Sulfuric acid magnesium salt (1:1) → 4-Benzyl-cis-2-methyl-6-(trifluoromethyl)morpholine

HRID 922774Notes

Reaction equation

HRID 922774 reaction equation
[CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C@H:10]([CH3:18])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH2:1]([N:8]1[CH2:13][C@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C@H:10]([CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 24083Sulfuric acid magnesium salt (1:1)HCID 21226445Aluminium lithium hydrideHCID 89543806(2R,6R)-4-Benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one

Product 1

HCID 588470294-Benzyl-cis-2-methyl-6-(trifluoromethyl)morpholineYield 66%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (4-4) was added 1M LAH (48 ml, 48.0 mmol) in THF slowly at rt. After the addition was complete the mixture was heated to reflux. After 1 hr the mixture was cooled to rt then 0° C. The mixture was slowly quenched with 2M NaOH until gas evolution had ceased and a fine white precipitate formed. Anhydrous MgSO4 was added and the mixture stirred for 15 minutes The slurry was filtered through a pad of celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (120 g, 0-10% EtOAc/hexanes, 15 minute gradient) to give a afford (2R,6R)-4-benzyl-2-methyl-6-(trifluoromethyl)morpholine (4-5, 4.1 g, 66% over 3 steps) as clear oil. 1H NMR (400 MHz, CDCl3): δ 7.35-7.26 (m, 5H); 4.02 (dqd, J=10.7, 6.4, 2.5 Hz, 1H); 3.76-3.69 (m, 1H); 3.60-3.48 (m, 2H); 2.89 (d, J=11.1 Hz, 1H); 2.73-2.68 (m, 1H); 2.16-2.04 (m, 1H); 1.91-1.79 (m, 1H); 1.19 (d, J=6.3 Hz, 3H).

Workup

  1. additionAfter the addition
  2. temperaturewas heated to reflux
  3. custom0° C
  4. customThe mixture was slowly quenched with 2M NaOH until gas evolution
  5. customa fine white precipitate formed
  6. filtrationwas filtered through a pad of celite
  7. washwashing with EtOAc
  8. concentrationthen concentrated
  9. customwas subjected to silica gel chromatography (120 g, 0-10% EtOAc/hexanes, 15 minute gradient)

Sources & evidence

ORD record
ord-b53f76298cee40a6a77b4e341f7ea5da
Source dataset
uspto-grants-2016_03
Patent number
US09278960B2

Reaction notes

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