반응 #69374

반응 방정식

MeOCHO

3,5-difluorobenzoic acid

TMEDA

HCl

n-BuLi

→

title compound

수율 35.6%

3,5-difluoro-4-formylbenzoic acid

수율 35.6%

용매

2-methyltetrahydrofuran

반응 조건

후처리

1. 1
   기타remained at less than −65° C
2. 2
   온도to be maintained at less than −65° C
3. 3
   온도to warm at room temperature
4. 4
   온도maintained a room temperature
5. 5
   workup.STIRRINGwhile being stirred for 18 hr
6. 6
   온도The mixture was then cooled to 0-5° C.
7. 7
   기타The phases were then separated
8. 8
   추출the aqueous layer was extracted 3 times with 2-methyltetrahydrofuran (3×500 mL)
9. 9
   세척The combined organic phases were washed with saturated brine
10. 10
    건조dried over MgSO4
11. 11
    여과filtered
12. 12
    농축concentrated under vacuum
13. 13
    workup.DISSOLUTIONThe residue was dissolved in ethyl acetate (350 mL)
14. 14
    온도at reflux
15. 15
    온도cooled to room temperature
16. 16
    workup.ADDITIONHexanes (480 mL) were then added
17. 17
    온도the resulting mixture was further cooled to −15° C
18. 18
    여과The solid was collected by filtration
19. 19
    세척rinsed with hexanes
20. 20
    기타dried under mechanical vacuum

실험 절차

To a solution of 3,5-difluorobenzoic acid (291 g, 1.84 mol) in 2-methyltetrahydrofuran (4.35 L) was added TMEDA (604 mL, 4.03 mol) at room temperature. The resulting solution was cooled to −78° C. Afterward, n-BuLi (2.5 M in hexane) (1.77 L, 4.43 mol) was added drop-wise, during which the temperature of the mixture remained at less than −65° C. The mixture was then stirred at −78° C. for 1.5 hr. Anhydrous MeOCHO (239 mL, 3.88 mol) was added dropwise at a rate that allowed the temperature to be maintained at less than −65° C. The resulting solution was allowed to warm at room temperature, and then maintained a room temperature while being stirred for 18 hr. The mixture was then cooled to 0-5° C., and excess base was quenched with 6M aqueous HCl (2.2 L, 13.2 mol). The phases were then separated, and the aqueous layer was extracted 3 times with 2-methyltetrahydrofuran (3×500 mL). The combined organic phases were washed with saturated brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was dissolved in ethyl acetate (350 mL) at reflux, and cooled to room temperature. Hexanes (480 mL) were then added, and the resulting mixture was further cooled to −15° C. The solid was collected by filtration, rinsed with hexanes, and dried under mechanical vacuum to form the title compound (122 g, 35%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.63-7.70 (m, 2H), 10.23 (s, 1H); MS m/z 187.17 [M+H]+ (ESI).

출처