Glycerol → 6-Bromo-7-methoxyquinoline

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In a 100 mL round-bottom flask, a solution of concentrated sulfuric acid (2.1 mL, 39.6 mmol) in water (2.4 mL) was treated with 3-nitrobenzenesulfonic acid (2.06 g, 10.1 mmol) and glycerol (2.5 mL, 34.8 mmol) to give a thick grey suspension. The mixture was heated to 110° C. (oil bath) and 4-bromo-3-methoxyaniline (1.952 g, 9.66 mmol) was added portion-wise, resulting in an immobile slurry. Additional portions of water (3 mL), glycerol (3 mL), and concentrated sulfuric acid (3 mL) were added and the temperature increased to 140° C. After three hours the mixture had become a homogeneous dark brown solution, and LCMS analysis indicated reaction completion. The solution was cooled to RT, poured onto ice, and the pH was adjusted to 8 by addition of concentrated (30%) aqueous ammonium hydroxide. The mixture was partitioned between ethyl acetate and water, washed with water, brine, dried over magnesium sulfate and concentrated to a brown liquid. Purification by flash column chromatography (24 g silica gel, gradient of 0-20% ethyl acetate in dichloromethane over 25 column volumes) provided 6-bromo-7-methoxyquinoline (1.18 g, 46.2%) as a light brown fluffy solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.86 (dd, J=4.0, 1.5 Hz, 1H), 8.01-8.12 (m, 2H), 7.53 (s, 1H), 7.34 (dd, J=8.1, 4.5 Hz, 1H), 4.07 (s, 3H). NMR indicates the presence of about 10% 7-methyoxyquinoline. The mixture was taken on without further purification.

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