(3aR,7aS)-3a,4,7,7a-tetrahydroisoindole-1,3-dione

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

Procedure: Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. The mixture was filtered then evaporated

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

Procedure: 30.2 g of cis-1,2,3,6-tetrahydrophthalimide was dissolved in 200 ml of N,N-dimethylformamide. After adding 38.7 g of potassium carbonate and 30.4 g of benzyl chloride, the resulting mixture was stirred at 50° C. for 3 hours and further at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were ground and washed with diisopropyl ether and n-hexane followed by filtration. Thus 39.1 g of the title compound was obtained as pale yellow crystals. washed with water The aqueous layer was extracted with ethyl acetate The organic layer was washed successively with water a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate After filtering the solvent was distilled off under reduced pressure The crude crystals thus obtained washed with diisopropyl ether and n-hexane followed by filtration

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

Procedure: A solution of (3aR,7aS)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (3.0 g, 19.9 mmol) and 10% Pd/C (300 mg) in MeOH (100 mL) was shaken in an H2 atmosphere (300 psi) in a Parr apparatus for 24 h. The reaction mixture was filtrated and the liquids concentrated to dryness, affording the title compound (2.6 g, 16.99 mmol), that was sued without any further purification, as a white powder. The reaction mixture was filtrated the liquids concentrated to dryness

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of lithium aluminum hydride (21.4 g, 0.562 mol) in THF (700 mL) at room temperature was treated with cis-1,2,3,6-tetrahydrophthalimide (Aldrich; 37 g, 0.245 mol) in small portions. The reaction mixture was stirred at 60° C. overnight then cooled to room temperature and quenched carefully by the sequential addition of water (22 mL), THF (22 mL), 15% aqueous KOH (22 mL), and water (80 mL). The mixture was diluted with diethyl ether (100 mL), stirred at room temperature for 1 hour, and then filtered (methylene chloride wash). The filtrate was concentrated under reduced pressure to provide the title compound as an oil (26.1 g). 1H NMR (CDCl3, 300 MHz) δ 1.76–2.02 (m, 2H), 2.10–2.33 (m, 3H), 2.34–2.56 (m, 2H), 2.61–2.79 (m, 2H), 2.87–3.17 (m, 2H), 5.53–6.03 (m, 2H); MS (DCI/NH3) m/z 124 (M+H)+. then cooled to room temperature quenched carefully by the sequential addition of water (22 mL), THF (22 mL), 15% aqueous KOH (22 mL), and water (80 mL) The mixture was diluted with diethyl ether (100 mL) stirred at room temperature for 1 hour filtered (methylene chloride wash) The filtrate was concentrated under reduced pressure

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

Procedure: Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. The mixture was filtered then evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15.1 g. of cis-1,2,3,6-tetrahydrophthalimide are dissolved in 15 ml of methanol in which has previously been dissolved, 2.3 g of sodium metal. The mixture is evaporated to dryness under reduced pressure. 14 g. of 3-bromo-1-propanol are added to the solid, warming occurs. When the heating subsides, 40 ml of dimethylformamide are added with heating under reflux for 6 hours. After cooling, 200 ml of water and 100 ml of methylene chloride are added. The mixture is shaken and the aqueous phase discarded. The organic extract is washed with water (2×50 ml) and the methylene chloride solution is dried over anhydrous sodium sulfate. The solution is concentrated to about 50 ml and hexane added near the cloud point. Cooling to 0° C. precipitates 3-(cis-1,2,3,6-tetrahydrophthalimido)-1-propanol (1b). has previously been dissolved The mixture is evaporated to dryness under reduced pressure of 3-bromo-1-propanol are added to the solid warming When the heating subsides, 40 ml of dimethylformamide are added with heating under reflux for 6 hours After cooling 200 ml of water and 100 ml of methylene chloride are added The organic extract is washed with water (2×50 ml) the methylene chloride solution is dried over anhydrous sodium sulfate The solution is concentrated to about 50 ml and hexane added near the cloud point precipitates 3-(cis-1,2,3,6-tetrahydrophthalimido)-1-propanol (1b)

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

Procedure: Cis-4-cyclohexene-1,2-dicarboximide (10.9 g) was hydrogenated over 10% palladium on carbon (1 g) in absolute ethanol (420 ml) at 50 psi for 10 minutes. The mixture was filtered then evaporated to give cis-cyclohexane-1,2-dicarboximide (10.6 g). To anhydrous diethyl ether (200 ml) was cannulated under nitrogen a 1M diethyl ether solution (200 ml) of lithium aluminium hydride. To the foregoing solution, under reflux, was added cis-cyclohexane-1,2-dicarboximide (10.6 g) portionwise over 10 minutes. The reaction mixture was heated to reflux for 3 hours. After cooling to 0° C., water (7 ml) was added followed by 4N sodium hydroxide (7.6 ml) and water (23 ml). The white suspension was stirred whilst warming to room temperature. The solid was removed by filtration then the filtrate dried (sodium sulphate) and evaporated to give a cream oil. The mixture was filtered then evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 15.1 g. of cis-1,2,3,6-tetrahydrophthalimide are dissolved in 15 ml of methanol in which has previously been dissolved, 2.3 g of sodium metal. The mixture is evaporated to dryness under reduced pressure. 14 g. of 3-bromo-1-propanol are added to the solid, warming occurs. When the heating subsides, 40 ml of dimethylformamide are added with heating under reflux for 6 hours. After cooling, 200 ml of water and 100 ml of methylene chloride are added. The mixture is shaken and the aqueous phase discarded. The organic extract is washed with water (2×50 ml) and the methylene chloride solution is dried over anhydrous sodium sulfate. The solution is concentrated to about 50 ml and hexane added near the cloud point. Cooling to 0° C. precipitates 3-(cis-1,2,3,6-tetrahydrophthalimido)-1-propanol (1b). has previously been dissolved The mixture is evaporated to dryness under reduced pressure of 3-bromo-1-propanol are added to the solid warming When the heating subsides, 40 ml of dimethylformamide are added with heating under reflux for 6 hours After cooling 200 ml of water and 100 ml of methylene chloride are added The organic extract is washed with water (2×50 ml) the methylene chloride solution is dried over anhydrous sodium sulfate The solution is concentrated to about 50 ml and hexane added near the cloud point precipitates 3-(cis-1,2,3,6-tetrahydrophthalimido)-1-propanol (1b)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using a 250 mL round-bottomed flask equipped with a magnetic stir bar and an ice/salt bath, a suspension of cis-4-cyclohexene-1,2-dicarboximide (15.1 g, 100 mmol), cyanogen bromide (11.7 g, 110 mmol), and 100 mL of acetone was cooled to 0° C. Triethylamine (16.0 mL, 115 mmol) was added via syringe over a 12 minute period. The resulting peach slurry was allowed to stir for 15 minutes. The mixture was diluted with ethyl acetate and filtered to remove solid triethylamine hydrobromide. The filter cake was rinsed with ethyl acetate and the filtrate was concentrated using a rotary evaporator. The crude paste was partitioned between water and a 2:1 mixture of ethyl acetate/hexanes. The organic phase was washed with brine, dried (MgSO4), and concentrated to give a light brown solid. The crude product was purified by recrystallization using ethyl acetate/pet ether or ethyl acetate/hexanes to afford 11.5 g (65%) of a glossy off white solid, mp 136°-138° C.: IR (nujol) 2256 (nitrile), 1749 (carbonyl) cm-1 ; 1H NMR (200 MHz, CDCl3) δ 2.30 (ddd, 2, J=15, 4.4, 2.75 Hz), 2.64 (ddd, 2, J=15, 3.8, 2.75 Hz), 3.35 (dd, 2, J=3.5, 2.75 Hz), 5.98 (ddd, 2, J= 3.9, 1.7, 1.5 Hz); 13C NMR (50 MHz, CDCl3) δ 173.48, 127.52, 100.72, 40.08, 23.26; GC/MS m/e (relative intensity) 176 (29.5), 147 (11.1), 107 (20.0), 105 (23.3), 80 (44.0), 79 (100), 78 (35.1). equipped with a magnetic stir bar and an ice/salt bath filtered to remove solid triethylamine hydrobromide The filter cake was rinsed with ethyl acetate the filtrate was concentrated a rotary evaporator The crude paste was partitioned between water a 2:1 mixture of ethyl acetate/hexanes The organic phase was washed with brine dried (MgSO4) concentrated to give a light brown solid The crude product was purified by recrystallization to afford 11.5 g (65%) of a glossy off white solid, mp 136°-138° C.

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

Procedure: 30.2 g of cis-1,2,3,6-tetrahydrophthalimide was dissolved in 200 ml of N,N-dimethylformamide. After adding 38.7 g of potassium carbonate and 30.4 g of benzyl chloride, the resulting mixture was stirred at 50° C. for 3 hours and further at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure. The crude crystals thus obtained were ground and washed with diisopropyl ether and n-hexane followed by filtration. Thus 39.1 g of the title compound was obtained as pale yellow crystals. washed with water The aqueous layer was extracted with ethyl acetate The organic layer was washed successively with water a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate After filtering the solvent was distilled off under reduced pressure The crude crystals thus obtained washed with diisopropyl ether and n-hexane followed by filtration

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

Procedure: A solution of (3aR,7aS)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (3.0 g, 19.9 mmol) and 10% Pd/C (300 mg) in MeOH (100 mL) was shaken in an H2 atmosphere (300 psi) in a Parr apparatus for 24 h. The reaction mixture was filtrated and the liquids concentrated to dryness, affording the title compound (2.6 g, 16.99 mmol), that was sued without any further purification, as a white powder. The reaction mixture was filtrated the liquids concentrated to dryness

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of lithium aluminum hydride (21.4 g, 0.562 mol) in THF (700 mL) at room temperature was treated with cis-1,2,3,6-tetrahydrophthalimide (Aldrich; 37 g, 0.245 mol) in small portions. The reaction mixture was stirred at 60° C. overnight then cooled to room temperature and quenched carefully by the sequential addition of water (22 mL), THF (22 mL), 15% aqueous KOH (22 mL), and water (80 mL). The mixture was diluted with diethyl ether (100 mL), stirred at room temperature for 1 hour, and then filtered (methylene chloride wash). The filtrate was concentrated under reduced pressure to provide the title compound as an oil (26.1 g). 1H NMR (CDCl3, 300 MHz) δ 1.76–2.02 (m, 2H), 2.10–2.33 (m, 3H), 2.34–2.56 (m, 2H), 2.61–2.79 (m, 2H), 2.87–3.17 (m, 2H), 5.53–6.03 (m, 2H); MS (DCI/NH3) m/z 124 (M+H)+. then cooled to room temperature quenched carefully by the sequential addition of water (22 mL), THF (22 mL), 15% aqueous KOH (22 mL), and water (80 mL) The mixture was diluted with diethyl ether (100 mL) stirred at room temperature for 1 hour filtered (methylene chloride wash) The filtrate was concentrated under reduced pressure