Citric Acid → 4-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrile

HRID 2267037Notes

Reaction equation

HRID 2267037 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([OH:16])[C:8]=1[CH2:17][CH2:18][CH3:19].Br[C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[CH:22]=[CH:21][CH:20]=2)=[C:8]([CH2:17][CH2:18][CH3:19])[C:9]=1[OH:16])(=[O:15])[CH3:14]

Participants

9

Reactant 6

HCID 311Citric AcidHCID 10796Cesium carbonateHCID 12162Benzonitrile, 4-bromo-HCID 2855718-Crown-6HCID 634876Binap, (A+-)-HCID 145235601-{4-[(3-Aminophenyl)methoxy]-2-hydroxy-3-propylphenyl}ethan-1-one

Product 1

HCID 685330004-[3-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrileYield 63%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Combine 1-[4-(3-amino-benzyloxy)-2-hydroxy-3-propyl-phenyl]-ethanone (1.00 g, 3.34 mmol), 4-bromo-benzonitrile (553 mg, 3.03 mmol), cesium carbonate (1.39 g, 4.25 mmol), and 18-crown-6 (80 mg, 0.304 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl] (284 mg, 0.456 mmol), and palladium acetate (68 mg, 0.304 mmol). Purge reaction vessel with argon. Heat to 100° C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with 30% ethyl acetate:hexanes to yield the title compound as a yellow solid (760 mg, 63%): 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.58 (sextet, 2H), 2.56 (s, 3H), 2.69 (t, 2H), 5.15 (s, 2H), 6.07 (bs, 1H), 6.47 (d, 1H), 6.98 (d, 2H), 7.13 (t, 2H), 7.23 (m, 1H), 7.38 (t, 1H), 7.49 (d, 2H), 7.58 (d, 1H), 12.75 (s, 1H).

Workup

  1. customPurge
  2. customreaction vessel with argon
  3. customPurge
  4. customreaction vessel with argon
  5. temperaturecool to ambient temperature
  6. extractionextract with ethyl acetate
  7. dry with materialdry with sodium sulfate
  8. filtrationfilter
  9. concentrationconcentrate to dryness
  10. customPurify the resulting residue by flash chromatography
  11. washeluting with 30% ethyl acetate

Sources & evidence

ORD record
ord-d9df4083870846aa9ecdd4ad8aaa6ffd
Source dataset
uspto-grants-2010_12
Patent number
US07858646B2

Reaction notes

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