4-aminoisoindole-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:

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

Procedure: A solution of 16.2 g (100 mmol) of 6-aminophthalimide, 9.6 g (100 mmol) of methanesulfonic acid, and 4.0 g of 10% Pd/C in 140 mL of TFA was hydrogenated overnight at 50 psi. The catalyst was filtered off and and the filtrate concentrated on a rotary evaporator. The residue was diluted with 70 mL of ice water, adjusted to pH 8 with K2CO3, and chilled in an ice bath. The resulting solid was filtered to give 6.7 g of a 5:4 ratio of 5-amino:6-amino lactam isomers. Recrystallization from hot ethanol/water afforded 1.45 g of undesired isomer. The filtrate was preabsorbed onto silica gel and chromatographed with TEA:MeOH:methylene chloride (1:2:47). The resulting solid was slurried in methylene chloride/MeOH and filtered to afford a low yield of 5-amino-2,3-dihydro-isoindol-1-one: 1H NMR (DMSO-d6): δ4.13 (s, 2H), 5.67 (s, 2H), 6.55 (dd, J=8.7, 1.9 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.83 (s, 1H); APCI−MS m/z 149 (M+H)+. The catalyst was filtered off the filtrate concentrated on a rotary evaporator The residue was diluted with 70 mL of ice water chilled in an ice bath The resulting solid was filtered to give 6.7 g of a 5:4 ratio of 5-amino Recrystallization from hot ethanol/water afforded 1.45 g of undesired isomer The filtrate was preabsorbed onto silica gel chromatographed with TEA:MeOH:methylene chloride (1:2:47) filtered

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

Procedure: A solution of 16.2 g (100 mmol) of 6-aminophthalimide, 9.6 g (100 mmol) of methanesulfonic acid, and 4.0 g of 10% Pd/C in 140 mL of TFA was hydrogenated overnight at 50 psi. The catalyst was filtered off and and the filtrate concentrated on a rotary evaporator. The residue was diluted with 70 mL of ice water, adjusted to pH 8 with K2CO3, and chilled in an ice bath. The resulting solid was filtered to give 6.7 g of a 5:4 ratio of 5-amino:6-amino lactam isomers. Recrystallization from hot ethanol/water afforded 1.45 g of undesired isomer. The filtrate was preabsorbed onto silica gel and chromatographed with TEA:MeOH:methylene chloride (1:2:47). The resulting solid was slurried in methylene chloride/MeOH and filtered to afford a low yield of 5-amino-2,3-dihydro-isoindol-1-one: 1H NMR (DMSO-d6): δ4.13 (s, 2H), 5.67 (s, 2H), 6.55 (dd, J=8.7, 1.9 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.83 (s, 1H); APCI−MS m/z 149 (M+H)+. The catalyst was filtered off the filtrate concentrated on a rotary evaporator The residue was diluted with 70 mL of ice water chilled in an ice bath The resulting solid was filtered to give 6.7 g of a 5:4 ratio of 5-amino Recrystallization from hot ethanol/water afforded 1.45 g of undesired isomer The filtrate was preabsorbed onto silica gel chromatographed with TEA:MeOH:methylene chloride (1:2:47) filtered

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

Procedure: A mixture of 4 g (21 mmol) of the preceeding diamine, 4.6 g (21 mmol) of di-tert-butyl dicarbonate, and 100 mL of dry CH2Cl2 was stirred for 12 hours at room temperature. Solvent and volatile by-products were removed by evaporation under reduced pressure, leaving 6 g (100% yield) of 6-(tert-butyloxycarbonylamino)-1-diethylamino-2-hydroxyhexane as an oil which was not further purified. It was dissolved in 100 mL of dry tetrahydrofuran (THF) along with 3.27 g (22 mmol) of phthalimide, 5.77 g (22 mmol) of triphenylphosphine, and 3.83 g (22 mmol) of diethyl azodicarboxylate (DEAD). The solution was stirred at room temperature for 12 hours at which point, to complete the reaction, an additional 1.64 g (11 mmol) of phthalimide and 1.92 g (11 mmol) of DEAD were added and stirring continued for 1 hour. Solvent was removed and the residual oil partitioned between ether and 1% hydrochloric acid. The aqueous phase was separated, made basic with NaOH solution, and extracted with ether. The ether extract was dried over anhydrous MgSO4, filtered and evaporated. A pale yellow oil resulted which was dried under high vacuum to afford 9.2 g of the protected amino-phthalimide as a pale yellow oil. the reaction stirring continued for 1 hour Solvent was removed the residual oil partitioned between ether and 1% hydrochloric acid The aqueous phase was separated extracted with ether The ether extract was dried over anhydrous MgSO4 filtered evaporated A pale yellow oil resulted which was dried under high vacuum

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

Procedure: A mixture of 4 g (21 mmol) of the preceeding diamine, 4.6 g (21 mmol) of di-tert-butyl dicarbonate, and 100 mL of dry CH2Cl2 was stirred for 12 hours at room temperature. Solvent and volatile by-products were removed by evaporation under reduced pressure, leaving 6 g (100% yield) of 6-(tert-butyloxycarbonylamino)-1-diethylamino-2-hydroxyhexane as an oil which was not further purified. It was dissolved in 100 mL of dry tetrahydrofuran (THF) along with 3.27 g (22 mmol) of phthalimide, 5.77 g (22 mmol) of triphenylphosphine, and 3.83 g (22 mmol) of diethyl azodicarboxylate (DEAD). The solution was stirred at room temperature for 12 hours at which point, to complete the reaction, an additional 1.64 g (11 mmol) of phthalimide and 1.92 g (11 mmol) of DEAD were added and stirring continued for 1 hour. Solvent was removed and the residual oil partitioned between ether and 1% hydrochloric acid. The aqueous phase was separated, made basic with NaOH solution, and extracted with ether. The ether extract was dried over anhydrous MgSO4, filtered and evaporated. A pale yellow oil resulted which was dried under high vacuum to afford 9.2 g of the protected amino-phthalimide as a pale yellow oil. the reaction stirring continued for 1 hour Solvent was removed the residual oil partitioned between ether and 1% hydrochloric acid The aqueous phase was separated extracted with ether The ether extract was dried over anhydrous MgSO4 filtered evaporated A pale yellow oil resulted which was dried under high vacuum

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

Procedure: 3-Aminophthalimide (2.00 g, 12.3 mmol) was dissolved in methanol (200 mL), and the solution was added with N-bromosuccinimide (2.19 g, 12.3 mmol), followed by stirring at room temperature for 50 minutes. The obtained solid was collected by filtration and washed with methanol to obtain 3-amino-6-bromophthalimide (2.21 g, yield 74%). The obtained solid was collected by filtration washed with methanol

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

Procedure: 3-Aminophthalimide (2.00 g, 12.3 mmol) was dissolved in methanol (200 mL), and the solution was added with N-bromosuccinimide (2.19 g, 12.3 mmol), followed by stirring at room temperature for 50 minutes. The obtained solid was collected by filtration and washed with methanol to obtain 3-amino-6-bromophthalimide (2.21 g, yield 74%). The obtained solid was collected by filtration washed with methanol

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

Procedure: A mixture of 4 g (21 mmol) of the preceeding diamine, 4.6 g (21 mmol) of di-tert-butyl dicarbonate, and 100 mL of dry CH2Cl2 was stirred for 12 hours at room temperature. Solvent and volatile by-products were removed by evaporation under reduced pressure, leaving 6 g (100% yield) of 6-(tert-butyloxycarbonylamino)-1-diethylamino-2-hydroxyhexane as an oil which was not further purified. It was dissolved in 100 mL of dry tetrahydrofuran (THF) along with 3.27 g (22 mmol) of phthalimide, 5.77 g (22 mmol) of triphenylphosphine, and 3.83 g (22 mmol) of diethyl azodicarboxylate (DEAD). The solution was stirred at room temperature for 12 hours at which point, to complete the reaction, an additional 1.64 g (11 mmol) of phthalimide and 1.92 g (11 mmol) of DEAD were added and stirring continued for 1 hour. Solvent was removed and the residual oil partitioned between ether and 1% hydrochloric acid. The aqueous phase was separated, made basic with NaOH solution, and extracted with ether. The ether extract was dried over anhydrous MgSO4, filtered evaporated. A pale yellow oil resulted which was dried under high vacuum to afford 9.2 g of the protected amino-phthalimide as a pale yellow oil. the reaction stirring continued for 1 hour Solvent was removed the residual oil partitioned between ether and 1% hydrochloric acid The aqueous phase was separated extracted with ether The ether extract was dried over anhydrous MgSO4 filtered evaporated A pale yellow oil resulted which was dried under high vacuum