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Synlett 2007(4): 0595-0598  
DOI: 10.1055/s-2007-970739
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Dipak Prajapati*, Kalyan Jyoti Borah, Mukut Gohain
Department of Medicinal Chemistry, Regional Research Laboratory, Jorhat 785 006, Assam, India
Fax: +91(376)2370011; e-Mail: dr_dprajapati2003@yahoo.co.uk;
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Publication History

Received 13 September 2006
Publication Date:
21 February 2007 (online)

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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.

Key words

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

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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): νmax = 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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.