3,5-Bis(trifluoromethyl)benzoyl chloride → 2-(R)-(3,5-Bis(trifluoromethyl)benzoyloxy)-3-(S)-phenyl-4-benzyl Morpholine

HRID 1956499Notes

Reaction equation

HRID 1956499 reaction equation
[C:1]1([C@H:7]2[C:12](=[O:13])[O:11][CH2:10][CH2:9][N:8]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C1COCC1>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([O:13][C@H:12]1[O:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:41]

Participants

5

Reactant 3

HCID 1018563,5-Bis(trifluoromethyl)benzoyl chlorideHCID 3611392Lithium tri-s-butylborohydride2×HCID 15871960(3S)-4-Benzyl-3-phenylmorpholin-2-one

Product 1

HCID 105296672-(R)-(3,5-Bis(trifluoromethyl)benzoyloxy)-3-(S)-phenyl-4-benzyl MorpholineYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of 2.67 g (10.0 mmol) of 3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) in 40 mL of dry THF was cooled to -78° C. The cold solution was treated with 12.5 mL of 1.0M L-Selectride®, solution in THF, maintaining the internal reaction temperature below -70° C. Alternatively, only a 6% excess of L-Selectride® may be required. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 mL (20.0 mmol) of 3,5-bis(trifluoro-methyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. Alternatively, acetic acid may be used for the quench. The quenched mixture was partitioned between 300 mL of ether and 50 mL of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 mL of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid.

Workup

  1. temperaturemaintaining the internal reaction temperature below -70° C
  2. stirringThe resulting yellow mixture was stirred cold for 30 minutes
  3. customthe reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution
  4. customThe quenched mixture was partitioned between 300 mL of ether and 50 mL of water
  5. customthe layers were separated
  6. dry with materialThe organic layer was dried over magnesium sulfate
  7. extractionThe aqueous layer was extracted with 300 mL of ether
  8. customthe extract was dried
  9. concentrationThe combined organics were concentrated in vacuo

Sources & evidence

ORD record
ord-0be2d653d15b4b81ad700d3a687ccae3
Source dataset
uspto-grants-1998_07
Patent number
US05780467

Reaction notes

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