4-Bromo-2-fluoroanisole → tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

Participants

Reaction Steps

To a solution of 4-bromo-2-fluoro-1-methoxybenzene (2 g, 9.7 mmol) in tetrahydrofuran (100 mL) at −78° C. was added a solution of n-butyllithium (1.6 M in hexanes, 7.9 mL, 12.7 mmol). The reaction mixture was stirred in the cold for 2 h, and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.94 g, 9.7 mmol) in THF (10 mL) was added dropwise. The mixture was then allowed to warm to rt and stir for 12 h. It was quenched with a saturated NH4Cl solution and diluted with ethyl acetate. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by silica gel chromatography to provide 2.0 g (63%) of the desired compound; 1H NMR (400 MHz, DMSO-d6) δ 7.29 (dd, J=13.3, 2.3 Hz, 1H), 7.24-7.18 (m, 1H), 7.10 (t, J=8.0 Hz, 1H), 5.09 (s, 1H), 3.85 (br. s., 2H), 3.82 (s, 3H), 1.86-1.68 (m, 2H), 1.56 (d, J=12.0 Hz, 3H), 1.46-1.38 (m, 11H).

Provenance & Evidence