Lithium Hexamethyldisilazide → 4-[2-(5-Bromo-2-chloropyridin-4-yl)acetyl]piperidine-1-carboxylic acid tert-butyl ester
Reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:11][C:12]1[C:13]([CH3:19])=[CH:14][C:15]([Cl:18])=[N:16][CH:17]=1.C([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)=O)C>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:22])[CH2:19][C:13]2[C:12]([Br:11])=[CH:17][N:16]=[C:15]([Cl:18])[CH:14]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]Participants
Reactant 3
Product 1
Reagents, catalysts & solvents 1
Conditions
- Temperature
- -40 °C
Procedure
Lithium bis(trimethylsilyl)amide (1.0 mol/L in tetrahydrofuran; 11.00 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (0.95 g) dissolved in tetrahydrofuran (15 mL) at −40° C. under argon atmosphere. The mixture is stirred for 2 h at −35 to −45° C. prior to addition of piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.33 g) dissolved in tetrahydrofuran (15 mL). The reaction mixture is allowed to warm to room temperature over a period of 1 h. Ice-cold water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40) to give the title compound. Mass spectrum (ESI+): m/z=417/419/421 (Cl+Br) [M+H]+.
Workup
- temperatureto warm to room temperature over a period of 1 h
- additionIce-cold water is added
- extractionthe mixture is extracted with ethyl acetate
- washThe combined extracts are washed with brine
- dry with materialdried (MgSO4)
- concentrationconcentrated
- customThe residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40)
Sources & evidence
- ORD record
- ord-9de86a7215744c3287a12a5e49770470
- Source dataset
- uspto-grants-2015_03
- Patent number
- US08975277B2
Reaction notes
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