tert-Butyl acetate → (7-Chloro-2-methyl-quinolin-8-yl)-acetic acid tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

n-Butyl lithium (1.6 M in hexane, 5.3 ml, 8.52 mmol, 1.5 equiv) was added at −78° C. under an atmosphere of argon to a degassed solution of hexamethyl disilazide (1.38 g, 8.52 mmol, 1.5 equiv) in toluene (16 ml). After stirring at −78° C. for 15 minutes and at room temperature for 15 minutes, Pd2(dba)3 (156 mg, 0.17 mmol, 0.03 equiv) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (141 mg, 0.36 mmol, 0.063 equiv) were added. After stirring at room temperature for 10 minutes, the reaction mixture was cooled to −10° C. and treated dropwise with acetic acid tert-butyl ester (858 mg, 7.38 mmol, 1.3 equiv). After stirring for 10 minutes at −10° C., trifluoro-methanesulfonic acid 7-chloro-2-methyl-quinolin-8-yl ester (1.85 g, 5.68 mmol) was added in one portion, and the cooling bath was removed. The temperature of the reaction mixture rose to 29° C. within the next 30 minutes. After 40 minutes, TLC analysis indicated formation of unwanted side products (e.g. 4-(7-chloro-2-methyl-quinolin-8-yl)-3-oxo-butyric acid tert-butyl ester). The reaction mixture was diluted with water, filtered, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via flash chromatography (gradient of toluene/EtOAc 100:0 to 95:5) to afford the title compound (662 mg, 40%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=7.98 (d, J=12.8 Hz, 1H), 7.63 (d, J=12.8 Hz, 1H), 7.47 (d, J=12.8 Hz, 1H), 7.26 (d, J=12.8 Hz, 1H), 4.43 (s, 2H), 2.72 (s, 3H), 1.47 (s, 9H). MS (ES+): 292.2 (M+H)+.

Provenance & Evidence