Synthesis and reactions of a new series of 1,2,4-triazolo[4,3-c] quinazolines

Article abstract of DOI:10.3987/COM-10-12093

3-Ethoxycabonyl-1,2,4-triazolo[4,3-c]quinazoline (2) has been synthesized in excellent yield by the condensation of 4-hydrazinoquinazoline (1) with diethyl oxalate and was converted into 3-carbohydrazide 3. The later product was treated with potassium thi

Full text of DOI:10.3987/COM-10-12093

HETEROCYCLES, Vol. 83, No. 2, 2011
339
HETEROCYCLES, Vol. 83, No. 2, 2011, pp. 339 - 349. © The Japan Institute of Heterocyclic Chemistry
Received, 27th October, 2010, Accepted, 29th November, 2010, Published online, 1st December, 2010
DOI: 10.3987/COM-10-12093
SYNTHESIS AND REACTIONS OF A NEW SERIES OF 1,2,4-
TRIAZOLO[4,3-c]QUINAZOLINES
Kamal F. M. Atta,* Mohamed G. Marei, and Fatma A. M. Mohamed
Chemistry Department, Faculty of Science, Alexandria University, Ibrahimia P.O.
Box 426, Alexandria 21321, Egypt. E-mail: prof.kf_atta@yahoo.com
Abstract – 3-Ethoxycabonyl-1,2,4-triazolo[4,3-c]quinazoline (2) has been
synthesized in excellent yield by the condensation of 4-hydrazinoquinazoline (1)
with diethyl oxalate and was converted into 3-carbohydrazide 3. The later product
was treated with potassium thiocyanate, phenylisothiocyanate or carbon disulfide
followed by reaction with hydrazine hydrate to give the respective new 1,2,4-
triazolo[4,3-c]quinazoline derivatives 4, 8 or 12. Dehydrative cyclization of the
later compounds with concentrated sulphuric acid, sodium hydroxide, m-
bromobenzoic acid, carbon disulfide, oxalic acid, phenacyl bromide or benzoin
yielded the target heterocycles namely, 1,3,4-thiadiazole, 1,2,4-triazole, 1,2,4-
triazolo[3,4-b]-1,3,4-thiadiazole
or
1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine
incorporating 1,2,4-triazolo[4,3-c]quinazoline ring. The structure of the above
compounds was confirmed from their spectral characteristics.
Quinazoline derivatives are multitarget agents with a broad spectrum of biological activity.1–12 A number
of quinazolines act as anticancer,13,14 which have a wide range of activity against different kinds of human
cancer.8,13,15,16 Some of them (ZD1836, ZD 6474, OSI-774 and GW-2016) are currently in clinical testing.
Also, certain 1,2,4-triazoles have a broad spectrum of pharmacological activities.17 Several methods are
reported for the synthesis of 1,2,4-triazoloquinazoline from 4-hydrazino-quinazolines.18-21

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HETEROCYCLES, Vol. 83, No. 2, 2011
Based on the above mentioned behavior of quinazoline and triazole rings, a new series of 1,2,4-
triazolo[4,3-c]quinazoline system bearing a variety of mono- and fused heterocyclic moiety were
synthesized.
Condensation of 4-hydrazinoquinazoline (1)22 with diethyl oxalate yielded 3-ethoxycarbonyl-1,2,4-
triazolo[4,3-c]quinazoline (2) (Sheme 1). Its formation can be explained to be a consequence of the role
of ethyl oxalate that acts as oxaloylating agent for the hydrazine moiety, forming the oxaloyl hydrazine
residue that underwent dehydrative cyclization to form the triazoloquinazoline 2. The structure of 2 was
deduced from its spectral analysis. Thus, the IR spectrum of 2 showed an absorption band at 1746 cm-1 for
the ester group. Also, it's 1H NMR spectrum revealed the absence of NH signal and the presence of ethyl
ester group as triplet at  1.33 (CH3) and a quartet at 4.29 (CH2). Treatment of compound 2 with
hydrazine hydrate in ethanolic solution afforded the key compound 1,2,4-triazolo[4,3-c]quinazoline-3-
carbohydrazide (3) as confirmed from its spectral data. Its IR spectrum showed the absence of ester
absorption band and the presence of amide absorption band at 1670 cm-1.
Reaction of the key compound 3 with potassium thiocyanate in the presence of concentrated hydrochloric
acid led to the formation of hydrazinecarbothioamide 4. Dehyrative cyclization of 4 can be attempted
either in acidic or alkaline medium whereupon two different heterocycles were obtained; 1,3,4-thiadiazole
or 1,2,4-triazole, respectively. Therefore, treatment of compound 4 with concentrated sulfuric acid yielded
5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-1,3,4-thiadiazole-2-amine (5). Its IR spectrum showed the
presence of NH2 group absorption band at 3424 and 3330 cm-1, while it's MS revealed a molecular ion
peak at m/z 269. On the other hand, dehydrative cyclization of compound 4 with sodium hydroxide gave
5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4H-1,2,4-triazole-3-thiol (7).
Refluxing of compound 5 with phenacyl bromides in the presence of sodium bicarbonate afforded
imidazo[2,1-b]-1,3,4-thiadiazole derivatives 6a,b as confirmed from their IR spectra, which showed the
disappearance of NH2 stretching bands. The mass spectrum of 6a showed a molecular ion peak at m/z 369.
Moreover, the reaction of hydrazide 3 with phenylisothiocyanate afforded 2-(1,2,4-triazolo[4,3-c]-
quinazoline-3-carbonyl)-N-phenylhydrazinecarbothioamide (8). Ringclosure of the later to 3-thiolo-1,2,4-
triazole 9 was attempted with either triethylamine in ethanol or with sodium hydroxide solution, which
gave better yield. The IR spectrum showed the disappearance of the carbonyl absorption band and
appearance of SH stretching band at 2632 cm-1,23 in addition to the characteristic absorption bands of the
triazoloquinazoline nucleus. The mass spectrum of 9 revealed a molecular ion peak at m/z 345.
Hydrazinolysis of 9 yielded 5-hydrazino-4-phenyl-4H-1,2,4-triazole derivative 10. Its IR spectrum
showed only NHNH2 absorptions at 3419, 3320 and 3280 cm-1,24 which can be used for further
conversion to fused heterocycles.25

HETEROCYCLES, Vol. 83, No. 2, 2011
341
NHNH2
N
N
[CO2Et]2
CO2Et
N
N
N
N
(1)
(2)
NH2NH2
H2O
H
N
S
C
H
N
S
C
N
N
N
Ph
TQ
TQ
H
CONHNH2
C
O
N
N
C
O
N
N
H
PhNCS
KSCN
HCl
N
H
H
H
(8)
(3)
(4)
H
O
NaOH or Et3N
a
concd.
H2SO4
N
TQ
N
N
TQ
N
N
S
N
N
TQ
N
N
NH2
H
SH
Ph
SH
(9)
(5)
(7)
Br
O
3
H2C
C
NH2NH2
H2O
X
TQ
N
N
N
S
N
X
TQ
N
N
Ph
NHNH2
6a X=H
6b X= Br
(10)
N
N
N
TQ =
N
Scheme 1
Furthermore, the hydrazide 3 reacted with carbon disulfide in the presence of potassium hydroxide to
produce the potassium salt 11 (Scheme 2), which underwent dehydrative cyclization upon treatment with
hydrazine hydrate to give 4-amino-4H-1,2.4-triazole-3-thiol derivative 12. The structure of 12 was
1
confirmed by spectral data. It's H NMR spectrum revealed three exchangeable singlets at  8.26, 8.29
and 13.51 for NH2 and SH protons, respectively.
5-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12) is considered as key
starting for the synthesis of diverse heterocyclic compounds upon treatment in one-step with one and two

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HETEROCYCLES, Vol. 83, No. 2, 2011
carbon cyclizing reagents (Scheme 2). Thus, the reaction of compound 12 with m-bromobenzoic acid
yielded 3-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-6-(3-bromophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole
1
(13). It’s H NMR spectrum showed the disappearance of NH2 and SH proton signals of the starting
material. Moreover, treatment of compound 12 with carbon disulfide in the presence of potassium
hydroxide led to the formation of 3-([1,2,4]triazolo[4,3-c]quinazolin-3-yl)-[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazole-6(5H)-thione (14). The mass spectrum of 14 showed a molecular ion peak at m/z 326. The
structure of 14 was also confirmed by methylation with methyl iodide affording 3-(1,2,4-triazolo[4,3-c]-
quinazolin-3-yl)-6-(methylthio)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (15). On the other hand, the
reaction of 14 with oxalic acid in the presence of phosphoryl chloride gave 3,3'-di([1,2,4]triazolo[4,3-c]-
1
quinazolin-3-yl)]-6,6'-bi[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole) (16). It’s H NMR spectrum showed the
disappearance of NH2 and SH proton signals. Compound 12 can be also used as a precursor for the
synthesis of 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine derivatives. Thus, treatment of 12 with phenacyl
bromide under reflux afforded 3-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-6-phenyl-7H-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazine (17), whereas its reaction with benzoin gave 3-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-
6,7-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (18). The structures of both compounds was
confirmed from their spectral data. The mass spectrum of 18 showed a molecular ion peak at m/z 460.
The spectroscopic data and elemental analyses of these compounds were consistent with the assign
structures.
H
S
H
N
TQ
TQ
N
C
H
CS2 / KOH
C
O
N
H
C
O
N
H
SK
(3)
(11)
-H O
NH2NH2
2
NH2
TQ
H
TQ
N
Br
N
Ph
N
N
S
OH)Ph
hCOCH(
P
TQ
SH
N
m
-BrC6H4CO2H
N
N
N
N
N
N
S
Ph
(12)
(18)
(13)
2
O 3
(CO2H)2
C
H
a
N
TQ
N
TQ
TQ
N
TQ
N
H
N
N
N
S
Ph
N
S
N
MeI
N
N
N
SMe
N
S
N
S
N
N
S
N
(15)
(16)
(17)
(14)
Scheme 2

HETEROCYCLES, Vol. 83, No. 2, 2011
343
EXPERIMENTAL
Melting points were determined on a Kofler Block and are uncorrected. TLC were done on Merck Kiesel
gel 60-f 254 precoated plastic plates. Infrared spectra were measured with Fourier Transform infrared
1
8400 spectrophotometer for potassium bromide pellets. The H NMR spectra were recorded on a JEOL
JNM ECA 500 MHZ with tetramethylsilane as internal standard. Mass spectra were recorded at 70 ev by
5980 series II GC coupled with 5989 B mass spectrometer. Microanalysis were performed by the
microanalytical unit, Cairo university, Cairo.
4-Hydrazinoquinazoline (1).
This compound 1 was prepared as described earlier.22
3-Ethoxycarbonyl-1,2,4-triazolo[4,3-c]quinoxaline (2). A mixture of 4-hydrazinoquinoxaline (1, 5 g,
31.2 mmol) and diethyl oxalate (100 mL) was heated under reflux for 3 h. The reaction mixture was
evaporated under reduced pressure the residue was poured onto crushed ice and kept in refrigerator
overnight. The product was filtered, washed with Et2O and crystallized from EtOH to give the titled
compound 2 as colorless needles (6 g, 80% yield); mp 175-176 oC; IR: 1746 (CO2Et), 1590 (triazole ring
C=N), 1476 (pyrimidine ring C=N) and 1420 cm-1 (pyrimidine ring C=C); 1H NMR (DMSO-d6):  1.33 (t,
3H, -CH2CH3), 4.29 (q, 2H, -CH2CH3), 7.25 (t, 1H, aromatic-H), 8.03 (t, 1H, aromatic-H), 8.19 (d, 1H,
aromatic-H), 8.60 (d, 1H, aromatic-H) and 8.82 (s, 1H, pyrimidine-H); MS: m/z (%): 242 (M+, 48), 197
(M+ -CO2Et, 6), 170 (M+ -CO2C2H4, 100), 115 (M+ -C4H5N3O2, 9) and 89 (M+ -C5H5N4O2, 3); Anal. Calcd
for C12H10N4O2 (242.08): C, 59.5; H, 4.2; N 23.1%. Found: C, 59.4; H, 4.6; N, 23.3%.
1,2,4-Triazolo[4,3-c]quinazoline-3-carbohydrazide (3). A solution of 3-ethoxycarbonyl-1,2,4-
triazolo[4,3-c]quinazoline (2, 0.5 g, 2 mmol) and hydrazine hydrate (99%, 0.5 mL) in EtOH (40 mL) was
heated under reflux for 10 h. The reaction mixture on cooling gave a solid mass, which was filtered,
washed with EtOH and crystallized from DMF to give the titled compound 3 as colorless needles (0.4 g,
85% yield); mp 245-246 °C; IR: 3326 (NH), 3100, 3071 (NH2), 1670 (CON), 1595 (triazole ring C=N),
1474 (pyrimidine ring C=N) and 1438 cm-1 (pyrimidine ring C=C); 1H NMR (DMSO-d6):  =7.33 (t, 1H,
aromatic-H), 8.03 (t, 1H, aromatic-H), 7.93 (d, 1H, aromatic-H), 8.09 (d, 1H, aromatic-H), 9.40 (s, 1H,
pyrimidine-H), 12.81 (s, 1H, exchangeable, NH) and 13.29, 13.50 (2s, 2H, exchangeable, NH2); MS: m/z
(%): 228 (5, M+), 213 (50, M+ -NH), 197 (5, M+ -NHNH2), 143 (17, M+ -C2H3N3O) and 117 (8, M+
-C3H3N4O); Anal. Calcd for C10H8N6O (228.21): C, 52.63; H, 3.53; N, 36.83%. Found: C, 52.41; H, 3.12;
N, 37.01%.
2-(1,2,4-Triazolo[4,3-c]quinazoline-3-carbonyl)hydrazinecarbothioamide (4). A mixture of 1,2,4-
triazolo[4,3-c]quinazoline-3-carbohydrazide (3, 1 g, 4 mmol) and potassium thiocyanate (1 g, 10 mmol)

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HETEROCYCLES, Vol. 83, No. 2, 2011
was added to 5 mL of water containing 1 mL of concd HCl. The mixture was warmed on a water bath
for 2 h, then cooled, poured onto crushed ice and the product was filtered, washed with water, dried and
crystallized from EtOH to give the titled compound 4 as colorless needles (1g, 83% yield); mp 221-
222 °C; IR: 3181 (NH), 3388, 3290 (NH2), 1691 (CON), 1520 (triazole ring C=N), 1448 (pyrimidine ring
1
C=N), 1420 (pyrimidine ring C=C) and 1310 cm-1 (C=S); H NMR (DMSO-d6): δ = 7.27 (t, 1H,
aromatic-H), 7.45 (t, 1H, aromatic-H), 8.19 (d, 1H, aromatic-H), 8.67 (d, 1H, aromatic-H), 8.79 (s, 1H,
pyrimidine-H), 9.37 (s, 1H, exchangeable, NH), 10.84 (s, 1H, exchangeable, NH), 12.79 and 14.57 (2s,
2H, exchangeable, NH2); Anal. Calcd for C11H9N7OS (287.30): C, 45.99; H, 3.16; N, 34.13; S, 11.16%.
Found: C, 46.3; H, 3.01; N, 34.02; S, 11.65%.
5-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-1,3,4-thiadiazole-2-amine (5). A mixture of 2-(1,2,4-triazolo-
[4,3-c]quinazolin-3-carbonyl)hydrazinecarbothioamide (4, 0.4 g, 1.3 mmol) in cold concd H2SO4 (4 mL)
was stirred for 10 min. Then, the mixture was allowed to cool at room temperature. After stirring for an
additional 30 min, the resulting solution was poured onto ice-cold water and made alkaline to pH 8 with
20% NH4OH. The precipitated product was filtered, washed with water, dried and crystallized from EtOH
to give the titled compound 5 as brown needles (0.24 g, 64% yield); mp 261-262 °C; IR: 3424, 3330
(NH2), 1548 (triazole ring C=N), 1492 (pyrimidine ring C=N) and 1382 cm-1 (pyrimidine ring C=C); MS:
m/z (%): 269 (10, M+), 213 (14, M+ -CH2N3), 185 (100, M+ -CH2N5), 129 (30, M+ -C3H2N5S), 76 (4, M+
-C5H3N7S) and 78 (98, M+ -C5HN7S); Anal. Calcd for C11H7N7S (269.29): C, 49.06; H, 2.62; N, 36.41; S,
11.91%. Found: C, 49.20; H, 2.43; N, 36.75; S, 11.51%.
2-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-6-phenylimidazo[2,1-b]-1,3,4-thiadiazole (6a). A mixture of
5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-1,3,4-thiadiazole-2-amine (5, 0.1 g, 0.3 mmol) and phenacyl
bromide (0.15 g, 0.7 mmol) in absolute EtOH (10 mL) was heated under reflux for 24 h. The reaction
mixture was slowly quenched onto crushed ice with stirring and it was neutralized with 10% aqueous
sodium bicarbonate solution. The precipitate which separated out after standing overnight was filtered,
washed with cold water, dried and crystallized from absolute EtOH to give the titled compound 6a as
brown needles (0.1 g, 76% yield); mp 181-182 °C; IR: 1593 (triazole ring C=N), 1496 (pyrimidine ring
C=N) and 1468 cm-1 (pyrimidine ring C=C); MS: m/z (%): 369 (2, M+), 313 (2, M+ -2N2), 185 (100, M+
-C9H6N5) and 129 (30, M+ -C11H6N5S); Anal. Calcd for C19H11N7S (369.40): C, 61.78; H, 3.00; N, 26.54;
S, 8.68%. Found: C, 61.61; H, 3.10; N, 26.30; S, 8.24%.
2-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-6-(4-bromophenyl)imidazo[2,1-b]-1,3,4-thiadiazole (6b). A
solution 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-1,3,4-thiadiazole-2-amine (5, 0.15 g, 0.3 mmol) and
4-bromophenacyl bromide (0.15 g, 0.5 mmol) in absolute EtOH (10 mL) was heated under reflux for 24 h.

HETEROCYCLES, Vol. 83, No. 2, 2011
345
The reaction mixture was slowly quenched onto crushed ice with stirring and it was neutralized with 10%
aqueous sodium bicarbonate solution. The precipitate which separated out after standing overnight was
filtered, washed with cold water, dried and crystallized from absolute EtOH to give the titled compound
6b as brown needles (0.1 g, 62% yield); mp 159-160 °C; IR: 1587 (triazole ring C=N), 1482 (pyrimidine
ring C=N) and 1425 cm-1 (pyrimidine ring C=C); Anal. Calcd for C19H10BrN7S (448.30): C, 50.90; H,
2.25; Br, 17.82; N, 21.87%. Found: C, 50.80; H, 2.60; Br, 17.41; N, 21.90%.
5-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-4H-1,2,4-triazole-3-thiol (7). To a solution of (20 mL, 5%
NaOH) and 2-(1,2,4-triazolo[4,3-c]quinazolin-3-carbonyl)hydrazinecarbothioamide (4, 2.87 g, 10 mmol)
was added and refluxed for 3 h. The reaction mixture was cooled, poured onto crushed ice, neutralized
with concd HCl . The resulting solid was filtered, washed with water, dried and crystallized from EtOH
to give the titled compound 7 as pale yallow needles (2 g, 74% yield); mp 281-282 °C; IR: 3458 (NH),
2586 (SH), 1595, 1548 (triazole ring C=N), 1478 (pyrimidine ring C=N) and 1420 cm-1 (pyrimidine ring
1
C=C); H NMR (DMSO-d6):  = 6.96 (t, 1H, aromatic-H), 7.24 (t, 1H, aromatic-H), 7.92 (d, 1H,
aromatic-H), 8.59 (d, 1H, aromatic-H), 8.80 (s, 1H, pyrimidine-H), 14.03 (s, 1H, exchangeable, SH/NH)
and 14.25 (s, 1H, exchangeable, SH/NH); Anal. Calcd for C11H7N7S (269.29): C, 49.06; H, 2.62; N,
36.41; S, 11.91%. Found: C, 49.20; H, 2.82; N, 36.11; S, 11.54%.
2-(1,2,4-Triazolo[4,3-c]quinazoline-3-carbonyl)-N-phenylhydrazinecarbothioamide (8). A mixture of
1,2,4-triazolo[4,3-c]quinazoline-3-carbohydrazide (3, 2.28 g, 10 mmol) and phenylisothiocyanate (1.79
ml, 15 mmol) in EtOH (50 mL) under reflux for 10 h. The reaction mixture was cooled and the product
was filtered, washed with EtOH and crystallized from dioxan to give the titled compound 8 as pale yellow
needles (2.6 g, 71% yield); mp 324-325 °C; IR: 3424, 3226 (3NH), 1680 (CON), 1590 (triazole ring
C=N), 1454 (pyrimidine ring C=N), 1420 (pyrimidine ring C=C) and 1308 cm-1 (C=S); Anal. Calcd for
C17H13N7OS (363.40): C, 56.19; H, 3.61; N, 26.98; S, 8.82%. Found: C, 56.00; H, 3.50; N, 27.31; S,
8.34%.
5-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (9). Method A. A solution
of 2-(1,2,4-triazolo[4,3-c]quinazoline-3-carbonyl)-N-phenylhydrazinecarbothioamide (8, 36.3 g, 10
mmol) in 2 N NaOH (20 mL) was refluxed for 3 h. The resulting solution was cooled to room
temperature, poured onto crushed ice and acidified to pH 3-4 with 37% HCl. The product formed was
filtered, washed with cooled water, dried and crystallized from EtOH to give the titled compound 9 as
colorless needles (1.5 g, 61% yield); mp 291-292 °C; IR: 2632 (SH), 1596, 1543 (triazole ring C=N),
1498 (pyrimidine ring C=N) and 1461 cm-1 (pyrimidine ring C=C); MS: m/z (%): 345 (7, M+), 184 (4, M+
-C8H5N2S), 185 (100, M+ -C8H4N2S) and 158 (14, M+ -C9H5N3S); Anal. Calcd for C17H11N7S (345.38): C,

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HETEROCYCLES, Vol. 83, No. 2, 2011
59.12; H, 3.21; N, 28.39; S, 9.28%. Found: C, 59.30; H, 3.10; N, 28.74; S, 9.71%.
Method B. A solution of 2-(1,2,4-triazolo[4,3-c]quinazoline-3-carbonyl)-N-phenylhydrazinecarbothio-
amide (8, 1 g, 2.7 mmol) and Et3N (15 mL) in EtOH (50 mL) was refluxed for 24 h. The resulting
solution was cooled to room temperature and the product was filtered, washed with EtOH and crystallized
from EtOH to give the titled compound 9 as colorless needles (0.5 g, 52% yield); mp and mixed mp 291-
292 °C.
3-(5-Hydrazinyl-4-phenyl-4H-1,2,4-triazol-3-yl)-1,2,4-triazolo[4,3-c]quinazoline (10). A suspension
of 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol (9, 0.3 g, 0.8 mmol) and
hydrazine hydrate (99%, 3 mL) in EtOH (50 mL) was heated under reflux for 24 h. The product was
filtered, washed with EtOH and crystallized from dioxan to give the titled compound 10 as colorless
needles (0.18 g, 64% yield); mp 229-230 °C; IR: 3419 (NH), 3320, 3280 (NH2), 1591, 1517 (triazole ring
C=N), 1463 (pyrimidine ring C=N) and 1420 cm-1 (pyrimidine ring C=C); MS: m/z (%): 343 (3, M+), 185
(100, M+ -C8H6N4), 158 (18, M+ -C9H7N5) and 159 (6, M+ -C9H6N5); Anal. Calcd for C17H13N9 (343.35):
C, 59.47; H, 3.82; N, 36.72%. Found: C, 59.40; H, 3.44; N, 36.91%.
Potassium 2-(1,2,4-triazolo[4,3-c]quinazolin-3-carbonyl)hydrazinecarbodithioate (11). To a solution
of KOH (0.84 g, 15 mmol) in absolute EtOH (250 mL), 1,2,4-triazolo[4,3-c]quinazoline-3-carbo-
hydrazide (3, 2.28 g, 10 mmol) and carbon disulfide (1.14 g, 15 mmol) in absolute EtOH (250 mL) were
added. The reaction mixture was agitated for 12-16 h, where upon a yellow precipitate was separated. Dry
Et2O (200 mL) was then added to complete the precipitation of the titled compound. The obtained product
was collected by filtration, washed with dry Et2O and dried in a desiccator. The potassium salt prepared as
described above, was obtained in nearly quantitative yield and was employed without further purification
for the next step.
5-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12). A suspension of
potassium dithiocarbazinate (11, 3.43 g, 10 mmol) and hydrazine hydrate (95%, 1 mL, 20 mmol) in water
(5 mL) was heated and stirred under reflux for 2 h. The color of the reaction mixture changed to green,
hydrogen sulfide evolved and homogenous solution resulted. The reaction mixture was cooled, diluted
with ice-cold water (100 mL) and subsequent acidification with concd HCl gave a white precipitate. It
was collected by filtration, washed with ice-cold water (100 mL), dried and crystallized from EtOH to
give the titled compound 12 as colorless needles (2 g, 70% yield); mp 223-224 °C; IR: 3308, 3260 (NH2),
2360 (SH), 1550 (triazole ring C=N), 1449 (pyrimidine ring C=N) and 1385 cm-1 (pyrimidine ring C=C);
1H NMR (DMSO-d6):  = 7.29 (t, 1H, aromatic-H), 7.52 (t, 1H, aromatic-H), 7.95 (s, 1H, pyrimidine-H),
8.14 (d, 1H, aromatic-H), 8.26, 8.29 (2s, 2H, exchangeable, NH2), 8.60 (d, 1H, aromatic-H) and 13.51 (s,

HETEROCYCLES, Vol. 83, No. 2, 2011
347
1H, exchangeable, SH); MS: m/z (%): 284 (100, M+), 256 (7, M+ -N2), 255 (11, M+ -HN2), 227 (15, M+
-HN5), 185 (50, M+ -CH3N7), 129 (60, M+ -C3H3N7S) and 103 (14, M+ -C4H3N8S); Anal. Calcd for
C11H8N8S (284.30): C, 46.47; H, 2.84; N, 39.41; S, 11.28%. Found: C, 46.70; H, 2.54; N, 39.11; S,
11.78%.
3-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-6-(3-bromophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole
(13). A mixture of 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12, 0.28 g,
1 mmol) and m-bromobenzoic acid (0.22 g, 1.1 mmol) in POCl3 (5 mL) was refluxed for 7 h. The
reaction mixture was slowly quenched onto crushed ice with stirring and neutralized with 10% aqueous
sodium bicarbonate solution. The product which separated after standing overnight was filtered, washed
with cold water, dried and crystallized from CHCl3-EtOH to give the titled compound 13 as yellow
needles (0.2 g, 56% yield); mp 131-132 °C; IR: 1560, 1541 (triazole ring C=N), 1505 (pyrimidine ring
C=N), 1461 (pyrimidine ring C=C), 1261 (N-N=C) and 679 cm-1 (C –S-C); 1H NMR (DMSO-d6):  =
7.25 (s, 1H, aromatic-H), 7.31 (t, 1H, aromatic-H), 7.42 (t, 1H, aromatic-H), 7.52 (t, 1H, aromatic-H),
7.84 (d, 2H, aromatic-H), 8.12 (d, 2H, aromatic-H) and 8.33 (s, 1H, pyrimidine-H); Anal. Calcd for
C18H9BrN8S (449.29): C, 48.12; H, 2.02; Br, 17.78; N, 24.94; S, 7.14%. Found: C, 48.20; H, 2.22; Br,
17.54; N, 24.87; S, 7.61%.
3-([1,2,4]Triazolo[4,3-c]quinazolin-3-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6(5H)-thione (14). A
mixture of 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12, 0.28 g, 10
mmol), KOH (0.6 g, 10 mmol ) and carbon disulfide (4 mL) in MeOH (100 mL) was refluxed for 24 h,
and then evaporated to dryness and 50% aqueous HCl (50 mL) was added, the product was filtered off,
washed with water, dried and crystallized from MeOH to give the titled compound 14 as yellow needles
(0.2 g, 61% yield); mp 259-260 °C; IR: 3414 (NH), 1593, 1538 (triazole ring C=N), 1472 (pyrimidine
ring C=N), 1429 (pyrimidine ring C=C) and 1304 cm-1 (C=S); MS: m/z (%): 326 (2, M+), 197 (2, M+
-C8H5N2), 198 (2, M+ -C8H4N2), 122 (2, M+ -C9H4N2S2), 123 (2, M+ -C9H3N2S2), 108 (13, M+ -C9H4N3S2),
109 (2, M+ -C9H3N3S2) and 68 (13, M+ -C10H4N5S2); Anal. Calcd for C12H6N8S2 (326.36): C, 44.16; H,
1.85; N, 34.33; S, 19.65%. Found: C, 44.00; H, 2.01; N, 34.62; S, 19.34%.
3-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-6-(methylthio)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole (15). A
solution of 3-([1,2,4]triazolo[4,3-c]quinazolin-3-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-6(5H)-thione
(14, 0.3 g, 1 mmol) and anhydrous sodium acetate (1 g, 15 mmol ) in dioxan (100 mL) was treated with
CH3I (0.14 mL, 1 mmol) gradually with constant stirring for 24 h. The solvent was removed and the
residue was poured into ice-cold water. The compound that precipitated was filtered, washed, dried and
crystallized from EtOH to give the titled compound 15 as pale green needles (0.2 g, 64% yield); mp 229-

348
HETEROCYCLES, Vol. 83, No. 2, 2011
230 °C; IR: 3107 (SCH3), 1591, 1544 (triazole ring C=N), 1459 (pyrimidine ring C=N) and 1427 cm-1
(pyrimidine ring C=C); Anal. Calcd for C13H8N8S2 (340.39): C, 45.87; H, 2.37; N, 32.92; S, 18.84%.
Found: C, 45.81; H, 2.61; N, 32.54; S, 19.27%.
3,3'-Di([1,2,4]triazolo[4,3-c]quinazolin-3-yl)-6,6'-bi([1,2,4]triazolo[3,4-b][1,3,4]thiadiazole) (16). A
mixture of 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12, 0.5 g, 17
mmol), oxalic acid (0.08 g, 0.8 mmol) and phosphoryl chloride (1.4 mL) was refluxed for 1 h. The
reaction mixture was poured onto crushed ice and the product was filtered, washed with cold water, dried
and crystallized from EtOH to give the titled compound 16 as colorless needles (0.37 g, 67% yield ); mp
239-240 °C; IR: 1560, 1543 (triazole ring C=N), 1463 (pyrimidine ring C=N), 1420 (pyrimidine ring
C=C) and 690 cm-1 (C–S-C); 1H NMR (DMSO-d6):  = 7.68 (t, 2H, aromatic-H), 7.93 (t, 2H, aromatic-H),
8.53 (d, 2H, aromatic-H), 8.70 (d, 2H, aromatic-H) and 9.18 (s, 2H, pyrimidine-H); Anal. Calcd for
C24H10N16S2 (586.57): C, 49.14; H, 1.72; N, 38.21; S, 10.93%. Found: C, 49.40; H, 1.90; N, 38.11; S,
10.44%.
3-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-6-phenyl-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (17). A
mixture of 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12, 0.27 g, 1
mmol) and phenacyl bromide (0.24 g, 1.2 mmol) in absolute EtOH (20 mL) was refluxed for 24 h. The
reaction mixture was slowly quenched onto crushed ice with stirring and was neutralized with 10%
aqueous sodium bicarbonate. The product which separated after standing overnight was filtered, washed
with cold water, dried and crystallized from MeOH to give the titled compound 17 as yellow needles
(0.22 g, 61% yield); mp 281-282 °C; IR: 1592, 1539 (triazole ring C=N), 1505 (pyrimidine ring C=N),
1463 (pyrimidine ring C=C), 1232 (N-N=C) and 677 cm-1 (C–S-C); Anal. Calcd for C19H12N8S (384.42):
C, 59.36; H, 3.15; N, 29.15; S, 8.34%. Found: C, 59.31; H, 3.51; N, 29.00; S, 8.80%.
3-(1,2,4-Triazolo[4,3-c]quinazolin-3-yl)-6,7-diphenyl-5H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine (18).
A mixture of 5-(1,2,4-triazolo[4,3-c]quinazolin-3-yl)-4-amino-4H-1,2,4-triazole-3-thiol (12, 1.59 g, 0.005
mol) and benzoin (1.06 g, 5 mmol) in EtOH (30 mL) was heated to get a clear solution and to the hot
solution was added 2N KOH solution (0.5 mL). The reaction mixture was refluxed with stirring for 2h,
then concentrated and cooled to room temperature. The product was filtered, washed with water, dried
and crystallized from EtOH to give the titled compound 18 as pale yellow needles (1.6 g, 64% yield); mp
299-300 °C; IR: 3455 (NH), 1593, 1576 (triazole ring C=N), 1450 (pyrimidine ring C=N), 1389
(pyrimidine ring C=C) and 640 cm-1 (C–S-C); MS: m/z (%): 460 (2, M+), 355 (3, M+ -C6H5N2), 105 (65,
M+ -C21H15N4S) and 78 (100, M+ -C22H16N5S); Anal. Calcd for C25H16N8S (460.51): C, 65.20; H, 3.50; N,
24.33; S, 6.96%. Found: C, 65.41 H, 3.44; N, 24.62; S, 7.35%.

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REFERENCES
1. T. M. Abdel-Rahman, Boll. Chim. Farm., 1998, 137, 43.
2. A. M. Farghaly, I. Chaaban, M. A. Khalil, and A. A. Bekhit, Arch. Pharmacol., 1990, 323, 833.
3. E. Pomarnacka, S. Angielski, and A. Hoppe, Acta Polon. Pharm., 1984, 4, 141.
4. M. J. Kornet, J. Heterocycl. Chem., 1992, 29, 103.
5. M. Shimoyama, K. Ogino, Y. Tanaka, T. Ikeda, and I. Hisatome, Diabetes, 1999, 3, 609.
6. C. M. Sorenson and M. A. Barry, J. Natl. Cancer Inst., 1990, 82, 749.
7. P. K. Naithani, G. Palit, V. K. Srivastava, and K. Shankar, Indian J. Chem., 1989, 28B, 745.
8. S. Jantova, M. Urbancikova, T. Maliar, M. Mikulasova, and P. Rauko, Neoplasma, 2001, 1, 52.
9. S. Jantova, M. Theiszova, and M. Mikulasova, Neoplasma, 2004, 51, 436.
10. S. Jantova, R. Ovadekova, S. Letasiova, K. Spirkova, and S. Stankovsky, Folia Moicrobiol., 2005, 50,
90.
11. S. Jantova, S. Letasiova, A. Repicky, R. Ovadekova, and B. Lakatos, Cell Biochem. Funct., 2006, 24,
519.
12. S. Jantova, A. Repicky, and L. Cipak, Neoplasma, 2009, 56, 494.
13. M. Loriga, G. Vitale, and G. PagliettIi, Farmaco., 1998, 53, 139.
14. R. R. Sotelo-Mundo, J. Ciesla, and J. M. Dzik, Biochemistry, 1990, 38, 1087.
15. M. Ranson, Br. J. Cancer, 2004, 90, 2250.
16. S. B. Kaye, Br. J. Cancer, 1998, 78, 1.
17. K. Sztanke, T. Tuzimski, J. Rzymowska, K. Pastemak, and M. Kandefer, Eur. J. Med. Chem., 2008,
43, 404.
18. P. C. Lima, L. M. Lima, K. C. M. da Silva, P. H. O. Leda, A. L. P. de Miranda, C. A. M. Fraga, and
E. J. Barreiro, Eur. J. Med. Chem., 2000, 35, 187.
19. M. El. Enany and S. Botros, Pharmazie, 1981, 36, 62.
20. G. S. Sidhu, G. Thyarajan, and N. Rao, Naturwissenschaften., 1963, 50, 732 (Chem. Abstr., 1964, 60,
684).
21. M. A. E. Shaban and A. Z. Nasr, Adv. Heterocycl. Chem., 1990, 49, 277.
22. M. Claesen and H. Vanderhaeghe, Bull. Soc. Chim. Belg., 1959, 68, 220 (Chem. Abstr., 1960, 54,
9939h).
23. S. K. Pandey, A. Singh, and Nizamuddin, Eur. J. Med. Chem., 2009, 44, 1188.
24. L. J. Bellany, "The Infrared Spectra of Complex Mol.," Matheuew London, 1959, 249.
25. K. F. Atta and M. G. Marei, unpublished results.