Ethyl Acetate → (2S,3S)-2-(4-Fluorophenyl)-3,5,5-trimethylmorpholin-2-ol

HRID 1399530Notes

Reaction equation

HRID 1399530 reaction equation
[CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])=[CH:14][CH:13]=1

Participants

6

Reactant 4

HCID 8857Ethyl AcetateHCID 25517Ammonium ChlorideHCID 46837646HCID 46837646, compoundHCID 178418676HCID 178418676, compound

Product 1

HCID 46837653(2S,3S)-2-(4-Fluorophenyl)-3,5,5-trimethylmorpholin-2-olYield 28.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 15 (166 mg, 1.16 mmol) in dry THF (1.2 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-fluorophenylmagnesium bromide (1.3 equiv., 1.5 mmol, 1.9 mL, 0.8 M solution in THF). The reaction mixture was stirred at −78° C. for 3 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc (5 mL) was added to the reaction vessel and the organic layer was separated. The aqueous phase was extracted with EtOAc (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH (90:10) as the eluent to afford 80 mg of 4h as a white solid: [α]22D +31.2° (c 0.5, CHCl3); 1H NMR (CDCl3) δ 7.60-7.55 (m, 2H), δ 7.08-7.00 (m, 2H), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.17 (q, 1H, J=6.4 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.4 Hz); 13C NMR (CDCl3) δ 128.0, 127.9, 114.87, 114.58, 103.2, 98.4, 96.8, 69.5, 53.5, 27.3, 22.8, 16.4; LCMS (ESI) m/z 240.0 [(M+H)+, M=C13C18FNO2].

Workup

  1. temperatureto warm to room temperature
  2. customthe organic layer was separated
  3. extractionThe aqueous phase was extracted with EtOAc (three times)
  4. washThe combined organic extracts were washed (water, brine)
  5. dry with materialdried (Na2SO4)
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography on silica gel

Sources & evidence

ORD record
ord-145176cb605c480c88d26bcc1b0f9559
Source dataset
uspto-grants-2014_12
Patent number
US08906908B2

Reaction notes

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