15N NMR studies of 1,2,4-benzotriazine N-oxides 949
7.88–7.92 (m, 3 H, H-7, NH2); 13C NMR υ 160.2, 148.7, 135.6,
129.8, 125.8, 124.6, 119.8.
°
°
(15.2 g, 0.36 mmol) was melted at 100 C, cooled to ca 40 C
and conc. HCl (10 ml) was added dropwise. The resulting
exotherm was allowed to subside and the mixture was heated
Preparation of 3-chloro-1,2,4-benzotriazine 1-oxide (8).
A mixture of alcohol 7 (9.30 g, 57.0 mmol), dimethylfor-
mamide (0.5 ml), and phosphoryl oxychloride (40 ml) was
stirred at reflux temperature for 1 h and then poured onto ice
and stirred for 30 min. The resulting solid was filtered and
washed with water (3 ð 10 ml). The filtrate was extracted
with ethyl acetate (3 ð 50 ml), dried, and the solvent evap-
orated. The combined solids were purified by chromatog-
raphy, eluting with 5% ethyl acetate/petroleum ether, to
give the 3-chloride 8 (9.52 g, 92%) as a pale yellow pow-
°
°
at 100 C for 1 h. The mixture was cooled to ca 40 C and
30% sodium hydroxide solution (50 ml) added carefully. The
°
°
mixture was stirred at 100 C for 2 h, cooled to 25 C, diluted
with water (50 ml) and stirred for 30 min. The suspension was
filtered, washed with water (2 ð 10 ml), washed with diethyl
ether (2 ð 5 ml) and dried under vacuum to give 1-oxide
2 (10.3 g, 88%) as a yellow powder: mp (methanol/ethyl
acetate) 267–269 C [lit. mp (ethanol) 269 C]; 1H NMR
υ 8.14 (d, J D 8.7 Hz, 1 H, H-8), 7.79 (dd, J D 8.6, 7.0 Hz, 1 H,
H-6), 7.54 (d, J D 8.6 Hz, 1 H, H-5), 7.32–7.38 (m, 3 H, H-7,
NH2).
19
°
°
12
°
der: mp (dichloromethane) 119–119.5 C [lit. (methanol)
1
°
117–118 C]; H NMR υ 8.38 (dd, J D 8.7, 1.0 Hz, 1 H, H-8),
8.16 (ddd, J D 8.3, 7.0, 1.3 Hz, 1 H, H-6), 8.06 (dd, J D 8.2,
1.0 Hz, 1 H, H-5), 7.90 (ddd, J D 8.7, 6.9, 1.3 Hz, 1 H, H-7);
13C NMR υ 155.3, 146.9, 137.2, 133.9, 131.5, 128.0, 119.9.
Preparation of 1,2,4-benzotriazine (9). A solution of 3-
chloride 8 (300 mg, 1.65 mmol) in ethanol/ethyl acetate
(1 : 1, 50 ml) was stirred vigorously with palladium on
carbon (100 mg) under H2 (60 psi) for 2 h. The mixture was
filtered through celite, washed with ethanol (2 ð 10 ml),
and the solvent evaporated. The residue was purified
by chromatography, eluting with a gradient (0–5%) of
methanol/dichloromethane, to give 9 (90 mg, 33%) as a
Preparation of 1,2,4-benzotriazin-3-amine 1,4-dioxide (1).
Compound 1 was prepared by the method of Seng and Ley.20
Oxidation of 1-oxide 2 using peracetic acid gave 1,4-dioxide
20
°
°
1 as a red powder: mp (acetic acid) 198–199 C (lit. 220 C);
1 H NMR υ 8.21 (d, J D 8.8 Hz, 1 H, H-8), 8.14 (d, J D 8.7 Hz,
1 H, H-5), 8.04 (br s, 2 H, NH2), 7.95 (ddd, J D 8.7, 7.1, 1.4 Hz,
1 H, H-6), 7.58 (ddd, J D 8.8, 7.1, 1.4 Hz, 1 H, H-7).
Preparation of 1,2,4-benzotriazin-3-amine (5). A solution
of 1-oxide 2 (1.98 g, 14.3 mmol) and sodium dithionite (5.0 g,
28.7 mmol) in 70% aqueous ethanol (100 ml) was heated
at reflux temperature for 3 h. The hot suspension was
filtered and the filtrate extracted with chloroform (3 ð 50 ml).
The combined organic fraction was dried and the solvent
evaporated. The combined solid and extracts were purified
by chromatography, eluting with a gradient (0–2%) of
methanol/chloroform, to give benzotriazine 5 (1.58 g, 67%)
°
white solid: mp (ethyl acetate/petroleum ether) 75–76 C
1
[lit.21 mp (light petrol) 76–77 C]; H NMR υ 10.11 (s, 1 H,
°
H-3), 8.59 (d, J D 8.6 Hz, 1 H, H-8), 8.16–8.23 (m, 2 H, H-5,
H-6), 8.09 (ddd, J D 8.6, 7.0, 1.0 Hz, 1 H, H-7).
Oxidation of 1,2,4-benzotriazin-3-amine (5). A solu-
tion of m-chloroperbenzoic acid (0.89 g, 3.6 mmol) in
dichloromethane (5 ml) was added dropwise to a stirred
solution of 5 (0.50 g, 3.4 mmol) in 10% methanol/dichloro-
°
as a yellow solid: mp (methanol/chloroform) 200–203 C
1
(lit.13 mp 207 C); H NMR υ 8.20 (dd, J D 8.3, 0.9 Hz, 1 H,
°
H-8), 7.78–7.83 (m, 1 H, H-6), 7.62 (br s, 2 H, NH2), 7.54 (d,
J D 8.4 Hz, 1 H, H-5), 7.43–7.48 (m, 1 H, H-7).
°
°
methane (50 ml) at 20 C and the solution stirred at 20 C
for 3 h. The solution was washed with dilute aqueous NH3
solution (50 ml), dried, and the solvent evaporated. The
residue was purified by chromatography, eluting with a
gradient (0–5%) of methanol/chloroform, to give (i) 1,2,4-
benzotriazin-3-amine 2-oxide (3) (405 mg, 70%) as a yellow
Preparation of 1,2,4-benzotriazine 1-oxide (6). t-Butyl
nitrite (90%, 1.05 ml, 8.0 mmol) was added to a stirred solu-
tion of 1-oxide 2 (254 mg, 1.6 mmol) in dimethylformamide
°
(10 ml) and the solution stirred at 60 C for 2 h. The solvent
13
was evaporated and the residue partitioned between ethyl
acetate (50 ml) and water (50 ml). The organic fraction was
washed with water (2 ð 25 ml), washed with brine (20 ml),
dried, and the solvent evaporated. The residue was puri-
fied by chromatography, eluting with a gradient (0–10%)
of ethyl acetate/dichloromethane, to give 6 (120 mg, 52%)
as a pale yellow solid: mp (ethyl acetate/dichloromethane)
°
powder: mp (methanol/dichloromethane) 175–180 C [lit.
mp (acetic acid) 200 C]; H NMR υ 8.20 (br s, 2 H, NH2), 7.68
1
°
(d, J D 8.2 Hz, 1 H, H-8), 7.60–7.65 (m, 1 H, H-6), 7.53 (d,
J D 7.6 Hz, 1 H, H-5), 7.45–7.49 (m, 1 H, H-7); followed by
(ii) 1,2,4-benzotriazin-3-amine 1-oxide (2) (65 mg, 11%) as a
°
yellow powder: mp 266–268 C, spectroscopically identical
with the sample prepared above; and (iii) 1,2,4-benzotriazin-
3-amine 4-oxide (4) (51 mg, 9%) as pale yellow solid: 1H
NMR υ 8.29 (d, J D 8.6 Hz, 1 H, H-8), 8.20 (br s, 2 H, NH2),
8.16 (d, J D 8.6 Hz, 1 H, H-5), 7.91 (ddd, J D 8.6, 7.0, 1.2 Hz,
1 H, H-6), 7.65 (ddd, J D 8.6, 7.0, 1.1 Hz, 1 H, H-7); MS m/z 162
(MC, 100%), 146 (10); HRMS calcd for C7H6N4O ꢀMCꢁ m/z
162.0542, found 162.0540.
12
1
°
°
138–139 C [lit. mp (methanol) 138–140 C]; H NMR υ 9.19
(s, 1 H, H-3), 8.41 (d, J D 8.6 Hz, 1 H, H-8), 8.10–8.13 (m,
2 H, H-5, H-6), 7.90–7.94 (m, 1 H, H-7).
Preparation of 1,2,4-benzotriazin-3-ol 1-oxide (7). Sodium
nitrite (10.0 g, 145 mmol) was added in small portions
to a stirred solution of 1-oxide 2 (11.7 g, 72 mmol) in
°
trifluoroacetic acid (80 ml) at 0 C and the mixture stirred
°
at 20 C for 2 h. The mixture was poured into ice/water
NMR
(800 ml) and stirred for 30 min. The precipitate was filtered,
washed with water, and dried to give 3-hydroxy-1-oxide
NMR data were collected on a Bruker Avance 400 spectrom-
eter operating at frequencies 400.13 MHz (1H), 100.62 MHz
(13C) and 40.55 MHz (15N) and equipped with a 5-mm,
triple-resonance (1H/13C/15N), inverse-detection probe with
19
°
7 (9.40 g, 80%) as a yellow powder: mp 209–212 C; [lit.
mp (H2O) 219 C]; 1H NMR υ 8.14 (d, J D 8.4 Hz, 1 H,
°
H-8), 7.77–7.81 (m, 1 H, H-6), 7.54 (d, J D 8.4 Hz, 1 H, H-5),
Copyright 2006 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2006; 44: 948–954
DOI: 10.1002/mrc