Pyridazine derivatives and related compounds, part 17:1 The synthesis of some 3-substituted pyridazino[3′,4′:3,4]pyrazolo[5,1-c] -1,2,4-triazines and their antimicrobial activity

Article abstract of DOI:10.1080/10426500500272038

The reaction of the hydrazide of pyridazino[3′, 4′:3,4] pyrazolo[5,1-c]-1,2,4-triazine-3-carboxylic acid 3 with carbon disulfide in the presence of potassium hydroxide gave the 1,3,4-oxadiazole-2-thione derivative 4. The methylation of this product in an

Full text of DOI:10.1080/10426500500272038

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Pyridazine Derivatives and
Related Compounds, Part
17: The Synthesis of Some 3-
Substituted Pyridazino[3′,
4′:3, 4]pyrazolo[5, 1-
c]-1,2,4-triazines and Their
Antimicrobial Activity
Fatma El-Mariah a , Mona Hosny a & Ali Deeb b
a Department of Chemistry, Faculty of Science, Ain-
Shams University, Cairo, Egypt
b Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt
Version of record first published: 15 Aug 2006
To cite this article: Fatma El-Mariah, Mona Hosny & Ali Deeb (2006): Pyridazine
Derivatives and Related Compounds, Part 17: The Synthesis of Some 3-Substituted
Pyridazino[3′, 4′:3, 4]pyrazolo[5, 1-c]-1,2,4-triazines and Their Antimicrobial Activity,
Phosphorus, Sulfur, and Silicon and the Related Elements, 181:4, 809-818
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Phosphorus, Sulfur, and Silicon, 181:809–818, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500272038
Pyridazine Derivatives and Related Compounds, Part 17:1
The Synthesis of Some 3-Substituted
Pyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazines
and Their Antimicrobial Activity
Fatma El-Mariah
Mona Hosny
Department of Chemistry, Faculty of Science, Ain-Shams University,
Cairo, Egypt
Ali Deeb
Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
The reaction of the hydrazide of pyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine-
3-carboxylic acid 3 with carbon disulfide in the presence of potassium hydroxide
gave the 1,3,4-oxadiazole-2-thione derivative 4. The methylation of this product
in an alkaline medium proceeds at the sulfur atom. The reaction of 3 with KOH
and carbon disulfide followed by addition of hydrazine hydrate afforded the 4-
amino-1,2,4-triazole derivative 6. Compound 3, when heated either with ammo-
nium thiocyanate or with potassium thiocyanate, afforded the same product 7,
which underwent cyclodehydration in the presence of acetyl chloride, which led
to the 2-acetylamino-1,3,4-thiadiazole derivative 8. In a basic medium, the prod-
uct was 1,2,4-triazole-3-thione derivative 9. The reaction of 3 with phenyl isoth-
iocyanate provided thiosemicarbazide derivative 10, which underwent cyclodehy-
dration in a basic medium and gave the 1,2,4-triazole derivative 11. The reaction
of 3 with formic acid yielded the 3-carboxyl-2ꢀ-(formyl)hydrazine derivative 12.
The refluxing of the latter with phosphorus pentasulfide in xylene yielded com-
pound 14 (65%). The reaction of compound 12 with phosphorus pentoxide af-
forded compound 15. Some representative examples were screened for antimicrobial
activity.
Keywords 1,2,4-triazole-3-thion; 1,3,4-oxadiazole-2-thione; 1,3,4-thiadiazole; antimi-
crobial activity
Received February 7, 2005; accepted April 7, 2005.
The author acknowledges the help of Prof. Y. El-Zawahry, Department of Microbiology,
Faculty of Science, Zagazig University, Zagazig, Egypt, for carrying out the antimicrobial
activity.
Address correspondence to Ali Deeb, Zagazig University, Department of Chemistry,
Faculty of Science, Zagazig, Egypt. E-mail: dralideeb@hotmail.com
809

810
F. El-Mariah et al.
INTRODUCTION
Pyrazolopyridazines and pyrazolotriazines are well known for diverse
biological activities.2 Sometimes the fusion of heterocyclic nucli en-
hances the pharmacological activities much more than its parent nu-
cleus. On the other hand, several 1,3,4-thiadiazole3 derivatives and
their bioisosteres 1,3,4-oxadiazoles4 and 1,2,4-triazoles5 have antibac-
terial and antifungal activity. Hence, it was thought that the incorpora-
tion of the latter hetero-cyclic moieties into a pyridazine condensed sys-
tem might modify their biological activities. The present investigation
is in continuation of our previous work6 on the synthesis and antimicro-
bial activity of other pyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c] -1,2,4-triazine
derivatives.
RESULTS AND DISCUSSION
The required ethyl 4-methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyraz-
olo[5,1-c] -1,2,4-triazine-3-carboxylate (2) was prepared (92.6%) as yel-
low crystals (m.p. 248–250◦C) by the coupling of 3-diazo-4,5-diphenyl-
pyrazolo[3,4-c]pyridazine (1) with ethyl acetoacetate (Scheme 1). This
carboxylate 2 on refluxing with hydrazine hydrate gave the acid hy-
drazide 36 in a high yield.
SCHEME 1
Compound 4 was prepared from the reaction of the corresponding
acid hydrazide 3 and carbon disulfide in the presence of potassium

Pyridazine Derivatives and Related Compounds, Part 17
811
hydroxide followed by the treatment of the resulting anionic form with
hydrochloric acid (Scheme 2). Product 4 in the solid state exists as the
SCHEME 2 a, CS2/KOH; b, HCl; c, Mel; d, N2H4; e, NH4SCN or KSCN;
f, AcCl; g, NaOH; and h, PhNCS.
thione form as indicated by its IR spectrum, displaying bands for NH
(3192 cm−1) and C S group (1332 cm−1) but lacking a band at 2600–
2500 cm−1 (SH stretching vibrations). The finding of these bands is
in accord with the data of Ainsworth7 for various 5-substituited 1,3,4-
oxadiazole-2-thiones. Oxadiazolethion 4 undergoes methylation upon
reaction with methyl iodide in boiling ethanol with sodium hydroxide
and led to the SMe derivative 5. The structure of compound 5 was

812
F. El-Mariah et al.
established from analytical and spectral data. The mass spectra showed
the expected molecular ion peaks. The most salient features of the IR,
1H-NMR, and mass spectra are given in the Experimental section.
On the other hand, the reaction of the acid hydrazide 3 with KOH and
carbon disulfide followed by the addition of hydrazine hydrate afforded
4-amino-1,2,4-triazole derivative 6 in a moderate yield. In the infrared
spectrum compound 6 absorbs strongly at 3445, 3320, 3151, 1613, and
1423 cm−1. The 3445 cm−1 and 3320 cm−1 bands were assigned to NH2,
the band at 1613 cm−1 to endocyclic C N, and the band at 1423 cm−1
,
referred to C S. Moreover, the mass spectra recorded a molecular ion
peak at m/z 452. Compound 6 was also prepared unequivocally by the
ring transformation of oxadiazolethione derivative 5 when it reacted
with hydrazine hydrate.
Compound 3, when heated either with ammonium thiocyanate
in absolute ethanol or with potassium thiocyanate, afforded the
same product. The isolated product was proven to be 4-methyl-
9,10-diphenylpyridaz-ino
[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine-3-
carbothiosemicarbazide (7).
The cyclodehydration of 7 in the presence of acetyl chloride led to
2-acetylamino-1,3,4-thiadiazole derivative 8. When the thiosemicar-
bazide 7 was cyclized under a basic condition (NaOH), the 1,2,4-triazole-
3-thione derivative 9 was obtained.
The treatment of the acid hydrazide 3 with phenyl isothiocyanate
provided the 3-(1ꢀ-phenylthiocarbamyl)hydrazino carbonyl derivative
10 in a 64% yield (Scheme 2). The IR spectra of 10 showed vibrational
bands due to NH, C O, and CNS amide. The thiosemicabazide 10 was
then cyclo-dehydrated with 4% aqueous NaOH to produce the 1H-4-
phenyl-5-thio-1,2,4-triazole derivative 11. The IR, 1H-NMR, and mass
spectra of 11 were consistent with the assigned structure. The IR spec-
trum showed absorption due to the C N and NCS amide function in-
dicating that they exist in the triazolinethione rather than in the mer-
1
captotriazole form. The H-NMR spectra showed a highly deshielded
signal at 14.08–14.25 ppm assigned for the NH proton of the triazoline
ring
The refluxing compound 3 with formic acid for 5 h gave 3-carboxyl-2ꢀ-
(formyl)hydrazine derivative 12 in a high yield (Scheme 3). Refluxing
compound 12 with phosphorus pentasulfide gave 1,3,4-thiadiazole
derivative 14 (65%).
The usual reaction for the formation of 1,3,4-oxadiazole, namely the
reaction of compound 3 with ethyl orthoformate, did not give the desired
compound 15. In the latter reaction, ethoxyformaldehyde 3-carboxy-
hydrazone 13 was formed. Heating compound 13 to its melting point
gave compound 15 (66%). Compound 15 also could be obtained in a

Pyridazine Derivatives and Related Compounds, Part 17
813
SCHEME 3 a, HCOOH; b, CH(OEt)3; c, P2S5; d, P2O5; and e, heat.
yield of 58% by refluxing compound 12 with phosphorus pentoxide in
xylene.
Antimicrobial Activity
Representative compounds were screened for their antibacterial ac-
tivity against gram-negative bacteria E. coli, K. pneumoniae, and
P. aeruginosa and gram positive bacteria S. aureus at 500, 1,000,
5,000, and 10,000 ppm concentration; the antifungal activity against
C. albicans and A. fumogitus also was determined. The compounds
were screened for their biological activity using the inhibition zone
technique.6 The results obtained for antibacteria are given in Table
I. No significant inhibition was shown by any of the tested compounds
against A. fumigatus and C. albicans.
TABLE I Mean Value of Area of Inhibition in mm. A,
P. aeruginosa; B, S. aureus; (−) = no inhibition zones
Organism
A
B
Compoundsa
500
1000 5000 10000 500
1000
5000
10000
4
5
6
7
8
–
–
2
1
–
–
–
–
–
3
3
–
–
–
2
–
4
5
3
–
–
4
–
6
7
6
–
–
2
–
1
–
1
–
1
5
1
4
–
3
–
2
6
4
5
–
6
3
3
8
6
15
–
7
5
10
12
4
a No significant inhibition was shown against: E. coli and K. pneumoniae.

814
F. El-Mariah et al.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are un-
corrected. The IR spectra of the compounds were recorded on a Perkin-
Elmer spectrophotometer model 1430 as potassium bromide pellets,
1
and frequencies are reported in cm−1. The H-NMR spectra were ob-
served on a Perkin-Elmer R12B spectrometer, and chemical shifts (δ)
are in ppm relative to internal TMS; mass spectra were recorded on
a Mass Spectrometer HP model MS 5988 E1 70 eV. Reactions were
routinely followed by thin layer chromatography on silica gel F254 alu-
minium sheets (Merck). The spots were detected by UV irradiation at
254–365 nm.
5-(4-Methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-
1,2,4-triazin-3-yl)-2,3-dihydro-1,3,4-oxadiazole-2-thion 4
To a solution of compound 3 (1.5 g, 3.87 mmol) in ethanol (10 mL) at
0◦C carbon disulfide (0.7 g, 9.2 mmol) and potassium hydroxide (0.22 g,
3.9 mmol) were added. The mixture was refluxed for 7 h. The solvent was
evaporated. The residue was dissolved in water (100 mL) and acidified
with conc. HCl (pH = 6). The precipitate was filtered and recrystallized
from ethanol to give 1.5 g (90%) of 4, m.p. 232–234◦C; IR: 3192 (NH),
3090 (CH aromatic), 1635 (C N), 1332 (C S) cm−1. Anal. calcd. for
C22H14N8OS: C, 60.26; H, 3.22; N, 25.56. Found: C, 60.00; H, 3.10; N,
25.30.
5-(4-Methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-
1,2,4-triazin-3-yl)-2-methylthio-1,3,4-oxadiazole 5
To a stirred solution of compound 4 (1.0 g, 2.28 mmol) in ethanol (15 mL)
and sodium hydroxide (1 N, 1 mL), methyl iodide (0.32 g, 2.28 mmol) was
added. After half an hour, the precipitate was filtered and recrystallized
from ethyl acetate to give 0.8 g (77.6%) of 5, m.p. 130–131◦C; IR: 3135
(CH aromatic), 1615 (C N) cm−1; ms: m/z (%) 452 (M+, 0.4), 407 (0.43),
366 (1.0), 315 (11), 301 (100). Anal. calcd. for C23H16N8OS: C, 61.05; H,
3.56; N, 24.77. Found: C, 60.90; H, 3.40; N, 24.50.
4-Amino-5-(4-methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]-
pyrazolo[5,1-c]-1,2,4-triazin-3-yl)-2,3-dihydro-1,2,4-
triazole-3-thione 6
To a solution of potassium hydroxide (0.2 g, 3.56 mmol) in abso-
lute ethanol (10 mL), compound 3 (1.0 g, 2.52 mmol) was added
with stirring. After a few minutes, a slight excess of carbon disulfide

Pyridazine Derivatives and Related Compounds, Part 17
815
(0.3 g, 3.94 mmol) was added, and the mixture was held at reflux for 10
h. A solid product appeared occasionally during the addition of carbon
disulfide but was usually dissolved upon heating. Evaporation of the
solvent by distillation in vacuo left a residue that was washed with cold
absolute ethanol and ether. A mixture of the potassium salt and hy-
drazine hydrate 85% (5 mL) in absolute ethanol (20 mL) was refluxed
for 1 h. The reaction mixture then was diluted with cold water (100 mL)
and acidified by dropwise concentrated hydrochloric acid. The precipi-
tate, separated by filtration, was dried and recrystallized (ethanol) to
give 0.65 g (65%) of 6, m.p. 178–180◦C; IR: 3445, 3320, 3151, 1613, 1423
cm−1; ms: m/z (%) 451 (M+−1, 0.09), 443 (0.1), 433 (0.12), 423 (0.13),
420 (0.25), 286 (100). Anal. calcd. for C22H16N10S: C, 58.39; H, 3.56; N,
30.96. Found: C, 58.10; H, 3.40; N, 30.70.
4-Methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-
1,2,4-triazine-3-carbothiosemicarbazide 7
Method A
Compound 3 (1.0 g, 2.52 mmol) was suspended in 12 mL of alcoholic
hydrogen chloride solution and then was evaporated under reduced
pressure. The residue was dried by evaporation using small amounts of
alcohol. The product was heated under reflux for 18 h with a solution
of dry ammonium thiocyanate (0.2 g, 2.62 mmol) in absolute ethanol
(10 mL). The solid was filtered, washed several times with water, and
recrystallized (ethanol) to give 7 (0.8 g, 69.6%), m.p. 248–249◦C; IR:
3433, 3333, 3271, 3163, 1617, 1590 cm−1; ms: m/z (%) 450 (M+−5, 0.07),
449 (1.13), 435 (2.02), 420 (1.51), 411 (1.1), 206 (100). Anal. calcd. for
C22H17N9OS: C, 58.01; H, 3.76; N, 27.68. Found C, 57.80; H, 3.80; N,
27.90.
Method B
A mixture of compound 3 (1.0 g, 2.52 mmol), potassium thiocyanate
(0.5 g, 5.14 mmol), water (50 mL) and concentrated hydrochloric acid
(2.5 mL) was refluxed for 3 h. After cooling, the precipitate was fil-
tered off and recrystallized (ethanol) to give 0.9 g, 78.3% of compound
7, m.p. 248–250◦C. It was identical in every respect with that prepared
by Method A.
2-Acetylamino-5-(4-methyl-9,10-diphenylpyridazino-
[3ꢀ,4ꢀ:3,4]pyr-azolo[5,1]-1,2,4-triazin-3-yl)-1,3,4-thiadiazole 8
Compound 7 (0.5 g, 1.09 mmol) and acetyl chloride (2 mL, 25.48 mmol)
were mixed in an ice bath and afterwards were gently heated under

816
F. El-Mariah et al.
reflux for 3 h. After the vigorous reactions subsided, heating was con-
tinued for 15 min. To the cold reaction mixture water (100 mL) was
added. The insoluble material was collected, washed several times
with water, and recrystallized (ethanol) to give 8 (0.3 g, 57.03%), m.p.
268–270◦C; IR: 3447, 3263, 3180, 3056, 1612 cm−1. Anal. calcd. for
C24H17N9OS: C, 60.11; H, 3.57; N, 26.29. Found: C, 59.90; H, 3.20; N,
26.40.
5-(4-Methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]- pyrazolo[5,1-c]-
1,2,4-triazin-3-yl)-2,3-dihydro-1,2,4- triazole-3-thione 9
A solution of 7 (1.0 g, 2.19 mmol) in 2 N NaOH (10 mL) was refluxed for
3 h. The mixture was cooled and acidified with dil. HCl (pH 5.6), and
the separated solid was filtered, dried, and recrystallized (ethanol) to
give 9 (0.8 g, 83%), m.p. 238–240◦C; IR: 3445, 3326, 3153, 3058, 1612,
1564, 1423 cm−1. Anal. calcd. for C22H15N9S: C, 60.40; H, 3.46; N, 28.82.
Found: C, 60.30; H, 3.30; N, 28.60.
4-Methyl-9,10-diphenyl-3-(1ꢀ-phenylthiocarbomyl)-
hydrazinocarbonylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo-
[5,1-c]-1,2,4-triazine 10
To a solution of 3 (1.5 g, 3.78 mmol) in hot absolute ethanol (10 mL)
phenyl isothiocyanate (1.0 ml, 7.29 mmol) was added. The mixture was
refluxed while stirring for 3 h. The separated solid was washed with
ethanol and recrystallized (ethyl acetate/pet. ether 40–60◦C) to give
10 (1.3 g, 64.67%), m.p. 162–163◦C; IR: 3445, 3378, 3155, 3057, 1598
cm−1. Anal. calcd. For C28H21N9OS: C, 63.26; H, 3.98; N, 23.71. Found:
C, 63.00; H, 3.80; N, 23.50.
1H-4-Phenyl-3-(4-methyl-9,10-diphenylpyidazino[3ꢀ,4ꢀ:3,4]-
pyrazolo-[5,1-c]-1,2,4-triazin-3-yl)-1,2,4-triazole-5-thione 11
A solution of 10 (0.4 g, 0.75 mmol) in 2 N NaOH (10 mL) was refluxed
for 3 h. The mixture was cooled and acidified with dil. HCl (pH = 6),
and the separated solid was recrystallized (ethanol) to give 11 (0.25
g, 64.7%), m.p. 198–200◦C; IR: 3400–3250 (NH), 1600 (C N), 1590,
1510–1490 (C C), 1550–1520, 1380–1360, 1270–1250, 980–970 cm−1
;
1H-NMR (CDCl3) ppm: 14.25–14.08 (br s, 1H, NH), 7.6–7.2 (m, 10H,
2Ph), 1.4 (s, 3H, CH3); ms: m/z (%) 509 (M+− 4, 0.4), 495 (0.3), 481 (0.2),
368 (3.5), 313 (3.1). Anal. calcd. for C28H19N9S: C, 65.48; H, 3.73; N,
24.55. Found: C, 65.20; H, 3.80; N, 24.70.

Pyridazine Derivatives and Related Compounds, Part 17
817
3-Carboxyl-2ꢀ-(formyl)hydrazino-4-methyl-9,10-
diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine 12
A solution of compound 3 (1.5 g, 3.78 mmol) in formic acid (10 mL) was
refluxed for 5 h. After cooling, the precipitate was filtered and recrystal-
lized (ethanol) to give 12 (1.2 g, 75%), m.p. 268–270◦C; IR: 3439, 3384,
3148, 1702, 1562 cm−1. Anal. calcd. for C22H16N8O2: C, 62.26; H, 3.80;
N, 26.40. Found: C, 62.00; H, 3.50; N, 26.10.
2-(4-Methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-
1,2,4-triazin-3-Yl)-1,3,4-thiadiazole 14
To a solution of compound 12 (1.0 g, 2.35 mmol) in xylene (50 mL) was
added phosphorus pentasulfide (1.0 g). The mixture was refluxed for
45 min and filtered. The solvent was evaporated. To the residue was
added dimethyl sulfoxide (10 mL), and the mixture was filtered. The
precipitate was collected, dried, and recrystallized (ethanol) to give 14
(0.65 g, 65.65%), m.p. 210–212◦C; IR: 3125, 1610, 1560, 1500, 1350; 1H-
NMR (CDCl3) ppm: 8.8 (s, 1H, oxadiazole), 7.8–7.2 (m, 10H, 2Ph), 2.4
(s, 3H, CH3); ms: m/z (%) 422 (M+, 0.2), 365 (0.3), 351 (0.2), 315 (37).
Anal. calcd. for C22H14N8S: C, 62.54; H, 3.34; N, 26.53. Found: C, 62.30;
H, 3.10; N, 26.20.
Ethoxyformaldehyde 3-Carboxyhydrazone-4-methyl-9,10-
diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-1,2,4-triazine 13
A mixture of compound 3 (0.4 g, 1.0 mmol) and ethyl orthoformate
(5 mL) was heated under reflux for 3 h. After cooling, the precipitate was
filtered and recrystallized (methylene chloride/diethyl ether) to give (0.3
g, 65.78%) of compound 13, m.p. 126–127◦C; IR: 3055, 2979, 1624, 1562,
1428 cm−1. Anal. calcd. for C24H20N8O2: C, 63.71; H, 4.46; N, 24.77.
Found: C, 63.50; H, 4.20; N, 24.50.
2-(4-Methyl-9,10-diphenylpyridazino[3ꢀ,4ꢀ:3,4]pyrazolo[5,1-c]-
1,2,4-triazin-3-yl)-1,3,4-oxadiazole 15
Method A
Compound 13 (0.5 g, 1.1 mmol) was heated at 125–130◦C for 30 min.
The residue was triturated with diethyl ether to give (0.3 g, 66.8%) of
compound 15, recrystallized (ethanol), m.p. 270–272◦C; IR: 3055, 1631,
1558, 1490 cm−1; ms: m/z (%) 406 (M+, 5.2), 286 (100), 257 (11.4), 243
(18.2), 189 (48.8). Anal. calcd. for C22H14N8O: C, 65.02; H, 3.47; N, 27.57.
Found: C, 65.10; H, 3.20; N, 27.30.

818
F. El-Mariah et al.
Method B
To a solution of compound 12 (0.4 g, 0.94 mmol) in xylene (10 mL),
phosphorus pentoxide (0.5 g) was added. The mixture was refluxed for
3 h. The solvent was evaporated and the residue was recrystallized
(ethanol) to give (0.2 g, 52.6%) of compound 15, m.p. 270–272◦C. It was
identical in every respect with that prepared by Method A.
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