 2 h. The reaction mixture is poured on 1 M aqueous HCl and extracted with ethyl acetate. The combined organic phases are dried over MgSO4 and concentrated in vacuo. The residue is triturated with water and subsequently crystallized from EtOH. Yield: 17.1 g. extracted with ethyl acetate The combined organic phases are dried over MgSO4 concentrated in vacuo The residue is triturated with water subsequently crystallized from EtOH

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-(2-methoxyethoxy)phthalimide (332 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 7 hours. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4, followed by the addition of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (364 mg, 1.0 mmol), and the reaction stirred for 15 hours at 30° C. 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-{4-chloro-[(2-methoxyethoxyimino)phenylmethyl]phenyl}trifluoromethanesulfonamide 234 (324 mg, 74%), as a colorless oil. 1H n.m.r. (400 MHz, CDCl3) (2:1 mixture of E- and Z-isomers) δ 11.06, br s, 1H; 8.87, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.54-7.31, m, 13H; 7.10, d, J=2.4 Hz, 1H; 6.92, d, J=2.4 Hz, 1H; 4.33, m, 4H; 3.67, m, 4H; 3.46, s, 3H; 3.38, s, 3H. HRMS (M+) 436.0465. the reaction stirred for 15 hours at 30° C 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 radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19)

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

Procedure: 2E was deprotected as previously described in 2A, Step 2 to give tert-butyl 2-(aminooxy)ethylcarbamate (2F, 1.26 g, 58% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (s, 9H) 3.37 (q, J=5.31 Hz, 2H) 3.62-3.85 (m, 2H) 4.90 (br. s., 1H) 5.47 (br. s., 2H).