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

HRID 1622231Notes

Reaction equation

HRID 1622231 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 drop wise to 5-bromo-2-chloro-4-picoline (950 mg) in tetrahydrofuran (15 mL) at −40° C. under an 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 5): 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-d41cc7773989475ab6bbfc0f56b07334
Source dataset
uspto-grants-2014_07
Patent number
US08778926B2

Reaction notes

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