Dimethylformamide → 1-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine

HRID 1417819Notes

Reaction equation

HRID 1417819 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CN(C=O)C.[CH2:28](I)[CH3:29]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:28][CH3:29])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 6340Iodoethane2×HCID 24758Sodium hydrideHCID 116877404-(4-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

Product 1

HCID 232888571-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A mixture of 1-(tert-butyloxycarbonyl)-4-(4-hydroxyphenyl)piperazine (XXII, 0.602 g, 2.2 mmol) in dry THF (4 ml) is added to an ice-cooled slurry of sodium hydride (0.1013 g, 2.5 mmol-60% in oil) in THF (1 ml). DMF (15.3 ml) is added to solubilize the solids that had precipitated, after which ethyl iodide (0.34 ml, 4.3 mmol) is added. The ice/water bath is removed and the mixture stirred for five hr. Another portion of ethyl iodide (0.35 ml, 4.4 mmol) is added and the mixture is allowed to stir over the weekend at 20°-250, at which time it is concentrated and the resulting solids are partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The combined organic phases are dried over magnesium sulfate, concentrated, and the residue chromatographed on silica gel eluting with methanol/dichloromethane (1/99) containing ammonium hydroxide (0.5%), followed by methanol/dichloromethane (2/98) containing ammonium hydroxide (0.5%). The appropriate fractions are pooled and concentrated to give 1-(tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII). 1-(Tert-butyloxycarbonyl)-4-(4-ethoxyphenyl)piperazine (XXIII, 0.43 g) is dissolved in methanol and methanol saturated with hydrochloric acid gas is added. After stirring at 20°-25° for 5 hours the slurry is concentrated and ether is added. The solids are collected, washed with ether, and dried to give 1-(4-ethoxyphenyl)piperazine dihydrochloride (XXIV), MS (m/z) 206; IR (mineral oil) 1253, 1511, 2542, 2432, 1475 and 2622 cm-1.

Workup

  1. customhad precipitated
  2. customThe ice/water bath is removed
  3. stirringto stir over the weekend at 20°-250
  4. concentrationat which time it is concentrated
  5. customthe resulting solids are partitioned between ethyl acetate and aqueous saturated sodium bicarbonate
  6. dry with materialThe combined organic phases are dried over magnesium sulfate
  7. concentrationconcentrated
  8. customthe residue chromatographed on silica gel eluting with methanol/dichloromethane (1/99)
  9. additioncontaining ammonium hydroxide (0.5%)
  10. additioncontaining ammonium hydroxide (0.5%)
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-69269206ae7344219ede03a983844374
Source dataset
uspto-grants-1999_03
Patent number
US05877317

Reaction notes

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