N,N,N',N'-Tetramethylethylenediamine → 3-[2-Benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one

HRID 1278948Notes

Reaction equation

HRID 1278948 reaction equation
[CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:23])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)CCN(C)C.CN1CCCC1=O.[Br:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[O:45])=[C:42]([F:48])[CH:41]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:16]([CH:15]([CH:44]([C:43]1[CH:46]=[CH:47][C:40]([Br:39])=[CH:41][C:42]=1[F:48])[OH:45])[C:14]([N:3]1[CH:2]([CH3:1])[CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4]1=[O:13])=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1

Participants

7

Reactant 4

HCID 8037N,N,N',N'-TetramethylethylenediamineHCID 13387N-methyl-2-pyrrolidone2×HCID 1435174-Bromo-2-fluorobenzaldehydeHCID 13461718(4R,5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)oxazolidine-2-one

Product 1

HCID 777603853-[2-Benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one

Reagents, catalysts & solvents 2

HCID 24193Titanium TetrachlorideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-70 °C

Procedure

To a solution of (4R, 5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1.50 g, 4.8 mmol) in dichloromethane (23 mL) at −70° C. was added titanium tetrachloride (0.6 mL, 5.3 mmol) giving a yellow-orange solution which was stirred for 15 minutes at −70° C. N,N,N′,N′-Tetramethylethylenediamine(2.2 mL, 15 mmol) was added over 10 minutes giving a dark red reaction mixture which was stirred for 70 minutes at −78° C. 1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes at −70° C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol) in dichloromethane (5 mL) was added dropwise while maintaining a reaction temperature of less than or equal to −68° C. The reaction mixture was stirred at −70° C. for 60 minutes and then allowed to warm to 0 C. over 90 minutes, at which point it was quenched with 15 mL of saturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixture was stirred overnight at room temperature and filtered. The phases were separated and the organic phase was washed three times with water and once with brine, dried over magnesium sulfate, and concentrated under vacuum to 2.76 g of an oil containing the title compound and 1.2 equivalents of 1 -methyl-2-pyrrolidinone: 1H NMR (400 MHz, CDCl3) 67 7.48 (t, J=8.1 Hz, 1 H), 7.09-7.34 (m, 1 2H), 5.35 (d, J=7.3 Hz, 1 H), 5.32 (d, J=4.9 Hz, 1 H), 4.89-4.92 (m, 1 H), 4.51-4.55 (m, 1 H), 3.65 (bs, 1 H), 3.35 (dd, J=7.1, 7.1 Hz, 2H), 3.03-3.06 (m, 2 H), 2.81 (s, 3H), 2.34 (dd, J=8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3 H).

Workup

  1. customgiving a yellow-orange solution which
  2. customgiving
  3. customa dark red reaction mixture which
  4. stirringwas stirred for 70 minutes at −78° C
  5. stirringthe reaction mixture was stirred for 30 minutes at −70° C
  6. temperaturewhile maintaining a reaction temperature of less than or equal to −68° C
  7. stirringThe reaction mixture was stirred at −70° C. for 60 minutes
  8. temperatureto warm to 0 C
  9. waitover 90 minutes
  10. customat which point it was quenched with 15 mL of saturated aqueous ammonium chloride and 1.2 g
  11. stirringThis mixture was stirred overnight at room temperature
  12. filtrationfiltered
  13. customThe phases were separated
  14. washthe organic phase was washed three times with water
  15. dry with materialonce with brine, dried over magnesium sulfate
  16. concentrationconcentrated under vacuum to 2.76 g of an oil

Sources & evidence

ORD record
ord-365e132239844d3fbadc51e936c8122f
Source dataset
uspto-grants-2002_09
Patent number
US06444826B1

Reaction notes

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