反应详情

温度

-78 °C

An ether solution (2 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (0.200 g, 0.826 mmol) was stirred in an oven-dried round bottom flask at −78° C. under Ar. To this solution, n-BuLi (2.0 M in cyclohexane, 0.41 mL, 0.82 mmol, 1.0 eq) was added dropwise. The resulting solution was stirred at −78° C. for 30 min. 5-Fluoropicolinonitrile (0.101 g, 0.828 mmol, 1.0 eq), prepared as described in Procedure 1, was added as a solid via addition funnel The resulting red solution was stirred at −78° C. for 1 h. The reaction mixture was quenched with HCl (10 mL, 1.0 M) and extracted with EtOAc (3×10 mL). The combined organic portions were dried over Na2SO4, decanted and the volume was reduced to 5 mL under reduced pressure. The resulting oil was loaded directly onto a silica gel ISCO cartridge (40 g). Gradient elution from 0-70% EtOAc in hexane over 20 min yielded (3-fluoro-5-(trifluoromethyl)phenyl)(5-fluoropyridin-2-yl)methanone as a pale brown oil at a retention time of 7 min (0.117 g, 49% yield). LCMS: RT=1.91 min [M+H] 288.2 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.69 min (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm, purity 97%); NMR: 400 MHz 1H(CDCl3) ppm 8.50 (d, J=2.4 Hz, 1 H), 8.19 (dd, J=4.0 and J=8.0 Hz, 1 H), 8.15 (s, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 7.57 (ddd, J=3.08, J=2.4 and J=8.0 Hz).

1. additionwas added as a solid via addition funnel The resulting red solution
2. stirringwas stirred at −78° C. for 1 h
3. customThe reaction mixture was quenched with HCl (10 mL, 1.0 M)
4. extractionextracted with EtOAc (3×10 mL)
5. dry with materialThe combined organic portions were dried over Na2SO4
6. customdecanted
7. washGradient elution from 0-70% EtOAc in hexane over 20 min