反应详情

温度

-78 °C

To an oven-dried 500-mL round bottom flask equipped with a magnetic stir bar was added 2-fluoro-1,4-dimethoxybenzene (6 g, 38.4 mmol, 1 equiv). The flask was purged with N2, and anhydrous degassed tetrahydrofuran (250 mL) was added. The solution was cooled to −78 ° C., and n-butyllithium (15.4 mL, 38.4 mmol, 1 equiv, 2.5 M in hexanes) was added dropwise over 12 minutes The mixture was stirred for another 30 minutes, and mesitylmagnesium bromide (38.4 mL, 38.4 mmol, 1 equiv, 1M tetrahydrofuran) was slowly added over 16 minutes. The reaction mixture was stirred at −78 ° C. for an additional hour, then removed from the cold bath to warm to room temperature. After 2 hours at room temperature, the reaction mixture was cooled in an ice bath to 0 ° C. and added a fresh solution of iodine (46.1 mL, 46.1 mmol, 1.2 equiv, 1M in tetrahydrofuran) was added dropwise over 10 minutes. The flask was removed from the ice bath and stirred for an additional hour. Then the reaction mixture was concentrated to afford a red oil. The oil was dissolved in dichloromethane (100 mL), washed with aqueous saturated sodium thiosulfate (2 ×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to furnish a brown-yellowish oil. Purification of the crude product by column chromatography (330-g column; gradient: 1.5 column volumes heptane, ramp up to 89:11 heptane:ethyl acetate over 8 column volumes, hold at 89:11 for 2 column volumes) followed by crystallization in heptane (20 mL) and a minimal amount of methyl tert-butyl ether, filtration, washing with cold heptane, and drying under vacuum afforded the title compound (6.64 g, >99 area % by HPLC, 45% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.99-6.96 (m, 2H), 6.94 (d, J=8.9 Hz, 1H), 6.82 (d, J=8.9 Hz, 1H), 3.90 (s, 3H), 3.69 (s, 3H), 2.37 (s, 3H), 1.93 (s, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 152.4, 150.9, 137.6, 136.7, 135.8, 135.3, 127.7, 110.9, 109.3, 94.5, 56.9, 56.4, 21.6, 20.1.

1. customTo an oven-dried 500-mL round bottom flask equipped with a magnetic stir bar
2. customThe flask was purged with N2
3. customanhydrous degassed tetrahydrofuran (250 mL)
4. additionwas added
5. stirringThe reaction mixture was stirred at −78 ° C. for an additional hour
6. customremoved from the cold bath
7. temperatureto warm to room temperature
8. waitAfter 2 hours at room temperature
9. temperaturethe reaction mixture was cooled in an ice bath to 0 ° C.
10. additionwas added dropwise over 10 minutes
11. customThe flask was removed from the ice bath
12. stirringstirred for an additional hour
13. concentrationThen the reaction mixture was concentrated
14. customto afford a red oil
15. washwashed with aqueous saturated sodium thiosulfate (2 ×50 mL) and brine (50 mL)
16. dry with materialdried over sodium sulfate
17. filtrationfiltered
18. concentrationconcentrated
19. customto furnish a brown-yellowish oil
20. customPurification of the crude product by column chromatography (330-g column
21. customfollowed by crystallization in heptane (20 mL)
22. filtrationa minimal amount of methyl tert-butyl ether, filtration
23. washwashing with cold heptane
24. customdrying under vacuum