Methyl iodide → 1-tert-Butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate

Participants

Reaction Conditions

Reaction Steps

To a flame-dried round bottom flask under Argon atmosphere was added THF (100 mL), then it was cooled to −30° C. To this cold solvent were added n-butyllithium (40.1 ml, 64.1 mmol), and diisopropylamine (10.80 ml, 76 mmol) drop wise. The resultant solution was stirred at −25° C. for 1 hour. To the above solution 1-tert-butyl 3-ethyl piperidine-1,3-dicarboxylate (15 g, 58.3 mmol) in THF (20 mL) was added drop wise at −78° C. (maintain temperature <−70° C.). After the addition, the reaction was stirred at −70° C. for 1 h, and then methyl iodide (4.74 mL, 76 mmol) was added drop wise. This reaction mixture was stirred at same temperature for 1 h, then slowly warmed to RT and stirred for 16 h. The reaction mixture was quenched with sat. aq. NH4Cl (50 mL), extracted with EtOAc (2×200 mL), the combined organics extracts was washed with sat. NH4Cl (100 mL), brine (50 mL), dried (Na2SO4) and concentrated to get crude compound. The crude residue was purified by ELSD ISCO on 120 g silica column, eluted the compound around 20% ethyl acetate in hexanes, the pure fractions were collected and concentrated to give desired product 1-tert-butyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (15.14 g, 52.5 mmol, 90% yield) as a colorless oil. Anal. Calcd. for C14H25NO4 m/z 271.3, found: 172.2 (M-Boc+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 4.13 (q, J=7.0 Hz, 2 H), 3.82 (d, J=13.5 Hz, 1 H), 3.46-3.38 (m, 1 H), 3.32-3.19 (m, 1 H) 3.13 (d, J=13.2 Hz, 1 H) 2.07-1.97 (m, 1 H) 1.60-1.50 (m, 2 H) 1.48-1.40 (m, 10 H), 1.25 (t, J=7.15 Hz, 3 H), 1.15 (s, 3 H)

Provenance & Evidence