Tert-butyl 3-oxopyrrolidine-1-carboxylate → 1,1-Dimethylethyl 3-hydroxy-3-(6-methoxy-3-pyridinyl)-1-pyrrolidinecarboxylate

HRID 1260283Notes

Reaction equation

Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOCC>[OH:27][C:24]1([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23]1

Participants

Conditions

Temperature: -78 °C

Procedure

5-bromo-2-methoxypyridine (324 μL, 2.50 mmol) was added dropwise to a stirred suspension of n-butyllithium (1.72 mL of a 1.6 M hexanes solution, 2.75 mmol) in ether (10.0 mL) at −78° C. After 10 min, a solution of N-Boc-3-pyrrolidinone (463 mg, 2.50 mmol) in ether (2.00 mL) was added dropwise, and the reaction mixture was allowed to stir at −78° C. After 2 h, the reaction was quenched with satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-80% EtOAc/hexanes as eluent) afforded the title compound i-5a. m/z (ES) 295 (MH)+. 1H NMR (500 MHz, CDCl3): δ 8.31 (s, 1H), 7.71 (d, 1H, 7.1 Hz), 6.79 (dd, 1H, J=2.2, 8.6 Hz), 3.97 (s, 3H), 3.40-3.80 (m, 4H), 2.25 (m, 2H), 1.51 (s, 9H).

Workup

waitAfter 2 h
customthe reaction was quenched with satd
extractionaq. NH4Cl and extracted with EtOAc
washThe combined organics were washed with brine
dry with materialdried (sodium sulfate)
concentrationconcentrated in vacuo
customPurification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-80% EtOAc/hexanes as eluent)

Sources & evidence

ORD record: ord-f1421cec05c34d0fae906b8fd4005548
Source dataset: uspto-grants-2013_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08470819B2

Reaction notes

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