ACCEPTED MANUSCRIPT
5
158.2, 158.1, 135.3, 132.2, 122.4, 116.5, 112.9, 65.7, 47.9, 23.7,
19.3, 15.0, 14.8.
1585 cm-1.1H NMR (CDCl3, δ ppm): 10.0 (brs, 1H, NH O), 8.18
(dd, J 1.5, 7.8 Hz, 1H, 6-H of C6H4), 7.50 (t, J 8.5 Hz, 1H, 4-H of
C6H4), 7.11 (t, J 7.6 Hz, 1H,5-H of C6H4), 7.04 (d, J 8.3 Hz, 1H, 3-H
of C6H4), 4.26 (q, J 7 Hz, 2H, CH2O), 2.65 (s, 3H, CH3C), 2.63 (s,
3H, CH3C), 1.56 (t, J 7.1 Hz, 3H, CH3). MS (ESI, matrix CCA):
[M+H]+ found 285.3. C15H16N4O2 requires 285.1273.
4.6.3. N-{1-[3-(2-Ethoxyphenyl)-5-oxo-4,5-dihydro-[1,2,4]triazin-
6-yl]ethyl}butyroamide 13c. The title product 13c was obtained as
a light yellow oil yield (0.42 g, 69%); [Found: C, 61.67; H, 6.68; N,
16.92. C17H22N4O3 requires C, 61.80; H, 6.71; N, 16.96%]; Rf
(EtOAc) 0.28. 1H NMR (CDCl3, δ ppm): 12.42 (s, 1H, NH O), 8.56
(dd, J 1.5 and 7.8 Hz, 1H, 6-H of C6H4), 7.56 (td, J 8.5 and 1.5 Hz,
1H, 4-H of C6H4), 7.16 (t, J 7.8 Hz, 1H, 5-H of C6H4), 7.07 (d, J 8.3
Hz, 1H, 3-H of C6H4), 6.95 (d, J 8.8 Hz, 1H, NHCO), 5.24 (dd, J 9
and 6.8 Hz, 1H, CHN), 4.35 (q, J 6.8 Hz, 2H, CH2O), 2.19 (t, J 7.6
Hz, 2H, CH2CO), 1.66 (m, 2H, CH3CH2CH2), 1.60 (t, J 6.8 Hz, 3H,
CH3CH2O),1.52 (d, J 7.3 Hz, 3H, CH3CH), 0.93 (t, J 7.3 Hz, 3H,
CH3CH2). 13C NMR (CDCl3, δ ppm): 172.7, 158.0, 135.2, 132.0,
122.3, 116.5, 112.9, 65.7, 47.4, 39.0, 29.9, 19.5, 19.3, 15.0, 14.0.
4.7.2. 2-(2-Ethoxyphenyl)-5-methyl-7-ethyl-imidazo[5,1-f][1,2,4]-
triazin-4(3H)-one 14b. The title compound was prepared from 13b
(1.028 g, 0.0032 mol). The final product was crystallised from ethyl
acetate to afford the title product 14b (0.7 g, 72%) as a light yellow
solid, m.p. 176-178 ºC; [Found: C, 64.53; H, 6.10; N, 18.83.
C16H18N4O2 requires C, 64.41; H, 6.08; N, 18.78%]; Rf (petroleum
ether/EtOAc, 1:1) 0.23. νmax(crystal): 3307, 2979, 2941, 2916, 1697,
1618, 1597cm-1. H NMR (CDCl3, δ ppm): 10.03 (bs, 1H, NH O),
1
8.19 (dd, J 1.5, 7.8 Hz, 1H, 6-H of C6H4), 7.53 (dt, J 1.7, 7.8 Hz, 1H,
4-H of C6H4), 7.15 (dt, J 0.9, 8.3 Hz, 1H, 5-H of C6H4), 7.07 (d, J 8.3
Hz, 1H, 3-H of C6H4), 4.29 (q, J 7 Hz, 2H, CH2O), 3.10 (q, J 7.65
Hz, 2H, CH2C), 2.68 (s, 3H, CH3C), 1.58 (t, J 7.1 Hz, 3H,
CH3CH2O), 1.45 (t, J 7.6 Hz, 3H, CH3CH2C). MS (ESI, matrix
CCA): m/z [M+H]+ found 299.4. C16H18N4O2 requires 299.1430.
4.6.4.
N-{1-[3-(2-Ethoxy-phenyl)-5-oxo-4,5-dihydro-[1,2,4]
triazin-6-yl]ethyl}benzamide 13d. The title product 13d was
obtained as a light yellow oil yield (0.55 g, 82%); [Found: C, 65.85;
H, 5.51; N, 15.32. C20H20N4O3 requires C, 65.92; H, 5.53; N,
15.38%]; Rf (EtOAc) 0.5. 1H NMR (CDCl3, δ ppm): 12.50 (brs, 1H,
NH O), 8.56 (dd, J 1.7 and 8.1 Hz, 1H, 6-H of C6H4), 7.835 (d, J
7.3 Hz, 3H, C6H5), 7.57 (td, J 1.7, 8.8 Hz, 1H, 4-H of C6H4), 7.48 (t,
J 7.3 Hz, 1H, C6H5), 7.42 (t, J 7.3 Hz, 2H, C6H5), 7.15 (t, J 7.6 Hz,
1H, 5-H of C6H4), 7.07 (d, J 8.3 Hz, 1H, 3-H of C6H4), 5.48 (m, 1H,
CHN), 4.34 (q, J 7 Hz, 2H, CH2O), 1.65 (d, J 6.8 Hz, 3H, CH3CH),
1.60 (t, J 6.8 Hz, 3H, CH3CH2O). 13C NMR (CDCl3, δ ppm): 166.8,
158.1, 135.3, 134.5, 132.1, 131.8, 128.7, 127.4, 122.3, 116.5, 112.9,
65.7, 48.2, 19.7, 15.0.
4.7.3.
2-(2-Ethoxyphenyl)-5-methyl-7-propyl-imidazo[5,1-f]
[1,2,4]triazin-4(3H)-one 14c. The title compound was prepared
from 13c (0.26 g, 0.0008 mol). The final product was crystallised
from ethyl acetate to afford the title product 14c (0.19 g, 78%) as a
light yellow solid, m.p. 142-144 ºC; [Found: C, 65.45; H, 6.43; N,
17.88. C17H20N4O2 requires C, 65.37; H, 6.45; N, 17.94%]. Rf
(petroleum ether/EtOAc, 1:1) 0.31. νmax(crystal): 3284, 2965, 2954,
2929, 1683, 1612, 1598 cm-1. H NMR (CDCl3, δ ppm): 9.98 (brs,
1
1H, NH O), 8.16 (dd, J 1.5, 7.8 Hz, 1H, 6-H of C6H4), 7.49 (t, J 8.5
Hz, 1H, 4-H of C6H4), 7.13 (t, J 7.6 Hz, 1H, 5-H of C6H4), 7.05 (d, J
8.3 Hz, 1H, 3-H of C6H4), 4.26 (q, J 7 Hz, 2H, CH2O), 3.0 (t, J 7.6
Hz, 2H, CH2C), 2.64 (s, 3H,CH3C), 1.90-1.86 (m, J 7.5 Hz, 2H,
CH2CH2CH3), 1.56 (t, J 7.1 Hz, 3H, CH3CH2O), 1.02 (t, J 7.3 Hz,
3H, CH3CH2C). 13C NMR (CDCl3, δ ppm): 157.2, 155.2, 146.3,
146.1, 139.9, 133.3, 130.3, 121.9, 117.8, 114.1, 113.3, 65.5, 28.2,
21.2, 14.9, 14.7, 14.2. MS (ESI, matrix CCA): [M+H]+ found 313.3.
C17H20N4O2 requires 313.1586.
4.6.5. N-{1-[3-(2-Ethoxyphenyl)-5-oxo-4,5-dihydro-[1,2,4]triazin-
6-yl]ethyl}oxalamic acid ethyl ester 13e. The title product 13e was
obtained as a light yellow oil (0.38 g, 57%); [Found: C, 56.63; H,
5.62; N, 15.51. C17H20N4O5 requires C, 56.66; H, 5.59; N, 15.55%];
1
Rf (hexane/EtOAc, 3:7) 0.29. H NMR (CDCl3, δ ppm): 12.03 (brs,
1H, NH O), 8.56 (dd, J 1.5, 7.8 Hz, 1H, 6-H of C6H4), 8.29 (d, J 8.8
Hz, 1H, NHCO), 7.57 (td, J 8.5, 1.5 Hz, 1H, 4-H of C6H4), 7.15(t, J
7.8 Hz, 1H, 5-H of C6H4), 7.07 (d, J 8.3 Hz, 1H, 3-H of C6H4), 5.33-
5.30 (m, 1H, CHN), 4.35-4.33 (m, 4H, CH2O), 1.63-1.59 (m, 6H,
CH3CH+CH3CH2O), 1.37 (t, J 7.1 Hz, 3H, CH3CH2O). 13C NMR
(CDCl3, δ ppm): 160.6, 158.1, 156.1, 135.3, 132.1, 122.3, 116.4,
112.9, 65.8, 63.4, 47.4, 19.2, 15.0
4.7.4.
2-(2-Ethoxyphenyl)-5-methyl-7-phenyl-imidazo[5,1-f]
[1,2,4]triazin-4(3H)-one 14d. The title compound was prepared
from 13d (0.37 g, 0.001 mol). The final product was crystallised
from ethyl acetate to afford the title product 14d (0.27 g, 77%) as a
light yellow solid, m.p. 181-182 ºC; [Found: C, 69.55; H, 5.26; N,
16.21. C20H18N4O2 requires C, 69.35; H, 5.24; N, 16.17%]; Rf
(petroleum ether/EtOAc, 1:1) 0.48. νmax(crystal): 3266, 2981, 1697,
1617, 1597 cm-1. 1H NMR (CDCl3, δ ppm): 10.18 (brs, 1H, NH O),
8.39 (d, J 7.8 Hz, 2H, C6H5), 8.18 (d, J 8.3 Hz, 1H, 6-H of C6H4),
7.51 (q, J 7.2 Hz, 3H, C6H5), 7.45 (t, J 7.1 Hz, 2H, 4-H of C6H4),
7.13 (t, J 7.6 Hz, 1H, 5-H of C6H4), 7.04 (d, J 8.3 Hz, 1H, 3-H of
C6H4), 4.26 (q, J 6.8 Hz, 2H, CH2O), 2.74 (s. 3H, CH3C), 1.57 (t, J
7.1 Hz, 3H, CH3CH2O). 13C NMR (CDCl3, δ ppm): 157.3, 155.0,
146.9, 142.4, 141.0, 133.5, 130.3, 129.7, 129.0, 128.7, 122.0, 117.4,
115.5, 113.2, 65.5, 14.9, 14.8. MS (ESI, matrix CCA): [M+H]+ found
347.2. C20H18N4O2 requires 347.1430.
4.7. General procedure for the synthesis of the 2(2-ethoxy-
phenyl)-7-alkyl-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(3H)-one
14
To a magnetically stirred solution of 13 (0.0010 mol) in toluene (35
mL), phosphorus oxychloride (0.17 ml, 0.0019 mol) was added at
room temperature. The resulting mixture was heated under reflux for
2 h and then cooled to room temperature. The solvent and an excess
of phosphorus oxychloride were evaporated in vacuo and the residue
was treated with saturated aqueous sodium bicarbonate solution (15
mL) and chloroform (15 mL). The mixture was shaken vigorously
until all solid had dissolved. The chloroform layer was separated and
the aqueous phase was extracted with another portion of chloroform
(2×15 mL). The chloroform extracts were combined, dried (MgSO4),
filtered and the solvent was evaporated. The residue was purified by
column chromatography on silica gel (chloroform) afforded a
product which was then crystallised from an appropriate solvent.
4.7.5. 2-(2-Ethoxyphenyl)-5-methyl-7-carboethoxy-imidazo[5,1-f]
[1,2,4]triazin-4(3H)-one 14e. The title compound was prepared
from 13e (1.0 g, 0.0028 mol). Crystallisation from ethyl acetate
afforded the title product 14e (0.69 g, 73%) as a light yellow solid,
m.p. 214-216 ºC; [Found: C, 59.65; H, 5.32; N, 16.31. C17H18N4O4
requires C, 59.64; H, 5.30; N, 16.37%]; Rf (petroleum ether/EtOAc,
1:1) 0.21. νmax(crystal): 3278, 2971, 2919, 1720, 1698, 1614, 1592
4.7.1.
2-(2-Ethoxyphenyl)-5,7-dimethyl-imidazo[5,1-f][1,2,4]-
triazin 4(3H)-one 14a. The title compound was prepared from 13a
(0.12 g, 0.0004 mol). The final product was crystallised from ethyl
acetate/ethyl ether to give the title product 14a (46 mg, 41%) as
white crystals, m.p. 209-210 ºC; [Found: C, 63.61; H, 5.65; N, 19.65.
C15H16N4O2 requires C, 63.37; H, 5.67; N, 19.71%]; Rf (petroleum
ether/EtOAc, 1:1) 0.16. νmax(crystal): 3280, 2981, 2923, 1695, 1619,
1
cm-1. H NMR (CDCl3, δ ppm): 10.56 (brs, 1H, NH O), 8.41 (d, J
7.8 Hz, 1H, 6-H of C6H4), 7.56 (t, J 7.8 Hz, 1H, 4-H of C6H4), 7.18
(t, J 7.6 Hz, 1H, 5-H of C6H4), 7.08 (d, J 8.8 Hz, 1H, 3-H of C6H4),
4.56 (q, J 7 Hz, 2H, CH2O), 4.323 (q, J 7 Hz, 2H, CH2O), 2.74 (s,