Synthesis and spectral characterisation of some phthalazinone derivatives

Article abstract of DOI:10.3184/174751912X13274297624330

1,2,4-Triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3-dioxoisoindolin-2-yl, 1H-pyrazol-4-yl, phthalazin-1(2H)one, 5H-2,3-benzodiazepine-1,4-dione and pyridazine-1,4-dione derivatives were prepared via the reaction of the readily obtainable starting material 1-oxo-1,2-dihydrophthalazin-4-carbohydrazide with one carbon donor like phenyl isothiocyanate, phenyl isocyanate, triethylorthoformate, formic acid and different electrophilic reagents such as anhydrides, chromen-1,3-dione, chloroacetyl chloride, acetic anhydride, arylidene malononitrile, ethoxymethylene malononitrile and ethyl acetoacetate.

Full text of DOI:10.3184/174751912X13274297624330

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 75
FEBRUARY, 75–82
Synthesis and spectral characterisation of some phthalazinone
derivatives
Mahmoud R. Mahmoud, Wael S.I. Abou-Elmagd*, Hamed A. Derbala and Mohamed H. Hekal
Chemistry Department, Faculty of Science, Ain Shams University, Abassia 11566, Cairo, Egypt
1,2,4-Triazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,3-dioxoisoindolin-2-yl, 1H-pyrazol-4-yl, phthalazin-1(2H)one, 5H-2,3-benzodi-
azepine-1,4-dione and pyridazine-1,4-dione derivatives were prepared via the reaction of the readily obtainable
starting material 1-oxo-1,2-dihydrophthalazin-4-carbohydrazide with one carbon donor like phenyl isothiocyanate,
phenyl isocyanate, triethylorthoformate, formic acid and different electrophilic reagents such as anhydrides, chro-
men-1,3-dione, chloroacetyl chloride, acetic anhydride, arylidene malononitrile, ethoxymethylene malononitrile and
ethyl acetoacetate.
Keywords: phthalazinone, carbohydrazide, oxadiazole, triazole, pyrazole
Hypertension is one of the most common cardiovascular dis-
eases that can cause coronary disease, myocardial infarction,
kidney failure, stroke and sudden death.1 Hence, great efforts
are continuously being made to find novel antihypertensive
agents acting through different mechanisms.2,3
synthesis of some phthalazine derivatives bearing another
heterocycles have a broad spectrum of biological activities like
pyrazole, triazole and oxadiazole.
Results and discussion
Hydralazine (1-hydrazinophthalazine), was one of the first
antihypertensive agents developed in the 1950s, which has
attracted much attention in the last decade because of its direct
vasodilator action.4 Structural modification of hydralazine led
to the discovery of some pyridazinones and other phthalazine
derivatives with a broad spectrum of action on the cardiovas-
cular system,5,6 including antihypertensive effects,7,8 inhibition
of platelet aggregation9,10 and of phosphodiesterases.11,12 Some
of them also displayed antiasthmatic,13,14 antipsychotic,15 anti-
diabetic,16 anticonvulsant,17 antineoplastic,18 antimicrobial,19
antifungal20 and antiparasitic 21,22 activities.
The hydrazide 1 was previously prepared by our research
group.23 Refluxing the hydrazide 1 with phenylisothiocyanate
or phenylisocyanate in boiling pyridine gave 1-(1-oxo-1,2-
dihydrophthalazine-4-carbonyl)-4-phenylthiosemicarbazide
2a and 1-(1-oxo-1,2-dihydrophthalazine-4-carbonyl)-4-phenyl-
semicarbazide 2b, respectively. The structure 2 was deduced
from the analytical and spectroscopic data.
On the other hand, when compound 1 was allowed to
react with phenylisothiocyanate in sodium hydroxide (10%)
followed by acidification gave 4-[4-phenyl-5-thioxo-1H-1,2,
4-triazol-3-yl]phthalazin-1-(2H)-one 3. Moreover, when com-
pound 2a was allowed to react with sodium hydroxide (10%)
These reported diverse biological activities initiated our
interest to utilise the phthalazine hydrazide derivative 1 for the
Scheme 1
* Correspondent. E-mail: waelmagd97@yahoo.com

76 JOURNAL OF CHEMICAL RESEARCH 2012
produced the same compound 3 (identify by m.p, mixed m.p
and TLC). The structure of 3 was confirmed by the correct
analytical and spectroscopic data. Refluxing the hydrazide 1
with formic acid for 10 h yielded N-formyl-4-oxo-3,4-dihy-
drophthalazine-1-carbonyl hydrazide 4 which easily cyclised
through dehydration upon heating with phosphorus pentaoxide
in dry toluene to give 4-(1,3,4-oxadiazol-2-yl)phthalazin-1(2H)-
one 5 (Scheme 1).
Compound 5 was obtained as the sole product in fairly good
yield upon refluxing compound 1 with one carbon donor such
as triethylorthoformate for three days which consider another
clue for the structure 5. The reaction of the carbohydrazide 1
with triethyl orthoformate could be postulated as follows
(Scheme 2).
reaction of the hydrazide derivative 1 with phthalic anhydride
in refluxing dioxane in acetic acid which gave N-(1,3-
dioxoisoindolin-2-yl)-4-oxo-3,4-dihydrophthalazine-1-
carboxamide 6. The reaction of 1 with isochromene-1,3-dione
derivatives 7a,b under the same conditions gave 5-(3,4-dime-
thoxybenzylidene)-3-(1-oxo-1,2-dihydrophthalazine-4-
carbonyl)-2,3-dihydro-5H-2,3-benzodiazepine-1,4-dione 8a and
5-[(1,3-diphenyl-1H-pyrazol-4-yl)methylene]-3-(1-oxo-1,2-
dihydrophthalazine-4-carbonyl)-2,3-dihydro-5H-2,3-benzodi-
azepine-1,4-dione 8b (Scheme 3). The structure of compounds
6 and 8 a,b were substituted from the analytical and spectro-
scopic data.
The conversion of 1 to compounds 6 and 8a,b via the reac-
tion with phthalic anhydride and chromen-1,3-dione derivative
can be visualised as shown in Scheme 4.
Furthermore, the reaction of the hydrazide 1 with norbornene
dicarboxylic acid anhydride derivative 9 in boiling dioxane
It has been reported that the reaction of hydrazide and
hydrazine derivative with phthalic anhydride yielded the
N-phthalimide or phthalazine derivatives.24 We now report the
Scheme 2
Scheme 3

JOURNAL OF CHEMICAL RESEARCH 2012 77
Scheme 4
gave the pyridazine-1,4-dione derivative 10. The IR spectrum
of the product is devoid of the absorption bands characteristic
of the symmetric and antisymmetric stretching vibrational
coupling. The formation of 10 could took place through the
nucleophilic addition by the nitrogen nucleophile of the hydra-
zide on the carbonyl group of the anhydride leading to ring
opening followed by cyclisation with elimination of the water
molecule.
When compound 1 was allowed to react with activated
nitrile such as 1,3-diphenyl pyrazol-4-yl methylene malononi-
trile 11 in refluxing dioxane in the presence of a catalytic
amount of piperidine it gave the Shiff’s like base N-[(1,
3-diphenyl-1H-pyrazol-4-yl)-methylene]-4-oxo-3,4-dihy-
drophthalazine-1-carbohydrazide 12. This was confirmed by
spectroscopic data and comparison with an authentic sample
prepared from the condensation of the acid hydrazide 1 with
1,3-diphenylpyrazole-4-carboxaldehyde,25 in refluxing diox-
ane in a catalytic amount of piperidine (Scheme 5).
Reaction of the hydrazide 1 with ethoxymethylenemalono-
nitrile26 in boiling pyridine gave the pale yellow solid product
with molecular formula C18H12N6O4 [M+ = 376 (23.8%)] which
was analysed and assigned as 4-oxo-N-(1-oxo-1,2-dihydroph-
thalazine-4-carbonyl)-3,4-dihydrophthalazine-1-carbohydra-
zide 13. Evaporation of the excess solvent after acidification of
the filtrate left 4-oxo-3,4-dihydrophthalazine-1-carboxamide
14. The formation of compounds 14 and 15 can be postulated
as shown in Scheme 7.
It has been reported27 that the hydrazine or hydrazide deriva-
tive reacted with a β-ketoester such as ethyl acetoacetate in
refluxing ethanol gave the pyrazolone derivative. The reaction
of compound 1 with ethyl acetoacetate in refluxing pyridine
gave 4-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbonyl)
phthalazin-1(2H)-one 15 (Scheme 5). Acylation of the hydra-
zide 1 using chloroacetyl chloride in DMF in the cold for
one hour gave the chloroacetyl derivative 16 which is easily
cyclised through dehydration upon heating in pyridine to give
4-(5-(chloro-methyl)-1,3,4-oxadiazol-2-yl)phthalazin-1(2H)-one
17 (Scheme 8).
The formation of 12 can be visualised as shown in Scheme 6.

78 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 5
Scheme 6
(20 mL) was refluxed for 6 h. The reaction mixture was allowed to
cool and then acidified with cold dilute hydrochloric acid. The residue
was filtered off and then recrystallised from dioxane to give 2a and 2b
respectively.
The nucleophilic substitution reaction takes place through
the tetrahedral mechanism shown in Scheme 9.
Acylation of 1 using freshly distilled acetic anhydride at
different times afforded mono- , di- and tri-acetylated products
18–20. Isatin and benzil condensed with the hydrazide
derivative 1 in boiling dioxane to give the corresponding
condensation product 21 and 22 respectively (Scheme 9).
1-(1-Oxo-1,2-dihydrophthalazine-4-carbonyl)-4-phenylthiosemi-
carbazide (2a): Yellow crystals; m.p. 280–283 °C, yield 55%. IR
1
(KBr) (υmax, cm−1): 3465(w), 3237(br.) (NH), 1666 (C=O). H NMR
(DMSO-d6): δH (ppm) 7.15–8.65 (m, 9Harom.), 9.8 (br.s, 2H, 2NH,
exchangeable with D2O), 10.57 (s, 1H, NH, exchangeable with D2O),
13.07 (s, 1H, NH, NHCOphth, exchangeable with D2O). MS, m/z (%):
339 (M+, 1.75), 285 (2.3), 245 (5.6),173 (2.48), 129 (31.9), 70(100).
Anal. Calcd for C16H13N5O2S (339): C, 56.63; H, 3.86; N, 20.64; S,
9.45. Found: C, 56.42; H, 3.53; N, 20.76; S, 9.60%.
1-(1-Oxo-1,2-dihydrophthalazine-4-carbonyl)-4-phenylsemicarba-
zide (2b): Colourless crystals; m.p > 300 °C, yield 50%. IR (KBr)
(υmax, cm−1): 3417 (br.), 3171(br.) (NH), 1666 (C=O). MS, m/z (%):
323 (M+, 1.11), 204 (52.36), 173 (68.8),145 (65.12), 117 (41), 102
(29.9), 90 (68.4), 79 (100). Anal. Calcd for C16H13N5O3 (323): C,
59.44; H, 4.05; N, 21.66. Found: C, 59.12; H, 3.93; N, 21.73%.
Experimental
Melting points were measured on an electrothermal melting point
apparatus. Elemental analyses were performed using a Heraeus
CHN Rapid analyser at the Microanalytical unit, Cairo University. IR
Spectra were measured on a Unicam SP-1200 spectrophotometer
using KBr Wafer technique. 1H NMR spectra were measured in
DMSO-d6 on a Varian plus instrument (300 MHz). Mass spectra were
recorded on a Shimadzu GC-MS QP1000 EX instrument operating at
70 eV in EI mode.
Reaction of the hydrazide 1 with phenylisothiocyanate and phenyliso-
cyanate; general procedure
A mixture of 1 (1 g, 4.9 mmole) and phenylisothiocyanate (0.8 mL,
4-(4-Phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phthalazin-
1(2H)-one (3)
Method 1: A mixture of 1 (2.04 g, 10 mmole) and phenylisothiocya-
nate (1.6 mL, 10 mmole) in (10%) sodium hydroxide (20 mL) was
4.9 mmole) or phenylisocyanate (0.5 mL, 4.9 mmole) in pyridine

JOURNAL OF CHEMICAL RESEARCH 2012 79
Scheme 7
Scheme 8
refluxed for 3 h. The reaction mixture was allowed to cool and then
acidified with cold dilute hydrochloric acid. The deposited solid was
filtered off, washed several times with cold water, dried and then
recrystallised from dioxane to give 3.
Method 2: Compound 2a (3.39 g, 10 mmole) was heated under
reflux with (10%) sodium hydroxide (20 mL) for 3 h. The reaction
mixture was allowed to cool and then acidified with cold dilute
hydrochloric acid. The deposited solid was filtered off, washed several
times with cold water, dried and then recrystallised from dioxane to
give 3.
4-(4-Phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)phthalazin-
1(2H)-one (3): Colourless crystals; m.p. 220–222 °C, yield 30%.
IR (KBr) (υmax, cm−1): 3325, 3285, 3195, 3132 (NH), 1650 (C=O).
1H NMR (DMSO-d6): δH (ppm) 6.9–8.8 (m, 9Harom.), 9.8 (s, 1H, NH,

80 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 9
exchangeable with D2O), 12.98 (s, 1H, NH, NHCOphth, exchangeable
with D2O). MS, m/z (%): 321 (M+, 76.3), 259 (16.3), 219 (23.8), 173
(16.3), 102 (36.3), 51 (100). Anal. Calcd for C16H11N5OS (321): C,
59.80; H, 3.45; N, 21.79; S, 9.98. Found: C, 59.62; H, 3.73; N, 21.73;
S, 9.67%.
dried and then recrystallised from dioxane/DMF mixture to give 6.
Colourless crystals; m.p 312–314 °C, yield 63%. IR (KBr) (υmax, cm−1):
3373, 3168 (NH), 1796, 1739 (coupling bands), 1707, 1667 (CO). 1H
NMR (DMSO-d6): δH (ppm) 7.9–8.5 (m, 8Harom.), 11.36 (s, 1H, NH,
NHCHO, exchangeable with D2O), 13.27 (s, 1H, NH, NHCOphth
,
exchangeable with D2O). MS, m/z (%): 334 (M+, 21.2), 173 (100), 145
(65.8). Anal. Calcd for C17H10N4O4 (334): C, 61.08; H, 3.02; N, 16.76.
Found: C, 61.37; H, 3.23; N, 16.37%.
Reaction of 1 with formic acid; synthesis of N-formyl-4-oxo-3,4-dihy-
dro-phthalazine-1-carbohydrazide 4
A solution of 1 (1 g, 4.9 mmole) in formic acid (10 mL) was heated
under reflux. The deposited solid during heating after 7 h was filtered
off, washed several times with water, dried and then recrystallised
from dioxane to give 4. Colourless crystals; m.p. 262–264 °C, yield
55%. IR (KBr) (υmax, cm−1): 3428, 3295, 3171(NH), 1702(C = Oformyl),
1662 (C = Ohydrazide). 1H NMR (DMSO-d6): δH (ppm) 7.89–8.4 (m,
5H, 4Harom. + aldehydic protone CHO), 10.1 (s, 1H, NH, NHCHO,
exchangeable with D2O), 10.5 (s, 1H, NH, NHCO, exchangeable with
D2O), 13.03 (s, 1H, NH, NHCOphth, exchangeable with D2O). MS, m/z
(%): 232 (M+, 9.9), 204 (53.8), 173 (81.9), 145 (100), 117 (35.2), 90
(91.2). Anal. Calcd for C10H8N4O3 (232): C, 51.73; H, 3.47; N, 24.13.
Found: C, 51.47; H, 3.73; N, 24.37%.
4-(1,3,4-Oxadiazol-2-yl)phthalazin-1(2H)-one (5): A mixture of
compound 4 (1 g, 4.3 mmole) and phosphorus pentaoxide (1 g) in dry
toluene (20 mL) was refluxed for 8 h. The deposited solid during
reflux was filtered off, washed several times with water, dried and
then recrystallised from ethanol/dioxane mixture to give 5. The
same product 5 formed when a mixture of the acid hydrazide 1 (1 g,
4.9 mmole) and triethylorthoformate (10 mL) was heated under
reflux for 72 h. After cooling, the solid deposited was filtered off and
recrystallised from ethanol/dioxane mixture to give 5 (identity m.p.,
mixed m.p., IR, MS and TLC comparison). Pale yellow powder; m.p
> 300 °C, yield 60%. IR (KBr) (υmax, cm−1): 3438, 3216(w), 3166(w)
(NH), 1671 (CO). MS, m/z (%): 214 (M+, 67.4), 171 (8.4), 145 (20.2),
129 (100), 117 (14), 102 (30.4), 88 (41.1). Anal. Calcd for C10H6N4O2
(214): C, 56.08; H, 2.82; N, 26.16. Found: C, 56.37; H, 2.73; N,
26.37%.
5-(3,4-Dimethoxybenzylidene)-3-(1-oxo-1,2-dihydrophthalazine-4-
carbonyl)-2,3-dihydro-5H-2,3-benzodiazepine-1,4-dione (8a):
A
mixture of 1 (1 g, 4.9 mmole) and 4-(3,4-dimethoxybenzylidene)-4H-
isochromene-1,3-dione 7a (1.5 g, 4.9 mmole) in dioxane (30 mL) in
the presence of glacial acetic acid (1 mL) was refluxed for 5 h. The
excess solvent was removed under reduced pressure, the obtained
yellow solid was filtered off, dried and then recrystallised from etha-
nol/dioxane mixture to give 8a. Yellow crystals; m.p 310–312 °C,
yield 52%. IR (KBr) (υmax, cm−1): 3444, 3222 (NH), 1682, 1662 (CO).
MS, m/z (%): 496 (M+, 17.2), 360 (24.1), 266 (34.5), 189 (34.5), 163
(100), 120 (48.3), 103 (20.7). Anal. Calcd for C27H20N4O6 (496): C,
65.32; H, 4.06; N, 11.29. Found: C, 65.27; H, 3.83; N, 11.37%.
5-((1,3-Diphenyl-1H-pyrazol-4-yl)methylene)-3-(1-oxo-1,2-dihydro-
phthalazine-4-carbonyl)-2,3-dihydro-5H-2,3-benzodiazepine-1,
4-dione (8b): A mixture of 1 (1 g, 4.9 mmole) and 4-((1,3-diphenyl-
1H-pyrazol-4-yl)methylene)isochromen-1,3-dione 7b (1.9 g, 4.9 mmole)
in dioxane (30 mL) in the presence of glacial acetic acid (1 mL) was
refluxed for 5 h. The excess solvent was removed under reduced pres-
sure. The deposited solid was collected by filtration, dried and then
recrystallised from dioxane/DMF mixture to give 8b as yellow crys-
tals; m.p. 286–288 °C, yield 45%. IR (KBr) (υmax, cm−1): br.3182
(NH), 1680 (CO). MS, m/z (%): 578 (M+, 11.1), 334 (16.2), 189
(17.7), 173 (34.8), 145 (36.9), 77(100) . Anal. Calcd for C34H22N6O4
(578): C, 70.58; H, 3.83; N, 14.53. Found: C, 70.37; H, 3.53; N,
14.25%.
Reaction of the acid hydrazide 1 with norbornenedicarboxylic acid
anhydride derivative; synthesis of the pyridazine-1,4-dione derivative
10
A mixture of the acid hydrazide 1 (1 g, 4.9 mmole) and norborn-
enedicarboxylic acid anhydride derivative 9 (0.4 mL, 4.9 mmole) in
dioxane (20 mL) in the presence of glacial acetic acid (1 mL) was
N-(1,3-Dioxoisoindolin-2-yl)-4-oxo-3,4-dihydrophthalazine-1-car-
boxamide (6): A mixture of 1 (1 g, 4.9 mmole) and phthalic anhydride
(0.72 g, 4.9 mmole) in dioxane (30 mL) in the presence of glacial
acetic acid (1 mL) was refluxed for 6 h. The excess solvent was
removed under reduced pressure, the deposited solid was filtered off,

JOURNAL OF CHEMICAL RESEARCH 2012 81
heated under reflux for 5 h. Evaporation of excess solvent left the
solid product which recrystallised from benzene/ethanol mixture to
give 10. Colourless crystals; m.p. 160–162 °C, yield 50%. IR (KBr)
(υmax, cm−1): br.3268 (NH), 1725, 1673 (CO). MS, m/z (%): 364 (M+,
9.3), 284 (13), 173 (57.4), 145 (33.0), 90 (36.9), 80 (100). Anal. Calcd
for C19H16N4O4 (364): C, 62.63; H, 4.43; N, 15.38. Found: C, 62.41;
H, 4.55; N, 15.26%.
1674 (CO). MS, m/z (%): 280 (M+, 10.9), 173 (100), 145 (61.1), 114
(22.2), 90 (44.2). Anal. Calcd for C11H9ClN4O3 (280.5): C, 47.04; H,
3.23; Cl, 12.63; N, 19.96. Found: C, 47.33; H, 3.46; Cl, 12.49; N,
19.74%.
Cyclisation of 16; synthesis of 4-(5-(chloromethyl)-1,3,4-oxadiazol-2-
yl) phthalazin-1(2H)-one 18
Solution of the chloroacetyl derivative 16 (1 g, 3.5 mmole) in pyridine
(15 mL) was heated under reflux for 6 h. The solid precipitated during
heating was filtered off and recrystallised from DMF to give 17.
Colourless powder; m.p. 306–308 °C, yield 80%. IR (KBr) (υmax, cm−1):
3247 (NH), 1665 (CO), 1635 (C = N). MS, m/z (%): 263 (M+, 1.2),
213 (3.5), 171 (4.1), 145 (5.2), 129 (11.3), 117 (2.9), 102 (1.7), 90
(7.4), 52 (100). Anal. Calcd for C11H7ClN4O2 (262.5): C, 50.30; H,
2.69; Cl, 13.50; N, 21.33. Found: C, 50.15; H, 2.48; Cl, 13.21; N,
21.27%.
Reaction of 1 with activated nitrile; synthesis of N-((1,3-diphenyl-1H-
pyrazol-4-yl)methylene)-4-oxo-3,4-dihydro-phthalazine-1-carbohy-
drazide 12
A mixture of 1(1 g, 4.9 mmole) and 2-[(1,3-diphenyl-1H-pyrazol-4-yl)
methylene] malononitrile 11 (1.5 g, 4.9 mmole) in dioxane (30 mL) in
the presence of piperidine (1 mL) was heated under reflux for 3 h. The
reaction mixture was allowed to cool and then acidified with cold
dilute hydrochloric acid. The precipitated was collected by filtration,
washed several times with water, dried and then recrystallised from
dioxane/DMF mixture to give 12. Colourless crystals; m.p. 296–
298 °C, yield 54%. IR (KBr) (υmax, cm−1): br.3442, 3230 (OH, NH),
1671 (CO). 1H NMR (DMSO-d6): δH (ppm) 7.5–8.6 (m, 15Harom.), 9.03
(s, 1H, N = CH), 12.01 (s, 1H, NH, NHCO, exchangeable with D2O),
13.07 (s, 1H, NH, NHCOphth, exchangeable with D2O). MS, m/z (%):
434 (M+, 46.98), 245 (100), 189 (30.54), 173 (11.83), 145 (16.15),
117 (15.56), 104 (25.50), 90 (28.71). Anal. Calcd for C25H18N6O2
(434): C, 69.11; H, 4.18; N, 19.34. Found: C, 69.32; H, 4.23; N,
19.11%.
Acetylation of 1; general procedure
A mixture of 1 (1 g, 4.9 mmole) and freshly distilled acetic anhydride
(10 mL) was heated under reflux for different times 10 min., 30 min.
and 60 min. The excess solvent was removed under reduced pressure,
the obtained solid was collected by filtration and then recrystallised
from ethanol/dioxane mixture to give the mono-, di-, and tri-acety-
lated products 18–20 respectively.
N-Acetyl-4-oxo-3,4-dihydrophthalazine-1-carbohydrazide
(18):
Colourless crystals; m.p; 296–298 °C, yield 42%. IR (KBr) (υmax, cm−1):
1
3321 (NH), 1714, 1683 (CO). H NMR (DMSO-d6): δH (ppm) 1.88
Synthesis of authentic sample 12
(s, 3H, CH3), 7.8–8.4 (m, 4Harom.), 9.99 (s, 1H, NH, NHCOCH3,
exchangeable with D2O), 10.3 (s, 1H, NH, NHCO, exchangeable with
D2O), 12.99 (s, 1H, NH, NHCOphth, exchangeable with D2O). MS, m/z
(%): 246 (M+, 12.7), 204 (70.7), 173 (100), 145 (64.7), 117 (20.7), 90
(52), 63 (38). Anal. Calcd for C11H10N4O3 (246): C, 53.66; H, 4.09; N,
22.75. Found: C, 53.37; H, 4.23; N, 22.47%.
To a solution of the hydrazide 1 (1 g, 4.9 mmole) in dioxane (20 mL),
1,3-diphenyl-1H-pyrazole-4-carbaldehyde (1.2 g, 4.9 mmole) and
piperidine (1 mL) were added and the whole mixture was heated
under reflux for 3 h. Evaporation of excess solvent left the solid prod-
uct which recrystallised from dioxane to give 12 (identity m.p., mixed
m.p., IR and TLC).
N,N-diacetyl-4-oxo-3,4-dihydrophthalazine-1-carbohydrazide
(19): Colourless crystals; m.p. 240–242 °C, yield 30%. IR (KBr) (υmax
,
Reaction of the acid hydrazide 1 with ethoxymethylene malononitrile;
synthesis of 4-oxo-N-(1-oxo-1,2-dihydro-phthalazine-4-carbonyl)-
3,4-dihydrophthalazine-1-carbohydrazide 13 and 4-oxo-3,4-dihy-
drophthalazine-1-carboxamide 14
A mixture of 1(1 g, 4.9 mmole) and ethoxymethylene malononitrile
(0.6 g, 4.9 mmole) in pyridine (15 mL) was refluxed for 1 h. The solid
precipitated during heating was filtered off and recrystallised from
DMF to give 13. Acidification of the filtrate with cold dilute hydro-
chloric acid followed by evaporation of the excess solvent left beige
precipitate which recrystallised from ethanol/dioxane mixture to give
14.
4-Oxo-N-(1-oxo-1,2-dihydrophthalazine-4-carbonyl)-3,4-dihy-
drophthalazine-1-carbohydrazide (13): Pale yellow crystals m.p.
326–327 °C, yield 40%. IR (KBr) (υmax, cm−1): 3398, 3241, 3169
(NH), 1673 (CO). MS, m/z (%): 376 (M+, 23.8), 173 (100), 145 (60),
117 (27.9), 90 (44.1). Anal. Calcd for C18H12N6O4 (376): C, 57.45; H,
3.21; N, 22.33. Found: C, 57.23; H, 3.45; N, 22.19%.
cm−1): 3375, 3303, 3168 (NH), 1729, 1714, 1617 (CO). H NMR
(DMSO-d6): δH (ppm) 2.37 (s, 6H, N(COCH3)2), 7.9–8.5 (m, 4Harom.),
11.1 (s, 1H, NH, NHCO, exchangeable with D2O), 13.19 (s, 1H, NH,
NHCOphth, exchangeable with D2O). MS, m/z (%): 288 (M+, 3.7), 246
(40.7), 204 (100), 173 (72.2), 145 (50.9), 117 (21.3), 90 (58.3), 63
(29.6). Anal. Calcd for C13H12N4O4 (288): C, 54.17; H, 4.20; N, 19.44.
Found: C, 54.35; H, 4.53; N, 19.21%.
1
N,N,O-Triacetyl-4-oxo-3,4-dihydrophthalazine-1-carbohydrazide
(20): Colourless crystals; m.p. 198–200 °C, yield 51%. IR (KBr) (υmax
,
1
cm−1): 3167 (NH), 1736 (COester), 1686 (COphth), 1671 (COamide). H
NMR (DMSO-d6): δH (ppm) 2.372 (s, 9H, 3 COCH3), 7.815–7.817 (d,
1Harom., H = 0.6Hz ), 7.91–7.99 (m, 2Harom.), 8.321–8.326 (d, 1Harom.
H = 1.5Hz ), 13.09 (s, 1H, NH, exchangeable with D2O). Anal. Calcd
for C15H14N4O5 (330): C, 54.55; H, 4.27; N, 16.96. Found: C, 54.25;
H, 4.53; N, 16.77%.
,
Reaction of the hydrazide 1 with isatin; synthesis of 4-oxo-N-(2-oxoin-
dolin-3-ylidene)-3,4-dihydrophthalazine-1-carbohydrazide 21
A mixture of the hydrazide 1 (1 g, 4.9 mmole) and isatin (0.7 g,
4.9 mmole) in dioxane (20 mL) was heated under reflux for 2 h.
The deposited solid during reflux was filtered off, dried and then
recrystallised from DMF to give 21. Yellow powder; m.p > 300 °C,
yield 65%. IR (KBr) (υmax, cm−1): 3226(w), 3165(w), 3109 (NH), 1713
(COphthalazinone), 1683 (COhydrazide) MS, m/z (%):334 (M+1, 52.2%), 333
(30.4), 159 (82.6), 132 (100), 104 (48.8), 77 (88.9). Anal. Calcd for
C17H11N5O3 (333): C, 61.26; H, 3.33; N, 21.01. Found: C, 61.34; H,
3.76; N, 21.25%.
4-Oxo-3,4-dihydrophthalazine-1-carboxamide (14): Beige crystals.
m.p. 240–242 °C, yield 37%. IR (KBr) (υmax, cm−1): 3228, 3162 (NH2,
NH), 1666 (CO), 1629 (C = N). MS, m/z (%): 189 (M+, 77.8), 173
(40), 145 (26.7), 130 (68.9), 117 (66.7), 103 (42.2), 88 (100). Anal.
Calcd for C9H7N3O2 (189): C, 57.14; H, 3.73; N, 22.21. Found: C,
57.33; H, 3.45; N, 22.43%.
4-(3-Methyl-5-oxo-4,5-dihydro-1H-pyrazole-1-carbonyl)
phthalazin-1(2H)-one (15): A mixture of 1 (1 g, 4.9 mmole) and ethyl
acetoacetate (0.6 mL, 4.9 mmole) in pyridine (15 mL) was refluxed
for 3 h. The deposited solid during reflux was filtered off, dried and
then recrystallised from dioxane/DMF mixture to give 15. Pale yellow
crystals; m.p 306–308 °C, yield 57 %. IR (KBr) (υmax, cm−1): 3225,
3170 (NH), br.1673 (CO). MS, m/z (%): 268 (M-2, 28), 173 (44), 145
(100), 103 (48), 90 (76). Anal. Calcd for C13H10N4O3 (270): C, 57.78;
H, 3.73; N, 20.73. Found: C, 57.53; H, 3.56; N, 20.44%.
Reaction of the hydrazide 1 with benzyl; synthesis of 4-oxo-N-(2-oxo-
1,2-diphenylethylidene)-3,4-dihydro-phthalazine-1-carbohydrazide
22
A mixture of the hydrazide 1 (1 g, 4.9 mmole), benzil (1 g, 4.9 mmole)
and ammonium acetate (1 g) in dioxane (25 mL) was heated under
reflux for 6 h (TLC). Evaporation of excess solvent left a solid product
which washed with water, dried and then recrystallised from ethanol/
dioxane mixture to give 22. Pale yellow powder; m.p. 160–163 °C,
yield 70%. IR (KBr) (υmax, cm−1): 3307, 3162 (NH), 1714, 1688, 1647
(CO). MS, m/z (%): 396 (M+, 0.6), 291 (74), 204 (85.6), 173 (84.8),
145 (87.3), 102 (25.9), 90 (100). Anal. Calcd for C23H16N4O3 (396): C,
69.69; H, 4.07; N, 14.13. Found: C, 69.33; H, 3.86; N, 14.24%.
Acylation of 1 using chloroacetyl chloride; synthesis of N-(2-chloro-
acetyl)-4-oxo-3,4-dihydrophthalazine-1-carbohydrazide 16
A mixture of the hydrazide 1 (1 g, 4.9 mmole) and chloroacetyl
chloride (0.5 mL, 4.9 mmole) in DMF (15 ml) was stirred at room
temperature for 1 h. The reaction mixture was poured on water, the
obtained solid precipitate was collected by filtration, dried and then
recrystallised from dioxane to give 16. Colourless powder; m.p. 284–
286 °C, yield 72%. IR (KBr) (υmax, cm−1): 3342, 3297 (NH), 1699,

82 JOURNAL OF CHEMICAL RESEARCH 2012
15 X. Cockcrof, K.J. Dillon, L. Dixon, J. Drzewiecki, P. Everseley, S. Gomes,
J. Hoare, F. Kirrigan, I. Nalthews, K.A. Menear, N.M. Martin, R. Newton,
J. Paul, G.C. Smith, J. Vile and A.J. Whittler, Bioorg. Med. Chem. Lett.,
2006, 16, 1040.
Received 27 November 2011; accepted 16 January 2012
Paper 1101009 doi:10.3184/174751912X13274297624330
Published online: 23 February 2012
16 X. Cockcrof, K.J. Dillon, L. Dixon, J. Drzewiecki, F. Kirrigan, V.M. Loh,
N.M. Martin, K.A. Menear and G.C. Smith, Bioorg. Med. Chem. Lett.,
2005, 15, 2235.
17 J.S. Kim, H. Lee, M. Suh, H.P. Choo, S.K. Lee, H.J. Park, C. Kim, S.W.
Park and C. Lee, Bioorg. Med. Chem., 2004, 12, 3683.
18 N. Haider, J. Kabicher, J. Kaferbock and A. Plenk, Molecules, 2007, 12,
1900.
References
1
J.A. Oartes, The pharmacological basis of therapeutics, 9th edn, Pergamon
Press, New York, 2001, p. 780.
2
S. Szasz and Z. Budvavi-Bavauy, Pharmacological chemistry of
antihypertensive agents, Vol. 3. CRC Press, Boca Raton, 1991.
P.A. Van Zwieten and W. Greenlee, J. Antihypertensive Drugs, 1997, 1.
J. Florez, J.A. Armijo, A. Mediavilla, Farmacologı Humana, 3rd edn,
Masson S.A., Barcelona, 2000, p. 671.
3
4
19 S. Demirayak, K. Karaburun and R. Beis, Eur. J. Med. Chem., 2004, 39,
1089.
5
6
7
G. Heinisch and H. Kopelent-Frank, Prog. Med. Chem., 1990, 27, 1.
G. Heinisch and H. Kopelent-Frank, Prog. Med. Chem., 1992, 29, 141.
V.D. Piaz, M.P. Giovannoni, R. Languna and E. Cano, Eur. J. Med. Chem.,
1994, 29, 249.
S. Demirayak, A.C. Karaburun, I. Kayagil, K. Erol and B. Sirmagul, Arch.
Pharm. Res., 2004, 27, 13.
20 A. Goodman and L.S. Gilman, The pharmacological basis of therapeutics,
11th edn, McGraw-Hill, New York, 2006, p. 860.
21 K.M. Shubin, V.A. Kuznetsov and V.A. Galishev, Tetrahedron Lett., 2004,
45, 1407.
8
9
22 H. Brad, G. Guo-Qiang, P.C. Partha, R.F. Games, P. Liping, M.R. Robert,
B.R. Anthony, R. Andreas, S. Kelvin, T. Maya, P.W. Ryan, X. Shimin, Z.
Dawei, H. Faye, R.L. Matthew, S. Rashed, L. Vivian, G. David, H.P.
Matthew, H. Bradley, S. Lisa, M. Scot, M.W. Lu and S.T. Andrew, J.Med.
Chem., 2008, 51, 6271.
N. Haider, R.W. Hartmann and A. Steinwender, Arch.Pharm. Pharm Med.
Chem., 1999, 332, 408.
10 E. Sotelo, N. Fraiz, M. Yanez, V. Terades, R. Laguna, E. Cano and E.
Ravina, Bioorg. Med. Chem., 2002, 10, 2873.
11 M.Van der Mey, H. Boss, D. Couwenberg, A. Hatzelmann, G.J. Sterk, K.
Goubitz and H. Timmerman, J. Med. Chem., 2002, 45, 2526.
12 M. Van der Mey, K.M. Bommele, H. Boss, A. Hatzelmann, M. Van
Slingerland, G.J. Sterk and H. Timmerman, J. Med. Chem., 2003, 46,
2008.
23 M.R. Mahmoud, W.S.I. Abou-Elmagd, H.A. Derbala and M.H. Hekal,
Chinese J. Chem., 2011, 29, 1446.
24 B.M. Khadilkar and S.D. Samant, Indian J. Chem., 1993, 11, 1137.
25 M.A. Kira, M.O. Abdel-Rahman and K.Z. Gadalla, Tetrahedron Lett.,
1969,10,109.
26 M. Abdel-Aziz, G.E.A. Abuo-Rahma andA.A. Hassan, Eur. J. Med. Chem.,
13 M.Yamaguchi, T. Koga, K. Kamei, M.Akima, N. Maruyama and T. Kuroki,
Chem. Pharm. Bull. (Tokyo), 1994, 42, 1850.
2009, 44, 3480.
27 A.H. El-Masry, H.H. Fahmy and S.H.A. Abdelwahed, Molecules, 2000, 5,
1429.
14 M. Yamaguchi, N. Maruyama, T. Koga, K. Kamei, M. Akima and T.
Kurokki, Chem. Pharm. Bull. (Tokyo), 1995, 43, 236.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.