3-Bromopyridine → tert-Butyl 4-nicotinoylpiperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

A solution of n-butyllithium (14.2 mL of a 2.51M solution in hexanes, 35.54 mmol) in tetrahydrofuran (50 mL) was cooled to ←85° C. and treated dropwise with a solution of 3-bromopyridine (5.90 g, 37.31 mmol) in tetrahydrofuran (50 mL). The resulting pale yellow-green solution was stirred at ←85° C. for 15 min, then was treated with a solution of N-methoxy-N-methyl 1-(1,1-dimethylethyloxycarbonyl)-4-piperidine carboxamide (8.80 g, 32.31 mmol) in tetrahydrofuran (50 mL). The reaction mixture was allowed to warm to -20° C. over 1 h, then was cooled to -60° C. and quenched by addition of water (20 mL). The mixture was vaned to 0° C., acidified to pH~ 2 by addition of 3M hydrochloric acid and stirred at 0° C. for 10 min. The mixture was then poured into 10% aqueous sodium hydroxide (50 mL) and extracted with ethyl acetate (3×150 mL). The organic extracts were washed sequentially with 1N aqueous sodium hydroxide (100 mL) and brine (100 mL), combined, dried over Na2SO4, filtered and concentrated to leave a yellow semi solid mass. This mass was triturated with hexane (50 mL) and the solid which formed was removed by filtration. The solid was rinsed with hexane (25 mL) and dried to afford the title ketone (6.62 g, 22.8 mmol, 71%) as off-white needles. From the filtrate, an additional 300 mg (1.03 mmol, 3%) of the ketone was obtained. 1H NMR CDCL3 : δ9.16 (d, J=2.2 Hz, 1H, H--C(2')), 8.79 (dd, J=1.7 Hz, 4.8 Hz, 1H, H--C(6')), 8.23 (ddd, J=1.7, 2.2, 8.0 Hz, 1H, H--C(4')), 7.45 (dd, J=4.8, 8.0 Hz, 1H, H--C(5')), 4.17 (brd, J=11 Hz, 2H, eq-H--C(2)), 3.39 (m, 1H, H--C(4)), 2.92 (dd, J=11.6, 11.6 Hz, 2H, ax-H--C(2)), 1.87 (m, 2H, eq-H--C(3)), 1.71 (m, 2H, ax-H--C(3)), 1.47 (s, 9H, (CH3)3C).

Provenance & Evidence