反应详情

温度

75 °C

To a stirred suspension of magnesium turnings (1.55 g; 63.76 mmol) in THF (50 mL) under an atmosphere of N2 was added 1,2-dibromoethane (135 uL). The mixture was heated to 75° C. and 3,5-bis(trifluoromethyl)bromo benzene (4.59 mL; 26.79 mmol) was slowly added to maintain a gentle reflux. The reaction was heated at gentle reflux for 2.5 h and then cooled to room temperature. In a separate flask, isopropyl magnesium chloride (18 mL; 36 mmol) was added dropwise to a stirred solution of benzyl-{3-[methoxy(methyl)amino]-1-methyl-3-oxopropyl}carbamate (Step B; 5 g; 17.86 mmol) in THF (30 mL) at −20° C. The resultant solution was stirred at −20° C. for 40 min prior to dropwise addition of the Grignard solution. The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was quenched with 1 N HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% acetone/hexanes gradient) to afford benzyl {3-[3,5-bis(trifluoromethyl)phenyl]-1-methyl-3-oxopropyl}carbamate as a white solid. LCMS=434.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.39 (s, 2H), 8.07 (s, 1H), 7.37-7.29 (m, 5H), 5.16-5.04 (m, 3 h), 4.31-4.23 (m, 1H), 4.16-4.10 (m, 1H), 3.19 (dd, J=16.8, 6.5 Hz, 1H), 1.34 (d, J=6.9 Hz, 3H).

1. temperatureto maintain a gentle reflux
2. temperatureThe reaction was heated
3. temperatureat gentle reflux for 2.5 h
4. temperaturecooled to room temperature
5. additionto dropwise addition of the Grignard solution
6. temperatureto warm to room temperature
7. customThe reaction was quenched with 1 N HCl (100 mL)
8. extractionextracted with EtOAc (3×100 mL)
9. washThe combined extracts were washed with brine (100 mL)
10. dry with materialdried (MgSO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customThe residue was purified by flash silica gel chromatography (0-10% acetone/hexanes gradient)