2-Methyl-2-butene → 6-cyano-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

A solution of 3-formyl-5-[4-(1-hydroxycyclobutyl)phenyl]-1H-indole-6-carbonitrile (223 mg, 0.705 mmol) in tetrahydrofuran (6 mL) and tert-butanol (6 mL) was treated with 2-methyl-2-butene (2.25 mL, 21.2 mmol) and cooled to 0° C. The reaction mixture was then treated with a solution of sodium chlorite (594 mg, 7.0 mmol) and sodium phosphate monobasic hydrate (1.0 g, 7.2 mmol) and warmed to room temperature. The reaction mixture was stirred vigorously at room temperature for 7 hours, and was then poured into saturated aqueous ammonium chloride (40 mL). The product was extracted with ethyl acetate (4×25 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified using flash chromatography eluting with heptanes/ethyl acetate (with 0.2% formic acid) (85:15 to 0:100). The fractions containing product were combined, concentrated in vacuo, diluted with toluene (40 mL) and concentrated in vacuo to give the title compound (157 mg, 67%) as a white solid. This material was dissolved in ethanol (3.5 mL) with heating at 80° C., and treated with water (ca. 3 mL) dropwise with heating at 80° C. The resulting solution was stored at room temperature for two hours, then at 8° C. for 2 hours. The resulting crystals were collected by filtration, washed with water (2 mL) and dried in vacuo at 60° C. for 14 hours to give the title compound (100 mg, 42.7%) as an off-white crystalline solid.

Provenance & Evidence