740
V. Jakubkiene, V. Cepla, M. M. Burbuliene, and P. Vainilavicius
Vol 49
Anal. calcd. for C21H21BrN4O2 (441.32): C 57.15; H 4.80. Found: C
57.43; H 5.02.
2CH2), 3.65 (t, J = 4.8 Hz, 4H, 2CH2), 4.51 (s, 2H, NCH2), 5.60
(s, 1H, CH), 10.43 (s, 1H, NH) ppm; 13C-NMR (DMSO-d6): d 24.1,
36.9, 46.1, 66.2, 100.8, 147.2, 149.6, 161.0, 165.1 ppm. Anal. calcd.
for C11H15N5O2 (249.27): C 53.00; H 6.07. Found: C 53.35; H 6.34.
8-Methyl-3-piperidin-1-yl-1,4-dihydro-6H-pyrimido[2,1-c] [1,2,4]
triazin-6-one (14). Yield 0.086 g (70%), white solid, mp 244–245ꢀC
(5-Bromo-2-butylamino-6-methyl-4-oxopyrimidin-3(4H)-yl)-
N-butylacetamide (9). A mixture of 0.31 g (1 mmol) of hydrazide
5 and 1.2 mL (0.89 g, 12 mmol) of butylamine was heated at reflux
for 8 h. The cold reaction mixture was worked up with 4 mL of
methanol to give a solid, which was filtered, washed with
methanol-ether (1:1), and crystallized from methanol to yield 9,
0.17 g (46%) as a white precipitate, mp 197–199ꢀC; IR: 1648,
(dimethylformamide-water); IR: 1687 (C═O), 3242 (NH) cmÀ1
;
1H-NMR (DMSO-d6): d 1.55 (s, 6H, 3CH2), 2.04 (s, 3H, CH3), 3.22
(s, 4H, 2CH2), 4.49 (s, 2H, NCH2), 5.58 (s, 1H, CH), 10.39 (s, 1H,
NH) ppm; 13C-NMR (DMSO-d6): d 24.2, 24.6, 25.5, 36.9, 46.6,
100.5, 147.0, 150.0, 161.1, 165.1 ppm. Anal. calcd. for C12H17N5O
(247.30): C 58.28; H 6.93. Found: C 58.41; H 6.98.
1
1668 (C═O), 3091, 3267, 3328 (NH) cmÀ1; H-NMR (DMSO-
d6): d 0.84–0.95 (m, 6H, 2CH3), 1.22–1.56 (m, 8H, 2CH2CH2),
2.26 (s, 3H, CH3), 3.02–3.12 (m, 2H, NHCH2), 3.24–3.35 (m,
2H, NHCH2), 4.55 (s, 2H, NCH2), 7.17 (t, J = 5.4 Hz, 1H, NH),
8.08 (t, J = 5.4 Hz, 1H, NH) ppm; 13C-NMR (DMSO-d6): d
14.3, 14.4, 20.1, 20.2, 25.6, 31.3, 31.9, 39.2, 41.7, 45.0, 96.6,
153.1, 158.8, 162.3, 166.3 ppm. Anal. calcd. for C15H25BrN4O2
(373.29): C 48.26; H 6.75. Found: C 48.08; H 6.76.
General procedure for the synthesis of compounds 15–19. To a
suspension of 0.147 g (0.75 mmol) of compound 10 in 5 mL of
methanol, 0.115 mL (0.076 g, 0.75 mmol) of triethylamine was
added and the mixture was stirred at room temperature for 3 min. To
a reaction mixture, 0.75 mol of corresponding alkylation agent (in the
case of compound 15—0.083 mL of ethyl bromoacetate, 16—0.047
mL of chloroacetonitrile, 17—a solution of 0.139 g of iodoacetamide
in 1 mL of methanol, 18 – 0.048 mL of epichlorohydrin, 19—a
solution of 0.15 g of 2-bromoacetophenone in 1 mL of methanol)
was added, and stirring was continued at room temperature for 10min
(in the case of compound 16—3 h, 19—1 h). The precipitate was
filtered off, washed with ether, and crystallized.
Ethyl[(8-methyl-6-oxo-1,6-dihydro-4H-pyrimido[2,1-c][1,2,4]
triazin-3-yl)thio]acetate (15). Yield 0.18 g (86%), white solid, mp
214–215ꢀC (methanol); IR: 1687, 1743 (C═O), 3144, 3210 (NH)
cmÀ1; 1H-NMR (DMSO-d6): d 1.21 (t, J = 7.2 Hz, 3H, CH3), 2.08
(s, 3H, CH3), 3.92 (s, 2H, SCH2), 4.14 (q, J = 7.2 Hz, 2H, CH2),
4.47 (s, 2H, NCH2), 5.76 (s, 1H, CH), 11.26 (s, 1H, NH) ppm;
13C-NMR (DMSO-d6): d 14.7, 24.1, 32.4, 40.0, 61.9, 103.4,
144.1, 149.0, 160.3, 165.2, 168.8 ppm. Anal. calcd. for
C11H14N4O3S (282.32): C 46.80; H 5.00. Found: C 46.96; H 5.09.
[(8-Methyl-6-oxo-1,6-dihydro-4H-pyrimido[2,1-c][1,2,4]triazin-
3-yl)thio]acetonitrile (16). Yield 0.145 g (82%), white solid, mp
234–236ꢀC (methanol); IR: 1703 (C═O), 2250 (CꢁN), 3141,
3211 (NH) cmÀ1; 1H-NMR (DMSO-d6): d 2.08 (s, 3H, CH3), 4.14
(s, 2H, SCH2), 4.52 (s, 2H, NCH2), 5.78 (s, 1H, CH), 11.45 (s,
1H, NH) ppm; 13C-NMR (DMSO-d6): d 15.7, 24.1, 40.2, 103.7,
118.0, 142.5, 148.8, 160.3, 165.2, 168.8 ppm. Anal. calcd. for
C9H9N5OS (235.27): C 45.95; H 3.86. Found: C 46.16; H 4.01.
[(8-Methyl-6-oxo-1,6-dihydro-4H-pyrimido[2,1-c][1,2,4]
8-Methyl-3-thioxo-1,2,3,4-tetrahydro-6H-pyrimido[2,1-c]
[1,2,4]triazin-6-one (10). To a hot solution of 1.8 g (10 mmol) of
compound 3 in 30 mL of dry toluene and 20 mL abs.
hexamethylphosphoramide, 2.84 g (7 mmol) of Lawesson’s
reagent was added. The reaction mixture was stirred and heated at
reflux for 2 h, and the toluene was evaporated in vacuum. The hot
residual solution was diluted with water till precipitates appear
and then left at room temperature for 2 h. The precipitate formed
was collected by filtration, washed with water, and dried to yield
10, 1.58
g (81%) as a
yellow solid, mp 280–282ꢀC
(dimethylformamide-water); IR: 1472 (C═S), 1687 (C═O), 3242
1
(NH) cmÀ1; H-NMR (DMSO-d6): d 2.01 (s, 3H, CH3), 4.48 (s,
2H, NCH2), 5.23 (s, 1H, CH), 11.04, 12.22 (2s, 2H, 2NH) ppm;
13C-NMR (DMSO-d6): d 19.0, 48.1, 96.5, 114.5, 153.2, 160.6,
177.4 ppm. Anal. calcd. for C7H8BrN4OS (196.23): C 42.84; H
4.11. Found: C 43.02; H 4.15.
General procedure for the synthesis of compounds 11–14. A
mixture of 0.098 g (0.5 mmol) of compound 10 and 0.5 mol of the
corresponding amine was heated at reflux (in the case of compound
11 at 130–140ꢀC) for 10 min. To a reaction mixture, 5 mL of
2-propanol was added and heating at reflux was continued for
5 min. After cooling to room temperature, the precipitate formed
was filtered off, washed with ethanol, and dried.
3-Benzylamino-8-methyl-1,4-dihydro-6H-pyrimido[2,1-c] [1,2,4]
triazin-6-one (11). Yield 0.11 g (82%), white solid, mp > 290ꢀC
(dimethylformamide); IR: 1654 (C═O), 3307 (NH) cmÀ1
;
triazin-3-yl)thio]acetamide (17).
Yield 0.24 g (95%), white
1H-NMR (DMSO-d6): d 2.03 (s, 3H, CH3), 4.29 (d, J = 5.4 Hz,
2H, NHCH2), 4.41 (s, 2H, NCH2), 5.55 (s, 1H, CH), 7.06 (t, J =
5.4 Hz, 1H, NH), 7.22–7.4 (m, 5H, Ar-H), 10.18 (s, 1H, NH) ppm;
13C-NMR (DMSO-d6): d 24.2, 37.6, 45.0, 100.3, 127.5, 128.0,
129.0, 140.0, 146.4, 150.8, 161.1, 165.0 ppm. Anal. calcd. for
C14H15N5O (269.30): C 62.44; H 5.61. Found: C 62.58; H 5.66.
3-Butylamino-8-methyl-1,4-dihydro-6H-pyrimido[2,1-c][1,2,4]
triazin-6-one (12). Yield 0.105 g (89%), white solid, mp 297–298ꢀC
solid, mp 286–287ꢀC (dimethylformamide-water); IR: 1684
(C═O), 3196, 3363 (NH) cmÀ1; H-NMR (DMSO-d6): d 2.08
1
(s, 3H, CH3), 3.71 (s, 2H, SCH2), 4.45 (s, 2H, NCH2), 5.76 (s,
1H, CH), 7.24, 7.61 (2s, 2H, NH2), 11.22 (s, 1H, NH) ppm;
13C-NMR (DMSO-d6): d 24.1, 34.0, 40.3, 103.3, 144.9, 149.1,
160.4, 165.2, 169.2 ppm. Anal. calcd. for C9H11N5O2S
(253.28): C 42.68; H 4.38. Found: C 42.75; H 4.36.
3-[(3-Chloro-2-hydroxypropyl)thio]-8-methyl-1,4-dihydro-6H-
pyrimido[2,1-c][1,2,4]triazin-6-one (18). Yield 0.18 g (83%),
white solid, mp 196–197ꢀC (acetonitrile); IR: 1680 (C═O), 3131
1
(dimethylformamide); IR: 1654 (C═O), 3326 (NH) cmÀ1; H-NMR
(DMSO-d6): d 0.89 (t, J = 7.2 Hz, 3H, CH3), 1.24–1.4 (m, 2H, CH2),
1.4–1.54 (m, 2H, CH2), 2.03 (s, 3H, CH3), 3.0–3.12 (m, 2H, NHCH2),
4.32 (s, 2H, NCH2), 5.53 (s,1H, CH), 6.52 (t, J = 4.8 Hz, 1H, NH),
10.15 (br s, 1H, NH) ppm; 13C-NMR (DMSO-d6): d 14.4, 20.5, 24.2,
31.1, 37.6, 41.1, 100.1, 146.7, 150.9, 161.1, 165.0 ppm. Anal. calcd.for
C11H17N5O (235.29): C 56.15; H 7.28. Found: C 56.31; H 7.18.
8-Methyl-3-morpholin-4-yl-1,4-dihydro-6H-pyrimido[2,1-c] [1,2,4]
triazin-6-one (13). Yield 0.1 g (80%), white solid, mp 287–288ꢀC
(NH), 3407 (OH) cmÀ1 1H-NMR (DMSO-d6): d 2.07 (s, 3H,
;
CH3), 3.02–3.28 (m, 2H, SCH2), 3.57–3.72 (m, 2H, CH2Cl),
3.88–4.0 (m, 1H, CH), 4.43 (s, 2H, NCH2), 5.69 (d, J = 5.1 Hz,
1H, OH), 5.75 (s, 1H, CH), 11.21 (s, 1H, NH) ppm; 13C-NMR
(DMSO-d6): d 24.1, 34.1, 40.5, 49.2, 69.2, 103.3, 145.1, 149.1,
160.4, 165.2 ppm. Anal. calcd. for C10H13ClN4O2S (288.76): C
41.59; H 4.54. Found: C 41.60; H 4.38.
(dimethylformamide); IR: 1679 (C═O), 3078, 3440 (NH) cmÀ1
1H-NMR (DMSO-d6): d 2.05 (s, 3H, CH3), 3.20 (t, J = 4.8 Hz, 4H,
;
8-Methyl-3-[(2-oxo-2-phenylethyl)thio]-1,4-dihydro-6H-pyrimido
[2,1-c][1,2,4]triazin-6-one (19). Yield 0.28 g (89%), white solid,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet