反应详情

温度

-78 °C

4-Chloro-2-methyl-N-(tetrahydro-pyran-4-yl)-benzamide (2.09 g, 8.24 mmol) and diisopropylamine (0.15 equiv. 1.24 mmol, 125 mg.) were dissolved in anhydrous THF (100 mL). The solution was cooled to −78° C. When cooled at −78° C. it becomes a white suspension. To this solution was added sec-BuLi (1.4 M, in cyclohexane; 13 mL, 18.5 mmol, 2.25 equiv.), the reaction mixture turns into orange color, stirred for 5 min, and then submerged into ice-water bath (0° C.) for 15 min, the reaction becomes a clear orange solution, re-cooled to −78° C. Powdered formaldehyde (1.48 g, 49.44 mmol, 36 equiv.) was added. The dry ice-acetone bath was replaced with an ice-water and stirring was continued for 30 min. The red-brown color faded away to a light yellow color. The reaction was quenched with water, diluted with EtOAc. The two layers were separated and the aqueous was extracted with EtOAc (2×10 mL). The combined EtOAc solution was washed with brine (20 mL). Then, the EtOAc solution was dried over anhydrous granular K2CO3, filtered, and concentrated in vacuo. The crude product showed 2 peaks at 2.348 min, MS 284; 2.150 min, MS 254 at 2.808 (SM). The compound was purified on a 70-g silica gel column eluted with 1-5 min. 0-2.5% MeOH in DCM to obtain 1.25 g (54% yield) of the title compound as a white solid.

1. temperatureWhen cooled at −78° C. it
2. customsubmerged into ice-water bath
3. wait(0° C.) for 15 min
4. temperaturere-cooled to −78° C
5. stirringstirring
6. waitwas continued for 30 min
7. customThe reaction was quenched with water
8. additiondiluted with EtOAc
9. customThe two layers were separated
10. extractionthe aqueous was extracted with EtOAc (2×10 mL)
11. washThe combined EtOAc solution was washed with brine (20 mL)
12. dry with materialThen, the EtOAc solution was dried over anhydrous granular K2CO3
13. filtrationfiltered
14. concentrationconcentrated in vacuo
15. customat 2.348 min
16. custom2.150 min, MS 254
17. customThe compound was purified on a 70-g silica gel column
18. washeluted with 1-5 min