Practical One-Pot Four-Step Synthesis of Isocoumarin-3-Carboxylic Acids

Abstract

We report a facile and versatile, one-pot four-step synthesis of functionalized isocoumarin-3-carboxylic acids on a 70–100 g scale. Commercially available substituted anthranilic acids are converted into the corresponding 2-carboxydiazonium bromides, which subsequently undergo the CuBr-catalyzed Meerwein reaction with methyl-2-fluoroacrylate to afford 2-(2-bromo-2-fluoro-3-methoxy-3-oxopropyl)benzoic acids, whereas o-bromobenzoic acids are formed as minor impurities in the concomitant Sandmeyer reactions. The treatment of the reaction mixture with CH₂Cl₂ and aqueous NaHCO₃ removes the salts of the o-bromobenzoic acids into the aqueous phase while 2-(2-bromo-2-fluoro-3-methoxy-3-oxopropyl)benzoic acids cyclize to give methyl 3-fluoro-isocoumarin-3-carboxylates whose trituration with AcOH/HCl/H₃BO₃ eliminates HF and hydrolyses the ester groups to afford substituted isocoumarin-3-carboxylic acids in overall 42–53% yield.

Keywords

Isocoumarin - One-pot synthesis - Meerwein reaction - Heterocyclization - Eliminations - Hydrolysis

Publication History

Received: 09 July 2025

Accepted after revision: 11 August 2025

Accepted Manuscript online:
12 August 2025

Article published online:
18 September 2025

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• 35a General procedure for one-pot four-step preparation of isocoumarin-3-carboxylic acids
• 35b Diazotization. A 48% aqueous solution of HBr (200 mL) was added to a stirred solution of the corresponding anthranilic acid 1 (0.75 mol) in acetone (400 mL). A solution of sodium nitrite (59 g, 0.86 mol) in deionized water (200 mL) was slowly added to the suspension formed at −5 to 0 °C and the reaction mixture was stirred at 0 °C for 1 hour
• 35c The Meerwein reaction. The cold solution (or suspension) of arenediazonium bromide 2 was poured in small portions into a stirred mixture of methyl 2-fluoroacrylate (76 g, 0.73 mol), CuBr (5 g, 35 mmol), and hydroquinone (2 g, 18 mmol) at a temperature between 40 and 45 °C. The reaction is exothermic with the rapid release of nitrogen gas. After the end of the gas release, the reaction mixture was diluted with water (700 mL) and methylene chloride (300 mL). The organic layer was washed with water (3 × 100 mL) until neutral pH of the aqueous layer
• 35d Cyclization and hydrolysis. The organic layer was separated and mixed with a solution of sodium hydrocarbonate (100 g) in water (1 L), and the reaction mixture was vigorously stirred at room temperature for 12 h. The organic layer was separated, washed with water (2 × 500 mL), and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of glacial acetic acid (350 mL), boric acid (10 g, 160 mmol), and concentrated HCl (50 mL). The resulting mixture was stirred under reflux for 48 h and then cooled down on an ice bath. The precipitated product was filtered off, washed with a 10% aqueous acetic acid (3 × 150 mL), and dried in a vacuum
• 35e 7-Methyl-isocoumarin-3-carboxylic acid (7c). Off-white crystalline powder. Yield 75 g (49%). M. p. 288–290 °C. ¹H NMR (400 MHz, DMSO-d ₆) δ 8.02 (s, 1H), 7.81 – 7.71 (m, 2H), 7.64 (s, 1H), 2.48 (s, 3H). ¹³C NMR (101 MHz, DMSO-d ₆) δ 161.1, 160.5, 142.6, 141.1, 136.4, 132.5, 128.7, 128.0, 121.8, 111.8, 21.0. LCMS (ESI, pos.): m/z = 205.2 [M+H]⁺. HRMS calcd for C₁₁H₉O₄ 205.0495, found 205.0507 [M+H]⁺. Anal. calcd (%) for C₁₁H₈O₄: C, 64.71; H, 3.95. Found: C, 64.61; H, 4.04
• 35f 6-Fluoro-isocoumarin-3-carboxylic acid (7d). Beige crystalline powder. Yield 81.1 g (52%). M. p. 238–240 °C. ¹H NMR (400 MHz, DMSO-d ₆) δ 13.98 (s, 1H), 8.26 (dd, J = 8.8, 5.5 Hz, 1H), 7.76 (dd, J = 9.2, 2.6 Hz, 1H), 7.67 (s, 1H), 7.62 – 7.54 (m, 1H). ¹³C NMR (101 MHz, DMSO-d ₆) δ 165.8 (d, J = 254.1 Hz), 160.8, 159.7, 144.3, 138.0 (d, J = 11.3 Hz), 132.7 (d, J = 10.4 Hz), 118.8, 118.6, 113.7 (d, J = 23.2 Hz), 111.02 (d, J = 2.8 Hz). ¹⁹F NMR (376 MHz, DMSO-d ₆) δ −104.39 to −104.48 (m). LCMS (ESI, pos.): m/z = 209.2 [M+H]⁺. HRMS calcd for C₁₀H₆FO₄ 209.0245, found 209.0243 [M+H]⁺. Anal. calcd (%) for C₁₀H₅FO₄: C, 57.71; H, 2.42. Found: C, 57.66; H, 2.45