Acetic Acid → 1-(4-Fluorophenyl)-5-[(2-methyl-2H-tetrazol-5-yl)methyl]-1H-indole

Participants

Reaction Conditions

Reaction Steps

A solution of the cyanomethyl compound, sodium azide, triethylamine hydrochloride in 1,2-dimethoxyethane was boiled at reflux for 2 days. After cooling to room temperature, the reaction mixture was filtered and the volatile solvents were evaporated in vacuo. Water (100 mL) and glacial acetic acid (15 mL) were added and the resulting mixture was extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with water (200 mL) and brine (200 mL) and subsequently dried (Na2SO4). Evaporation of the solvents in vacuo gave 1-(4-fluorophenyl)-5-(tetrazol-5-ylmethyl)-1H-indole as an oil containing some residual acetic acid (14 g). A solution of the crude tetrazole in NMP (200 mL) was cooled with ice and potassium tert-butoxide (6.4 g) was added cautiously at 10-20° C. over 20 minutes. When the addition was complete the reaction mixture was cooled at 0° C. and iodomethane (7 mL) was added. After stirring at room temperature for 2 h, water (200 mL) was added and the resulting mixture was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water (2×200 mL) and brine (2×250 mL), dried (Na2SO4) and the volatile solvents evaporated in vacuo. The resulting mixture of 1- and 2-methyl-substituted tetrazoles was separated by column chromatography on silica gel (ethyl acetate/heptane 1:2). Evaporation of the fastest eluting fractions in vacuo afforded pure 1-(4-fluorophenyl)-5-(2-methyltetrazol-5-ylmethyl)-1H-indole (11a) as an oil (3.7 g): 1H NMR (CDCl3) δ 4.25 (s, 3H), 4.30 (s, 2H), 6.60 (d, 1H), 7.10-7.20 (m, 3H), 7.20 (d, 1H), 7.30-7.45 (m, 3H), 7.60 (broad s,1H).

Provenance & Evidence