Actions of Bisnucleophiles on (E)-3-[3-(2-Hydroxyaryl)-3-oxoprop-1-en-1-yl]chromones: Versatile Transformations into Oxygen- and Nitrogen-Containing Heterocycles

Abstract

The transformations of (E)-3-[3-(2-hydroxyaryl)-3-oxoprop-1-en-1-yl]chromones in the presence of methylhydrazine and aromatic bisnucleophiles are described. The reactions generally lead to chromone ring transformation via pyrone ring-opening and heterocyclization to give novel diazoles and (Z)-3-aminomethylenechromanones, respectively. Piperazine catalyzes chromanone ring closure of the starting substrate to afford chromone–chromanone dyads.

Key words

chromones - α,β-unsaturated carbonyl systems - Michael additions - bisnucleophiles - X-ray diffraction - heterocycles - 2D NMR

• References and Notes

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• 18 Transformations of (E)-3-[3-(2-Hydroxyaryl)-3-oxoprop-1-en-1-yl]chromones 1a,b; General procedure Methylhydrazine, phenylenediamine, 2-aminophenol or piperazine (2 mmol) was added to a stirred solution of (E)-3-[3-(2-hydroxyaryl)-3-oxoprop-1-en-1-yl]chromone 1a,b (1 mmol) in THF (20 mL) at r.t., and the resulting mixture was allowed to stir overnight. After removal of the solvent under reduced pressure, the obtained resinous material was subjected to column chromatography. The product was recrystallized from a mixture of hexane–dichloromethane (1:1) by slow evaporation of the solvent at 6 °C to afford 2a,b, 3aa,ab or 4a,b. Good-quality single crystals suitable for X-ray analysis were only obtained for products 2a, 3aa and 4a,b.
• 19 2,2′-(1′,2-Dimethyl-3,4-dihydro-1′H,2H-[3,4′-bispyrazole]-3′,5-diyl)diphenol (2a) Yield: 0.20 g (57%); M _r = 348.41 g/mol; colorless crystals; mp 205–206 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.88 (s, 3 H, 1-N-CH ₃), 2.98 (dd, J = 18.0, 14.0 Hz, 1 H, H-4[A]), 3.69 (dd, J = 18.0, 10.0 Hz, 1 H, H-4[M]), 3.95 (s, 3 H, 1′-N-CH ₃), 4.40 (dd, J = 14.0, 10.0 Hz, 1 H, H-3[X]), 6.83–6.94 (m, 2 H, H-5′′, H-5′′′), 6.97–7.14 (m, 3 H, H-3′′, H-3′′′, H-6′′), 7.20–7.28 (m, 2 H, H-4′′, H-4′′′), 7.47 (dd, J = 7.8, 1.6 Hz, 1 H, H-6′′′), 7.61 (s, 1 H, H-5′), 10.73 (s, 1 H, 2′′′-OH), 10.97 (s, 1 H, 2′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 39.1 (1′-N-CH₃), 42.1 and 42.2 (1-N-CH₃ and C-4), 63.8 (C-3), 116.1 (C-1′′), 116.5 (C-3′′), 117.2 (C-1′′′), 117.3 (C-3′′′), 118.3 (C-4′), 119.1 (C-5′′), 119.2 (C-5′′′), 127.2 (C-6′′), 127.3 (C-6′′′), 129.1 (C-4′′), 130.4 (C-4′′′), 130.5 (C-5′), 147.9 (C-3′), 153.1 (C-5), 155.7 (C-2′′′), 157.6 (C-2′′). HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₁N₄O₂: 349.1665; found: 349.1668.
• 20 2-[3′-(2-Hydroxyphenyl)-1′,2-dimethyl-3,4-dihydro-1′H,2H-[3,4′-bispyrazol]-5-yl]-4-methoxyphenol (2b) Yield: 0.19 g (50%); M _r = 378.43 g/mol; white solid; mp 182–183 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.87 (s, 3 H, 1-N-CH ₃), 2.97 (dd, J = 18.0, 14.0 Hz, 1 H, H-4[A]), 3.65 (dd, J = 18.0, 10.0 Hz, 1 H, H-4[M]), 3.74 (s, 3 H, 5′′-OCH ₃), 3.95 (s, 3 H, 1′-N-CH ₃), 4.42 (dd, J = 14.0, 10.0 Hz, 1 H, H-3[X]), 6.62 (d, J = 2.9 Hz, 1 H, H-6′′), 6.81–6.95 (m, 3 H, H-4′′, H-3′′, H-5′′′), 7.06 (dd, J = 8.2, 1.2 Hz, 1 H, H-3′′′), 7.20–7.27 (m, 1 H, H-4′′′), 7.47 (dd, J = 7.8, 1.6 Hz, 1 H, H-6′′′), 7.61 (s, 1 H, H-5′), 10.56 (br s, 2 H, 2′′′-OH and 2′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 39.2 (1′-N-CH₃), 42.1 and 42.3 (1-N-CH₃ and C-4), 55.9 (5′′-O-CH₃), 63.9 (C-3), 112.2 (C-6′′), 116.3 (C-4′′), 117.1 (C-3′′), 117.3 (C-1′′′), 117.4 (C-3′′′), 118.4 (C-5′′′), 119.4 (C-4′), 127.3 (C-6′′′), 129.2 (C-4′′′), 130.7 (C-5′), 148.0 (C-3′), 151.9 (C-5′′), 152.3 (C-1′′), 152.9 (C-5), 155.8 and 156.0 (C-2′′ and C-2′′′). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₁H₂₂N₄O₃Na: 401.1590; found: 401.1581.
• 21 (Z)-3-{[(2-Aminophenyl)amino]methylene}-2-[2-(2-hydroxyphenyl)-2-oxoethyl]chroman-4-one (3aa) Yield: 0.27 g (68%), M _r = 400.43 g/mol; orange crystals; mp 140–141 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.43 (dd, J = 16.4, 7.0 Hz, 1 H, H-1′[AB]), 3.69 (dd, J = 16.4, 6.2 Hz, 1 H, H-1′[AB]), 3.70 (s, 2 H, 2′′′′-NH ₂), 5.73 (dd, J = 7.0, 6.2 Hz, 1 H, H-2[X]), 6.76–6.91 (m, 4 H, H-5′′′, H-3′′′, H-4′′′′, H-6′′′′), 6.93–7.12 (m, 4 H, H-8, H-6, H-3′′′′, H-5′′′′), 7.38–7.54 (m, 4 H, H-7, H-4′′′, H-1′′, H-6′′′), 7.97 (dd, J = 7.7, 1.3 Hz, 1 H, H-5), 11.80 (d, J = 12.0 Hz, 1 H, 1′′-NH), 12.18 (s, 1 H, 2′′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 44.3 (C-1′), 75.3 (C-2), 103.8 (C-3), 117.4 (C-3′′′′), 117.9 (C-6′′′′), 118.1 (C-4′′′′), 118.6 (C-8), 119.1 (C-5′′′), 119.5 (C-1′′′), 120.1 (C-3′′′), 121.9 (C-6), 122.8 (C-10), 125.6 (C-5′′′′), 126.5 (C-5), 128.2 (C-1′′′′), 130.1 (C-6′′′), 134.6 (C-7), 136.9 (C-4′′′), 137.2 (C-2′′′′), 144.5 (C-1′′), 157.3 (C-9), 162.6 (C-2′′′), 181.6 (C-4), 203.3 (C-2′). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₀N₂O₄Na: 423.1321; found: 423.1318.
• 22 (Z)-2-[2-(2-Hydroxyphenyl)-2-oxoethyl]-3-{[(2-hydroxyphenyl)amino]methylene}chroman-4-one (3ab) Yield: 0.27 g (76%); M _r = 401.41 g/mol; yellow solid; mp 140–141 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.38 (dd, J = 16.2, 6.6 Hz, 1 H, H-1′[AB]), 3.71 (dd, J = 16.2, 6.6 Hz, 1 H, H-1′[AB]), 5.74 (t, J = 6.6 Hz, 1 H, H-2[X]), 6.75–6.99 (m, 6 H, H-4′′′′, H-6′′′′, H-5′′′′, H-3′′′, H-5′′′, H-8), 7.03–7.17 (m, 2 H, H-6, H-3′′′′), 7.35–7.57 (m, 4 H, H-7, H-4′′′, H-6′′′, H-1′′), 8.01 (dd, J = 7.8, 1.7 Hz, 1 H, H-5), 11.99 (d, J = 12.0 Hz, 1 H, 1′′-NH), 12.11 (s, 1 H, 2′′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 44.4 (C-1′), 75.6 (C-2), 103.9 (C-3), 114.6 (C-3′′′′), 116.2 (C-6′′′′), 118.1 (C-4′′′′), 118.6 (C-8), 119.0 (C-5′′′), 119.6 (C-1′′′), 121.3 (C-3′′′), 121.8 (C-6), 122.9 (C-10), 124.3 (C-5′′′′), 126.6 (C-5), 128.5 (C-1′′′′), 130.1 (C-6′′′), 134.5 (C-7), 136.7 (C-4′′′), 141.8 (C-1′′), 145.5 (C-2′′′′), 157.5 (C-9), 162.7 (C-2′′′), 181.4 (C-4), 203.2 (C-2′). HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₁₉NO₅Na: 424.1161; found: 424.1131.
• 23 3-(4-Oxochroman-2-yl)-4H-chromen-4-one (4a) Yield: 0.18 g (61%); M _r = 292.29 g/mol; colorless crystals; mp 195–196 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.89 (dd, J = 16.9, 13.0 Hz, 1 H, H-3′[AB]), 3.25 (dd, J = 16.9, 3.0 Hz, 1 H, H-3′[AB]), 5.72 (ddd, J = 13.0, 3.0, 1.0 Hz, 1 H, H-2′[X]), 7.02–7.13 (m, 2 H, H-8′, H-6′), 7.40–7.57 (m, 3 H, H-6, H-8, H-7′), 7.72 (ddd, J = 8.7, 7.1, 1.7 Hz, 1 H, H-7), 7.95 (ddd, J = 8.6, 4.9, 3.6 Hz, 1 H, H-5′), 8.20–8.28 (m, 1 H, H-5), 8.24 (d, J = 1.0 Hz, 1 H, H-2). ¹³C NMR (75 MHz, CDCl₃): δ = 42.8 (C-3′), 73.0 (C-2′), 117.9 (C-8′), 118.2 (C-8), 121.1 (C-10′), 122.0 (C-6′), 122.9 (C-3), 123.8 (C-10), 125.5 (C-6), 125.9 (C-5), 127.3 (C-5′), 134.1 (C-7), 136.1 (C-7′), 153.3 (C-2), 156.3 (C-9), 161.2 (C-9′), 175.7 (C-4), 191.3 (C-4′). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₂O₄Na: 315.0633; found: 315.0636.
• 24 3-(6-Methoxy-4-oxochroman-2-yl)-4H-chromen-4-one (4b) Yield: 0.14 g (43%); M _r = 322.31 g/mol; colorless crystals; mp 195–196 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.85 (dd, J = 17.0, 13.1 Hz, 1 H, H-3′[AB]), 3.24 (dd, J = 17.0, 2.9 Hz, 1 H, H-3′[AB]), 3.83 (s, 3 H, 6′-OCH ₃), 5.67 (ddd, J = 13.1, 2.9, 1.0 Hz, 1 H, H-2′[X]), 7.00 (d, J = 9.0 Hz, 1 H, H-8′), 7.13 (dd, J = 9.0, 3.2 Hz, 1 H, H-7′), 7.37 (d, J = 3.1 Hz, 1 H, H-5′), 7.40–7.52 (m, 2 H, H-6, H-8), 7.72 (ddd, J = 8.6, 7.2, 1.7 Hz, 1 H, H-7), 8.21–8.28 (m, 1 H, H-5), 8.24 (d, J = 1.0 Hz, 1 H, H-2). ¹³C NMR (75 MHz, CDCl₃): δ = 42.7 (C-3′), 55.8 (6′-OCH₃) 73.1 (C-2′), 107.6 (C-5′), 118.2 (C-8), 119.2 (C-8′), 121.0 (C-10′), 123.0 (C-3), 123.8 (C-10), 125.2 (C-7′), 125.5 (C-6), 125.9 (C-5), 134.0 (C-7), 153.3 (C-2), 154.5 (C-6′), 155.8 (C-9′), 156.3 (C-9), 175.7 (C-4), 191.5 (C-4′). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₁₄O₅Na: 345.0739; found: 345.0748.
• 25 Crystal data for compound 2a (CCDC 1404991): C₂₀H₂₀N₄O₂, M = 348.40, triclinic, space group Pī, Z = 2, a = 8.7610(13) Å, b = 9.9194(16) Å, c = 11.871(2) Å, α = 66.580(7)°, β = 70.069(7)°, γ = 74.993(7)°, V = 880.8(3) Å³, μ(Mo-Kα) = 0.088 mm^–1, D _c = 1.314 g cm^–3, colorless block, crystal size = 0.22 × 0.16 × 0.10 mm³. Of a total of 19322 reflections collected, 4753 were independent (R _int = 0.0413). Final R1 = 0.0467 [I > 2σ(I)] and wR2 = 0.1267 (all data). Data completeness to θ = 25.24°, 99.9%.
• 26 Crystal data for compound 3aa (CCDC 1404990): C₂₄H₂₀N₂O₄, M = 400.42, monoclinic, space group P2₁/n, Z = 4, a = 14.9755(11) Å, b = 4.7510(3) Å, c = 26.6395(16) Å, β = 93.664(5)°, V = 1891.5(2) Å³, μ(Mo-Kα) = 0.097 mm^–1, D _c = 1.406 g cm^–3, orange plate, crystal size of 0.22 × 0.12 × 0.03 mm³. Of a total of 15482 reflections collected, 4999 were independent (R _int = 0.0475). Final R1 = 0.0505 [I > 2σ(I)] and wR2 = 0.1233 (all data). Data completeness to θ = 25.24°, 99.6%.
• 27 Crystal data for compound 4b (CCDC 1404989): C₁₉H₁₄O₅, M = 322.30, triclinic, space group Pī, Z = 2, a = 8.4108(9) Å, b = 8.5434(9) Å, c = 10.6878(11) Å, α = 83.293(3)°, β = 72.084(3)°, γ = 82.141(3)°, V = 721.61(13) Å³, μ(Mo-Kα) = 0.108 mm^–1, D _c = 1.483 g cm^–3, colorless plate, crystal size of 0.16 × 0.12 × 0.07 mm³. Of a total of 13854 reflections collected, 2640 were independent (R _int = 0.0256). Final R1 = 0.0553 [I > 2σ(I)] and wR2 = 0.1356 (all data). Data completeness to θ = 25.24°, 99.6%.