Methyl iodide → 6-methoxy-1-methyl-1H-indole-3-carboxylic acid

Participants

Reaction Conditions

Reaction Steps

To a stirring solution of 6-methoxy-1H-indole-3-carboxylic acid 16a (8.0 g, 41.2 mmole) in anhydrous DMF (100 ml) at 0° was added NaH (60% dispersion in oil, 4.12 g, 103 mmole) in a single portion. After stirring at 0° C. for 1.3 hour, iodomethane (7.5 ml, 120 mmole) was added via syringe. The resultant mixture was stirred for 18 hours, gradually warming to room temperature, then poured into 0.2N NaOH (1 L) and extracted with EtOAc (3×250 ml). The combined extracts were washed sequentially with 1N NaOH (50 ml), water (3×50 ml), and brine (50 ml) then dried over Na2SO4 and concentrated, in vacuo. The resulting crude 6-methoxy-1-methyl-1H-indole-3-carboxylic acid Methyl ester was triturated with hexanes and collected by filtration. This material was suspended in aqueous KOH (3.36 g, 60 mmol in 150 ml) and the resulting suspension heated at reflux for 3.5 hours. The mixture was then poured onto 200 g of ice and washed with CH2Cl2 (2×50 ml). The aqueous layer was acidified with 6N HCl to pH 2 resulting in a white precipitate which was collected by filtration, washed with water and air dried to yield 7.25 g (86%) of the title compound which was carried on without any further purification. 1H NMR (DMSO-d 6) δ11.84(1H, broad s), 7.88 (1H, s), 7.84 (1H, d, J=8.7 Hz), 7.02 (1H, d, J=2.2 Hz), 6.82 (1H, dd, J=2.2, 8.7 Hz), 3.81 (3H, s), 3.79 (3H, s). Anal. Calcd. for C11H11NO3.0.2 H2O: C, 63.27; H, 5.50; N, 6.71.

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