Methyl iodide → 1-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate

HRID 1777338Notes

Reaction equation

HRID 1777338 reaction equation
[CH2:1]([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14].CI.[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH2:13]([O:15][C:16]([C:18]1([CH3:1])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH3:14]

Participants

8

Reactant 5

HCID 6328Methyl iodideHCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 27588121-Tert-butyl 4-ethyl piperidine-1,4-dicarboxylateHCID 178418339Butyllithium

Product 1

HCID 162182761-tert-Butyl 4-ethyl 4-methylpiperidine-1,4-dicarboxylate

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 12679HexamethylphosphoramideSolvent

Conditions

Temperature
-70 °C

Procedure

n-Butyllithium (15% solution in n-hexane; 82 mL, 0.19 mol) is added to a stirred solution of diisopropyl amine (28.75 mL, 0.20 mol) in tetrahydrofuran (400 mL) at −70° C. under an atmosphere of nitrogen and stirred for 30 minutes. A solution of piperidine-1,4-dicarboxylic acid-1-tert-butyl ester 4-ethyl ester (30 g, 0.12 mol) in tetrahydrofuran (80 mL) is introduced at −70° C. Hexamethyl phosphoramide (45 mL) is added and reaction mixture is allowed to stir till the temperature reaches at −45° C. Reaction mixture again cooled to −70° C., methyl iodide (39.3 mL, 0.60 mol) is added and stirred for 1 hour. Saturated aqueous solution of ammonium chloride (100 mL) is added slowly into the reaction mixture at 0° C. and stirred for 10 minutes. It is extracted with ethyl acetate (3×200 mL). Combined organic layer is washed with brine solution (1×100 mL) and dried over sodium sulfate. Removal of solvent under reduced pressure gives a viscous liquid which is purified by column chromatography (silica gel 230-400, n-hexane:ethyl acetate, 9:1) to furnish 4-methyl piperidine-1,4-dicarboxylic acid-1-tert-butylester-4-ethyl ester.

Workup

  1. customreaction mixture
  2. stirringto stir till the temperature
  3. customreaches at −45° C
  4. customReaction mixture
  5. stirringstirred for 1 hour
  6. stirringstirred for 10 minutes
  7. extractionIt is extracted with ethyl acetate (3×200 mL)
  8. washCombined organic layer is washed with brine solution (1×100 mL)
  9. dry with materialdried over sodium sulfate
  10. customRemoval of solvent under reduced pressure
  11. customgives a viscous liquid which
  12. customis purified by column chromatography (silica gel 230-400, n-hexane:ethyl acetate, 9:1)

Sources & evidence

ORD record
ord-ecb81cddef664c4383d5ba32a46178f5
Source dataset
uspto-grants-2016_02
Patent number
US09266867B2

Reaction notes

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