1-(4-fluorophenyl)-3-methylbutan-1-one

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-diisopropylamidopyridine (3.2 g, 15.54 mmol) in anhydrous diethyl ether (160 mL) at −78° C. was added a 1M solution of LDA in diethyl ether (23.27 mL) and the reaction mixture stirred at −78° C. for 2 hours. A solution of 1-(4-fluorophenyl)-3-methylbutan-1-one (3.5 g, 19.42 mmol) in anhydrous diethyl ether (5 mL) was added dropwise, and the reaction was stirred at −78° C. for 30 min. The reaction mixture was quenched with brine (100 mL), extracted with ethyl acetate (3×50 mL), dried (MgSO4), and concentrated. The crude mixture was stirred with 6 N HCl (50 mL) for 12 hours, then cooled to 0° C. Sodium hydroxyde (15 g, 37.5 mmol) was added in 3 portions, the reaction mixture was stirred at 0° C. for 30 min, then extracted with ethyl acetate (3×100 mL). The organic layers were dried (MgSO4), concentrated and purified by column chromatography (40 g, SiO2, 0 to 40% ethyl acetate in hexanes) to provide 3-(4-fluorophenyl)-3-isobutylfuro[3,4-c]pyridin-1(3H)-one (296 mg, 7%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-0.91 (m, 6H), 1.54-1.66 (m, 1H), 2.06 (dd, J=14.88, 6.97 Hz, 1H), 2.48 (dd, J=15.07, 5.27 Hz, 1H), 7.04-7.14 (m, 2H), 7.46-7.56 (m, 2H), 7.77 (dd, J=5.09, 0.94 Hz, 1H), 8.85 (d, J=4.90 Hz, 1H), 9.01 (s, 1H); MS m/z 286 (M+H)+. the reaction was stirred at −78° C. for 30 min The reaction mixture was quenched with brine (100 mL) extracted with ethyl acetate (3×50 mL) dried (MgSO4) concentrated The crude mixture was stirred with 6 N HCl (50 mL) for 12 hours cooled to 0° C Sodium hydroxyde (15 g, 37.5 mmol) was added in 3 portions the reaction mixture was stirred at 0° C. for 30 min extracted with ethyl acetate (3×100 mL) The organic layers were dried (MgSO4) concentrated purified by column chromatography (40 g, SiO2, 0 to 40% ethyl acetate in hexanes)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-fluoro-benzonitrile (6 g, 49.5 mmol) in diethyl ether (200 mL) was added i-BuMgCl (1 M soln in THF) and the reaction mixture heated to reflux for 16 hours. The reaction mixture was cooled to room temperature and poured into a mixture 6 N H2SO4 (60 mL) and ice (500 mL), then stirred at 0° C. for 30 min. The aqueous layer was extracted with ethyl acetate (200 mL), the combined organic layers were washed with brine (100 mL), dried (MgSO4), and concentrated. The residue was purified by column chromatography (80 g, SiO2, 0 to 40% diethyl ether/dichloromethane 1:1 in hexanes) to provide 1-(4-fluorophenyl)-3-methylbutan-1-one as a colorless oil (3.72 g, 42%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J=6.78 Hz, 6H), 2.29 (dt, J=13.47, 6.64 Hz, 1H), 2.81 (d, J=6.78 Hz, 2H), 7.06-7.19 (m, 2H), 7.94-8.02 (m, 2H); MS m/z 172 (Dimer-OH)++. the reaction mixture heated to reflux for 16 hours The aqueous layer was extracted with ethyl acetate (200 mL) the combined organic layers were washed with brine (100 mL) dried (MgSO4) concentrated The residue was purified by column chromatography (80 g, SiO2, 0 to 40% diethyl ether/dichloromethane 1:1 in hexanes)