Diisopropylamine → 4-[4-Hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione

Participants

Reaction Conditions

Reaction Steps

To an oven-dried round bottom flask was added diisopropylamine (6.4 mL, 46 mmol) and THF (125 mL). It was cooled to −78° C., and a solution of nBuLi (18 mL of 2.5 M, 46 mmol) in hexane was added. It was stirred at 0° C. for 30 minutes and again cooled to −78° C. 1-(3-pyridyl)butane-1,3-dione (3.40 g, 21.0 mmol) in a solution of THF (25 mL) was added dropwise. After 30 minutes at −78° C., a solution of 1-(4-isopropoxy-3-methyl-benzoyl)piperidin-4-one (5.74 g, 20.8 mmol) in THF (25 mL) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride (100 mL). Volatiles were removed under reduced pressure to one-third volume. It was extracted with ethyl acetate (2×75 mL). Organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude brown oil was purified by column chromatography (100% ethyl acetate) to provide 4-[4-hydroxy-1-(4-isopropoxy-3-methyl-benzoyl)-4-piperidyl]-1-(3-pyridyl)butane-1,3-dione (5.85 g) as a yellow foaming solid. 1H NMR (400 MHz, CDCl3) δ 15.81 (s, 1H), 9.08 (d, J=1.9 Hz, 1H), 8.76 (dd, J=4.8, 1.5 Hz, 1H), 8.19 (dd, J=8.0, 1.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.24-7.17 (m, 2H), 6.80 (d, J=8.2 Hz, 1H), 6.20 (s, 1H), 4.55 (m, 1H), 4.51-4.25 (br s, 1H), 3.52-3.26 (m, 4H), 2.68 (s, 2H), 2.20 (s, 3H), 1.75-1.51 (m, 4H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 438.22, found 439.5 (M+1)+; Retention time: 1.37 minutes (3 min run).

Provenance & Evidence