Ethyl Acetate → (R)-3-phenylmorpholine

HRID 1615411Notes

Reaction equation

HRID 1615411 reaction equation
[C:1]1([C@H:7]2[NH:12][C:11](=O)[CH2:10][O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[OH-].[Na+]>C1COCC1.CO.O>[C:1]1([C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11][NH:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 14798Sodium HydroxideHCID 21226445Aluminium lithium hydride2×HCID 44195698(5R)-5-Phenylmorpholin-3-one

Product 1

HCID 13110207(R)-3-phenylmorpholine

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of (5R)-5-phenylmorpholin-3-one 5 (2.500 g, 14.11 mmol) in THF (57.02 mL) cooled in an ice bath was added lithium aluminium hydride (2M in THF) (9.170 mL of 2 M, 18.34 mmol) slowly over 5 mins. On complete addition mixture was warmed to 40° C. and stirred for 1 h. The reaction mixture was cooled down to rt then added more LAH (4.9 mL, 0.7 eq) and warmed back to 40° C. for a further 1 h. The reaction mixture was cooled in an ice bath and EtOAc (5 ml) was slowly added and the resulting mixture stirred at rt for 30 mins and then added very small amount of water until no vigorous reaction occurred. The reaction mixture turns thick so methanol (approx 50 mL) was added followed by a small amount of 1M NaOH to make mixture basic, filtered through celite, washing through with methanol. The filtrate was concentrated in vacuo and then loaded onto SCX2 (50 g) washed with methanol and filtrate discarded. The product was then eluted with 2M ammonia in methanol and the filtrate concentrated in vacuo to leave product as an orange oil that solidified on standing; 1H NMR (400.0 MHz, DMSO) d 2.85 (2H, m), 3.14 (1H, m), 3.45 (1H, m), 3.66 (1H, m), 3.78 (3H, m), 7.23 (1H, m) 7.31 (2H, m) and 7.41 (2H, m) ppm; MS (ES+) 164.1

Workup

  1. temperatureThe reaction mixture was cooled down to rt
  2. temperaturewarmed back to 40° C. for a further 1 h
  3. temperatureThe reaction mixture was cooled in an ice bath
  4. stirringthe resulting mixture stirred at rt for 30 mins
  5. customuntil no vigorous reaction
  6. additionwas added
  7. filtrationfiltered through celite
  8. washwashing through with methanol
  9. concentrationThe filtrate was concentrated in vacuo
  10. washwashed with methanol and filtrate
  11. washThe product was then eluted with 2M ammonia in methanol
  12. concentrationthe filtrate concentrated in vacuo
  13. customto leave product as an orange oil that solidified

Sources & evidence

ORD record
ord-05590f7cf8af4d329c63f83aff39cf23
Source dataset
uspto-grants-2014_07
Patent number
US08765751B2

Reaction notes

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