반응 #155552

반응 방정식

(3aR,4S)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole

n-Butyl lithium

2,2,6,6-tetramethylpiperidine

2-chloro-1,3-difluoro-benzene

→

title compound

수율 34.3%

(3aR,4S,6aS)-6a-(3-Chloro-2,4-difluorophenyl)-4-((trityloxy)methyl) hexahydrofuro[3,4-c]isoxazole

수율 34.3%

용매

THF

THF

THF

반응 조건

후처리

1. 1
   기타remained below −75° C
2. 2
   기타the reaction was quenched with saturated aqueous ammonium chloride
3. 3
   기타removed from the cooling bath
4. 4
   기타The mixture was partitioned between EtOAc and water
5. 5
   기타the layers were separated
6. 6
   추출The aqueous layer was extracted with EtOAc (3×)
7. 7
   세척The combined organic extracts were washed with brine (1×)
8. 8
   건조dried over (Na2SO4)
9. 9
   여과filtered
10. 10
    기타evaporated
11. 11
    기타The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane)

실험 절차

A stirred solution of 2,2,6,6-tetramethylpiperidine (1.31 mL, 7.78 mmol) in dry THF (20 mL) under nitrogen was cooled in an acetone/dry ice cooling bath. n-Butyl lithium (2.5 M in hexanes, 3.11 mL, 7.78 mmol) was added to this solution such that the internal temperature remained below −75° C. The pale yellow solution was stirred at this temperature for 15 minutes before the addition of a solution of 2-chloro-1,3-difluoro-benzene (0.86 mL, 7.78 mmol) in dry THF (2 mL). The solution was stirred for an additional 30 minutes at −78° C. before the addition of a solution of (3aR,4S)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (1.5 g, 3.89 mmol) in dry THF (12 mL). The reaction was stirred at −78° C. After 60 min, the reaction was quenched with saturated aqueous ammonium chloride and then removed from the cooling bath. The mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine (1×), then dried over (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound (712 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 3.23-3.35 (m, 2 H) 3.47 (dd, J=9.84, 6.42 Hz, 1 H) 3.86 (dd, J=8.31, 3.79 Hz, 1 H) 3.91 (dd, J=10.33, 1.90 Hz, 1 H) 4.08-4.20 (m, 2 H) 4.22-4.33 (m, 1 H) 6.92-7.00 (m, 1 H) 7.20-7.36 (m, 9 H) 7.41-7.48 (m, 6 H) 7.57-7.67 (m, 1 H).

출처