tert-butyl 6-bromo-2,2,4-trimethylquinoline-1(2H)-carboxylate synthesis

Yield:179894-35-0 94%

Reaction Conditions:

Stage #1: 6-bromo-2,2,4-trimethyl-1,2-dihydroquinolinewith n-butyllithium in tetrahydrofuran;hexane at -78 - 0; for 0.5 h;
Stage #2: di-tert-butyl dicarbonate in tetrahydrofuran;hexane at 20 - 25; for 3 h;

Steps:

52 tert-Butyl 6-bromo-2,2,4-trimethylquinoline-1(2H)-carboxylate

A tetrahydrofuran (40mL) solution of 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline (4.04g, 16.0 mmol) was cooled to -78°C, and 1.56M n-butyllithium-hexane solution (10.9mL, 17.0 mmol) was added thereto and kept -78°C for 30 minutes. After that, the reaction mixture was allowed to be warmed to 0°C and a tetrahydrofuran (5mL) solution of di-tert-butyl dicarbonate (Boc₂O) (3.92g, 18.0 mmol) was added dropwise. The reaction solution was warmed to 20-25°C and stirred for 3 hours. An aqueous ammonium chloride solution was added to the reaction solution, which was followed by extraction with ethyl acetate. The separated organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane/diethyl ether = 30/1 - 10/1) to give tert-butyl 6-bromo-2,2,4-trimethylquinoline-1(2H)-carboxylate (5.29g, 94%). ¹H-NMR (CDCl₃) δ: 1.48(6H,s), 1.51(9H,s), 1.98(3H,d,J=1.5Hz), 5.47(1H, d,J=1.3Hz), 7.05(1H,d,J=7.5Hz), 7.19(1H,d,J=2.4Hz), 7.23(1H,dd,J=7.5, 2.4Hz)

References:

EP1844768,2007,A1 Location in patent:Page/Page column 34