benzyl 3,3-dimethyl-2-oxopyrrolidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate (0.0494 mol, 12.2 g) in 100 ml methanol. The mixture was cooled to −10° C. and sodium borohydride (0.247 mol, 9.35 g) was added slowly in portions with stirring, maintaining an internal temperature below −5° C. After the addition TLC (90:10 CHCl3:EtOAc) confirmed reaction was complete. The mixture was poured onto 500 ml saturated aqueous NH4Cl with crushed ice and stirred 16 hours, after which time the aqueous phase was extracted with Et2O (2×200 ml). The organics were dried over MgSO4, filtered and concentrated yielding 11.8 g (96%) of phenylmethyl 2-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=232 m/z ([M-OH]+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.39-7.33 (m, 5H), 5.25-5.14 (m, 2H), 4.99 and 4.92 (s, 1H), 3.61-3.38 (m, 2H), 1.97-1.91 (m, 1H), 1.62-1.56 (m, 1H), 1.12 (s, 3H), 1.02 (s, 3H). maintaining an internal temperature below −5° C reaction stirred 16 hours after which time the aqueous phase was extracted with Et2O (2×200 ml) The organics were dried over MgSO4 filtered concentrated

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate (0.0494 mol, 12.2 g) in 100 ml methanol. The mixture was cooled to −10° C. and sodium borohydride (0.247 mol, 9.35 g) was added slowly in portions with stirring, maintaining an internal temperature below −5° C. After the addition TLC (90:10 CHCl3:EtOAc) confirmed reaction was complete. The mixture was poured onto 500 ml saturated aqueous NH4Cl with crushed ice and stirred 16 hours, after which time the aqueous phase was extracted with Et2O (2×200 ml). The organics were dried over MgSO4, filtered and concentrated yielding 11.8 g (96%) of phenylmethyl 2-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=232 m/z ([M-OH]+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.39-7.33 (m, 5H), 5.25-5.14 (m, 2H), 4.99 and 4.92 (s, 1H), 3.61-3.38 (m, 2H), 1.97-1.91 (m, 1H), 1.62-1.56 (m, 1H), 1.12 (s, 3H), 1.02 (s, 3H). maintaining an internal temperature below −5° C reaction stirred 16 hours after which time the aqueous phase was extracted with Et2O (2×200 ml) The organics were dried over MgSO4 filtered concentrated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an oven-dried 1000 ml flask under argon was dissolved 3,3-dimethyl-2-pyrrolidinone (0.0718 mol, 8.13 g) in 200 ml THF. The resulting solution was cooled to −78° C., and lithium hexamethyldisilazide (0.0790 mol, 79 ml of a 1M solution in THF) was added over 15 min. Stirring was continued for 30 minutes, at which time benzyl chloroformate (0.0790 mol, 13.5 g) was added and the reaction was allowed to warm to room temperature and stir for 16 hr. The mixture was concentrated to ⅓ total volume and diluted with 500 ml ethyl acetate and washed with 1M HCl (2×200 ml), water (1×200 ml), and brine (1×100 ml). The organic phase was dried over MgSO4, filtered and concentrated. Purification of the crude residue on 120 g silica (ethyl acetate/hexanes) yielded 12.3 g (69%) of phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate as a light yellow oil. LCMS (ESI+)=248 m/z (M+), 270 m/z (MNa+). 1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.39-7.36 (m, 3H), 5.31 (s, 2H), 3.77-3.73 (t, 2H, J=6.96 Hz), 1.91-1.88 (t, 2H, J=7.08 Hz), 1.23 (s, 6H). 13C NMR (CDCl3) δ 178.83, 151.86, 135.35, 128.60, 128.34, 128.10, 68.00, 42.79, 42.16, 32.95, 24.28. was added to warm to room temperature stir for 16 hr The mixture was concentrated diluted with 500 ml ethyl acetate washed with 1M HCl (2×200 ml), water (1×200 ml), and brine (1×100 ml) The organic phase was dried over MgSO4 filtered concentrated Purification of the crude residue on 120 g silica (ethyl acetate/hexanes)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a 500 ml flask was dissolved phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate (0.0494 mol, 12.2 g) in 100 ml methanol. The mixture was cooled to −10° C. and sodium borohydride (0.247 mol, 9.35 g) was added slowly in portions with stirring, maintaining an internal temperature below −5° C. After the addition TLC (90:10 CHCl3:EtOAc) confirmed reaction was complete. The mixture was poured onto 500 ml saturated aqueous NH4Cl with crushed ice and stirred 16 hours, after which time the aqueous phase was extracted with Et2O (2×200 ml). The organics were dried over MgSO4, filtered and concentrated yielding 11.8 g (96%) of phenylmethyl 2-hydroxy-3,3-dimethyl-1-pyrrolidinecarboxylate as a clear oil which was used without further purification. LCMS (ESI+)=232 m/z ([M-OH]+). 1H NMR (400 MHz, CDCl3)— rotamers δ 7.39-7.33 (m, 5H), 5.25-5.14 (m, 2H), 4.99 and 4.92 (s, 1H), 3.61-3.38 (m, 2H), 1.97-1.91 (m, 1H), 1.62-1.56 (m, 1H), 1.12 (s, 3H), 1.02 (s, 3H). maintaining an internal temperature below −5° C reaction stirred 16 hours after which time the aqueous phase was extracted with Et2O (2×200 ml) The organics were dried over MgSO4 filtered concentrated

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In an oven-dried 1000 ml flask under argon was dissolved 3,3-dimethyl-2-pyrrolidinone (0.0718 mol, 8.13 g) in 200 ml THF. The resulting solution was cooled to −78° C., and lithium hexamethyldisilazide (0.0790 mol, 79 ml of a 1M solution in THF) was added over 15 min. Stirring was continued for 30 minutes, at which time benzyl chloroformate (0.0790 mol, 13.5 g) was added and the reaction was allowed to warm to room temperature and stir for 16 hr. The mixture was concentrated to ⅓ total volume and diluted with 500 ml ethyl acetate and washed with 1M HCl (2×200 ml), water (1×200 ml), and brine (1×100 ml). The organic phase was dried over MgSO4, filtered and concentrated. Purification of the crude residue on 120 g silica (ethyl acetate/hexanes) yielded 12.3 g (69%) of phenylmethyl 3,3-dimethyl-2-oxo-1-pyrrolidinecarboxylate as a light yellow oil. LCMS (ESI+)=248 m/z (M+), 270 m/z (MNa+). 1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (m, 2H), 7.39-7.36 (m, 3H), 5.31 (s, 2H), 3.77-3.73 (t, 2H, J=6.96 Hz), 1.91-1.88 (t, 2H, J=7.08 Hz), 1.23 (s, 6H). 13C NMR (CDCl3) δ 178.83, 151.86, 135.35, 128.60, 128.34, 128.10, 68.00, 42.79, 42.16, 32.95, 24.28. was added to warm to room temperature stir for 16 hr The mixture was concentrated diluted with 500 ml ethyl acetate washed with 1M HCl (2×200 ml), water (1×200 ml), and brine (1×100 ml) The organic phase was dried over MgSO4 filtered concentrated Purification of the crude residue on 120 g silica (ethyl acetate/hexanes)