Hydrochloric Acid → 3-(4'-Hydroxybiphenyl-4-yl)-3-hydroxy-quinuclidine hydrochloride

Participants

Reaction Steps

A solution of sec-butyllithium in cyclohexane (7.4 ml, 1.3M) was added dropwise, with stirring, to a solution of 4-bromo-4'-(tert-butyldimethylsilyloxy)biphenyl (2.9 g) in dry tetrahydrofuran (30 ml) under an atmosphere of argon at -78° C. The mixture was stirred for 5 minutes and a solution of quinuclidin-3-one (0.9 g) in dry tetrahydrofuran (12 ml) was then added over a period of 2 minutes. The mixture was stirred at -78° C. for a further 30 minutes and the mixture then allowed to warm to room temperature over 2 hours. Aqueous 2M hydrochloric acid (18 ml) was added to the reaction mixture, whilst keeping the temperature of the reaction mixture below 10° C. The aqueous layer was separated and washed with diethyl ether (2×20 ml) before the addition of excess sodium hydroxide solution (density 1.35 g/cm3) to pH 14. The mixture was extracted with warm ethyl acetate (50° C.) and the ethyl acetate phase separated, dried (Na2SO4) and evaporated. The residue was dissolved in dry tetrahydrofuran (20 ml) and added to a solution of tetrabutyl ammonium fluoride in tetrahydrofuran (1.6 ml, 1.0M). The mixture was stirred at room temperature for 2 hours. The tetrahydrofuran was evaporated, an excess of saturated ethereal hydrogen chloride solution was added to precipitate a solid which was crystallised from methanol/ethyl acetate to give as a colourless solid, 3-(4'-hydroxybiphenyl-4-yl)-3-hydroxy-quinuclidine hydrochloride (0.93 g), m.p. 270°-271° C., microanalysis, found: C, 66.5; H, 6.5; N, 4.1%; C19H21NO2.HCl.0.66H2O requires: C, 66.5: H, 6.8: N, 4.1%; NMR ([CD3 ]2SO): 1.4-1.6(1H, m), 1.7-1.9(2H, m), 2.3-2.4(2H, m), 3.1-3.4(5H, m), 3.8-3.9(1H, d), 5.9(1H, s), 6.9-7.5(4H, d of d), 7.6(4H, s), 9.6(1H, s); m/Z 296 (M+H).

Provenance & Evidence