Lithium Hexamethyldisilazide → 4-[2-(5-Bromo-2-chloropyridin-4-yl)acetyl]piperidine-1-carboxylic acid tert-butyl ester

HRID 533115Notes

Reaction equation

HRID 533115 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

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 27344275-Bromo-2-chloro-4-methylpyridineHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylate

Product 1

HCID 866748944-[2-(5-Bromo-2-chloropyridin-4-yl)acetyl]piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

Lithium bis(trimethylsilyl)amide solution (1.0 M in tetrahydrofuran; 11.00 mL) is added dropwise to 5-bromo-2-chloro-4-picoline (950 mg) in tetrahydrofuran (15 mL) at −40° C. under argon atmosphere. The mixture is stirred for 2 h at −35° C. to −45° C. prior to the 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 over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40) to give the title compound. LC (method 3): tR=1.43 min; Mass spectrum (ESI+): m/z=417, 419 [M+H]+.

Workup

  1. additionIce-cold water is added
  2. extractionthe mixture is extracted with ethyl acetate
  3. washThe combined extracts are washed with brine
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe residue is chromatographed on silica gel (cyclohexane/ethyl acetate 75:25→60:40)

Sources & evidence

ORD record
ord-5658ee1722aa4cfdbe4d07bc9c78c663
Source dataset
uspto-grants-2014_10
Patent number
US08853239B2

Reaction notes

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