Ammonium Chloride → (2S,3S)-2-(3,4-difluorophenyl)-3,5,5-trimethylmorpholin-2-ol
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:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][C:17]=1[F:18].[NH4+].[Cl-]>C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])[CH:15]=[CH:16][C:17]=1[F:18]Participants
Conditions
- Temperature
- -78 °C
Procedure
A solution of morpholin-2-one 15 (410 mg, 2.86 mmol) in anhydrous THF (2.9 mL, 1M) was cooled to −78° C. and treated with 3,4-difluorophenylmagnesium bromide (1.2 equiv., 3.43 mmol, 6.90 mL, 0.5 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. under an inert atmosphere for 1.5 h, saturated aqueous solution of NH4Cl was added to the reaction vessel. The reaction mixture was allowed to warm to room temperature and extracted with ether (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. Purification of the residue by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH—NH4OH (90:9:1) as the eluent gave 190 mg (25%) of 4m as a yellow solid: [α]22D +18.2° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.45-7.39 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.10 (m, 1H), 3.82 (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 122.40, 122.31 116.74, 116.51, 115.8, 115.6, 96.5, 69.6, 53.4, 49.8, 27.3, 22.8, 16.5; LCMS (ESI) m/z 258.6, [(M+H)+, M=C13H17F2NO2].
Workup
- temperatureto warm to room temperature
- extractionextracted with ether (three times)
- washThe combined organic extracts were washed (water, brine)
- dry with materialdried (Na2SO4)
- concentrationconcentrated
- customPurification of the residue by column chromatography on silica gel
Sources & evidence
- ORD record
- ord-3f73679c45044b2d965d68eeeebfa398
- Source dataset
- uspto-grants-2014_12
- Patent number
- US08906908B2
Reaction notes
Loading…