反应详情

温度

-78 °C

To a solution of 1-(4-fluorophenyl)-4-(methylsulfonyl)piperazine (Intermediate B1; 600 mg; 2.32 mmol) in THF (10 mL) was added Lithiumbis(trimethylsilyl)amide (4.65 mL of a 1.00 M solution in THF; 4.65 mmol) at −78° C. under N2. After 30 min, diethylchlorophosphate (0.38 mL; 2.56 mmol) was added and the mixture was stirred at −78° C. for one hour. A solution of 2,2-dimethyl-5-phenylpent-4-ynal (prepared as described by Cossy et al., 1997, Journal of Organic Chemistry, 62(23), 7900-7901, 432 mg; 2.32 mmol) in THF (5 mL) was cannulated and the reaction mixture was allowed to warm to rt and stirred for 12 h. Hydroxylamine (4.1 mL; 70 mmol was then added and the mixture was heated at 60° C. for 3 h. It was finally concentrated under reduced pressure, redissolved in is EtOAc, washed with a saturated solution of NH4Cl and with brine, dry over magnesium sulfate, filtrated and concentrated. Purification of the crude by flash chromatography on silica (EtOAc:c-Hex; gradient from 20:80 to 50:50) gave the title compounds as a yellow oil (710 mg, 66% yield). HPLC, Rt: 4.15 min (purity: 95.9%). LC/MS, M+(ESI): 460.2. 1H NMR (DMSO-d6) δ: 7.37 (m, 2H), 7.23 (m, 3H), 6.96 (m, 2H), 6.86 (m, 2H), 3.60 (dd, J=14.2, 10.1 Hz, 1H), 3.61 (m, 4H), 3.34 (dd, J=10.1, 1.8 Hz, 1H), 3.12 (m, 5H), 2.37 (AB, J=15.9, Δ=49.3 Hz, 2H), 1.12 (s, 3H), 1.14 (s, 3H).

1. customat −78° C.
2. temperatureto warm to rt
3. stirringstirred for 12 h
4. addition70 mmol was then added
5. temperaturethe mixture was heated at 60° C. for 3 h
6. concentrationIt was finally concentrated under reduced pressure
7. dissolutionredissolved in is EtOAc
8. washwashed with a saturated solution of NH4Cl and with brine
9. dry with materialdry over magnesium sulfate
10. filtrationfiltrated
11. concentrationconcentrated
12. customPurification of the crude by flash chromatography on silica (EtOAc:c-Hex; gradient from 20:80 to 50:50)