Synthesis of some new heterobicyclic nitrogen systems bearing 7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl moiety for biological interest

Article abstract of DOI:10.1002/jccs.200500021

Reaction of 6-mercapto-7H-1,2,4-triazolo[1,5-d]tetrazole (1) wtih l,2-phenylenediamine afforded Ar-{7H-l,2,4-triazolo[1,5-d]tetrazol-6-yl}-l,2- phenylenediamine which was cyclized to benzimidazolyl-1,2,4-triazolo[1 ,5-c/]tetrazoles using various one-carbo

Full text of DOI:10.1002/jccs.200500021

Journal of the Chinese Chemical Society, 2005, 52, 137-140
137
Synthesis of Some New Heterobicyclic Nitrogen Systems Bearing
7H-1,2,4-Triazolo[1,5-d]tetrazol-6-yl Moiety for Biological Interest
Mamdouh Ahmed Mohamed Taha
Chemistry Department, Faculty of Science, Cairo University at Faiyoum, Egypt
Reaction of 6-mercapto-7H-1,2,4-triazolo[1,5-d]tetrazole (1) wtih 1,2-phenylenediamine afforded
N-{7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl}-1,2-phenylenediamine which was cyclized to benzimidazolyl-
1,2,4-triazolo[1,5-d]tetrazoles using various one-carbon cyclizing agents. Also, the treatment of 1 with
maleic anhydride or phthalic anhydride gave the corresponding thio derivatives followed by hydrazinolysis to
afford the thio heterobicyclic systems. Former structures of the products have been established upon elemen-
tal and spectral analyses.
Keywords: 1,2,4-Triazolo[1,5-d]tetrazole; Reactions; Cyclization.
INTRODUCTION
In view of the varied biological properties of 1,2,4-
2 to furnish the same product 7. All attempts directly towards
the isolation of the intermediates were unsuccessful. Subse-
quent reaction of 2 with phenyl isocyanate or its sulfur analog
resulted in the formation of the isoable intermediates 8 and 9.
However, heating of 8 or 9 above their melting points gave a
single product which was found to be compound 10 through
the loss of water or hydrogen sulfide (Scheme I).
triazoles,1 tetrazoles,2 benzimdazoles,3-6 pyridazines,7 and
phthalazines,8,9 but there is little information in the literature
on the synthesis of 1,2,4-triazolotetrazoles,10-14 although a
good deal of work has been carried out on various other fused
1,2,4-triazoles. In light of these findings, the present work de-
scribes the synthesis of a variety of heterobicyclic derivatives
of biological interest.
Scheme I
RESULTS AND DISCUSSION
Reaction of 6-mercapto-7H-1,2,4-triazolo[1,5-d]tet-
razole (1) with 1,2-phenylenediamine in the presence of yel-
low mercury (II) oxide yielded 2 through the loss of hydrogen
sulfide. The 1H NMR spectrum of the product 2 revealed NH2
and NH proton signals. This provided the evidence that the
product should be assigned as N-{7H-1,2,4-triazolo[1,5-d]-
tetrazol-6-yl}-1,2-phenylenediamine (2). Compound 2 is the
key to prepare our target compounds with different one-car-
bon cyclizing reagents.
Heating of 2 with formic acid, acetic acid, or benzoic
acid in the presence of phosphorus oxychloride directly af-
forded the corresponding benzimidazolyl-1,2,4-triazolo-
[1,5-d]tetrazoles (3-5), respectively. On the other hand, treat-
ment of compound 2 with urea or ethyl chloroformate in
pyridine gave a single product in each case which was identi-
fied as 6.
Furthermore, the reaction of 1 with maleic anhydride or
phthalic anhydride resulted in the formation of the thio deriv-
atives 11 and 13 which showed IR absorptions characteristic
Likewise, thiourea or carbon disulfide also reacted with

138 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Taha
of NH, OH, and carbonyl groups. Cyclization of either 11 or
13 by heating with hyrazine hydrate furnished products
which showed NH and CON absorptions in the IR region. Ac-
cordingly, the products were assigned the thio-pyridazinyl
and phthalazinyl structures 12 and 14 (Scheme II).
(NH2), 3244 (NH), 1620 (C=N); 1H NMR (DMSO-d6, d/ppm)
12.10, 11.80 (2s, 1H each, 2NH), 7.40, 7.15 (m, 4H, ArH),
4.50 (s, 2H, NH2). Anal. calcd for C8H8N8: C, 44.4; H, 3.7; N,
51.9; Found: C, 44.1; H, 3.4; N, 60.2.
6-(Benzimidazol-1-yl)-7H-1,2,4-triazolo[1,5-d]tetrazole (3)
A mixture of 2 (1.0 g, 4.63 mmol) and formic acid (10
mL) was heated under reflux for 6 h then left to cool down at
room temperature, and the separated crystalline product was
collected by filtration and dried then recrystallized from etha-
nol to give 3 (0.79 g; 75.5% yield), mp 210 °C; IR (KBr,
n/cm-1): 3059 (NH), 1602 (C=N); 1H NMR (DMSO-d6,
d/ppm) 12.10 (s, 1H, NH), 8.60 (s, 1H, benzimidazole ring
H), 7.50-7.00 (m, 4H, ArH). Anal. calcd for C9H6N8: C, 47.8;
H, 2.7; N, 49.6; Found: C, 48.01; H, 3.0; N, 49.2.
Scheme II
6-(2-Methylbenzimidazol-1-yl)-7H-1,2,4-triazolo[1,5-d]tet-
razole (4)
A mixture of 2 (1.0 g, 4.63 mmol) in acetic acid (10 mL)
was heated under reflux for 4 h and then evaporated to dry-
ness. The obtained residue was crystallized from ethanol to
give 4 (0.71 g; 64% yield); mp 190 °C; IR (KBr, n/cm-1): 3081
1
(NH), 1620 (C=N); H NMR (DMSO-d6, d/ppm) 12.60 (s,
1H, NH), 8.00-7.00 (m, 4H, ArH), 2.30 (s, 3H, CH3). Anal.
calcd for C10H8N8: C, 50.0; H, 3.3; N, 46.7; Found: C, 49.6;
H, 3.5; N, 47.1.
EXPERIMENTAL SECTION
6-(2-Phenylbenzimidazol-1-yl)-7H-1,2,4-triazolo[1,5-d]tet-
razole (5)
Melting points were determined in open capillaries us-
ing a MEL-TEMP II melting apparatus and are uncorrected.
The infrared spectra (IR) were recorded on a Perkin-Elmer
FT Paragon 1000 and Pye-Unicam SP3-300 spectrometers.
1H NMR spectra were scanned on a Varian Mercury VXR-
3000 spectrometer using tetramethylsilane (TMS) as an inter-
nal standard. MS were recorded on a Shimadzu GCMs-QP
1000EX mass spectrometer at 70 ev. Microanalyses were car-
ried out at the Microanalytical Unit, Cairo University, Egypt.
A mixture of 2 (1.0 g, 4.63 mmol) and benzoic acid
(0.57 g, 4.63 mmol) in phosphorus oxychloride (5 mL) was
heated under reflux for 3 h. The reaction mixture was poured
onto ice-water and treated with sodium bicarbonate. The sep-
arated product was collected by filtration, washed with water,
and crystallized from ethanol to give 5 (0.81 g; 58% yield),
1
mp 220 °C; IR (KBr, n/cm-1): 3060 (NH), 1621 (C=N); H
NMR (DMSO-d6, d/ppm) 12.80 (s, 1H, NH), 8.00-7.00 (m,
9H, ArH); MS: m/z 303 (9%, M+1). Anal. calcd for C15H10N8:
C, 59.6; H, 3.3; N, 37.1; Found: C, 60.0; H, 3.6; N, 36.8.
N-{7H-1,2,4-Triazolo[1,5-d]tetrazol-6-yl}-1,2-phenylene-
diamine (2)
A mixture of 6-mercapto-7H-1,2,4-triazolo[1,5-d]tet-
razole15 1 (1.0 g, 7.04 mmol), 1,2-phenylenediamine (0.76 g,
7.03 mmol), yellow mercury (II) oxide (1.53 g, 7.06 mmol),
and ethanol (15 mL) was heated on a water-bath for 4 h. After
cooling the inorganic material was filtered and the filtrate
was evaporated, then the separated crystalline product was
collected by filtration, dried, and crystallized from ethanol to
give 2 (0.99 g; 65%, yield) mp 270 °C, IR (KBr, n/cm-1): 3343
6-(2-Oxobenzimidazol-1-yl)-7H-1,2,4-triazolo[1,5-d]tetra-
zole (6)
Method (A). A mixture of 2 (1.0 g, 4.63 mmol) and urea
(0.28 g, 4.63 mmol) was heated at 150 °C for 1.5 h. The ob-
tained residue was crystallized from ethanol to give 6 (0.72 g;
64% yield), mp 200 °C; IR (KBr, n/cm-1): 3329 (NH), 1675
1
(CON), 1626 (C=N); H NMR (DMSO-d6, d/ppm) 12.80,
11.82 (2s, 1H each, 2NH), 8.00-7.00 (m, 4H, ArH). Anal.

Synthesis of Some New Heterobicyclic Nitrogen Systems
J. Chin. Chem. Soc., Vol. 52, No. 1, 2005 139
calcd for C9H6N8O: C, 44.6; H, 2.5; N, 46.3; Found: C, 45.0;
H, 2.9; N, 46.7.
N, 36.4.
Method (B). A solution of 2 (1.0 g, 4.63 mmol) in
pyridine (2 mL) was treated with ethyl chloroformate (10
mL) and the mixture was heated at reflux for 4 h. The reaction
mixture was poured onto ice-water and the formed product
was collected by filtration, washed with water, and crystal-
lized from ethanol to give 6 (0.62 g; 55% yield).
6-(2-Phenylaminobenzimidazol-1-yl)-7H-1,2,4-triazolo[1,5-
d]tetrazole (10)
Method (A). Compound 8 (1.0 g, 2.99 mmol) was
heated at 275 °C in an oil bath for 1 h. The obtained residue
was crystallized from ethanol to give 10 (0.61 g; 64% yield),
1
mp 210 °C; IR (KBr, n/cm-1): 3371 (NH), 1605 (C=N); H
NMR (DMSO-d6, d/ppm) 12.80, 10.90 (2s, 1H each, 2NH),
8.00-7.00 (m, 9H, ArH); MS: m/z 317 (6%, M). Anal. calcd
for C15H11N9: C, 56.8; H, 3.5; N, 39.8; Found: C, 57.1; H, 3.9;
N, 40.1.
6-(2-Thioxobenzimidazol-1-yl)-7H-1,2,4-triazolo[1,5-d]tet-
razole (7)
Method (A). A mixture of 2 (1.0 g, 4.63 mmol) and
thiourea (0.35 g, 4.63 mmol) was heated at 200 °C for 2 h.
The solid remaining was crystallized from ethanol to give 6
(0.80 g; 67% yield), m.p: 190 °C; IR (KBr, n/cm-1): 3387
(NH), 1620 (C=N); 1H NMR (DMSO-d6, d/ppm) 12.80, 11.73
(2s, 1H each, 2NH), 8.08-7.22 (m, 4H, ArH). Anal. calcd for
C9H6N8S: C, 41.9; H, 2.3; N, 43.4; Found: C, 42.3; H, 2.7; N,
42.9.
Method (B). Compound 9 (1.0 g, 2.85 mmol) was
heated at 260 °C in an oil bath for 1 h. The obtained mass was
crystallized from ethanol to give 10 (0.61 g; 67% yield).
2-{7H-1,2,4-Triazolo[1,5-d]tetrazole-6-yl}thiosuccinic acid
(11)
A mixture of 1 (1.0 g, 7.04 mmol) and maleic anhydride
(0.69 g, 7.04 mmol) was heated in an oil bath at 190 °C for 30
min and then allowed to attain ambient temperature; the so-
lidified material was crystallized from ethanol to give 11
(1.02 g; 56% yield), mp 250 °C; IR (KBr, n/cm-1): 3423 (OH),
Method (B). A solution of 2 (1.0 g, 4.63 mmol) in
pyridine (2 mL) was treated with carbon disulfide (5 mL) and
the mixture was heated under reflux for 4 h and then evapo-
rated, and the formed residue was crystallized from ethanol to
give 7 (0.69 g; 58% yield).
1
2088 (NH), 1745 (acid-carbonyl, COOH), 1620 (C=N); H
NMR (DMSO-d6, d/ppm) 12.80 (s, 1H, NH), 6.02 (t, 1H,
CH), 4.11 (d, 2H, CH2), 3.51 (s, 2H, 2OH). Anal. calcd for
C6H6N6O4S: C, 27.9; H, 2.3; N, 32.6; Found: C, 28.3; H, 2.7;
N, 33.1.
2-(3¢-Phenylurea)-N-{7H-1,2,4-triazolo[1,5-d]tetrazol-6-yl}-
aniline (8)
A solution of 2 (1.0 g, 4.63 mmol) in ethanol (15 mL)
was treated with phenyl isocyanate (0.55 g, 4.63 mmol) and
the reaction mixture was refluxed for 2 h then allowed to cool
down to room temperature, and the product which separated
was filtered off then recrystallized from ethanol to give 8
(0.81 g; 52% yield), mp 270 °C; IR (KBr, n/cm-1): 3299 (NH),
4-{7H-1,2,4-Triazolo[1,5-d-tetrazol-6-yl}thio-1,2,4,5-tetra-
hydropyridazine-3,6-dione (12)
A mixture of 11 (1.0 g, 3.88 mmol) and hydrazine hy-
drate (0.19 g, 3.88 mmol) was heated under reflux for 2 h and
then allowed to attain ambient temperature. The product
which separated was filtered, washed, and crystallized from
ethanol to give 12 (0.59 g; 60% yield), mp 185 °C; IR (KBr,
1
1685 (CON), 1625 (C=N); H NMR (DMSO-d6, d/ppm)
12.80 (s, 1H, NH), 10.91 (s, 3H, 3NH), 8.02-7.22 (m, 9H,
ArH). Anal. calcd for C15H13N9O: C, 53.7; H, 3.9; N, 37.6;
Found: C, 54.2; H, 4.3; N, 37.1.
1
n/cm-1): 3032 (NH), 1686 (CON), 1578 (C=N); H NMR
(DMSO-d6, d/ppm) 12.80 (s, 1H, NH), 10.12 (s, 2H, 2NH),
6.11 (t, 1H, CH), 4.22 (d, 2H, CH2). Anal. calcd for C6H6N8O2S:
C, 28.4; H, 2.4; N, 44.1; Found: C, 28.09; H, 2.9; N, 44.4.
2-(3¢-Phenylthiourea)-N-{7H-1,2,4-triazolo[1,5-d]tetrazol-
6-yl}aniline (9)
A solution of 2 (1.0 g, 4.63 mmol) in ethanol (15 mL)
was treated with phenyl isothiocyanate (0.63 g, 4.63 mmol);
the reaction mixture was refluxed for 1.5 h. After cooling, the
solidified material was crystallized from ethanol to give 9
(0.91 g; 56% yield), mp 250 °C; IR (KBr, n/cm-1): 3371 (NH),
1624 (C=N); 1H NMR (DMSO-d6, d/ppm) 12.80 (s, 1H, NH),
10.81 (s, 3H, 3NH), 8.00-7.03 (m, 9H, ArH). Anal. calcd for
C15H13N9S: C, 51.3; H, 3.7; N, 35.9; Found: C, 51.8; H, 4.0;
6-Thio(2-carbobenzoic acid)-7H-1,2,4-triazolo[1,5-d]tetra-
zole (13)
A mixture of 1 (1.0 g, 7.04 mmol) and phthalic anhy-
dride (1.04 g, 7.04 mmol) was heated in an oil bath at 190 °C
for 30 min and then allowed to attain ambient temperature;
the obtained residue was crystallized from ethanol to give 13
(1.33 g; 65% yield), mp 210 °C; IR (KBr, n/cm-1): 3286 (OH),

140 J. Chin. Chem. Soc., Vol. 52, No. 1, 2005
Taha
2985 (NH), 1760, 1718 (C=O), 1613 (C=N); 1H NMR (DMSO-
d6, d/ppm) 12.78 (s, 1H, NH), 8.02-7.00 (m, 4H, ArH), 3.60
(s, 1H, OH). Anal. calcd for C10H6N6O3S: C, 41.4; H, 2.1; N,
29.0; Found: C, 42.09; H, 1.8; N, 29.5.
2. Goto, K.; Oda, M.; Saitoh, H.; Nishida, M.; Takada, M. Biol.
Pharm. Bull. 1998, 21, 1113.
3. Kumar, D.; Jacob, M. R.; Reynolds, R. B.; Kerwin, S. M.
Bioorg. Med. Chem. 2002, 10, 3997.
4. Cetinkaya, E.; Alici, B.; Gok, Y.; Durmaz, R.; Gunal, S. J.
Chemother. 1999, 11, 83.
1-{7H-1,2,4-Triazolo[1,5-d]tetrazol-6-yl}thiophthalazin-4-
one (14)
5. Tsuchiya, T.; Hisano, T.; Tanaka, A.; Takahashi, A. Toxical.
Lett. 1987, 38, 97.
A mixture of 13 (1.0 g, 3.45 mmol) and hydrazine hy-
drate (0.17 g, 3.45 mmol) was heated under reflux for 1.5 h.
The reaction mixture was allowed to attain ambient tempera-
ture, and the product which separated was filtered and crys-
tallized from ethanol to give 14 (0.69 g; 70% yield), mp 185
°C; IR (KBr, n/cm-1): 3055 (NH), 1674 (CON), 1612 (C=N);
1H NMR (DMSO-d6, d/ppm) 12.78 (s, 1H, NH), 10.89 (s, 1H,
NH), 8.00-6.87 (m, 4H, ArH). Anal. calcd for C10H6N8OS: C,
42.0; H, 2.1; N, 39.2; Found: C, 42.5; H, 2.5; N, 39.7.
6. Elnima, E.; Zubair, M. U.; Al-Badr, A. A. Antimicrob.
Agents Chemother. 1981, 19, 29.
7. Heinisch, G.; Kopelent-Frank, H. Progress in Medicinal
Chemisty; Ellis, G. P.; Luscombe, D. K. Ed.; Elsevier: Am-
sterdam, Netherlands, 1992; vol. 29, 141.
8. Comer, W. T.; Gomoll, A. W. Progress in Medicinal Chemis-
try; Burger, A. Ed.; Wiley-Interscience: New York, 1970;
1027.
9. Jaques, R. Helv. Physiol. Pharmacol. Acta. 1965, 23, 54.
10. Scott, F. L.; Butler, R. N.; Cronin, D. A. Angew. Chem. 1965,
77, 963.
Received August 2, 2004.
11. Butler, R. N.; Scott, F. L. J. Chem. Soc. C 1968, 1711, and
references cited therein.
12. Moustafa, M. A. A.; Ismaiel, A. M.; Eisa, H. M.; El-Emam,
A. A. J. Chin. Chem. Soc. 1991, 38, 199.
REFERENCES
13. Taha, M. A. M. Heterocycl. Commun. 2001, 7, 559.
14. Taha, M. A. M. Alex. J. Pharm. Sci. 2004, 18, 65.
15. Taha, M. A. M. Unpublished results.
1. Dobosz, M.; Wujec, M.; Wasko, A. Acta Pol. Pharm. 2003,
60, 41.