tert-Butyl piperazine-1-carboxylate → Tert-butyl 4-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperazine-1-carboxylate

HRID 900072Notes

Reaction equation

HRID 900072 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:12]1([C:10](=[O:11])[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([N:28]3[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]3)=[CH:3][CH:4]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1

Participants

6

Reactant 3

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 221798563-(4-Bromophenyl)-1-morpholinopropan-1-oneHCID 23676156Sodium t-butoxide

Product 1

HCID 22179854Tert-butyl 4-[4-(3-morpholin-4-yl-3-oxopropyl)phenyl]piperazine-1-carboxylateYield 59%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Procedure

A solution of Example 4B (400 mg, 1.342 mmol) in toluene (3.4 mL) at room temperature was treated with 1-tert-butoxycarbonylpiperazine (300 mg, 1.611 mmol), Pd2(dba)3 (61 mg, 0.0671 mmol), bis-tert-butyl biphenylphosphine (40 mg, 0.134 mmol) and sodium tert-butoxide (199 mg, 2.013 mmol), degassed three times by freeze-thaw cycle, stirred overnight and partitioned between ethyl acetate and saturated NH4Cl. The aqueous layer was extracted with ethyl acetate (3×30 mL) and the combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane to provide the desired product (317 mg, 59%). 1H NMR (300 MHz, CD3OD) δ 7.12 (2H, m), 6.91 (2H, br), 3.63 (8H, br), 3.53 (2H, t), 3.36 (2H, t), 3.10 (4H, br), 2.91 (2H, t), 2.58 (1H, t), 1.48 (9H, s).

Workup

  1. customdegassed three times by freeze-thaw cycle
  2. custompartitioned between ethyl acetate and saturated NH4Cl
  3. extractionThe aqueous layer was extracted with ethyl acetate (3×30 mL)
  4. dry with materialthe combined extracts were dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe concentrate was purified by flash column chromatography on silica gel with 66% acetonitrile in dichloromethane

Sources & evidence

ORD record
ord-3a81a085cc0e4394a0187d12f5e758b9
Source dataset
uspto-grants-2008_04
Patent number
US07358251B2

Reaction notes

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