Triethylamine → (Z)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylate

HRID 2099811Notes

Reaction equation

HRID 2099811 reaction equation
Cl.I[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[C:5]([CH3:11])[CH:4]=1.[CH2:12]([O:19][C:20]([C:22](=[CH2:27])[C:23]([O:25][CH3:26])=[O:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[NH2:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3](/[CH:27]=[C:22](\[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:21])/[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:5]=1[CH3:11]

Participants

7

Reactant 3

HCID 8471TriethylamineHCID 573482104-Iodo-2,6-dimethylaniline hydrochlorideHCID 66604662Methyl 2-(benzyloxycarbonyl)acrylate

Product 1

HCID 66605272(Z)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)acrylateYield 88.1%

Reagents, catalysts & solvents 3

HCID 70681Tetrabutylammonium ChlorideCatalystHCID 167845palladium(II) acetateCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A 2 L round bottom flask, was charged with 4-iodo-2,6-dimethylbenzenamine hydrochloride salt (55 g, 194 mmol), methyl 2-(benzyloxycarbonyl)acrylate (59.2 g, 252 mmol), tetrabutylammonium chloride (59.2 g, 213 mmol), palladium acetate (4.34 g, 19.4 mmol), and tetrahydrofuran (1.2 L, degassed by a flow of nitrogen for 30 min). The mixture was stirred to form a suspension and degassed by a flow of nitrogen for 30 min. Triethylamine (110 mL, 789 mmol) was then added and the resulting mixture was heated at reflux for 3 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and washed twice with tetrahydrofuran (2×100 mL). The solvents were removed and the residue was dissolved in methylene chloride which was extracted with water (3×), brine (2×), dried over sodium sulfate and concentrated. Column chromatography on silica gel using 1:9 ethyl acetate/methylene chloride as eluent afforded a tan solid, which was recrystalized from methanol (210 mL) and water (100 mL). After filtration, the solid was washed with ice cold 1:1 methanol/water mixture and then dried under high vacuum overnight at room temperature to afford the title compound (58.0 g, 65%) as a light tan solid. NMR shows a 2.7:1 ratio of Z and E isomers which were not separated. 1H-NMR (DMSO-d6) δ 8.79 (s, 0.73 H), 8.51 (s, 0.27 H), 7.40-7.21 (m, 8H), 5.24 (s, 2H), 5.13 (s, 1.46 H), 5.00 (s, 0.54 H), 3.68 (s, 2.2 H), 3.61 (s, 0.8 H), 2.05 (s, 6H); 13C-NMR (DMSO-d6) δ 166.0, 154.7, 146.9, 137.2, 135.8, 130.9, 128.3, 127.7, 127.3, 120.3, 120.0, 119.4, 65.3, 51.7, 17.8.

Workup

  1. customdegassed by a flow of nitrogen for 30 min)
  2. customto form a suspension
  3. customdegassed by a flow of nitrogen for 30 min
  4. temperaturethe resulting mixture was heated
  5. temperatureat reflux for 3 h
  6. filtrationthe reaction mixture was filtered through a pad of celite
  7. washwashed twice with tetrahydrofuran (2×100 mL)
  8. customThe solvents were removed
  9. dissolutionthe residue was dissolved in methylene chloride which
  10. extractionwas extracted with water (3×), brine (2×)
  11. dry with materialdried over sodium sulfate
  12. concentrationconcentrated
  13. customColumn chromatography on silica gel using 1:9 ethyl acetate/methylene chloride as eluent afforded a tan solid, which
  14. customwas recrystalized from methanol (210 mL) and water (100 mL)
  15. filtrationAfter filtration
  16. washthe solid was washed with ice cold 1:1 methanol/water mixture
  17. customdried under high vacuum overnight at room temperature

Sources & evidence

ORD record
ord-635a2b60a9eb4608817e4a05753feb0c
Source dataset
uspto-grants-2009_08
Patent number
US07569578B2

Reaction notes

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