4-Methylmorpholine → N-[4-(Hydroxymethyl)phenyl]-N-methylacetamide

HRID 1654538Notes

Reaction equation

HRID 1654538 reaction equation
[C:1]([N:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O.CN(C=O)C.COCCOC>[C:1]([N:4]([C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2]

Participants

8

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 2834714-[acetyl(methyl)amino]benzoic acidHCID 4311764Sodium borohydride

Product 1

HCID 54439979N-[4-(Hydroxymethyl)phenyl]-N-methylacetamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
-20 °C

Procedure

An oven dried flask, under nitrogen flow, was charged with a stir bar, 4-(N-acetyl-N-methylamino)benzoic acid (1.0 g, 5.18 mmol), prepared as in step 7, anhydrous DME (10.3 mL), and anhydrous DMF (3.0 mL). The resulting solution was cooled to -20° C., and 4-methylmorpholine (0.60 mL, 5.4 mmol) and isobutyl chloroformate (0.70 mL, 5.4 mmol) were added sequentially via syringe. The reaction mixture was stirred under N2 at -20° C. for 1 hour. The resultant yellow mixture was filtered and the precipitate washed with DME (2×~1 mL). The combined flitrate and washings were cooled to 0° C. and sodium borohydride (800 mg, 21.1 mmol) dissolved in water (2.0 mL) was added dropwise. The reaction was stirred at 0° C. for 15 min. and quenched with saturated aqueous ammonium chloride. The resulting mixture was partitioned between ethyl acetate and brine. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to give an oil. Purification by flash chromatography on silica gel (90% ethyl acetate/hexane) provided 4-(N-acetyl-N-methylamino)benzyl alcohol as a colorless oil which solidified on standing. Recrystallization from hexane provided the alcohol as a colorless solid (543.0 mg, 58.5%). mp 83.5°-85.5° C. 1H NMR (300 MHz, CDCl3) δ 7.45 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.75 (2H, s), 3.27 (3H, s), 1.90 (3H, MS m/e 180 (M+H)+, 197 (M+NH4)+.

Workup

  1. customAn oven dried flask
  2. additionunder nitrogen flow, was charged with a stir bar
  3. filtrationThe resultant yellow mixture was filtered
  4. washthe precipitate washed with DME (2×~1 mL)
  5. temperatureThe combined flitrate and washings were cooled to 0° C.
  6. additionwas added dropwise
  7. stirringThe reaction was stirred at 0° C. for 15 min.
  8. customquenched with saturated aqueous ammonium chloride
  9. customThe resulting mixture was partitioned between ethyl acetate and brine
  10. dry with materialThe combined organic layers were dried (MgSO4)
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto give an oil
  14. customPurification by flash chromatography on silica gel (90% ethyl acetate/hexane)

Sources & evidence

ORD record
ord-96a402ec4e0c4e1fb8f79c0c9411eeca
Source dataset
uspto-grants-1995_04
Patent number
US05407959

Reaction notes

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