An Efficient Regiospecific Synthesis of Highly Functionalized Novel Dihydropyrimido[4,5-d]pyrimidine Derivatives by a Three-Component One-Pot ­Condensation under Solvent-Free Conditions

Abstract

The environment-friendly three-component condensation of 6-[(dimethylamino)methylene]amino uracil, an aldehyde, and ammonium acetate in the presence of acetic acid afforded a one-pot synthesis of biologically significant novel dihydropyrimido[4,5-d]pyrimidine derivatives in high yields under solvent-free conditions.

pyrimido[4,5-d]pyrimidines - 6-[(dimethylamino)meth­ylene]amino uracil - solvent-free conditions - ammonium acetate

References and Notes

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15

Reaction of Uracil Amidine 1 with Carbonyl Compounds and Ammonium Acetate under Solvent-Free Conditions and Synthesis of Novel Dihydropyrimido[4,5- d ]pyr-imidine Derivatives 4.
An equimolar amount of 6-[(dimethylamino)methyl-ene]amino-1,3-dimethyl uracil (0.210 g, 1 mmol), tolualde-hyde (0.123 g, 1 mmol), NH₄OAc (0.077 g, 1 mmol) in the presence of AcOH (0.006 g, 0.1 mmol) were mixed well and heated about 2 h at 90 °C. After completion of the reaction (monitored by TLC) the reaction vessel was allowed to cool to r.t. and added 30 mL of cold H₂O. The crude product was extracted with EtOAc (3 × 30 mL) and washed with H₂O. The combined organic phases were dried over anhyd Na₂SO₄ and subjected to column chromatography using EtOAc-hexane (1:6) as the eluent to afford the corres-ponding dihydropyrimido[4,5-d]pyrimidine 4a in 90% yield; mp 206-209 °C. Similarly, dihydropyrimido[4,5-d]pyrimidines 4b-i were prepared and characterized as described below.
Compound 4a: IR (KBr): ν_max = 3255 (NH), 1687, 1644 (C=O), 1551 (C=N) cm^-1. ¹H NMR: δ = 3.10 (s, 3 H, NCH₃), 3.48 (s, 3 H, NCH₃), 2.30 (s, 3 H, CH₃), 5.44 (s, 1 H), 6.62-7.28 (m, 5 H, ArH and 1 H, CH=N-). ¹³C NMR: δ = 161.84 (C-2), 152.70 (C-4), 152.43 (C-8a), 150.99 (C-7), 141.35, 138.84, 129.86, 127.12, 90.53 (C-4a), 52.36 (C-5), 29.76 (C-9), 28.09 (C-10), 21.55 (C-Me). MS: m/z = 285 [M⁺ + 1]. Anal. Calcd (%) for C₁₅H₁₆N₄O₂: C, 63.38; H, 5.63; N, 19.72. Found: C, 63.47; H, 5.77; N, 19.65.
Compound 4b: IR (KBr): ν_max = 3260 (NH), 1690, 1645 (C=O), 1570 (C=N) cm^-1. ¹H NMR: δ = 3.24 (s, 3 H, NCH₃), 3.51 (s, 3 H, NCH₃), 5.60 (s, 1 H), 6.46 (br, 1 H, NH), 7.05-7.61 (m, 5 H, ArH and 1 H, CH=N-). ¹³C NMR: δ = 160.8 (C-2), 151.4 (C-4), 151.1 (C-8a), 149.2, 140.5, 139.1, 128.1, 126.1, 90.1 (C-4a), 54.1 (C-5), 29.1 (C-9), 275 (C-10). MS: m/z = 271 [M⁺ + 1]. Anal. Calcd (%) for C₁₄H₁₄N₄O₂: C, 62.22; H, 5.18; N, 20.74. Found: C, 62.31; H, 5.10; N, 20.82.
Compound 4c: IR (KBr): ν_max = 3265 (NH), 1700, 1650 (C=O), 1560 (C=N) cm^-1. ¹H NMR: δ = 3.20 (s, 3 H, NCH₃), 3.62 (s, 3 H, NCH₃), 5.55 (s, 1 H), 6.44 (br, 1 H, NH), 7.01-7.65 (m, 4 H, ArH and 1 H, CH=N-). MS: m/z 305 [M⁺ + 1]. Anal. Calcd (%) for C₁₄H₁₃N₄O₂Cl: C, 55.26; H, 4.27; N, 18.42. Found: C, 55.31; H, 4.32; N, 18.33.
Compound 4d: IR (KBr): ν_max = 3260 (NH), 1695, 1650 (C=O), 1570 (C=N) cm^-1. ¹H NMR: δ = 3.19 (s, 3 H, NCH₃), 3.51 (s, 3 H, NCH₃), 3.88 (s, 3 H, OCH₃), 5.54 (s, 1 H), 6.47 (br, 1 H, NH), 6.81 (d, 2 H, ArH), 7.26-7.85 (m, 2 H, ArH and 1 H, CH=N-). MS: m/z = 301 [M⁺ + 1]. Anal. Calcd (%) for C₁₅H₁₆N₄O₃: C, 60.00; H, 5.33; N, 18.67. Found: C, 60.12; H, 5.41; N, 18.55.
Compound 4e: IR (KBr): ν_max = 3255 (NH), 1700, 1650 (C=O), 1560 (C=N) cm^-1. ¹H NMR: δ = 3.12 (s, 3 H, NCH₃), 3.44 (s, 3 H, NCH₃), 5.58 (s, 1 H), 6.42 (br, 1 H, NH), 6.95-7.55 (m, 4 H, ArH and 1 H, CH=N-). MS: m/z = 316 [M⁺ + 1]. Anal. Calcd (%) for C₁₄H₁₃N₅O₄: C, 53.33; H, 4.12; N, 22.22. Found: C, 53.42; H, 4.23; N, 22.08.
Compound 4f: IR (KBr): ν_max = 3260 (NH), 1695, 1655 (C=O), 1560 (C=N) cm^-1. ¹H NMR: δ = 3.18 (s, 3 H, NCH₃), 3.58 (s, 3 H, NCH₃), 5.61 (s, 1 H), 6.45 (br, 1 H, NH), 7.05-7.66 (m, 4 H, ArH and 1 H, CH=N-). MS: m/z = 350 [M⁺ + 1]. Anal. Calcd (%) for C₁₄H₁₃N₄O₂Br: C, 48.13; H, 3.72; N, 16.04. Found: C, 48.22; H, 3.85; N, 15.94.
Compound 4g: IR (KBr): ν_max = 3320 (NH), 1685, 1650 (C=O), 1560 (C=N) cm^-1. ¹H NMR: δ = 3.20 (s, 3 H, NCH₃), 3.60 (s, 3 H, NCH₃), 5.45 (s, 1 H), 6.35 (br, 1 H, NH), 6.75 (dd, 1 H), 6.95-7.15 (m, 2 H), 7,65 (s, 1 H, CH=N-). MS: m/z = 277 [M⁺ + 1]. Anal. Calcd (%) for C₁₂H₁₂N₄O₂S: C, 52.17; H, 4.35; N, 20.29. Found: C, 52.23; H, 4.26; N, 20.36.
Compound 4h: IR (KBr): ν_max = 3310 (NH), 1700, 1655 (C=O), 1560 (C=N) cm^-1. ¹H NMR: δ = 0.95 (s, 3 H, CH₃), 1.25 (m, 6 H) 3.15 (s, 3 H, NCH₃), 3.45 (s, 3 H, NCH₃), 5.45 (s, 1 H), 6.40 (br, 1 H, NH), 7.65 (s, 1 H, CH=N-). MS: m/z = 251 [M⁺ + 1]. Anal. Calcd (%) for C₁₂H₁₈N₄O₂: C, 57.60; H, 7.20; N, 22.40. Found: C, 57.52; H, 7.32; N, 22.47.
Compound 4i: IR (KBr): ν_max = 3270 (NH), 1695, 1645 (C=O), 1565 (C=N) cm^-1. ¹H NMR: δ = 3.22 (s, 3 H, NCH₃), 3.55 (s, 3 H, NCH₃), 5.50 (s, 1 H), 6.40 (br, 1 H, NH), 6.66-7.65 (m, 7 H, ArH, CH=CH and 1 H, CH=N-). MS: m/z = 297 [M⁺ + 1]. Anal. Calcd (%): for C₁₆H₁₆N₄O₂: C, 64.86; H, 5.40; N, 18.92. Found: C, 64.93; H, 5.43; N, 18.83.

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