Hydrochloric Acid → Lithium diisopropylamide

Participants

Reaction Steps

Step1: N,N-Carbonyldiimidazole (20.3 g) was added portionwise to a stirred suspension of isonicotinic acid (15.4 g) in dry tetrahydrofuran (200 cm3). The gently effervescent mixture was stirred at room temperature for 90 minutes, forming an orange solution. A solution of lithium diisopropylamide was prepared by the addition of n-butyllithium (2.5 M, hexanes; 100 cm3) to a stirred solution of diisopropylamine (35 cm3) in dry tetrahydrofuran (250 cm3) at 0° C. under nitrogen. The solution was cooled to −78° C. for 15 minutes, followed by the dropwise addition of a solution of methyl 2-(4-methoxyphenyl)acetate (45 g) in dry tetrahydrofuran (50 cm3) at −78° C. The yellow enolate solution was stirred at —78° C. for 20 minutes, followed by addition of the imidazolide solution dropwise via cannula. After stirring at −78° C. for 45 minutes the bright yellow suspension was warmed to room temperature. The mixture was poured into aqueous hydrochloric acid (1.3 M; 700 cm3) and washed with hexane (200 cm3). The aqueous solution was basified to pH 3 with aqueous sodium hydroxide (4 M) and then to pH 7 with saturated aqueous sodium hydrogencarbonate. The neutralised solution was extracted with dichloromethane (2×400 cm3). The organic extracts were washed with brine (300 cm3), dried (magnesium sulphate), filtered and concentrated to give a brown oil that crystallised on standing. The material was triturated with ethyl acetate-diethyl ether (1:1; 50 cm3) and filtered to give 2-(4-methoxyphenyl)-3-oxo-3-(pyridin-4-yl)propionic acid methyl ester as an off-white solid (14.7 g; 42%). δH (250 MHz; CDCl3) 3.77 (3 H, s, OCH3), 3.79 (3 H, s, OCH3), 5.48 (1 H, s, MeO2CCH), 6.90 (2 H, d, J 9, methoxyphenyl H-2), 7.28 (2 H, d, J 9, methoxyphenyl H-3), 7.70 (2 H, d, J 6, pyridyl H-3) and 8.77 (2 H, d, J 6, pyridyl H-2).

Provenance & Evidence