18-Crown-6 → HCID 21480634, compound

Participants

Reaction Steps

To a cooled solution (0° C.) of pyrrolidine (0.417 mL, 5.00 mmol, 5 eq) in tetrahydrofuran (10 mL) under nitrogen was added n-butyllithium (2.5M in hexane, 1.92 mL, 4.80 mmol, 4.8 eq). This was followed by 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)-piperidin-4-ol (described in example 58) (0.400 g, 1.00 mmol) in tetrahydrofuran (10 mL). The bath was removed and the solution warmed to room temperature over 1.5 h. No reaction was evident after stirring for 18 h. To accelerate the reaction, 18-crown-6 (0.528 g, 2.00 mmol, 2.0 eq) was added and the solution was heated to 60° C. for 5 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (35 mL, eluent: 50% ethyl acetate in hexane) to yield 0.450 g (quantitative) of the title compound. TLC analysis (Rf 0.23, 50% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.35 (dd, J=1.7, 4.6 Hz, 1H), 7.63 (dd, J=1.8, 7.9 Hz, 1H), 7.22 (m, 4H), 7.12 (dd, J=7.9, 4.6 Hz, 1H), 6.93 (m, 4H), 4.27 (br s, 1H), 3.48 (s, 2H), 3.21 (m, 4H), 2.85 (m, 2H), 2.76 (m, 2H), 2.63 (d, J=1.3 Hz, 2H), 2.01 (m, 6H), 1.70 (m, 2H) MS (CI, CH4) m/z 452 (M+1,100), 480 (M+29,12), 434 (16). The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (60° C., 16 pascal, 18 h) to yield a white solid, mp 249°-253° C.

Provenance & Evidence