Diisopropylamine → 2-(4-aminophenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile

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Reaction Steps

A nitrogen-purged flask fitted with a septum and a nitrogen needle was charged with dry THF (all additions performed by syringe) (20 mL). Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) was added, and the solution was cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 M solution in hexane, 13.6 mmol) was added slowly. The flask was allowed to warm to room temperature briefly, and then was cooled to −78° C. A concentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile (2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A) was added slowly, and the resulting solution was maintained at −78° C. for 30 min. The flask was then transferred to a water-ice bath and allowed to come to 0° C. for about 15 minutes. The solution was once again cooled to −78° C., and ZnCl2 (0.5 M solution in THF, 27.0 mL, 13.5 mmol) was slowly added. A precipitate was observed at this point, which may have been the bis(indole)zinc compound, but the solution became homogeneous when the entire volume of zinc chloride solution was added. After about 10 minutes, the solution was allowed to come to room temperature, and a THF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8 mmol) and triphenylphosphine (338 mg, 1.29 mmol) was added. The septum was removed, and solid Pd2(dba)3 (295 mg, 0.322 mmol) was added. A reflux condenser was fitted to the flask, and the solution was degassed by three successive cycles of vacuum pumping/N2 purging. The solution was then heated to reflux overnight. After cooling to room temperature, the solution was poured into 4 volumes of water, and 4 volumes of ethyl acetate were added. The resulting mixture was vigorously stirred for 30 minutes, then filtered through celite (with ethyl acetate washing) to remove solid Zn-and Pd-containing material. The phases were separated, and the aqueous phase was extracted with more ethyl acetate. The organic phases were washed in sequence with saturated brine, combined, dried over anhydrous sodium sulfate, filtered and evaporated. A solid precipitate formed at this point, which was sufficiently pure product and was collected by trituration with ether and filtration. The remaining material was purified by column chromatography (eluting 1:2 ethyl acetate-hexane on silica gel 60). Total yield of the product, 2-(4-amino-phenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile, was 2.75 g (8.99 mmol, 70%).

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