Synthesis of 5-(2-Hydroxybenzoyl)-1,3-Disubstituted Uracils

Abstract

A new synthesis of novel nucleoside analogues is reported. These 5-(2-hydroxybenzoyl)-1,3-disubstituted uracils have been prepared by the coupling of chromone-3-carboxylic acid with carbodiimides, leading to 3-chromone-N-acylureas, which underwent organocatalyzed N-cyclization and chromone ring opening. In the case of ditolylcarbodiimide, the corresponding uracil was obtained by a one-pot, uncatalyzed reaction with chromone-3-carboxylic acid.

Key words

chromone derivatives - nucleoside analogues - uracil analogues - organic synthesis - 2D NMR

• References and Notes

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• 9 Synthesis of N,N-Disubstituted (Carbamoyl)-4-oxo-4H-chromene-3-carboxamide 3a and 3b: Chromone-3-carboxylic acid 1 (1 g, 5.26 mmol) was added to the appropriate carbodiimide 2 (5.26 mmol, 1 equiv) in CHCl₃ (20 mL) and the reaction mixture was heated to reflux for 30 min. The solvent was evaporated to dryness and the resulting resinous solid was recrystallized from EtOH to afford compound 3a. In the case of 3b, the recrystallization solvent was a mixture of light petroleum and EtOAc (5:1). N-Cyclohexyl-N-(cyclohexylcarbamoyl)-4-oxo-4H-chromene-3-carboxamide (3a): Yield: 1.550 g (74%); white solid; mp 185 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.87–2.01 (m, 20 H, CH₂-cyclohexyl), 3.40–3.53 (m, 1 H, H-1′′′), 4.19 (tt, J = 11.7, 3.8 Hz, 1 H, H-1′′), 6.49 (d, J = 7.2 Hz, 1 H, 4′-NH), 7.42–7.53 (m, 2 H, H-6, H-8), 7.73 (ddd, J = 8.7, 7.1, 1.7 Hz, 1 H, H-7), 8.07 (s, 1 H, H-2), 8.22 (dd, J = 8.0, 1.7 Hz, 1 H, H-5). ¹³C NMR (75 MHz, CDCl₃): δ = 24.4, 25.19, 25.26, 26.0, 30.7 and 32.1 (CH₂-cyclohexyl), 49.7 (C-1′′′), 55.7 (C-1′′), 118.3 (C-8), 123.9 (C-3), 124.1 (C-10), 125.9 (C-6, C-5), 134.5 (C-7), 153.2 (C-3′), 154.2 (C-2), 156.1 (C-9), 162.3 (C-1′), 175.4 (C-4). MS (ESI⁺): m/z = 419 [C₂₃H₂₈N₂O₄ + Na]⁺. Anal. Calcd for C, 69.67; H, 7.12; N, 7.07. Found: C, 69.69; H, 7.14; N, 7.07. N-Isopropyl-N-(isopropylcarbamoyl)-4-oxo-4H-chromene-3-carboxamide (3b): Yield: 1.324 g (80%); white solid; mp 137–138 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.99 (d, J = 6.6 Hz, 6 H, 2′′′-CH₃), 1.42 (d, J = 6.8 Hz, 6 H, 2′′-CH₃), 3.72–3.89 (m, 1 H, H-1′′′), 4.50 (sept, J = 6.8 Hz, 1 H, H-1′′), 6.74 (br s, 1 H, 4′-NH), 7.42–7.54 (m, 2 H, H-6, H-8), 7.74 (ddd, J = 8.6, 7.1, 1.7 Hz, 1 H, H-7), 8.08 (s, 1 H, H-2), 8.23 (dd, J = 8.0, 1.7 Hz, 1 H, H-5). ¹³C NMR (75 MHz, CDCl₃): δ = 20.7 (2′′-CH₃), 21.9 (2′′′-CH₃), 42.8 (C-1′′′), 48.8 (C-1′′), 118.3 (C-8), 124.1 (C-3), 124.2 (C-10), 126.0 (C-6, C-5), 134.5 (C-7), 153.2 (C-3′), 154.2 (C-2), 156.1 (C-9), 163.4 (C-1′), 175.1 (C-4). MS (ESI⁺): m/z = 339 [C₁₇H₂₀N₂O₄ + Na]⁺. Anal. Calcd for C, 64.54; H, 6.37; N, 8.86. Found: C, 64.51; H, 6.34; N, 8.84.
• 10 Synthesis of 1,3-Disubstituted-5-(2-hydroxybenzoyl)-pyrimidine-2,4(1H,3H)-dione 4a and 4b: Chromone-3-carboxylic acid 1 (1 g, 5.26 mmol) was added to the appropriate carbodiimide 2a–b (5.26 mmol, 1 equiv) in CHCl₃ (20 mL). The reaction mixture was heated to reflux for 30 min. After complete consumption of 1, and formation of 3a or 3b (TLC), 4-PPy (0.04 g, 0.05 equiv) was added to the reaction mixture, which was then heated to reflux for a further 30 min. The solvent was then evaporated to dryness and the resulting resinous solid was recrystallized from EtOH to afford compound 4a or 4b. 1,3-Dicyclohexyl-5-(2-hydroxybenzoyl)pyrimidine-2,4(1H,3H)-dione 4a: Yield: 1.342 g (64%); white solid; mp 80 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.07–2.04 and 2.35–2.48 (m, 20 H, CH₂-cyclohexyl), 4.46–4.58 (m, 1 H, H-1′), 4.84 (tt, J = 12.2, 3.7 Hz, 1 H, H-1′′), 6.85–6.91 (m, 1 H, H-5′′′′), 6.97–7.02 (m, 1 H, H-3′′′′), 7.44–7.53 (m, 2 H, H-4′′′′, H-6′′′′), 7.71 (s, 1 H, H-6), 11.77 (s, 1 H, 2′′′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 24.9, 25.1, 25.5, 26.1, 28.2 and 32.0 (CH₂-cyclohexyl), 54.7 (C-1′′), 56.3 (C-1′), 113.0 (C-5), 118.0 (C-3′′′′), 118.5 (C-5′′′′), 119.3 (C-1′′′′), 132.5 (C-6′′′′), 136.5 (C-4′′′′), 143.0 (C-6), 150.3 and 159.8 (C-2, C-4), 162.4 (C-2′′′′), 195.4 (C-1′′′). MS (ESI⁺): m/z = 397 [C₂₃H₂₈N₂O₄ + H]⁺. Anal. Calcd for C, 69.67; H, 7.12; N, 7.07. Found: C, 69.65; H, 7.11; N, 7.05. 1,3-Diisopropyl-5-(2-hydroxybenzoyl)pyrimidine-2,4(1H,3H)-dione 4b: Yield: 0.846 g (51%); white solid; mp 128 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.39 (d, J = 6.8 Hz, 6 H, 2′-CH₃), 1.51 (d, J = 6.9 Hz, 6 H, 2′′-CH ₃), 4.95 (sept, J = 6.8 Hz, 1 H, H-1′), 5.24 (sept, J = 6.9 Hz, 1 H, H-1′′), 6.89 (ddd, J = 8.2, 7.2, 1.2 Hz, 1 H, H-5′′′′), 7.00–7.04 (m, 1 H, H-3′′′′), 7.47–7.54 (m, 2 H, H-4′′′′, H-6′′′′), 7.69 (s, 1 H, H-6), 11.79 (s, 1 H, 2′′′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 19.1 (2′′-CH₃), 21.5 (2′-CH₃), 46.6 (C-1′′), 48.8 (C-1′), 113.5 (C-5), 118.3 (C-3′′′′), 118.6 (C-5′′′′), 119.4 (C-1′′′′), 132.6 (C-6′′′′), 136.8 (C-4′′′′), 142.5 (C-6), 150.2 and 159.9 (C-2, C-4), 162.7 (C-2′′′′), 195.5 (C-1′′′). MS (ESI⁺): m/z = 339 [C₁₇H₂₀N₂O₄ + Na]⁺. Anal. Calcd for C, 64.54; H, 6.37; N, 8.86. Found: C, 64.56; H, 6.40; N, 8.90.
• 11 Synthetic Procedure for 1,3-Ditolyl-5-(2-hydroxy-benzoyl)pyrimidine-2,4(1H,3H)-dione (4c): Chromone-3-carboxylic acid 1 (1 g, 5.26 mmol) was added to ditolylcarbodiimide 2c (1.17 g, 5.26 mmol, 1 equiv) in chloroform (20 mL) and the reaction mixture was heated to reflux for 30 min. The solvent was then evaporated to dryness and the resulting resinous solid was recrystallized from ethanol to afford 4c. Yield: 1.682 g (77%); yellowish white solid; mp 224 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.39 and 2.40 (s, 6 H, 4′/4′′-CH₃, tolyl), 6.88 (ddd, J = 8.1, 7.2, 1.0 Hz, 1 H, H-5′′′′), 7.00 (dd, J = 8.4, 1.0 Hz, 1 H, H-3′′′′), 7.17–7.20 (m, 8 H, H-2′/2′′,6′/6′′ and H-3′/3′′,5′/5′′), 7.48 (ddd, J = 8.4, 7.2, 1.6 Hz, 1 H, 4′′′′), 7.66 (dd, J = 8.1, 1.6 Hz, 1 H, H-6′′′′), 7.94 (s, 1 H, H-6), 11.71 (s, 1 H, 2′′′′-OH). ¹³C NMR (75 MHz, CDCl₃): δ = 21.1 and 21.2 (4′/4′′-CH₃,), 114.3 (C-5), 118.1 (C-3′′′′), 118.8 (C-5′′′′), 119.3 (C-1′′′′), 126.0 and 127.8 (C-2′/2′′,6′/6′′), 130.0 and 130.2 (C-3′/3′′,5′/5′′), 131.6 (C-1′′), 132.8 (C-6′′′′), 135.8 (C-1′), 136.9 (C-4′′′′), 139.0 and 139.6 (C-4′/4′′), 147.4 (C-6), 150.3 and 160.0 (C-2, C-4), 162.7 (C-2′′′′), 194.6 (C-1′′′). MS (ESI⁺): m/z = 435 [C₂₅H₂₀N₂O₄ + Na]⁺. Anal. Calcd for C, 72.80; H, 4.89; N, 6.79. Found: C, 72.85; H, 4.91; N, 6.79.
• 12 The described method allowed the synthesis of only 1,3-disubstituted uracil derivatives, and depends upon the range of carbodiimide derivatives and chromone-3-carboxylic acids available