Copper-Catalyzed Regioselective C–H Iodination of Aromatic Carboxamides

Abstract

A concise and efficient copper-catalyzed C–H iodination of 8-aminoquinoline-based aromatic carboxamides was reported. The reaction has the broad substrate scope and shows moderate to high yields, also offers other attractive advantages including simplicity of operation, compatibility with heteroarenes, and the use of low-cost copper catalyst. The new approach was further applied to cyanation of N-(quinolin-8-yl)benzamide, offering a potentially attractive alternative to the synthesis of aromatic nitriles.

Key words

aryl halide - aromatic carboxamides - C–H halogenation - copper catalyst - heteroarenes - regioselective iodination

• References and Notes

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• 20 The Preparation of Aromatic Carboxamide – General Procedure To a 50 mL three-necked flask, isonicotinic acid (2.5 g, 20 mmol), DMF (5 drops), and anhydrous CH₂Cl₂ (30 mL) were added under a N₂ atmosphere. Oxalyl chloride (2.1 mL, 24 mmol, 1.2 equiv) was added dropwise at 0 °C resulting in vigorous bubbling. The mixture was stirred for 5 h at room temperature, and the solvent was then removed in vacuo. The resulting acid chloride was used immediately without further purification. To a 100 mL three-necked flask, 8-aminoquinoline (3.8 g, 26 mmol, 1.3 equiv), Et₃N (5.7 mL, 40 mmol, 2 equiv), and anhydrous CH₂Cl₂ (30 mL) were added. A solution of the acid chloride in anhydrous CH₂Cl₂ (10 mL) was added dropwise to the solution at 0 °C, and the solution was then warmed to room temperature. After stirring overnight, the reaction system was quenched with NaHCO₃ (30 mL of sat. aq solution) and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (2 × 15 mL). The combined organic layers were washed with aq HCl (30 mL, 1 M) and brine (30 mL), dried over MgSO₄, filtered, and evaporated in vacuo. The obtained crude amide was purified by column chromatography on silica gel (eluant: CH₂Cl₂–PE = 5:1) to afford the desired amide. Copper-Catalyzed C–H Iodination of Aromatic Carboxamides; General Procedure A mixture of 1 (74.5 mg, 0.3 mmol), I₂ (76.2 mg, 0.3 mmol), PhI(OAc)₂ (193.2 mg, 0.6 mmol), and Cu(OAc)₂ (10.9 mg, 0.06 mmol) in NMP (2 mL) was stirred at 100 °C under O₂ (1 atm) for 20 h. The reaction mixture was cooled to room temperature and diluted with CH₂Cl₂ (2 mL). The suspension was filtered through a pad of Celite, and the residue was washed three times with CH₂Cl₂ (3 × 5 mL). The filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to afford the desired product. Analytical Data of Some Typical Compounds 4-Methyl-N-(quinolin-8-yl)benzamide (2) Brown solid (yield, 62%). ¹H NMR (300 MHz, CDCl₃): δ = 10.72 (s, 1 H), 8.92 (d, 1 H), 8.85 (d, 1 H), 8.21 (d, 1 H), 8.0 (d, 2 H) 7.62–7.47 (m, 3 H), 7.34 (d, 3 H), 2.45 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 165.18, 148.48, 142.14, 140.33, 139.10, 138.16, 135.50, 131.95, 131.01, 129.30, 127.12, 122.96, 117.67, 89.01, 21.50. ESI-HRMS: m/z calcd for C₁₇H₁₄N₂O [M + H]⁺: 263.1179; found: 263.1227. 4-Methyl-N-(5-iodoquinolin-8-yl)benzamide (2a) White solid (yield, 93%). ¹H NMR (300 MHz, CDCl₃): δ = 10.73 (s, 1 H), 8.86–8.82 (m, 1 H), 8.75–8.69 (d, 2 H), 8.44–8.37 (m, 1 H), 8.16 (d, 1 H), 8.00–7.92 (d, 2 H), 7.60–7.54 (m, 1 H), 7.39–7.32 (d, 2 H), 2.45 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 165.16, 148.58, 140.53, 138.16, 131.92, 131.95, 129.30, 129.47, 127.12, 122.95, 117.67, 89.91, 21.35. ESI-HRMS: m/z calcd for C₁₇H₁₃IN₂O [M + H]⁺: 389.0145; found: 389.0160. N-(5-Iodoquinolin-8-yl)isonicotinamide (9a) White solid (yield, 75%). ¹H NMR (300 MHz, CDCl₃): δ = 10.82 (s, 1 H), 8.87–8.84 (m, 3 H), 8.69 (d, 1 H), 8.43 (d, 1 H), 8.16 (d, 1 H), 7.91 (d, 2 H), 7.62–7.59 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.18, 150.66, 149.14, 142.06, 140.98, 139.18, 138.27, 134.70, 129.77, 123.49, 121.20, 118.25, 90.64. ESI-HRMS: m/z calcd for C₁₅H₁₀N₃O [M + H]⁺: 375.9941; found: 375.9970. 3-Iodo-N-(5-iodoquinolin-8-yl)isonicotinamide (9b) Brown solid (yield, 17%). ¹H NMR (300 MHz, CDCl₃): δ = 10.23 (s, 1 H), 9.10 (d, 1 H), 8.76 (s, 1 H), 8.70 (d, 1 H), 8.66 (d, 1 H), 8.40 (d, 1 H), 8.16 (d, 1 H), 7.57–7.54 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 164.95, 158.74, 149.40, 149.14, 148.31, 140.89, 138.99, 138.18, 134.57, 129.77, 123.47, 122.74, 118.43, 91.50, 90.97. ESI-HRMS: m/z calcd for C₁₅H₉N₃O [M + H]⁺: 501.8908; found: 501.8941.