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

HRID 1399531Notes

Reaction equation

HRID 1399531 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.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl: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 178478191HCID 178478191, compound

Product 1

HCID 46837780(2S,3S)-2-(4-Chlorophenyl)-3,5,5-trimethylmorpholin-2-olYield 29%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 15 (357 mg, 2.50 mmol) in dry THF (2.5 mL, 1M) under an N2 atmosphere was cooled to −78° C. and treated with 4-chlorophenylmagnesium bromide (2 equiv., 5.00 mmol, 5.00 mL, 1M solution in ether). The reaction mixture was stirred at −78° C. for 2 h. A saturated aqueous solution of NH4Cl was added to the reaction vessel, and the mixture was allowed to warm to room temperature. EtOAc was added and the organic layer was separated and the aqueous phase was extracted with EtOAc (trice). 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 180 mg (29%) of 4i as a white solid: [α]23D +33° (c 0.4, CHCl3): 1H NMR (CDCl3) δ 7.54 (d, 2H, J=8.5 Hz), 7.32 (d, 2H, J=8.5 Hz), 3.83 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.18 (q, 1H, J=6.5 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 128.5, 128.1, 127.6, 127.2, 101.6, 95.9, 69.5, 53.4, 49.7, 27.3, 22.8, 16.4; LCMS (ESI) m/z 256.3 [(M+H)+, M=C13H18ClNO2].

Workup

  1. temperatureto warm to room temperature
  2. customthe organic layer was separated
  3. extractionthe aqueous phase was extracted with EtOAc (trice)
  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-320f760ddc494641a774dd44b931b548
Source dataset
uspto-grants-2014_12
Patent number
US08906908B2

Reaction notes

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