March 2009
New Dihydro-1,2,4-Triazolo[1,5-a]pyrimidines Based on Arylidene Derivatives
of 5-Acetylbarbituric and Dehydroacetic Acids
287
determined with a Kofler apparatus. The 1H and 13C NMR
spectra were recorded in DMSO-d6 at 200 MHz (50 MHz for
13C) on a Varian Mercury VX-200 spectrometer and analyzed
with ADVASPTM Analyzer program (Umatek International
Inc.). Chemical shifts are reported in ppm (dꢁscale), coupling
constants (J) in Hz, internal standard was Si(CH3)4. The EI
mass spectra were obtained on Varian 1200L with electron
energy 70 eV.
5-[6-Hydroxy-1H-pyrimidine-2,4-dion-5-yl]-7-(4-methoxy-
phenyl)-6,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine (3c).
Compound 3c was prepared similar to 3a from 1 and 5-acetyl-
barbituric acid 2c. Yield 2.3 g (65%); mp > 300ꢂC (from etha-
1
3
nol). H NMR: d 3.71 (s, 3H, CH3O); 4.17 (dd, 1H, J ¼ 6.6,
3
J ¼ 17.9, Ha-6); 4.41 (dd, 1H, J ¼ 6.0, Hb-6); 5.71 (dd, 1H,
H-7), 6.91 (m, 2H, m-ArH); 7.11 (m, 2H, o-ArH); 7.90 (s, 1H,
H-2); 11.0 (br.s. 1H, NH); 11.4 (br.s. 1H, NH); 14.2 (s, 1H,
OH); 13C NMR: d 33.3 (C-6); 55.2 (CH3O); 55.6 (C-7); 150.6
(C-2); 114.8 (m-CAr), 128.3 (o-CAr), 130.3 (i-CAr), 159.8
(p-CAr); 93.0 (C-5’), 146.5, 149.6, 163.9, 165.4, 168.6 (C-
3a þ C-4a þ CHetAr); MS (EI, m/z (rel. %)): 354 (100) [Mþ],
336 (14), 325 (24), 286 (18), 266 (14), 256 (14), 247 (19), 225
(17), 121 (34), 115 (19). Anal. Calcd. for C16H14N6O4: C,
54.24; H, 3.98; N, 23.72. Found C, 54.30; H, 3.99; N, 23.75.
5-(4-Hydroxy-6-methyl-pyran-2-on-3-yl)-7-(4-methoxy-
phenyl)-1,2,4-triazolo-[1,5-a]pyrimidine (4a). The mixture of
3-(4-hydroxy-6-methyl-2-oxo-2a-3-pyranyl)-1-(4-methoxy-phenyl)-
2-propene-1-one (2a, 0.286 g, 0.001 mol) and 1 (0.092 g 0.0011
mol) in dimethylformamide (0.5 mL) was refluxed for 30 min and
after cooling to room temperature diluted with benzene (10 mL).
The precipitate formed was filtered off and dried. Yield 0.15 g
6-Hydroxy-5-[3-(4-methoxyphenyl)-propenon-1-yl]-1,3-
dimethyl-pyrimidine-2,4-dione (2b). The mixture of 3.96 g
(0.02 mol) 5-acetyl-1,3-dimethylbarbituric acid, 2.72
g
(0.02 mol) of 4-methoxybenzaldehyde and 0.8 g (0.02 mol) of
sodium hydroxide in 20 mL of methanol was refluxed for
12 h. The reaction mixture was cooled to room temperature
and neutralized with concentrated HCl. The precipitate formed
was filtered off. Yield 4.0 g (63%), mp 190–191ꢂC (from
methanol); 1H NMR: d 3.19 (s, 6H, 2*CH3); 3.81 (s, 3H,
CH3O); 7.03 (m, 2H, m-ArH); 7.68 (m, 2H, o-ArH); 7.94 (d,
1H, J ¼ 15.8 Hz (a-H)); 8.34 (d, 1H, (b-H)); 17.0 (br. s, 1H,
(OH)). Anal. Calcd. for C16H16N2O5: C, 60.75; H, 5.10; N,
8.86. Found C, 60.45; H, 4.95; N, 8.77.
5-(4-Hydroxy-6-methylpyran-2-on-3-yl)-7-(4-methoxy-phenyl)-
6,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine (3a). Method A.
The mixture of 3-(4-hydroxy-6-methyl-2-oxo-2H-3-pyranyl)-1-
(4-methoxyphenyl)-2-propen-1-one (2a [8], 2.86 g, 0.01 mol)
and 3-amino-1,2,4-triazole (1, 0.92 g, 0.011 mol) in 15 mL of
n-buthanol was refluxed for 1 h. The reaction mixture was
cooled to room temperature, the precipitate that formed was
filtered off. The yield was 2.53 g (72%), mp 181–183ꢂC (from
ethanol).
Method B. The 2.86 g (0.01 mol) of 2a and 0.92 g
(0.011 mol) of 1 in 5 mL glacial acetic acid were refluxed for
2 h. The mixture was cooled and diluted with 10 mL of ace-
tone. The precipitate that formed was filtered off. Yield was
1.96 g (56%), mp 181–183ꢂC (from ethanol).
1H NMR (CDCl3): d 2.16 (s, 3H, CH3); 3.76 (s, 3H, CH3O);
3.98 (dd, 1H, 3J ¼ 7.1, 2J ¼ 18.7 Ha-6); 4.41 (dd, 1H, 3J ¼
5.6, Hb-6); 5.58 (dd, 1H, H-7); 5.82 (s, 1H, H-5’); 6.85 (m,
2H, m-ArH); 7.02 (m, 2H, o-ArH); 7.82 (s, 1H, H-2); 16.4 (br.
s, 1H, OH); 13C NMR: d 19.9 (CH3); 34.7 (C-6); 55.4
(CH3O); 55.6 (C-7); 97.4 (C-5’); 114.8 (m-CAr), 128.5 (o-CAr),
130.2 (i-CAr), 159.9 (p-CAr); 151.0 (C-2); 106.8, 146.5, 161.9,
166.2, 169.8, 185.4 (C-3a þ C-4a þ CHetAr); MS (EI, m/z (rel.
%)): 352 (96) [Mþ], 325 (46), 309 (12), 267 (22), 245 (100),
227 (12), 161 (14). Anal. Calcd. for C18H16N4O4: C, 61.36; H,
4.58; N, 15.90. Found C, 61.28; H, 4.57; N, 15.88.
1
(44%), mp 252–254ꢂC (from ethanol). H NMR: d 2.28 (s, 3H,
CH3), 3.88 (s, 3H, CH3O), 6.33 (s, 1H, H-5’), 7.20 (m, 2H, m-
ArH); 8.14 (m, 2H, o-ArH); 8.63 (s, 1H, C2-H), 8.67 (s, 1H, C6-H),
17.5 (br. s, 1H, OH). MS (EI, m/z (rel. %)): 350 (100) [Mþ], 335
(17), 307 (21), 265 (62), 251 (15). Anal. Calcd for C18H14N4O4: C,
61.71; H, 4.03; N, 15.99. Found C, 61.75; H, 4.05; N, 15.95.
5-(6-Hydroxy-1,3-dimethylpyrimidine-2,4-dion-5-yl)-7-(4-
methoxyphenyl)-1,2,4-triazole[1,5-a]pyrimidine (4b). Com-
pound 4b was prepared similar to 4a from 1 and 5-acetyl-1,3-
dimethylbarbituric acid 2b. Yield 0.18 g (47%), mp > 270ꢂC
1
(from ethanol). H NMR: d 3.23 (s, 6H, 2*CH3), 3.88 (s, 3H,
CH3O), 7.21 (m, 2H, m-ArH); 8.10 (m, 2H, o-ArH); 8.53 (s,
1H, C2-H), 8.87 (br. s, 1H, C6-H), 16.6 (br. s, 1H, OH). MS
(EI, m/z (rel. %)): 380 (100) [Mþ], 353 (15), 275 (73). Anal.
Calcd. for C18H16N6O4: C, 56.84; H, 4.24; N, 22.10. Found C,
56.90; H, 4.22; N, 22.07.
5-(6-Hydroxy-1H-pyrimidine-2,4-dion-5-yl)-7-(4-methoxy-
phenyl)-1,2,4-triazole[1,5-a]pyrimidine (4c). Compound 4c
was prepared similar to 4a from 1 and 5-acetylbarbituric acid
1
2c and 1. Yield 0.17 g (48%), mp > 300ꢂC (from ethanol). H
NMR: d 3.87 (s, 3H, CH3O), 7.19 (m, 2H, m-ArH); 8.07 (m,
2H, o-ArH); 8.51 (s, 1H, C2-H), 8.78 (br. s, 1H, C6-H), 16.5
(br. s, 1H, OH). MS (EI, m/z (rel. %)): 352 (100) [Mþ], 321
(29), 245 (82), 225 (15). Anal. Calcd for C16H12N6O4: C,
54.55; H, 3.43; N, 23.85. Found C, 54.45; H, 3.44; N, 23.81.
Transformation of 6,7-dihydro-1,2,4-triazolo[1,5-a]pyri-
midines 3a–c into 1,2,4-triazolo[1,5-a]pyrimidines (4a-c).
The 0.001 mol (0.35 g) of 3a in 1 mL DMF was heated for
30 min and diluted with 20 mL benzene after cooling. 0.28 g
(79%) of 4a was isolated.
5-[6-Hydroxy-1,3-dimethylpyrimidine-2,4-dion-5-yl]-7-(4-
methoxyphenyl)-6,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine
(3b). Compound 3b was prepared similar to 3a from 0.01 mol
of 1 and 5-acetyl-1,3-dimethylbarbituric acid 2b. Yield 2.48 g
(65%); mp 192–194ꢂC (from ethanol). 1H NMR: 3.12 (s, 3H,
CH3); 3.20 (s, 3H, CH3); 3.71 (s, 3H, CH3O); 4.17 (dd, 1H,
2
3
3J ¼ 6.8, J ¼ 18.2, Ha-6); 4.51 (dd, 1H, J ¼ 5.6 Hb-6); 5.76
(dd, 1H, H-7), 6.90 (m, 2H, m-ArH); 7.09 (m, 2H, o-ArH);
7.93 (s, 1H, H-2); 14.3 (s, 1H, OH); 13C NMR: d 28.3, 28.4
(CH3); 33.8 (C-6); 55.2 (CH3O); 55.7 (C-7); 130.4 (i-CAr);
114.8 (m-CAr), 128.2 (o-CAr), 159.8 (p-CAr); 150.8 (C-2), 93.4
(C-5’), 146.5, 150.6, 162.1, 165.6, 166.4 (C-3a þ C-4a þ CHe-
tAr); MS (EI, m/z (rel. %)): 382 (100) [Mþ], 355 (14), 275
(83), 266 (16). Anal. Calcd. for C18H18N6O4: C, 56.54; H,
4.74; N, 21.98. Found C, 56.50; H, 4.75; N, 21.93.
In analogous way, 4b and 4c were isolated with yields 75
and 84%, correspondingly.
REFERENCES AND NOTES
[1] (a) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.;
Nakamura, T. Yoshitomi Pharmaceutical Industries. U.S. Pat.
4,918,074 (1990); (b) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.;
Inui, J.; Nakamura, T. Chem Abstr 1991, 114, 81873.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet