Toluene → tert-Butyl 4-(3-formyl-4-hydroxyphenyl)piperazine-1-carboxylate

HRID 1883952Notes

Reaction equation

HRID 1883952 reaction equation
C1(C)C=CC=CC=1.Br[C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15].[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O>[C:27]([O:26][C:24]([N:18]1[CH2:23][CH2:22][N:21]([C:9]2[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=2)[CH:14]=[O:15])[CH2:20][CH2:19]1)=[O:25])([CH3:30])([CH3:28])[CH3:29]

Participants

8

Reactant 4

HCID 1140TolueneHCID 728635-BromosalicylaldehydeHCID 143452tert-Butyl piperazine-1-carboxylateHCID 23676156Sodium t-butoxide

Product 1

HCID 23508726tert-Butyl 4-(3-formyl-4-hydroxyphenyl)piperazine-1-carboxylateYield 51.2%

Reagents, catalysts & solvents 3

HCID 83681Tris(1,1-dimethylethyl)phosphineCatalystHCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 962WaterSolvent

Procedure

0.58 g of bis(dibenzylideneacetone)palladium and 0.16 g of tri-tert-butylphosphine are added under nitrogen to 200 ml of toluene, and the resultant solution, which becomes dark red, is stirred at 20° for 30 minutes. 10 g of 5-bromo-2-hydroxybenzaldehyde, 10.2 g of tert-butyl 1-piperazinecarboxylate and 7.2 g of sodium tert-butoxide are then added. The mixture is stirred at 60° for 24 hours and cooled, 800 ml of water are added, and the mixture is extracted with 2×500 ml of ethyl acetate. The organic phases are combined and washed with 300 ml of water, and the solvent is removed at 30° under reduced pressure. The dark-orange oil which remains (11 g) is purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres) leaving 7.8 g of pale-yellow crystals (51%), m.p. 84-86°; MS 306 (M+), 250 (100%), 233, 176, 164.

Workup

  1. stirringThe mixture is stirred at 60° for 24 hours
  2. temperaturecooled
  3. extractionthe mixture is extracted with 2×500 ml of ethyl acetate
  4. washwashed with 300 ml of water
  5. customthe solvent is removed at 30° under reduced pressure
  6. customis purified by chromatography (300 g of silica gel; MTB ether/heptane 5:1; 1.5 litres)

Sources & evidence

ORD record
ord-aaaec68fe48e45558648dbbd16890287
Source dataset
uspto-grants-2004_07
Patent number
US06762300B2

Reaction notes

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