New synthesis of pyrazolo[3,4-b][1,4,5]benzothiadiazepine, -[1,4,5]benzoxadiazepine, -[1,4,5]benzotriazepine and pyrazolo[3,4-b]quinoxaline derivatives

Article abstract of DOI:10.1002/jccs.200400129

New pyrazolo[3,4-b][1,4,5]benzothiadiazepine and its analogues 3 have been obtained by reaction of 4-nitrosopyrazoles 1 with 2-aminothiophenol 2a and its analogues 2b,c. Under fused conditions, dipyrazolyl derivatives 7a was obtained with a trace amount of quinoxaline 5a. On the other hand, 5b and 7b were obtained in equal amounts. A proposed pathway is presented.

Full text of DOI:10.1002/jccs.200400129

Journal of the Chinese Chemical Society, 2004, 51, 859-862
859
New Synthesis of Pyrazolo[3,4-b][1,4,5]benzothiadiazepine,
-[1,4,5]benzoxadiazepine, -[1,4,5]benzotriazepine and
Pyrazolo[3,4-b]quinoxaline Derivatives
Eman A. El-Rady
Chemistry Department, Faculty of Science, South Valley University, Aswan, Egypt
New pyrazolo[3,4-b][1,4,5]benzothiadiazepine and its analogues 3 have been obtained by reaction of
-nitrosopyrazoles 1 with 2-aminothiophenol 2a and its analogues 2b,c. Under fused conditions, dipyrazolyl
4
derivatives 7a was obtained with a trace amount of quinoxaline 5a. On the other hand, 5b and 7b were ob-
tained in equal amounts. A proposed pathway is presented.
Keywords: 2-Aminothiophenol; Quinoxaline; Dipyrazolyl.
INTRODUCTION
Previously, the utility of 4-nitrosopyrazoles (1) was re-
12 4
sponds to molecular formula C16H N S which is in accord
with elimination of two moles of water from the reactants.
1
Also, H NMR of 3a-d revealed signals at d 3.5 and 7.1-7.9
ported as an excellent synthon for new 1,4-oxazine deriva-
ppm assigned to methyl and phenyl protons, respectively.
On the other hand, repeating the reaction in the absence
of solvent and in the presence of fused ammonium acetate af-
forded completely different products. None of pyrazolo-
seven-membered derivatives 3 have been isolated or de-
tected. Instead, the pyrazolo[3,4-b]quinoxalines 5a,b and the
dipyrazolyl derivatives 7a,b have been obtained. A nucleo-
philic attack by the free electrons of both amino functions of
2-phenylenediamine 2c on the C-4 and C-5 of nitroso com-
pound 1 gives the intermediate 4 followed by simultaneous
elimination of both water and hydroxylamine molecules
yielding the pyrazolo[3,4-b]quinoxaline 5. However, a plau-
sible synthon lead to the dipyrazolyl compounds 7 would be a
pyrazole radical 6 which would result from the intermediate 4
via losing a molecule of the amine compound 2 and nitric ox-
ide. It is note worth that a brown vapour of nitric dioxide was
observed during the process of fusion. The structures of 5 and
7 were confirmed based on elemental and spectral analysis.
1
tives. This is in continuation of our interest directed to syn-
2
-4
thesis of new seven-membered rings in general and particu-
5
-10
larly those fused to the pyrazole ring due to their effects as
1
1
12
potential antidepressanst, as antiviral drugs for AIDS, and
1
3
as antimicrobial agents. Although the synthesis of seven-
membered rings based on 2-aminothiophenol and its ana-
logues are well documented, we report herein the first use of
4
-nitrosopyrazoles 1a,b in a simple and straight forward
one-step transformation to new pyrazolo[3,4-b][1,4,5]seven-
membered rings which has received little attention compared
with other seven-membered derivatives.
RESULTS AND DISCUSSION
Reaction of 4-nitroso-1-phenylpyrazoles 1a,b with 2-
aminobenzenethiol 2a, 2-aminophenol 2b and 2-phenylene-
diamine 2c in ethanol at reflux temperature in the presence of
piperidine yielded each of 3-methyl-1-phenylpyrazolo[3,4-
b][1,4,5]benzothiadiazepine 3a and its analogues 3b-f. The
IR spectra of products 3a-d showed no characteristic bands
+
The mass spectrum of 5b showed m/e at 322 (M , 100), and
1
its H NMR spectrum showed absorption only at the aromatic
region. The structure of pyrazolo[3,4-b]quinoxaline com-
pounds 5a,b have been chemically confirmed via either reac-
tion of 4,5-dioxopyrazole 8a,b which is obtained from the
-
1
over 1625 cm , whereas the spectra of 3e,f revealed an ab-
-
1
14
sorption band at 3180 cm assigned to the NH of the azepine
nitroso compounds 1a,b by an acid hydrolysis (5% HCl), or
ring. The mass spectrum of 3a showing m/e at 292 corre-
4-bromo- (or chloro)-3-methyl-1-phenylpyrazole 9 with 2-
*
Corresponding author. E-mail: emanelradi@hotmail.com

8
60 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
El-Rady
Scheme I
1
5-17
1
phenylenediamine 2c.
SP-1100 Spectrophotometer. H NMR spectra (deuterochlo-
roform and deuterodimethylsulfoxide, d in ppm) were run on
a Varian EM-390 Spectrometer using tetramethylsilane as in-
ternal standard. Mass spectra were recorded on a Varian
MAT 311 A spectrometer at 70 eV, and the elemental analy-
ses were determined at the Microanalytical Center, Cairo
University, Egypt. The reactions are controlled using tlc.
EXPERIMENTAL
Melting points are uncorrected. The ir spectra (potas-
-
1
sium bromide, n in cm ) were recorded on a Pye-Unicam

Synthesis of Pyrazolo[3,4-b][1,4,5]benzothiadiazepine
J. Chin. Chem. Soc., Vol. 51, No. 4, 2004 861
General procedure for the preparation of compounds
(275.32): C, 69.80; H, 4.76; N, 25.44. Found: C, 69.77; H,
4.50; N, 25.70.
(3a-f)
A solution of 1a (2 g, 1 mol), 2-aminothiophenol 2a
1.2 g, 1 mol), and 0.1 mL of piperidine in 30 mL of dry etha-
(
1,3-Diphenylpyrazolo[3,4-b][1,4,5]benzotriazepine (3f)
nol was heated to reflux for five hours and concentrated un-
der vacuum. The solid formed after addition of cold diluted
This compound was isolated (0.19 g, 57%) as orange
1
powder, mp. 210-211 °C; IR: 3182 (NH); H nmr (DMSO-
HCl (1 mL, 20 mL H
2
O) was collected by filtration, washed
d
6
): d 7.00-8.10 (m, 15H, Ar-H and NH); MS, m/e (%): 337
+
well with 100 mL of cold water and crystallised from metha-
nol to give 3a. Analogously, 1a,b (2 g, 1 mol) was reacted
with 2b,c (1 mol) to give 3c-f.
(M , 20). Anal. Calcd. For C21
H
15
N
5
(337.39): C, 74.76; H,
4.48; N, 20.76. Found: C, 74.67; H, 4.37; N, 20.81.
General procedure to prepare the compounds (5a,b) and
(7a,b)
3
-Methyl-1-phenylpyrazolo[3,4-b][1,4,5]benzothiadiaze-
pine (3a)
This compound was isolated (0.17 g, 59%) as red crys-
A mixture of 1b (0.78 g, 3 mmol), 2-phenylenediamine
2c (0.30 g, 3 mmol) and ammonium acetate (1 g, 13 mmol)
was fused at 120 °C for 30 minutes and then triturated with
methanol, filtered and washed with hot methanol, dried and
recrystallized from ethanol to give 5b. In analogy, 1a was
fused with 2c (3 mmol each) to give 5a and 7a.
Under the same fusion conditions, 1a,b reacted with
2a,b to yield 7a,b.
1
tals, mp. 182-184 °C; H nmr (DMSO-d
6
): d 3.5 (s, 3H, CH
3
),
+
7
.10-7.90 (m, 9H, Ar-H); MS, m/e (%): 292 (M , 35). Anal.
Calcd. For C16
12 4
H N S (292.36): C, 65.73; H, 4.14; N, 19.16;
S, 10.97. Found: C, 65.70; H, 4.08; N, 19.10; S, 10.90.
1
,3-Diphenylpyrazolo[3,4-b][1,4,5]benzothiadiazepine (3b)
This compound was isolated (0.20 g, 58%) as orange
1
crystals, mp. 237-239 °C; H nmr (DMSO-d
6
): d 7.10-8.30
3-Methyl-1-phenylpyrazolo[3,4-b]quinoxaline (5a)
+
(
m, 14H, Ar-H); MS, m/e (%): 354 (M , 30). Anal. Calcd. For
This compound was isolated (0.13 g, 7%) as yellow
1
C
21
H
14
N
4
S (354.43): C, 71.17; H, 4.00; N, 15.81; S, 9.05.
crystals, mp. 130-132 °C; H nmr (DMSO-d
6
): d 2.2 (s, 3H,
+
Found: C, 71.10; H, 4.08; N, 15.75; S, 9.12.
CH
3
), 7.0-7.9 (m, 9H, Ar-H); MS, m/z (%): 260 (M , 100).
Anal. Calcd. for C16
12 4
H N (260.30): C, 73.83; H, 4.65; N,
3
-Methyl-1-phenylpyrazolo[3,4-b][1,4,5]benzoxadiazepine
21.52. Found: C, 73.79; H, 4.50; N, 21.35.
(3c)
This compound was isolated (0.17 g, 62%) as brown
1,3-Diphenylpyrazolo[3,4-b]quinoxaline (5b)
1
powder, mp. 149-150 °C; H nmr (DMSO-d
6
): d 1.7 (s, 3H,
This compound was isolated (0.5 g, 52%) as yellow
+
1
CH
3
), 7.20-7.80 (m, 9H, Ar-H); MS, m/e (%): 276 (M , 25).
crystals, mp. 230-232 °C; H nmr (DMSO-d
6
): d 7.0-7.9 (m,
+
Anal. Calcd. For C16
H
12
N
4
O (276.30): C, 69.55; H, 4.38; N,
14H, Ar-H); MS, m/z (%): 322 (M , 100). Anal. Calcd. for
2
0.28. Found: C, 69.50; H, 4.30; N, 20.19.
C
21
H
14
N
4
(322.37): C, 78.24; H, 4.38; N, 17.38. Found: C,
7
8.27; H, 4.44; N, 17.46.
1
,3-Diphenylpyrazolo[3,4-b][1,4,5]benzoxadiazepine (3d)
This compound was isolated (0.17 g, 50%) as brown
Bis-4,4¢(3-methyl-5-oxo-1-phenylpyrazole) (7a)
1
powder, mp. 200-202 °C; H nmr (DMSO-d
6
): d 7.12-7.95
This compound was isolated (0.5 g, 50%) as colorless
+
1
(
m, 14H, Ar-H); MS, m/e (%): 338 (M , 20). Anal. Calcd. For
compound, mp. 325-327 °C; IR: 1715, 1720 (CO); H nmr: d
C
21
H
14
N
4
O (338.37): C, 74.54; H, 4.17; N, 16.56. Found: C,
2.1 (s, 6H, 2CH
3
), 7.3-7.9 (m, 12H, Ar-H); MS, m/e (%): 346
(346.39): C, 69.35; H,
+
7
4.62; H, 3.40; N, 16.30.
(M , 35). Anal. Calcd. for C20
H
18
N
4
O
2
5
.23; N, 16.17. Found: C, 69.47; H, 5.30; N, 16.29.
3
-Methyl-1-phenylpyrazolo[3,4-b][1,4,5]benzotriazepine
(3e)
Bis-4,4¢(1,3-diphenylpyrazol-5-one) (7b)
This compound was isolated (0.15 g, 55%) as brown
This compound was isolated (0.7 g, 50%) as orange
1
1
powder, mp. 118-120 °C; IR: 3180 (NH); H nmr (DMSO-
compound, mp. 248-250 °C; IR: 1716, 1722 (CO); H nmr: d
+
d
6
): d 2.2 (s, 3H, CH
3
), 7.28-7.90 (m, 10H, Ar-H and NH);
7.2-7.9 (m, 22H, Ar-H); MS, m/e (%): 470 (M , 30). Anal.
+
MS, m/e (%): 275 (M , 10). Anal. Calcd. For C16
H
13
N
5
22 4 2
Calcd. for C30H N O (470.53): C, 76.58; H, 4.71; N, 11.91.

8
62 J. Chin. Chem. Soc., Vol. 51, No. 4, 2004
El-Rady
Found: C, 76.65; H, 4.60; N, 11.78.
El-Maghraby, M. A. J. Heterocyclic Chem. 2002, 139, 299.
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5
6
7
8
Reaction of o-phenylenediamine 2c with 4,5-dioxo-1-
phenylpyrazole (8) and with 4-bromo (or chloro)-3-
methyl-1-phenylpyrazole (9)
Equimolar amounts (3 mmol) of 2c and 4,5-dioxo-1-
phenylpyrazole 8 and/or 4-bromo (or chloro)-3-methyl-1-
1
5,16
phenylpyrazole
9 were refluxed in ethanol containing
piperidine for 8 hours. The ethanol solution was evaporated
under vacuum and the resulting 1-phenylpyrazolo[3,4-b]-
quinoxalines 5a,b were crystallized from ethanol.
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4