A Quinoxalinone as Scaffold
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 14 3587
7.35 (m, 3H, ar), 7.85 (d, 2H, ar, J ) 9.2 Hz), 8.59 (d, 1H, H-9,
J ) 8.1 Hz), 11.94 (s, 1H, NH). Anal. (C17H14N4O3) C, H, N.
7: yield 89%; mp >300 °C (DMF); 1H NMR δ 7.53 (t, 1H, ar,
J ) 8.1 Hz), 8.13 (d, 1H, ar, J ) 7.0 Hz), 8.31 (d, 2H, ar, J )
9.5 Hz), 8.45 (d, 2H, ar, J ) 9.5 Hz), 8.99 (d, 1H, H-9, J ) 6.9
Hz), 11.38 (br s, 1H, NH); IR 1707, 3324. Anal. (C15H8N6O6)
C, H, N.
pressure, the residue was suspended in hot DMF (8 mL) and
the catalyst was filtered off. The solution was diluted with
water, and the solid was collected by filtration. Yield: 50%;
mp >300 °C (AcOH); 1H NMR δ 3.79 (s, 3H, CH3), 5.60 (s, 2H,
NH2), 6.68 (t, 1H, ar, J ) 8.4 Hz), 6.98 (t, 1H, ar, J ) 8.4 Hz),
7.09 (d, 2H, ar, J ) 8.8 Hz), 7.84 (d, 2H, ar, J ) 8.8 Hz), 7.93
(d, 1H, ar, J ) 8.4 Hz), 10.98 (s, 1H, NH). Anal. (C16H13N5O3)
C, H, N.
1
8: yield 85%; mp 262-264 °C (AcOH); H NMR δ 3.80 (s,
6-Am in o-2-(4-h yd r oxyp h en yl)-1,2,4,5-tetr a h yd r o-1,2,4-
tr ia zolo[4,3-a ]qu in oxa lin e-1,4-d ion e (12). A mixture of the
6-nitro derivative 9 (1.03 mmol) and 10% Pd/C (0.03 g) in
dimethylformamide (30 mL) was hydrogenated in a Parr
apparatus at 30 psi for 12 h. The catalyst was filtered off, and
the clear solution diluted with water gave a solid that was
collected by filtration and washed with water and ethanol.
3H, CH3), 7.12 (d, 2H, ar, J ) 9.16 Hz), 7.49 (t, 1H, H-8, J )
8.3 Hz), 7.85 (d, 2H, ar, J ) 9.1 Hz), 8.12 (d, 1H, H-7, J ) 8.3
Hz), 9.02 (d, 1H, H-9, J ) 8.1 Hz), 11.25 (s, 1H, NH). Anal.
(C16H11N5O5) C, H, N.
2-(4-Am in op h en yl)-1,2,4,5-t et r a h yd r o-1,2,4-t r ia zolo-
[4,3-a ]qu in oxa lin e-1,4-d ion e (2).18 The title compound was
prepared from 1 as described in ref 18.
1
Yield 94%; mp >300 °C (EtOH/DMF); H NMR δ 5.62 (s, 2H,
2-(4-Dim et h yla m in op h en yl)-1,2,4,5-t et r a h yd r o-1,2,4-
tr ia zolo[4,3-a ]qu in oxa lin e-1,4-d ion e (3). Aqueous formal-
dehyde (40%, 0.74 mL) was added to a suspension of 2 (0.85
mmol) in acetonitrile (15 mL). The mixture was stirred at room
temperature for 5 min, then sodium cyanoborohydride (2.9
mmol) was added. After the mixture was stirred for 6 h at
room temperature, a second portion of aqueous formaldehyde
(40%, 0.74 mL) and sodium cyanoborohydride (2.9 mmol) was
added and the suspension was left overnight at room temper-
ature. After dilution with water (10 mL), the mixture was
acidified with glacial acetic acid and the solid was collected
and washed with water. Yield: 95%; mp >300 °C (DMF/
EtOH); 1H NMR δ 2.94 (s, 6H, 2CH3), 6.85 (d, 2H, ar, J ) 9.1
Hz), 7.21-7.40 (m, 3H, ar), 7.71 (d, 2H, ar, J ) 9.1 Hz), 8.60
(d, 1H, H-9, J ) 8.1 Hz), 11.90 (s, 1H, NH); IR 1690, 1730,
3160 cm-1. Anal. (C17H15N5O2) C, H, N.
NH2), 6.70 (d, 1H, ar, J ) 7.3 Hz), 6.85-7.05 (m, 3H, ar), 7.72
(d, 2H, ar, J ) 8.9 Hz), 7.95 (d, 1H, ar, J ) 7.3 Hz), 9.56 (s,
1H, OH), 10.99 (s, 1H, NH). Anal. (C15H11N5O3) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 2-Ar yl-4-
ch lor o-1,2-d ih yd r o-1,2,4-t r ia zolo[4,3-a ]q u in oxa lin -1-
on es 30, 31, 32,16 33-35. Compounds 30, 31, 33, 34, and 35
were obtained from 1, 4, 7, 8 and 10, respectively, following
the reported procedure16 to obtain 32 from 1A. Briefly, a
mixture of 1,16,18 4, 7, 8, and 10 (2 mmol), phosphorus
pentachloride (4 mmol) in phosphorus oxychloride (40 mL), and
anhydrous pyridine (0.2 mL) was refluxed until the disap-
pearance (TLC monitoring) of the starting material (12-24
h). Evaporation of the excess phosphorus oxychloride at
reduced pressure gave a residue that was treated with iced
water (50 mL), collected, and washed with water and then
cyclohexane. The 4-chloro derivatives 30, 31, 33-35, obtained
in high overall yields (80-90%), were unstable upon recrys-
tallization; however, they were pure enough to be used without
purification.
2-(4-Hyd r oxyp h en yl)-1,2,4,5-tetr a h yd r o-1,2,4-tr ia zolo-
[4,3-a ]qu in oxa lin e-1,4-d ion e (5).18 The title compound was
obtained from 1A as described in ref 18.
2-(4-Acetoxyp h en yl)-1,2,4,5-tetr a h yd r o-1,2,4-tr ia zolo-
[4,3-a ]qu in oxa lin e-1,4-d ion e (6). A mixture of compound 518
(0.68 mmol), triethylamine (2.72 mmol), and acetyl chloride
(0.68 mmol) in anhydrous tetrahydrofuran (20 mL) was
refluxed for 3 h. After the mixture was cooled at room
temperature, the solid was filtered off and the solvent of the
clear solution was evaporated at reduced pressure. The residue
was purified on silica gel column, eluting with chloroform/
methanol (11:0.5). Evaporation of the solvent of the second
eluates afforded compound 6. Yield: 62%; mp 298-299 °C
1
30: H NMR δ 7.58-7.65 (m, 1H, ar), 7.78 (t, 1H, ar, J )
8.8 Hz), 7.91 (d, 1H, ar, J ) 8.8 Hz), 8.35 (d, 2H, ar, J ) 9.2
Hz), 8.47 (d, 2H, ar, J ) 9.2 Hz), 8.72 (d, 1H, H-9, J ) 7.3 Hz).
1
31: H NMR δ 1.33 (t, 3H, CH3, J ) 8.6 Hz), 4.05 (q, 2H,
CH2, J ) 8.6 Hz), 7.08 (d, 2H, ar, J ) 8.8 Hz), 7.22-8.05 (m,
5H, ar), 8.71 (d, 1H, H-9, J ) 8.1 Hz).
1
33: H NMR δ 7.95 (t, 1H, H-8, J ) 8.4 Hz), 8.09 (d, 1H,
H-7, J ) 8.4 Hz), 8.32-8.50 (m, 4H, ar), 8.91 (d, 1H, H-9, J )
6.7 Hz).
1
1
34: H NMR δ 3.81 (s, 3H, OCH3), 7.13 (d, 2H, ar, J ) 9.1
(DMF); H NMR δ 2.30 (s, 3H, CH3), 7.22-7.41 (m, 5H, ar),
Hz), 7.87-7.98 (m, 3H, ar), 8.05 (d, 1H, ar, J ) 6.6 Hz), 8.94
(d, 1H, ar, J ) 8.1 Hz).
8.02 (d, 2H, ar, J ) 9.2 Hz), 8.60 (d, 1H, H-9, J ) 8.1 Hz),
11.99 (s, 1H, NH); IR 1690, 1720, 1770, 3390 cm-1. Anal.
(C17H12N4O4) C, H, N.
35: 1H NMR δ 2.31 (s, 3H, COCH3), 7.37 (d, 2H, ar, J ) 8.8
Hz), 7.90-8.12 (m, 4H, ar), 8.93 (d, 1H, H-9, J ) 8.1 Hz).
Gen er a l P r oced u r e for th e Syn th esis of 4-Am in o-2-
ar yl-1,2-dih ydr o-1,2,4-tr iazolo[4,3-a ]qu in oxalin -1-on es 13,
15, 17-19, 1B.16 Compounds 13, 15, and 17-19 were prepared
as previously described to obtain 1B from 32,16 i.e., by heating
overnight at 120 °C in a sealed tube a suspension of 30, 31,
and 33-35 (2 mmol) in absolute ethanol (30 mL) saturated
with ammonia. After the mixture was cooled, the solid was
collected and washed with water.
2-(4-H yd r oxyp h en yl)-6-n it r o-1,2,4,5-t et r a h yd r o-1,2,4-
tr ia zolo[4,3-a ]qu in oxa lin e-1,4-d ion e (9). A suspension of
compound 8 (1.4 mmol) in glacial acetic acid (2 mL) and
hydrobromic acid (48%, 9 mL) was refluxed for 40 h. After the
mixture was cooled at room temperature, the solid was filtered
1
and washed with water. Yield: 86%; mp >300 °C (DMF); H
NMR δ 6.91 (d, 2H, ar, J ) 8.8 Hz), 7.47 (t, 1H, ar, J ) 8.4
Hz), 7.71 (d, 2H, ar, J ) 8.8 Hz), 8.10 (d, 1H, ar, J ) 8.4 Hz),
9.01 (d, 1H, H-9, J ) 8.4 Hz), 9.82 (s, 1H, OH), 11.22 (s, 1H,
NH); Anal. (C15H9N5O5) C, H, N.
13: yield 80%; mp >300 °C (DMF); 1H NMR δ 7.30-7.45
(m, 3H, ar), 7.61 (br s, 2H, NH2), 8.37 (d, 2H, ar, J ) 8.8 Hz),
8.47 (d, 2H, ar, J ) 8.8 Hz), 8.57 (d, 1H, H-9, J ) 6.7 Hz); IR
1713, 3434 cm-1. Anal. (C15H10N6O3) C, H, N.
2-(4-Acet oxyp h en yl)-6-n it r o-1,2,4,5-t et r a h yd r o-1,2,4-
tr ia zolo[4,3-a ]qu in oxa lin e-1,4-d ion e (10). A mixture of
compound 9 (0.58 mmol), acetyl chloride (0.87 mmol), and
triethylamine (0.87 mmol) in anhydrous tetrahydrofuran (20
mL) was refluxed for 12 h. The suspension was cooled at room
temperature, and the solid was collected by filtration and
1
15: yield 82%; mp 246-248 °C (2-ethoxyethanol); H NMR
δ 1.35 (t, 3H, CH3, J ) 7.0 Hz), 4.04 (q, 2H, CH2, J ) 7.0 Hz),
7.08 (d, 2H, ar, J ) 9.1 Hz), 7.21-7.47 (m, 5H, 3 ar + NH2),
7.88 (d, 2H, ar, J ) 9.1 Hz), 8.60 (d, 1H, H-9, J ) 7.7 Hz); IR
1718, 3299, 3461 cm-1. Anal. (C17H15N5O2) C, H, N.
1
washed with water. Yield: 90%; mp 266-268 °C (DMF); H
NMR δ 2.29 (s, 3H, CH3), 7.34 (d, 2H, ar, J ) 9.1 Hz), 7.50 (t,
1H, ar, J ) 8.4 Hz), 8.01 (d, 2H, ar, J ) 8.8 Hz), 8.14 (d, 1H,
ar, J ) 8.1 Hz), 9.01 (d, 1H, H-9, J ) 8.1 Hz), 11.30 (s, 1H,
NH). Anal. (C17H11N5O6) C, H, N.
1
17: yield 70%; mp >300 °C (DMF); H NMR δ 7.38 (t, 1H,
ar, J ) 8.1 Hz), 7.75 (d, 1H, ar, J ) 8.1 Hz), 8.21 (br s, 2H,
NH2), 8.36 (d, 2H, ar, J ) 9.1 Hz), 8.48 (d, 2H, ar, J ) 9.1 Hz),
8.73 (d, 1H, H-9, J ) 8.4 Hz); IR 1728, 3361, 3469 cm-1. Anal.
(C15H9N7O5) C, H, N.
6-Am in o-2-(4-m eth oxyp h en yl)-1,2,4,5-tetr a h yd r o-1,2,4-
tr ia zolo[4,3-a ]qu in oxa lin e-1,4-d ion e (11). A mixture of
compound 8 (0.79 mmol) and 10% Pd/C (30 mg) in hot ethyl
acetate (200 mL) was hydrogenated in a Parr apparatus at 30
psi for 1 h. After evaporation of the solvent at reduced
18: yield 85%; mp 289-291°C (AcOH/DMF); 1H NMR δ 3.80
(s, 3H, CH3), 7.11 (d, 2H, ar, J ) 9.1 Hz), 7.34 (t, 1H, ar, J )
8.4 Hz), 7.71 (d, 1H, ar, J ) 7.7 Hz), 7.89 (d, 2H, ar, J ) 9.1