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

HRID 447236Notes

Reaction equation

HRID 447236 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)acrylate

Reagents, catalysts & solvents 3

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

Procedure

A 2 L round bottom flask was charged 4-iodo-2,6-dimethylbenzenamine hydrochloride salt (55 g, 194 mmoles), methyl 2-(benzyloxycarbonyl)acrylate (59.2 g, 252 mmoles), tetrabutylammonium chloride (59.2 g, 213 mmoles), palladium (II) acetate (4.34 g, 19.4 mmoles), and tetrahydrofuran (1.2 L, degassed by a flow of nitrogen for 30 min). The mixture was stirred so that a suspension was formed and then degassed by a flow of nitrogen for 30 min. Triethylamine (110 mL, 789 mmoles) was 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, washed with tetrahydrofuran (2×100 mL), and concentrated. The residue was dissolved in dichloromethane, washed with water (3×) and brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography (silica gel, using 1:9 ethyl acetate/dichloromethane) gave a tan solid. The solid was recrystallized from warm methanol (210 mL) and water (100 mL). The mixture was held at room temperature overnight, then at 0° C. for 2 h, and finally at −15° C. for 2 h. The resulting solid was filtered, washed with ice cold 1:1 methanol/water, and dried under high vacuum overnight to give 44.7 g (65%) as a light tan solid which was a mixture of Z/E isomers (73:27). 1H-NMR (DMSO-d6) 6, 2.05 (s, 6H), 3.61 (s, 0.8H), 3.68 (s, 2.2H), 5.00 (s, 0.54H), 5.13 (s, 1.46H), 5.24 (s, 2H), 7.40-7.21 (m, 8H), 8.51 (s, 0.27 H), 8.79 (s, 0.73H); 13C-NMR (DMSO-d6) δ 17.8, 51.7, 65.3, 119.4, 120.0, 120.3, 127.3, 127.7, 128.3, 130.9, 135.8, 137.2, 146.9, 154.7, 166.0.

Workup

  1. customdegassed by a flow of nitrogen for 30 min)
  2. customwas formed
  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 with tetrahydrofuran (2×100 mL)
  8. concentrationconcentrated
  9. dissolutionThe residue was dissolved in dichloromethane
  10. washwashed with water (3×) and brine (2×)
  11. dry with materialdried over sodium sulfate
  12. concentrationconcentrated
  13. customFlash chromatography (silica gel, using 1:9 ethyl acetate/dichloromethane) gave a tan solid
  14. customThe solid was recrystallized
  15. temperaturefrom warm methanol (210 mL) and water (100 mL)
  16. waitat 0° C. for 2 h
  17. waitfinally at −15° C. for 2 h
  18. filtrationThe resulting solid was filtered
  19. washwashed with ice cold 1:1 methanol/water
  20. customdried under high vacuum overnight
  21. customto give 44.7 g (65%) as a light tan solid which
  22. additiona mixture of Z/E isomers (73:27)

Sources & evidence

ORD record
ord-c834b94731f6489a9abfd8d503da2795
Source dataset
uspto-grants-2013_07
Patent number
US08481546B2

Reaction notes

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