3,5-Bis(trifluoromethyl)benzyl alcohol → 4-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholine

HRID 2209977Notes

Reaction equation

HRID 2209977 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C:10](=[O:14])[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[F:35][C:36]([F:50])([F:49])[C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]O.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([O:14][CH2:40][C:39]2[CH:42]=[C:43]([C:45]([F:47])([F:48])[F:46])[CH:44]=[C:37]([C:36]([F:35])([F:49])[F:50])[CH:38]=2)[C@@H:9]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

8

Reactant 4

HCID 1229333,5-Bis(trifluoromethyl)benzyl alcoholHCID 516892Sodium BicarbonateHCID 3611392Lithium tri-s-butylborohydrideHCID 15871960(3S)-4-Benzyl-3-phenylmorpholin-2-one

Product 1

HCID 107438244-benzyl-2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenylmorpholineYield 73%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-75 °C

Procedure

A solution of 0.500 g (1.87 mmole) of N-benzyl-3-(S)-phenylmorpholin-2-one in 10 mL of dry THF was cooled to -75° C. under nitrogen and was treated dropwise with 2.06 mL (2.06 mmole) of a 1M solution of lithium tri(sec-butyl)-borohydride (L-Selectride®) in THF. After stirring the solution at -75° C. for 30 min, a solution of 3,5-bis(trifluoromethyl)benzyl alcohol, trifluoromethanesulfonate ester in toluene was added by cannula so that the internal temperature was maintained below -60° C. The resulting solution was stirred at -75° C. for 1 hr and then between -38° C. and -50° C. for 2 hr. The solution was then poured into a mixture of 25 mL of ethyl acetate and 20 mL of saturated aqueous sodium bicarbonate, and the layers were separated. The aqueous phase was extracted with 2×30 mL of ethyl acetate, the combined organic layers were dried over sodium sulfate, the mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on 130 g of silica eluting with 2L of 100:5 hexanes:ethyl acetate to give 0.68 g (73%) of an oil, which by 1H NMR is a 20:1 mixture of cis:trans morpholines.

Workup

  1. temperaturewas maintained below -60° C
  2. stirringThe resulting solution was stirred at -75° C. for 1 hr
  3. waitbetween -38° C. and -50° C. for 2 hr
  4. customthe layers were separated
  5. extractionThe aqueous phase was extracted with 2×30 mL of ethyl acetate
  6. dry with materialthe combined organic layers were dried over sodium sulfate
  7. filtrationthe mixture was filtered
  8. concentrationthe filtrate concentrated in vacuo
  9. customThe residue was purified by flash chromatography on 130 g of silica eluting with 2L of 100:5 hexanes

Sources & evidence

ORD record
ord-bff93641062447b4b5df75753b322af2
Source dataset
uspto-grants-1995_10
Patent number
US05457107

Reaction notes

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