Utilizing Solubility Differences to Achieve Regiocontrol in the Synthesis of Substituted Quinoline-4-carboxylic Acids

Abstract

A practical method for the regiocontrolled synthesis of substituted quinoline-4-carboxylic acids is described. Solubility differences between the product quinoline regioisomers enable their facile separation, thus avoiding any challenging chromatographic purifications and allowing access to highly substituted quinoline compounds in three steps from commercially available anilines.

Key words

heterocycles - quinolones - isatins - regioisomers - cyclization

• References and Notes

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• 21 4-Bromo-5-methylindoline-2,3-dione (17); Typical Procedure: To a stirred solution of aqueous sulfuric acid (18.1 M, 42.0 mL) at 60 °C, was added (2E)-N-(3-bromo-4-methylphenyl)-2-(hydroxyimino)acetamide (15.8 g, 61.8 mmol) portionwise. The reaction mixture was stirred in a heating block for 30 min at an internal temperature of 80 °C, then the mixture was cooled to room temperature. The solution was added slowly to a saturated water/ice mixture (79.5 mL) and stirred for 10 min at room temperature, then filtered. The resultant solid was dried under vacuum at 40 °C for 40 h, then added to isopropyl alcohol (10 mL), stirred at room temperature for 15 min, filtered and dried under vacuum at 40 °C for 16 h to give isatin 17 (13.0 g, 54.4 mmol, 88% yield, 4:1 r.r. in favor of the 4-bromo-5-methyl isomer over the 5-methyl-6-bromo isomer) as an orange solid. Data listed for both regioisomers: mp 236–238 °C. IR (thin film): 3289, 1728, 1605, 1458, 1273, 1211, 1152, 1042, 995, 980, 824, 635 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.07 (s, 0.8 H), 11.04 (s, 0.2 H), 7.53–7.51 (m, 2 H), 7.11 (s, 0.2 H), 6.81 (d, J = 8.0 Hz, 0.8 H), 2.30 (s, 0.6 H), 2.29 (s, 2.4 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 183.6, 182.0, 159.4, 158.6, 150.6, 149.2, 139.3, 133.9, 132.1, 131.6, 126.3, 121.7, 117.4, 116.6, 115.6, 111.2, 21.7, 20.7. HRMS (ESI⁺): m/z [M]⁺ calcd for C₉H₆BrNO₂ ⁺: 238.9582; found: 238.9575 (+2.99 ppm).
• 22 5-Bromo-2,6-dimethylquinoline-4-carboxylic Acid (30); Typical Procedure: To a stirred solution of KOH (15.3 g, 272 mmol) in H₂O (52.2 mL) in an ice-water bath was added isatin 17 (13.0 g, 54.4 mmol, 4:1 r.r. in favor of the 4-bromo-5-methyl isomer over the 5-methyl-6-bromo isomer) portionwise. The reaction mixture was stirred at room temperature for 10 min, then cooled in an ice-water bath and acetone (52.2 mL) was added dropwise. The reaction mixture was stirred in a 70 °C heating block for 5 h, then cooled in an ice-water bath and a solution of aqueous HCl (5 M, 49.0 mL, 245 mmol) was added dropwise until the mixture reached pH 5–6. The reaction mixture was stirred at room temperature for 10 min and then filtered. The resultant solid was dried under vacuum at 40 °C for 16 h, then added to isopropyl alcohol (10 mL), stirred at room temperature for 15 min, filtered, and dried under vacuum at 40 °C for 16 h. The solid was then added to ethyl acetate (10 mL), stirred at room temperature for 15 min, filtered, and dried under vacuum at 40 °C for 6 h to give quinoline 30 (6.26 g, 22.3 mmol, 41% yield, 2.6:1 r.r. in favor of the 5-bromo-6-methyl isomer over the 6-methyl-7-bromo isomer) as a golden brown solid. Data listed for both regioisomers: mp 245–251 °C (decomp.). IR (thin film): 1705, 1587, 1558, 1458, 1333, 1256, 1188, 1149, 1036, 910, 880, 826, 785, 733, 689 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.80 (br. s, 1 H), 8.59 (s, 0.3 H), 8.25 (s, 0.3 H), 7.94 (d, J = 8.6 Hz, 0.7 H), 7.86 (s, 0.3 H), 7.78 (d, J = 8.6 Hz, 0.7 H), 7.52 (s, 0.7 H), 2.70 (s, 0.8 H), 2.68 (s, 2.2 H), 2.57 (s, 2.2 H), 2.55 (s, 0.8 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.9, 167.2, 159.3, 158.2, 147.4, 147.4, 141.2, 137.6, 135.9, 135.6, 132.5, 131.3, 128.5, 126.6, 126.1, 123.5, 122.1, 121.9, 121.3, 119.5, 24.6, 24.1, 24.0, 23.0. HRMS (ESI⁺): m/z [M]⁺ calcd for C₁₂H₁₀BrNO₂ ⁺: 278.9895; found: 278.9901 (−2.09 ppm).
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