Hydrochloric Acid → 6-Chloro-7-methoxyquinoline

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A solution of sulfuric acid (35 mL) in water (35 mL) was treated with 3-nitrobenzenesulfonic acid (35.1 g, 159 mmol) and glycerol (80 ml, 1.1 mol) to give a thick grey suspension. The suspension was heated to 75° C. and 4-chloro-3-methoxyaniline (25.0 g, 159 mmol) was added. The mixture was stirred at 140° C. for 1 h. Additional quantities of water (35 mL), sulfuric acid (35 mL) and glycerol (40 mL) were added and the reaction was stirred an additional 2 h at 140° C. The solution was cooled to room temperature, poured onto ice, and the pH was adjusted to 13 by addition of concentrated ammonium hydroxide. The mixture was extracted with EtOAc (3×) and the extracts were washed with brine, dried over Na2SO4 and concentrated. Following the general procedure for quinoline purification described by Leir, C. M. J. Org. Chem., 1977, 42, 911, the residue was dissolved into 2 M HCl (500 mL) and zinc chloride (43.2 g, 317 mmol) was added, resulting in immediate formation of a precipitate. The mixture was stirred for 30 min. The solids were isolated by filtration, washing with cold 2 M HCl, 2-propanol, then water. The solids were added to concentrated ammonium hydroxide (400 mL) and the mixture was stirred for 10 min. EtOAc was added and the mixture was stirred for 5 min. The mixture was extracted with EtOAc (3×) and the extracts were washed with brine, dried over Na2SO4 and concentrated to a dark brown residue consisting of a mixture of the two possible cyclization regioisomers. Silica gel chromatography (15-100% gradient of EtOAc in DCM) provided 6-chloro-7-methoxyquinoline (7.03 g) as a beige solid. MS (M+1)=194.1, 1H NMR (400 MHz, Methanol-d 4) δ 8.78 (dd, J=4.5, 1.6 Hz, 1H), 8.24 (dd, J=8.4, 1.4 Hz, 1H), 8.01 (s, 1H), 7.47 (s, 1H), 7.43 (dd, J=8.3, 4.5 Hz, 1H), 4.06 (s, 3H).

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