tert-butyl 6-oxo-3,3a,4,5,7,7a-hexahydro-1H-isoindole-2-carboxylate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.9 g of oxalyl chloride was dissolved in 250 ml of dichloromethane and cooled to −78° C. in a nitrogen atmosphere. Then a solution of 4.83 g of dimethyl sulfoxide in dichloromethane (20 ml) was dropped thereinto over 17 minutes. Subsequently, a solution of 3.73 g of 8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol in dichloromethane (40 ml) was dropped thereinto over 10 minutes. After stirring for 10 minutes, 7.82 g of triethylamine was dropped thereinto over 10 minutes and stirring was continued for additional 1 hour. The reaction mixture was brought back to room temperature, diluted with dichloromethane, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.21 g of the title compound as a colorless oily substance. over 10 minutes over 10 minutes stirring was continued for additional 1 hour was brought back to room temperature washed with water a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate)

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

Procedure: To a solution of tert-butyl 5-oxohexahydro-1H-isoindole-2(3H)-carboxylate (11.97 g, 50 mmol) in EtOH (100 mL) were added a solution of NH3 in MeOH (7 M, 100 mL, 700 mmol) and Ti(OiPr)4 (28.42 g, 100 mmol). After addition, the reaction mixture was stirred at rt overnight and NaBH4 (3.78 g, 100 mmol) was added portionwise, then the resulting mixture was stirred at rt for another 5 h. The reaction was quenched with water (100 mL), stirred at rt for 1 h and filtered. The filter cake was washed with DCM (100 mL×3) and the filtrate was concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (100 mL) and water (100 mL), and extracted with EtOAc (250 mL×3). The combined organic phases were washed with brine (250 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as brown oil (12.02 g, 100%). After addition the resulting mixture was stirred at rt for another 5 h The reaction was quenched with water (100 mL) stirred at rt for 1 h filtered The filter cake was washed with DCM (100 mL×3) the filtrate was concentrated in vacuo The residue was dissolved in a mixture of EtOAc (100 mL) and water (100 mL) extracted with EtOAc (250 mL×3) The combined organic phases were washed with brine (250 mL) dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

Procedure: To a solution of tert-butyl 5-hydroxyhexahydro-1H-isoindole-2(3H)-carboxylate (48.98 g, 203.0 mmol) in DCM (500 mL) at 0° C. was added DMP (103.31 g, 243.6 mmol) portionwise. After addition, the reaction mixture was stirred at 0° C. for 0.5 h and then moved to rt overnight, cooled down to 0° C. and washed with a mixture of NaHCO3/Na2S2O3 saturated solution (v/v, 1/1, 500 mL), then stirred at 0° C. for 0.5 h and filtered. The filter cake was washed with DCM (250 mL×3) and the filtrate was extracted with DCM (250 mL×3). The combined organic phases were washed with brine (500 mL), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as yellow oil (48.58 g, 100%). After addition moved to rt overnight cooled down to 0° C. washed with a mixture of NaHCO3/Na2S2O3 saturated solution (v/v, 1/1, 500 mL) stirred at 0° C. for 0.5 h filtered The filter cake was washed with DCM (250 mL×3) the filtrate was extracted with DCM (250 mL×3) The combined organic phases were washed with brine (500 mL) dried over anhydrous Na2SO4 filtered concentrated in vacuo The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5)

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

Procedure: To a solution of tert-butyl 5-oxohexahydro-1H-isoindole-2(3H)-carboxylate (9.20 g, 36.31 mmol) in EtOH (290 mL) were added a solution of NH3 in MeOH (7 M, 290 mL, 2030 mmol) and Ti(Oi-Pr)4 (20.64 g, 72.62 mmol). After addition, the reaction mixture was stirred at rt for 6 h and NaBH4 (2.06 g, 54.47 mmol) was added portionwise. After addition, the resulting mixture was stirred at rt for 2 h, quenched with saturated ammonium hydroxide aqueous solution (150 mL), stirred at rt for 15 min and filtered. The filter cake was washed with DCM (150 mL) and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (200 mL) and extracted with water (150 mL×2). The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to give the product as yellow oil (7.34 g, 79.5%). After addition After addition the resulting mixture was stirred at rt for 2 h quenched with saturated ammonium hydroxide aqueous solution (150 mL) stirred at rt for 15 min filtered The filter cake was washed with DCM (150 mL) the filtrate was concentrated in vacuo The residue was dissolved in DCM (200 mL) extracted with water (150 mL×2) The organic phase was washed with brine (100 mL) dried over anhydrous Na2SO4 concentrated in vacuo The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.9 g of oxalyl chloride was dissolved in 250 ml of dichloromethane and cooled to −78° C. in a nitrogen atmosphere. Then a solution of 4.83 g of dimethyl sulfoxide in dichloromethane (20 ml) was dropped thereinto over 17 minutes. Subsequently, a solution of 3.73 g of 8-(tert-butoxycarbonyl)-8-azabicyclo[4.3.0]nonan-3-ol in dichloromethane (40 ml) was dropped thereinto over 10 minutes. After stirring for 10 minutes, 7.82 g of triethylamine was dropped thereinto over 10 minutes and stirring was continued for additional 1 hour. The reaction mixture was brought back to room temperature, diluted with dichloromethane, washed with water and a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 3.21 g of the title compound as a colorless oily substance. over 10 minutes over 10 minutes stirring was continued for additional 1 hour was brought back to room temperature washed with water a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate After filtration the solvent was distilled off under reduced pressure The residue thus obtained was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate)