Heim-Riether and Healy
Calcd for C10H17N3O2 (211.25): C, 56.85; H, 8.11; N, 19.89.
Found: C, 56.62; H, 7.85; N, 19.97.
organic layer was washed with saturated Na2CO3-solution,
brine, and dried over MgSO4. The solvent was removed in
vacuo, and the remaining solid was purified by flash chroma-
tography on silica gel eluting with 75% ethyl acetate in hexane.
Chloride 14 was obtained as a beige-white solid (309 mg, 45%).
3-Amino-5-methyl-2-propyl-3H-imidazole-4-carboxam-
ide (30) and 1-Amino-5-methyl-2-propyl-1H-imidazole-4-
carboxamide (30a). N-Amination of 29 (583 mg, 3.48 mmol)
followed the general procedure. Purification by flash chroma-
tography on silica gel eluting with 4% increasing to 10%
methanol in dichloromethane gave 30 as a pale yellow waxy
solid (259 mg, 41%) and 30a as a white solid (350 mg, 55%).
1
Rf 0.51 (50% EtOAc in hexane). H NMR (400 MHz, CDCl3):
δ 8.38 (s, 1H), 8.06 (s, 1H), 2.74 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 156.69, 146.9 (CH), 137.3, 131.3 (CH), 116.9, 15.6.
MS, m/z (%) 168.9 (100) [M+ + 1]. Anal. Calcd for C6H5ClN4
(168.59): C, 42.75; H, 2.99; Cl, 21.03; N, 33.23. Found: C,
42.98; H, 3.09; Cl, 20.87; N, 33.09.
1
30: Rf 0.32 (10% MeOH in DCM). H NMR (300 MHz, CD3-
OD): δ 2.72 (t, J ) 7.5 Hz, 2H), 2.41 (s, 3H), 1.76 (sextet, J )
7.5 Hz, 2H), 1.01 (t, J ) 7.5 Hz, 3H). 13C NMR (75 MHz, CD3-
OD): δ 165.1, 151.9, 141.9, 121.5, 28.4, 21.8, 15.1, 14.2. MS,
m/z (%) 183.2 (100) [M+ + 1]. Anal. Calcd for C8H14N4O
(182.23): C, 52.73; H, 7.53; N, 30.75. Found: C, 52.72; H, 7.53;
2,5-Dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (24).
To a solution of amino-imidazole 12 (200 mg, 1.18 mmol) in
acetonitrile (10 mL) was passed dry hydrogen chloride gas at
room temperature for 30 min. The reaction mixture was stirred
for 18 h. Upon concentration, a white solid precipitated and
was filtered off. The solid was taken up in absolute ethanol
(20 mL) and 5% aqueous sodium hydroxide (5 mL) and heated
under reflux for 6 h. The solvent was evaporated, and the
reaction mixture was dissolved in water and acidified with 6
N HCl. The precipitate was filtrated and washed with water.
After drying in vacuo, the product was obtained as a white
solid (172 mg, 89%). 1H NMR (300 MHz, [d6]-DMSO): δ 11.61
(sbr, 1H), 8.21 (s, 1H), 2.45 (s, 3H), 2.18 (s, 3H). 13C NMR (75
MHz, [d6]-DMSO): δ 155.5, 149.5, 138.7, 132.6, 114.3, 18.4,
14.6. MS, m/z (%) 165.0 (100) [M+ + 1]. Anal. Calcd for
C7H8N4O (164.17): C, 51.21; H, 4.91; N, 34.13. Found: C,
51.21; H, 4.73; N, 34.08.
1
N, 31.00. 30a: Rf 0.44 (10% MeOH in DCM). H NMR (300
MHz, CD3OD): δ 2.75 (t, J ) 7.3 Hz, 2H), 2.50 (s, 3H), 1.75
(sextet, J ) 7.3 Hz, 2H), 1.00 (t, J ) 7.3 Hz, 3H). 13C NMR (75
MHz, CD3OD): δ 168.5, 149.8, 136.4, 126.9, 28.9, 22.3, 14.1,
9.4.
General Procedure for the Preparation of Imidazo-
[5,1-f][1,2,4]triazin-4(3H)-ones. In a sealed tube, amino-
imidazole (1.00 mmol) in formamide (1-2 mL) was heated at
180 °C for 2-8 h. Upon cooling to rt, most imidazo[5,1-f][1,2,4]-
triazin-4(3H)-ones precipitated out and could be isolated by
filtration. The precipitate was washed with ethyl acetate. The
same solvent was used to precipitate out the products if
necessary. The products were obtained as white/beige solids
(52-89% yield).
2-Amino-5-methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-
one (25). To a solution of amino-imidazole 12 (145 mg, 0.857
mmol) and cyanamide (42 mg, 1.028 mmol) in dioxane (8 mL)
was added concentrated hydrochloric acid (0.5 mL). The
reaction mixture was heated under reflux under nitrogen
atmosphere for 24 h. The formed brown oil was separated from
the reaction mixture, and after the addition of a solution of
sodium hydroxide (41 mg, 1.028 mmol) in water (10 mL) it
was heated at 100 °C for 3 h. The cooled mixture was acidified
with hydrochloric acid (6 N) and was purified by reversed
phase HPLC, eluted with 0.1% TFA H2O/MeOH gradient, to
5-Methyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (13). Ac-
cording to the general procedure, amino-imidazole 12 (2.50 g,
1
14.77 mmol) gave beige crystals (1.96 g, 89%). H NMR (300
MHz, [d6]-DMSO): δ 11.32 (sbr, 1H), 8.28 (s, 1H), 7.79 (s, 1H),
2.45 (s, 3H). 13C NMR (75 MHz, [d6]-DMSO): δ 155.2, 140.8
(CH), 139.0, 133.1 (CH), 115.7, 14.7. MS, m/z (%) 150.9 (100)
[M+ + 1]. Anal. Calcd for C6H6N4O (150.14): C, 48.00; H, 4.03;
N, 37.32. Found: C, 48.25; H, 4.03; N, 37.29.
3H-Imidazo[5,1-f][1,2,4]triazin-4-one (1). According to
the general procedure, amino-imidazole 16 (110 mg, 0.779
1
1
give the product as a white solid (40 mg, 28%). H NMR (300
mmol) gave white crystals (55 mg, 52%). H NMR (300 MHz,
MHz, CD3OD): δ 7.84 (s, 1H), 2.52 (s, 3H). 13C NMR (75 MHz,
CD3OD): δ 155.7, 153.9, 134.2, 127.9, 116.5, 11.1. MS, m/z (%)
166.1 (100) [M+ + 1]. HPLC-Purity: 100% at 0.31 min (A )
10 µM CH3CO2NH4, BdCH3CN, Grad. 10-95% B in 2 min,
4.5 mL/min, Col: Luna phenylhexyl (Phenomenex) 50 mm ×
4.6 mm (3 µm) @ 45 °C, detection 220/250 nm).
[d6]-DMSO): δ 11.87 (sbr, 1H), 8.47 (s, 1H), 7.93 (s, 1H), 7.78
(s, 1H). 13C NMR (75 MHz, [d6]-DMSO): δ 154.2, 140.9 (CH),
135.0, 128.0 (CH), 120.4. MS, m/z (%) 137.0 (100) [M+ + 1].
Anal. Calcd for C5H4N4O (136.11): C, 44.12; H, 2.96; N, 41.16.
Found: C, 43.91; H, 2.70; N, 41.26.
5-Cyano-3H-imidazo[5,1-f][1,2,4]triazin-4-one (19). Ac-
cording to the general procedure, amino-imidazole 18 (96 mg,
0.653 mmol) gave the product (90% pure), which was purified
by reversed phase HPLC, eluted with 0.1% TFA H2O/MeOH
gradient, to give the product as a beige-white solid (87 mg,
83%). 1H NMR (300 MHz, [d6]-DMSO): δ 12.56 (sbr, 1H), 8.72
(s, 1H), 8.14 (s, 1H). 13C NMR (75 MHz, [d6]-DMSO): δ 152.7,
142.8 (CH), 136.4 (CH), 126.9, 114.2, 109.2. MS, m/z (%) 160.1
(100) [M+ - 1]. HPLC-Purity: 100% at 0.30 min (A ) 10 µM
CH3CO2NH4, BdCH3CN, Grad. 10-95% B in 2 min, 4.5 mL/
min, Col: Luna phenylhexyl (Phenomenex) 50 mm × 4.6 mm
(3 µm) @ 45 °C, detection 220/250 nm).
2-(2-Ethoxy-phenyl)-5-methyl-3H-imidazo[5,1-f][1,2,4]-
triazin-4-one (28). To a solution of aminoimidazole 12 (100
mg, 0.591 mmol) in anhydrous pyridine (2 mL) was added
2-ethoxy-benzoyl chloride (130 mg, 0.709 mmol). The reaction
mixture was stirred under nitrogen for 2 h at 100 °C before it
was transferred into a sealed tube. After addition of concen-
trated ammonium hydroxide (5 mL), the mixture was stirred
at 110 °C for 24 h. To the cooled reaction mixture was added
ethyl acetate, and the organic layer was extracted with water,
brine, and dried over MgSO4. After the solvent was removed
in vacuo, the crude product was purified by flash chromatog-
raphy on silica gel eluting with 0% increasing to 5% methanol
in dichloromethane. The product was obtained as a white solid
(20 mg, 13%). 1H NMR (300 MHz, CDCl3): δ 9.97 (sbr, 1H),
8.08 (dd, 3J ) 8.0 Hz, 4J ) 1.8 Hz, 1H), 7.99 (s, 1H), 7.43 (t, J
) 7.8 Hz, 1H), 7.05 (t, J ) 7.8 Hz, 1H), 6.97 (d, J ) 8.0 Hz,
1H), 4.19 (q, J ) 6.9 Hz, 2H), 2.58 (s, 3H), 1.49 (t, J ) 6.9 Hz,
3H). 13C NMR (75 MHz, CDCl3): δ 157.4, 154.9, 147.5, 141.4,
133.8, 133.5, 130.4, 122.2, 117.4, 113.5, 65.7, 15.1, 15.0. MS,
m/z (%) 271.1 (100) [M+ + 1]. Anal. Calcd for C14H14N4O2
(270.29): C, 62.21; H, 5.22; N, 20.73. Found: C, 62.03; H, 4.99;
N, 20.47.
5-Methyl-2-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-
one (22). According to the general procedure, amino-imidazole
1
21 (100 mg, 0.509 mmol) gave a white solid (67 mg, 68%). H
NMR (300 MHz, [d6]-DMSO): δ 11.51 (sbr, 1H), 7.76 (s, 1H),
2.79 (t, J ) 7.2 Hz, 2H), 2.43 (s, 3H), 1.69 (sextet, J ) 7.2 Hz,
2H), 0.90 (t, J ) 7.2 Hz, 3H). 13C NMR (75 MHz, [d6]-DMSO):
δ 155.3, 144.4, 139.9, 137.9, 115.2, 27.4, 20.6, 14.6, 14.0. MS,
m/z (%) 193.2 (100) [M+ + 1]. Anal. Calcd for C9H12N4O
(192.22): C, 56.24; H, 6.29; N, 29.15. Found: C, 55.94; H, 6.42;
N, 29.13.
4-Chloro-5-methyl-imidazo[5,1-f][1,2,4]triazine (14). Im-
idazotriazinone 13 (500 mg, 3.33 mmol) was heated under
reflux in phosphoryl chloride (10 mL) for 5 h. The reaction
mixture was cooled to room temperature and poured on ice
followed by extraction with dichloromethane (3 × 20 mL). The
3-(2-Ethoxy-benzoylamino)-5-methyl-2-propyl-3H-imi-
dazole-4-carboxamide (31). To a solution of aminoimidazole
30 (160 mg, 0.878 mmol) in anhydrous pyridine (10 mL) was
added 2-ethoxy-benzoyl chloride (194 mg, 1.054 mmol). The
7336 J. Org. Chem., Vol. 70, No. 18, 2005