Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4679
70 °C for 2 h. Yellow crystals. TLC eluent: i-propyl ether/
acetate/acetic acid 8:2:1 v/v/v. 1H NMR (CDCl3) δ 8.34 (d, 1H,
H-6), 8.00 (s, 1H, H-2), 7.55 (d, 1H, H-9), 7.23 (m, 5H, Ph), 7.01
(dd, 1H, H-7), 4.82 (m, 1H, CH), 3.09 (dd, 1H, CH2), 2.90 (dd,
1H, CH2), 1.38 (d, 3H, CH3). Anal. C, H, N.
3-Iodo-8-(2-methyl-2-phenylethoxy)pyrazolo[5,1-c][1,2,4]ben-
zotriazine 5-Oxide, 22((). From 126,28 and 2-phenylpropan-1-
ol, at 70 °C for 3 h. Yellow crystals. TLC eluent: toluene/ethyl
acetate/acetic acid 8:2:1 v/v/v. 1H NMR (CDCl3) δ 8.35 (d, 1H,
H-6), 8.00 (s, 1H, H-2), 7.55 (d, 1H, H-9), 7.25 (m, 5H, Ph), 7.05
(dd, 1H, H-7), 4.22 (dd, 1H, CH2O), 4.15 (dd, 1H, CH2O), 3.28
(m, 1H, CH), 1.40 (d, 3H, CH3). Anal. C, H, N.
3-Iodo-8-(2-naphthyloxy)pyrazolo[5,1-c][1,2,4]benzotriazine 5-
Oxide (23). From 1,26,28 and 2-phenylethanol, at 70 °C for 12 h.
Yellow crystals. TLC eluent: chloroform; 1H NMR (DMSO-d6)
δ 8.47 (d, 1H, H-6), 8.26 (s, 1H, H-2), 8.15 (d, 1H, H-40 napht.),
8.05 (d, 1H, H-80 napht.), 7.97 (d, 1H, H-50 napht.), 7.85 (d,
1H, H-9), 7.60 (m, 2H, H-70 and H80 napht.), 7.51 (d, 1H,
H-1 napht.), 7.46 (dd, 1H, h-30 napht.), 7.42 (dd, 1H, H-7). Anal.
C, H, N.
3-Chloro-8-phenoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxide
(24). From 226 and phenol, at 40 °C for 8 h. Yellow crystals. TLC
eluent: chloroform. 1H NMR (CDCl3) δ 8.50 (d, 1H, H-6), 8.00 (s,
1H, H-2), 7.68 (d, 1H, H-9), 7.50 (t, 2H, H-30 and H-50 Ph), 7.35 (t,
1H, H-40 Ph), 7.23 (dd, 1H, H-7), 7.20 (dd, 2H, H-20 and H-60 Ph).
Anal. C, H, N.
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cyclohexane 8:3 v/v. H NMR (CDCl3) δ 8.48 (d, 1H, H-6),
8.11 (s, 1H, H-2), 7.79 (d, 1H, H-9), 7.43 (d, 2H, H-20 and H-60
Ph), 7.21 (dd, 1H, H-7), 6.98 (d, 2H, H-30 and H-50 Ph), 5.24 (s,
2H, CH2O), 3.85 (s, 3H, OCH3). Anal. C, H, N.
3-Iodio-8-(o-trifluoromethoxybenzyloxy)pyrazolo[5,1-c][1,2,4]-
benzotriazine 5-Oxide (14). From 1,26,28 and o-trifluoromethox-
ybenzyl alcohol, at 70 °C for 2 h. Yellow crystals. TLC eluent:
toluene/ethyl acetate/acetic acid 8:2:1 v/v/v, 1H NMR (DMSO-
d6) δ 8.39(m, 2H, H-2 and H-6), 7.81 (d, 1H, H-9), 7.75(d, 1H, H-
30 Ph), 7.57 (dd, 1H, H-60 Ph), 7.48 (m, 2H, H-40 and H-50 Ph),
7.35 (dd, 1H, H-7), 5.50 (s, 2H, CH2O). Anal. C, H, N.
3-Iodio-8-(p-chlorobenzyloxy)pyrazolo[5,1-c][1,2,4]benzotriazine
5-Oxide (15). From 1,26,28 and p-chlorobenzyl alcohol, at 40 °C for
2.30 h. Yellow crystals. TLC eluent: chloroform. 1H NMR
(CDCl3) δ 8.49 (d, 1H, H-6), 8.11 (s, 1H, H-2), 7.77 (d, 1H,
H-9), 7.44 (s, 4H, Ph), 7.23 (dd, 1H, H-7), 5.29 (s, 2H, CH2O).
Anal. C, H, N.
3-Iodo-8-(1-phenylethoxy)pyrazolo[5,1-c][1,2,4]benzotriazine 5-
Oxide (16(()). From 1,26,28 and (()1-phenylethanol, at 50 °C for
12 h. Yellow crystals. TLC eluent: toluene/ethyl acetate/acetic
acid 8:2:1 v/v/v. 1H NMR (CDCl3) δ 8.41 (d, 1H, H-6), 8.04 (s,
1H, H-2), 7.62 (d, 1H, H-9), 7.42 (m, 4H, Ph), 7.32 (m, 1H, Ph),
7.17 (dd, 1H, H-7), 5.60 (q, 1H, CH), 1.78 (d, 3H, CH3). Anal. C,
H, N.
3-Iodo-8-(1-phenylethoxy)pyrazolo[5,1-c][1,2,4]benzotriazine 5-
Oxide (16(þ)). From 1,26,28 and (R)(þ)1-phenylethanol, at 50 °C
for 12 h. Yellow crystals. TLC eluent: i-propyl ether/cyclohexane
8:3 v/v. 1H NMR (CDCl3) δ 8.41 (d, 1H, H-6), 8.05 (s, 1H, H-2),
7.63 (d, 1H, H-9), 7.38 (m, 5H, Ph), 7.16 (dd, 1H, H-7), 5.60 (q,
1H, CH), 1.77 (d, 3H, CH3). [R]20°D = þ220. Anal. C, H, N.
3-Iodo-8-(1-phenylethoxy)pyrazolo[5,1-c][1,2,4]benzotriazine 5-
Oxide (16(-)). From 1,26,28 and (S)(-)1-phenylethanol, at 50 °C
for 12 h. Yellow crystals. TLC eluent: i-propyl ether/cyclohexane
8:3 v/v. 1H NMR (CDCl3) δ 8.41 (d, 1H, H-6), 8.05 (s, 1H, H-2),
7.63 (d, 1H, H-9), 7.38 (m, 5H, Ph), 7.16 (dd, 1H, H-7), 5.59 (q,
1H, CH), 1.78 (d, 3H, CH3). [R]20°D = -220. Anal. C, H, N.
3-Iodo-8-(pyridin-4-ylmethoxy)pyrazolo[5,1-c][1,2,4]benzotri-
azine 5-Oxide (17). From 1,26,28 and pyridine-4-methanol, at 70
°C for 25 min. The reaction rapidly changes color in function of
temperature: from yellow to brown and then green at hot
temperature. Yellow gold crystals. TLC eluent: chloroform/
methanol 10:1 v/v. 1H NMR (CDCl3) δ 8.70 (d, 2H, H-20 and H-
60 Py), 8.52 (d, 1H, H-6), 8.10 (s, 1H, H-2), 7.78 (d, 1H, H-9),
7.44 (d, 2H, H-30 and H-50 Py), 7.28 (dd, 1H, H-7), 5.35 (s, 2H,
CH2O). Anal. C, H, N.
3-(Thien-3-yl)-8-phenoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-
oxide (25). From 323 and phenol, at 60 °C for 12 h. Yellow
crystals. TLC eluent: toluene/ethyl acetate 8:3 v/v. 1H NMR
(CDCl3) δ 8.55 (d, 1H, H-6), 8.26 (s, 1H, H-2), 7.90 (d, 1H, H-20
thiophene), 7.70 (d, 1H, H-9), 7.66 (dd, 1H, H-40 thiophene), 7.52
(m, 2H, H-30 and H-50 Ph), 7.44 (m, 1H, H-50 thiophene), 7.36 (m,
1H, H-40 Ph), 7.25 (dd, 1H, H-7), 7.21 (m, 2H, H-20 and H-60 Ph).
Anal. C, H, N.
3-Ethoxycarbonyl-8-phenoxypyrazolo[5,1-c][1,2,4]benzotriazine
5-oxide (26). From 429 and phenol, at 40 °C for 8 h. Yellow
crystals. TLC eluent: toluene/ethyl acetate 8:3 v/v. 1H NMR
(CDCl3) δ 8.55 (d, 1H, H-6), 8.47 (s, 1H, H-2), 7.71 (d, 1H, H-
9),; 7.54 (t, 2H, H-30 and H-50 Ph), 7.38 (t, 1H, H-40 Ph), 7.33 (dd,
1H, H-7), 7.20 (dd, 2H, H-20 and H-60 Ph), 4.40 (q, 2H, CH2), 1.40
(t, 3H, CH3). Anal. C, H, N.
3-(2-Thienylmethoxycarbonylmethyl)-8-phenoxypyrazolo[5,1-
c][1,2,4]benzotriazine 5-Oxide (27). From 524 and phenol, at
30 °C for 2 h. Yellow crystals. TLC eluent: toluene/ethyl ace-
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tate/acetic acid 8:2:1 v/v/v. H NMR (CDCl3) δ 8.55 (d, 1H,
H-6), 8.47 (s, 1H, H-2), 7.71 (d, 1H, H-9), 7.53 (t, 2H, H-30 and
H-50 Ph), 7.35 (m, 3H, H-40 Ph, H-500 thiophene and H-7),
7.25 (dd, 1H, H-300 thiophene), 7.20 (d, 2H, H-20 and H-60 Ph),
7.03 (dd, 1H, H-400 thiophene), 5.52 (s, 2H, CH2). Anal. C,
H, N.
3-Iodo-8-(thien-2-ylmethoxy)pyrazolo[5,1-c][1,2,4]benzotriazine
5-Oxide (18). From 1,26,28 and thiophen-2-methanol, at 70 °C for
3 h. Yellow crystals. TLC eluent: toluene/ethyl acetate/acetic acid
8:2:1 v/v/v. 1H NMR (CDCl3) δ 8.50 (d, 1H, H-6), 8.11 (s, 1H, H-
2), 7.82 (d, 1H, H-9), 7.42 (dd, 1H, H-30 thiophene), 7.25 (m, 2H,
H-7 and H-50 thiophene), 7.08 (m, 1H, H-40 thiophene), 5.50 (s,
2H, CH2O). Anal. C, H, N.
3-(2-Methoxyphenoxycarbonylmethyl)-8-phenoxypyrazolo[5,1-
c][1,2,4]benzotriazine 5-Oxide (28). From 624 and phenol, at 30 °C
for 2 h. Yellow crystals. TLC eluent: toluene/ethyl acetate/acetic
acid 8:2:1 v/v/v. 1H NMR (CDCl3) δ 8.54 (d, 1H, H-6), 8.49 (s,
10H, H-2), 7.71 (d, 1H, H-9), 7.58 (d, 1H, H-600 Ph), 7.52 (t, 2H, H-
3 and H-50 OPh), 7.38 (t, 1H, H-40 OPh), 7.32 (m, 2H, H-7 and H-
400 Ph), 7.20 (d, 2H, H-20 and H-60 OPh), 7.01 (t, 1H, H-500 Ph),
6.91 (d, 1H, H-300 Ph), 5.50 (s, 2H, CH2), 3.90 (s, 3H, OCH3).
Anal. C, H, N.
8-Benzyloxypyrazolo[5,1-c][1,2,4]benzotriazine 5-Oxide (29).
From 729 and benzyl alcohol, at 30 °C for 2 h. Yellow crystals.
TLC eluent: toluene/ethyl acetate/acetic acid 8:2:1 v/v/v. 1H
NMR (CDCl3) δ 8.50 (d, 1H, H-6), 8.11 (d, 1H, H-2), 7.85 (d,
1H, H-9), 7.45 (m, 5H, Ph), 7.21 (dd, 1H, H-7), 6.73 (d, 1H, H-3),
5.35 (s, 2H, CH2). Anal. C, H, N.
3-Iodo-8-(fur-2-ylmethoxy)pyrazolo[5,1-c][1,2,4]benzotriazine
5-Oxide (19). From 3-iodo-8-chloropyrazolo[5,1-c][1,2,4]ben-
zotriazine 5-oxide26,28 and furan-2-methanol (furfuryl alcohol),
at 70 °C for 3 h. Yellow crystals. TLC eluent: toluene/ethyl ace-
1
tate/acetic acid 8:2:1 v/v/v. H NMR (CDCl3) δ 8.50 (d, 1H,
H-6), 8.12 (s, 1H, H-2), 7.85 (d, 1H, H-9), 7.52 (dd, 1H, H-30
furane), 7.20 (dd, 1H, H-7), 6.60 (dd, 1H H-50 furane), 6.43 (m,
1H, H-40 furane), 5.25 (s, 2H, CH2O). Anal. C, H, N.
3-Iodo-8-(2-phenylethoxy)pyrazolo[5,1-c][1,2,4]benzotriazine 5-
Oxide (20). From 126,28 and 2-phenylethanol, at 40 °C for 8 h.
1
Yellow crystals. TLC eluent: chloroform. H NMR (CDCl3) δ
8.44 (d, 1H, H-6), 8.08(s, 1H, H-2), 7.65 (d, 1H, H-9), 7.35 (m, 5H,
Ph), 7.15 (dd, 1H, H-7), 4.43 (t, 2H, CH2O), 3.23 (t, 2H, CH2).
Anal. C, H, N.
3-Iodo-8-(1-methyl-2-phenylethoxy)pyrazolo[5,1-c][1,2,4]ben-
zotriazine 5-Oxide (21(()). From 126,28 and 1-phenylpropan-2-
ol, at 70 °C for 3 h. Yellow crystals. TLC eluent: toluene/ethyl
3-Ethoxycarbonyl-8-benzyloxypyrazolo[5,1-c][1,2,4]benzotriazine
5-Oxide (30). From 429 and benzyl alcohol, at 30 °C for 2 h. Yellow
crystals. TLC eluent: toluene/ethyl acetate/acetic acid 8:2:1 v/v/v.
1H NMR (CDCl3) δ 8.53 (s, 1H, H-2), 8.49 (d, 1H, H-6), 7.84 (d,
1H, H-9), 7.45 (m, 5H, Ph), 7.30 (dd, 1H, H-7), 5.30 (s, 2H, CH2),
4.50 (q, 2H, CH2), 1.40 (t, 3H, CH3). Anal. C, H, N.