Synthesis of Highly Functionalized Benzofuran-2-carboxamides by Ugi Four-Component Reaction and Microwave-Assisted Rap–Stoermer Reaction

Abstract

A two-step, diversity-oriented synthesis of highly functionalized benzofuran-2-carboxamides has been developed. The Ugi four-component reaction of aromatic amines, isocyanides, 2-bromobenzaldehyde, and 2-bromoacetic acid was used to provide a collection of N-aryl 2-bromoacetamides. The latter were then reacted with selected salicyladehydes in the presence of Cs₂CO₃ in acetonitrile under controlled microwave heating at 90–140 °C for 15–40 minutes to furnish the benzofuran-2-carboxamides in moderate to good yields.

Key words

amides - heterocycles - microwave - multicomponent ­reaction - phenols

• References and Notes


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• 21 General procedure for Ugi and Rap–Stoermer reaction To a 25-mL round-bottom flask were added aniline (1 mmol), 2-bromobenzaldehyde (1 mmol), and MeOH (8 mL), and the resultant mixture was stirred for 15 min at room temperature. 2-Bromoacetic acid (1 mmol) was added to the mixture followed by stirring for another 5 min. Finally, cyclohexyl isocyanide (1.2 mmol) was added. The resultant mixture was stirred at 50 °C for 48 h. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel; 20% EtOAc plus 5% CHCl₃ in PE) to give 8a (457.4 mg, 90%). CHCl₃ was added to improve the solubility of the product in mixed EtOAc and PE. The yields of 8b–h are listed in Table 1. A 10-mL pressurized process vial was charged with the above U-4CR adduct 8a (0.1 mmol) and Cs₂CO₃ (0.25 mmol). The vial was tightly sealed with a cap containing a silicon septum. The vial was evacuated and backfilled with nitrogen several times by using a needle through the septum. MeCN (5 mL) was added by using a syringe through the septum. After stirring the mixture for 10 min at room temperature, salicyladehyde (9a; 0.12 mmol) was added (solid salicyladehydes were added prior to the evacuation–backfill cycles), and the loaded vial was then placed into a technical microwave reactor cavity and heated at 140 °C for 5 min with stirring. After cooling to room temperature, the reaction mixture was diluted with water and the resultant mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄, and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, 25% EtOAc in PE) to provide the benzofuran-2-carboxamide 10a (38.8 mg, 73%). The yields of other products are listed in Table 3. N-Cyclohexyl-2-[(2-bromoacetyl)phenylamino]-2-(2-bromophenyl)acetamide (8a): White crystalline solid; mp 226–228 °C (EtOAc–hexane); R_f = 0.33 (20% EtOAc in PE). IR (film): 3271, 3075, 2929, 2850, 1651, 1556, 1494, 1364, 1237, 1210, 1027 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.53–6.96 (m, 9 H), 6.38 (s, 1 H), 5.55 (d, J = 7.0 Hz, 1 H), 3.87–3.83 (m, 1 H), 3.67 (s, 2 H), 2.02 (d, J = 13.0 Hz, 1 H), 1.88 (d, J =14.5 Hz, 1 H), 1.73 (d, J = 14.0 Hz, 1 H), 1.67–1.63 (m, 2 H), 1.39–1.32 (m, 2 H), 1.21–1.02 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 167.9, 166.9, 138.5, 133.8, 132.8, 131.9, 130.1, 129.8 (br, ×2), 128.9 (×2), 128.8, 127.3, 126.4, 64.4, 49.0, 32.8, 32.7, 27.6, 25.5, 24.8, 24.8. MS (+ESI): m/z (%) = 511 (15.1) [M+4+H]⁺, 509 (28.3) [M+2+H]⁺, 507 (14.9) [M+H]⁺, 304 (96.4), 302 (100). Anal. Calcd for C₂₂H₂₄Br₂N₂O₂: C, 51.99; H, 4.76; N, 5.51. Found: C, 52.20; H, 4.74; N, 5.51. N-[(2-Bromophenyl)(cyclohexylcarbamoyl)-methyl]-N-phenylbenzofuran-2-carboxamide (10a): White crystalline solid; mp 194–195 °C (EtOAc–hexane); R_f = 0.29 (20% EtOAc in PE). IR (film): 3293, 3058, 2926, 1654, 1556, 1388, 1252, 1187 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.54 (dd, J = 8.0, 2.0 Hz, 1 H), 7.41–7.11 (m, 10 H), 7.10–7.00 (m, 2 H), 6.58 (s, 1 H), 5.90 (s, 1 H), 5.66 (d, J = 8.0 Hz, 1 H), 3.91–3.84 (m, 1 H), 2.05 (d, J = 11.6 Hz, 1 H), 1.89 (d, J = 10.8 Hz, 1 H), 1.75–1.55 (m, 3 H), 1.42–1.29 (m, 2 H), 1.27–1.00 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 168.0, 160.0, 154.4, 147.4, 139.2, 133.7, 132.7, 132.2, 130.6 (×2), 130.0, 128.6 (×2), 128.5, 127.2, 126.9, 126.6, 126.4, 123.1, 122.3, 112.6, 111.8, 64.8, 48.9, 32.8, 32.7, 25.4, 24.8, 24.7. MS (+EI): m/z (%) = 533 (10.5) [M+2+H]⁺, 531 (10.2) [M+H]⁺, 145 (100). Anal. Calcd for C₂₉H₂₇BrN₂O₃: C, 65.54; H, 5.12; N, 5.27. Found: C, 64.88; H, 5.09; N, 5.33.
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