Unusual Acid- and Base-Catalyzed C–N Bond Formation Approach through Reaction of Chromonyl Meldrum’s Acid and Nitrogen Binucleophiles

Abstract

Reaction of chromonyl Meldrum’s acid and N-substituted 2-aminobenzamides was studied in the presence of acidic and basic catalysts. The use of methanesulfonic acid as a catalyst in this reaction led to the synthesis of chromonyl quinazolinones through employing Meldrum’s acid as a carbon leaving group. However, in the presence of basic catalyst, this reaction gave functionalized 2-pyridones.

Keywords

chromonyl Meldrum’s acid - binucleophile - acid catalysis - base catalysis - chromonyl quinazolinines - domino Michael–elimination–cyclization reaction - functionalized 2-pyridones

• References and Notes

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• 12 General Procedure for the Synthesis of 3, 7, and 8 Typical Procedure for 3 To a solution of 3-formylchromone (1; 1 mmol, 174 mg) in EtOH–H₂O (4 mL; 1:1) was added Meldrum’s acid (2; 1 mmol, 144 mg), and the mixture was stirred for 3 h at ambient temperature. The precipitate formed was isolated by filtration. 2,2-Dimethyl-5-[(4-oxo-4H-chromen-3-yl)methylene]-1,3-dioxane-4,6-dione (3a) Yellow powder. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.78 (s, 6 H, 2 CH₃), 7.56 (t, 1 H, J = 7.6 Hz, HAr), 7.73 (d, 1 H, J = 8.4 Hz, HAr), 7.87 (t, 1 H, J = 7.5 Hz, HAr), 8.10 (d, 1 H, J = 7.5 Hz, HAr), 8.26 (s, 1 H, =CH), 9.31 [s, 1 H, (CO₂)₂C=CH]. ¹³C NMR (75 MHz, DMSO-d ₆): δ = 27.0, 104.9, 117.9, 118.0, 118.7, 123.1, 125.7, 126.7, 135.1, 145.5, 155.1, 159.8, 162.0, 162.2, 173.3. General Procedure for 7 To a solution of isatoic anhydride (4; 1 mmol, 163 mg) in EtOH (4 mL) was added the primary amine, aryl hydrazine, or aryl hydrazide 5a–h (1 mmol), and the mixture was heated for 1 h at 70 °C. This mixture was used for the synthesis of 7a–n or 8a–d without purification. To a solution of product 6a–h (1 mmol) in EtOH (10 mL) was added product 3 (1 mmol), and methanesulfonic acid (20 mol%, 20 mg), and the mixture was heated for 12 h at 70 °C. The reaction reached completion as indicated by TLC (EtOAc–n-hexane, 1:3), and the precipitate was filtered. The precipitate was washed with MeOH, and the resulting powder was pure product 7a–n (yields 48–84%). 2-(4-Oxo-4H-chromen-3-yl)-3-phenethyl-2,3-dihydroquinazolin-4(1H)-one (7c) Yellow powder, 285 mg (72%), mp 228–230 °C. IR (KBr): ν = 3327, 1724, 1632 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.88 (dt, 2 H, J = 15.0, 6.6 Hz, CH₂Ph), 3.10–3.14 (m, 1 H, CHPh), 4.05–4.09 (m, 1 H, CHN), 5.97 (s, 1 H, CH), 6.68 (t, 1 H, J = 7.1 Hz, HAr), 6.75 (d, 1 H, J = 7.9 Hz, HAr), 6.92 (s, 1 H, NH), 7.16 (d, 1 H, J = 6.6 Hz, HAr), 7.19–7.23 (m, 5 H, HAr), 7.45 (t, 1 H, J = 7.2 Hz, HAr), 7.53 (d, 1 H, J = 6.6 Hz, HAr), 7.68–7.77 (m, 2 H, HAr), 7.97 (s, 1 H, =CH), 8.04 (d, 1 H, J = 7.6 Hz, HAr). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 33.8, 46.2, 64.3, 114.8, 114.9, 117.5, 118.4, 121.4, 123.1, 124.9, 125.7, 126.1, 127.4, 128.3, 128.7, 133.1, 134.5, 138.9, 146.0, 153.2, 155.7, 162.1, 176.1. ESI-HRMS: m/z calcd for C₂₅H₂₁N₂O₃ [M + H]⁺: 397.1545; found: 397.1545. Colorless crystal (polyhedron), dimensions 0.270 × 0.150 × 0.130 mm³, crystal system monoclinic, space group C2/c, Z = 8, a = 21.6199(9) Å, b = 15.8126(7) Å, c = 12.0816(5) Å, α = 90°, β = 95.9595(18)°, γ = 90°, V = 4108.0(3) ų, ρ = 1.282 g cm^–3, T = 200(2) K, θ_max = 25.661°, radiation Mo Kα, λ = 0.71073 Å, 0.5° ω scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 4.29 and a completeness of 98.6% to a resolution of 0.83 Å, 17018 reflections measured, 3847 unique [R(int) = 0.0280], 2992 observed [I > 2σ(I)], intensities were corrected for Lorentz and polarization effects, an empirical absorption correction was applied using SADABS based on the Laue symmetry of the reciprocal space, μ = 0.09 mm^–1, T_min = 0.89, T_max = 0.96, structure refined against F² with a full-matrix least-squares algorithm using the SHELXL (Version 2014-3) software, 275 parameters refined, hydrogen atoms were treated using appropriate riding models, except H6 at N6, which was refined isotropically, goodness of fit 1.03 for observed reflections, final residual values R1(F) = 0.038, wR(F ²) = 0.090 for observed reflections, residual electron density –0.17 to 0.18 eÅ^–3. CCDC 1057685 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. General Procedure for the Synthesis of 8 To a solution of chromonyl Meldrum’s acid (3, 1 mmol) in EtOH (10 mL) was added product 6 (1 mmol) and K₂CO₃ (30 mol%, 50 mg), and the mixture was heated at 70 °C for 12 h, monitoring progress of reaction by TLC (eluent: EtOAc–n-hexane, 1:3). The EtOH was removed under vacuum, and further purification was carried out using preparative TLC (n-hexane–EtOAc, 2:1). The products were obtained as yellow oils. N-Benzyl-2-[5-(2-hydroxybenzoyl)-2-oxopyridin-1(2H)-yl]benzamide (8b) Yellow oil; 314 mg (74%). IR (KBr): ν = 3263, 1677, 1658 cm^–1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 4.31 (dd, 1 H, J = 15.0, 8.0 Hz, CH₂), 4.35 (dd, 1 H, J = 15.0, 6.0 Hz, CH₂), 6.53 (d, 1 H, J = 9.5 Hz, HAr), 6.88 (t, 1 H, J = 9.5 Hz, HAr), 6.94 (d, 1 H, J = 7.8 Hz, HAr), 7.18–7.30 (m, 5 H, HAr), 7.35 (t, 1 H, J = 7.4 Hz, HAr), 7.44 (d, 1 H, J = 7.4 Hz, HAr), 7.55–7.67 (m, 3 H, HAr), 7.85 (d, 1 H, J = 2.5 Hz, HAr), 7.89 (dd, 1 H, J = 8.7, 2.5 Hz, HAr), 9.00 (t, 1 H, J = 5.9 Hz, NH), 10.29 (s, 1 H, OH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 54.9, 116.3, 116.6, 116.7, 119.2, 119.4, 124.4, 124.5, 126.7, 127.0, 128.2, 128.4, 129.3, 129.9, 131.2, 132.8, 134.2, 138.1, 139.1, 139.2, 146.4, 155.8, 156.0, 161.3, 165.9, 191.6. ESI-MS: m/z = 425.0 [M + H]⁺. Anal. Calcd. for C₂₆H₂₀N₂O₄: C, 73.57; H, 4.75; N, 6.60. Found: C, 73.49; H, 4.79; N, 6.64.