1-((Tert-butoxy)carbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid → tert-Butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate
Reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]Participants
Procedure
To a solution of 4,4-difluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (Compound 2a) (1.5 g; 6.0 mmol) in tetrahydrofuran (15 mL) was added borane-dimethylsulfide complex (3.79 mL; 7.58 mmol) dropwise at ambient temperature. The reaction mixture was refluxed for 2 h. The resultant mixture was allowed to cool to room temperature. The mixture was partitioned between EtOAc and H2O. The organic phase was washed with H2O, and then dried over Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure to give the crude material. The crude material was purified by flash column chromatography (SiO2), eluting with a heptane-EtOAc gradient to afford Compound 2b (1.2 g; 84% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ4.08-4.23 (m, 2H), 3.61-3.87 (m, 4H), 2.45-2.57 (m, 1H), 2.15 (br.s, 1H), 1.49 (s, 9H).
Workup
- temperatureThe reaction mixture was refluxed for 2 h
- customThe mixture was partitioned between EtOAc and H2O
- washThe organic phase was washed with H2O
- dry with materialdried over Na2SO4
- filtrationThe mixture was filtered
- customthe filtrate was evaporated under reduced pressure
- customto give the crude material
- customThe crude material was purified by flash column chromatography (SiO2)
- washeluting with a heptane-EtOAc gradient
Sources & evidence
- ORD record
- ord-ff12beb31cd54f81b9c9c96c15a1ab38
- Source dataset
- uspto-grants-2014_04
- Patent number
- US08685990B2
Reaction notes
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