Synthesis of Novel and Complex Tetrahydroquinazolinedione and Dihydro­pyrido[2,3-d]pyrimidine Derivatives via a One-Pot [4+2]-Cycloadddition Strategy

Abstract

A mild and efficient protocol for the synthesis of various tetrahydroquinazolinedione and dihydropyrido[2,3-d]pyrimidine-2,4-dione templates from uracil derivatives utilizing a [4+2]-cycloaddition strategy in a one-pot reaction has been developed.

Key words

zwitterionic species - phase-transfer conditions - tetrahydroquinazolinediones - dihydropyrido[2,3-d]pyrimidines

• References and Notes

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• 9 General Procedure for the Synthesis of 3a–h A mixture of 6-[2-(dimethylamino)vinyl]-1,3-dimethyluracil (1, 1 mmol) and nitroalkene (2, 1 mmol) was dissolved in CHCl₃ (15 mL), and the mixture heated to reflux for 5 h. After completion (TLC), the reaction mixture was allowed to cool to ambient temperature, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using EtOAc–hexane (4:1) as the eluent to furnish pure tetrahydroquinazolinedione derivatives 3. Spectroscopic Data for Selected Products 7-(Dimethylamino)-1,3-dimethyl-6-nitro-5-phenyl-4a,5,6,7-tetrahydroquinazoline-2,4-dione (3a) Pale yellow solid; mp 166–168 °C. ¹H NMR (300 MHz, CDCl₃): δ = 6.98–7.28 (m, 5 H, ArH), 4.60–4.64 (dd, 1 H, J ₁ = 9.5 Hz, J ₂ = 8.5 Hz, CHNO₂), 4.46–4.49 (d, 1 H, J = 9.5 Hz, =CH), 3.43–3.37 (dd, 1 H, J ₁ = 8.5 Hz, J ₂ = 9.5 Hz, CH), 3.35 (s, 3 H, NCH₃), 3.13 (s, 3 H, NCH₃), 2.83 (d, 1 H, J = 8.5 Hz, CH), 2.72–2.66 (dd, 1 H, J ₁ = 9.5 Hz, J ₂ = 8.5 Hz, CH), 2.27 [s, 6 H, N(CH₃)₂]. ¹³C NMR (75 MHz, CDCl₃): δ = 160.57, 151.84, 146.96, 140.80, 128.99, 127.93, 126.51, 108.30, 92.88, 61.19, 46.24, 40.02, 31.61, 28.15. GC–MS: m/z = 358 [M]⁺. Anal. Calcd for C₁₈H₂₂N₄O₄: C, 60.32; H, 6.19; N, 15.63. Found: C, 60.11; H, 6.12; N, 14.87. 7-(Dimethylamino)-1,3-dimethyl-6-nitro-5-(4-tolyl)-4a,5,6,7-tetrahydroquinazoline-2,4-dione (3b) Red solid; mp 81–84 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.28–7.01 (m, 4 H, arom.), 4.64 (dd, 1 H, J ₁ = 9.5 Hz, J ₂ = 8.5 Hz, CHNO₂), 4.46–4.49 (d, 1 H, J = 9.5 Hz, =CH), 3.43–3.37 (dd, 1 H, J ₁ = 8.5 Hz, J ₂ = 9.5 Hz, CH), 3.35 (s, 3 H, NCH₃), 3.13 (s, 3 H, NCH₃), 2.83 (d, 1 H, J = 8.5 Hz, CH), 2.72–2.66 (dd, 1 H, J ₁ = 9.5 Hz, J ₂ = 8.5 Hz, CH), 2.62 (s, 3 H, CH₃), 2.27 [s, 6 H, N(CH₃)₂]. ¹³C NMR (75 MHz, CDCl₃): δ = 160.6, 151.8, 146.9, 140.8, 134.5, 134.3, 129.9, 128.6, 108.3, 92.8, 61.2, 46.2, 40.0, 31.6, 29.7, 21.0. GC–MS: m/z = 372 [M]⁺. Anal. Calcd for C₁₉H₂₄N₄O₄: C, 61.28; H, 6.50; N, 15.04. Found: C, 61.11; H, 5.59; N, 15.01. General Procedure for the Synthesis of 6a–h An equimolar mixture of N,N-dimethyl-N′-(1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)formimidamide (5, 1 mmol) and nitroalkene (2, 1 mmol, R = 4-MeC₆H₄) in H₂O (10 mL) in the presence of TBAB (10 mol%) was stirred at 60 °C for 14 h. Reaction progress was monitored by TLC. The crude product was filtered, washed with H₂O, dried, and purified by column chromatography (EtOAc–hexane = 9:1). Spectroscopic Data for Selected Products 3-Methyl-6-nitro-5-(4-tolyl)-5,8-dihydropyrido[2,3-d]pyrimidine-2,4-dione (6a) Yellow solid; mp 267–268 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.17 (s, NH), 10.29 (s, br, NH), 7.94 (s, 1 H), 7.19–7.04 (m, 4 H), 5.08 (s, 1 H), 3.34 (s, 3 H), 2.22 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.5, 150.4, 144.4, 141.3, 136.4, 134.3, 130.6, 129.0, 128.3, 92.3, 36.8, 29.6, 21.0. GC–MS: m/z = 314 [M]⁺. Anal. Calcd for C₁₅H₁₄N₄O₄: C, 57.32; H, 4.49; N, 17.38. Found: C, 56.92; H, 4.41; N, 17.30. 5-(4-Methoxyphenyl)-3-methyl-6-nitro-5,8-dihydropyrido[2,3-d]pyrimidine-2,4-dione (6b) Yellow solid; mp 254–256 °C. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.17 (s, NH), 10.30 (s, br, NH), 7.94 (s, 1 H), 7.21–6.79 (m, 4 H), 5.07 (s, 1 H), 3.69 (s, 3 H), 3.37 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.5, 158.5, 150.4, 144.4, 136.5, 134.3, 130.7, 129.4, 113.7, 92.3, 55.4, 36.3, 29.6. GC–MS: m/z = 330 [M]⁺. Anal. Calcd for C₁₅H₁₄N₄O₅: C, 54.55; H, 4.27; N, 16.96. Found: C, 54.41; H, 4.17; N, 16.88.