Phthalazines and phthalazine hybrids as antimicrobial agents: Synthesis and biological evaluation

Article abstract of DOI:10.1177/1747519819883840

Phthalazine and phthalazinone derivatives are important owing to their significant biological activities and pharmacological properties. Herein, a benzoic acid derivative (2), a benzoxazin-1-one derivative (3), and an oxophthalazin-2(1H)-yl)acetohydrazide (13) are utilized as precursors to construct a novel series of phthalazinones bearing various valuable functional groups in excellent yields via several simple and promising approaches. Finally, the antimicrobial activity of the newly synthesized phthalazines is screened against different microbial strains; namely, Gram-negative and Gram-positive bacteria utilizing Amoxicillin as a standard drug.

Full text of DOI:10.1177/1747519819883840

883840CHL0010.1177/1747519819883840Journal of Chemical ResearchMourad et al.
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Research Paper
Journal of Chemical Research
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Phthalazines and phthalazine hybrids
as antimicrobial agents: Synthesis
and biological evaluation
https://doi.org/10.1177/1747519819883840
DOI: 10.1177/1747519819883840
journals.sagepub.com/home/chl
Asmaa Kamal Mourad , Abdelmoneim Abdelsalam Makhlouf,
Ahmed Yousef Soliman and Samar Ahmed Mohamed
Abstract
Phthalazine and phthalazinone derivatives are important owing to their significant biological activities and pharmacological
properties. Herein, a benzoic acid derivative (2), a benzoxazin-1-one derivative (3), and an oxophthalazin-2(1H)-yl)
acetohydrazide (13) are utilized as precursors to construct a novel series of phthalazinones bearing various valuable
functional groups in excellent yields via several simple and promising approaches. Finally, the antimicrobial activity of the
newly synthesized phthalazines is screened against different microbial strains; namely, Gram-negative and Gram-positive
bacteria utilizing Amoxicillin as a standard drug.
Keywords
benzoxazinone, Friedel Craft’s reaction, 1,3,4-oxadiazole, phthalazine, pyrazole
Date received: 28 July 2019; accepted: 1 October 2019
owing to the fact that it can be constructed from hydrazine
which is an uncommon amine source in nature.
Introduction
Phthalazine, also known as benzo-orthodiazine, 2,3-diazon-
aphthalene, and benzo[d]pyridazine, is a compound in which
pyridazine is fused with a benzene ring.
Chemistry Department, Faculty of Science, Fayoum University, Fayoum,
Egypt
Although, N-containing heterocyclic compounds are
widely distributed in nature, the presence of two adjacent
nitrogen atoms in the phthalazine ring makes it rare and not
very familiar in isolated extracts from living organisms,
Corresponding author:
Asmaa Kamal Mourad, Chemistry Department, Faculty of Science,
Fayoum University, Fayoum 63514, Egypt.
Email: akk00@fayoum.edu.eg

2
Journal of Chemical Research 00(0)
Phthalazines, as an important class of bicyclic
N-heterocycles, have attracted sizable attention due to their
valuable biological and pharmacological activities.1,2
Phthalazines are popular pharmacophores as they are
the core chemical motifs in many commercially available
drugs such as Azelastin (antihistamine),3 Vatalanib (vascular
endothelial growth factor receptor (VEGFR) inhibitor),4 and
Hydralazine (antihypertensive agent).5 Phthalazine deriva-
tives are also considered as p38MAP kinase inhibitors,6
selective binders of gamma-aminobutyric acid (GABA)
receptors,7 cyclooxygenase-2 (COX-2) inhibitors,8 and
high-affinity ligands of voltages gated calcium channels.9
Like many other isomeric benzodiazines, phthalazine deriv-
atives reveal numerous pharmacological and biological activi-
ties such as antimicrobial,10–12 antidiabetic,13 analgesic,14,15
anticonvulsant,16,17 antitumor,18–20 antiproliferative,20 antie-
pileptic,21,22 anti-inflammatory,23,24 and vasorelaxant.25,26
In addition, phthalazines are known as serotonin reuptake
inhibitors and are considered as anti-depression agents.27
Also, they are crucial precursors in the synthesis of many
compounds with interesting pharmacological properties
like phosphodiesterase inhibitors and blood platelet aggre-
gation inhibitors.27–29
Scheme 1. Synthesis of o-benzoic acid derivative 2.
exploiting Friedel Craft’s reaction conditions was achieved
and 2-(4-isopropylbenzoyl)benzoic acid (2) was produced
and subsequently used as a scaffold to construct our desired
heterocyclic systems (Scheme 1).32
Having o-aroylbenzoic acid derivative 2 in hand encour-
aged us to study its behavior toward various nitrogen nucleo-
philes; for instance, hydroxylamine hydrochloride, hydrazine
hydrate, thiosemicarbazide, and thiocarbonohydrazide.
Initially, cyclization of 2-(4-isopropylbenzoyl)benzoic
acid (2) to the promising benzo[1,2]oxazinone derivative 3
was accomplished using hydroxylamine hydrochloride in
pyridine (Scheme 2). The structure of compound 3 was
established through its elemental analysis and spectral
data. The infrared (IR) spectrum of 3 exhibited the disap-
pearance of the hydroxy group broad absorption band at
3293–3455cm−1 and the appearance of a cyclic imine C=N
absorption frequency at 1596cm−1. Also, the mass spec-
trum of 3 revealed the molecular ion peak at m/z=265
(50%).
According to a reported procedure,32 phthalazin-1-one
derivatives were readily accessible through the condensa-
tion reaction of o-benzoyl benzoic acid with hydrazine
hydrate in boiling ethanol. Consequently, adopting this pro-
cedure and allowing 2-(4-isopropylbenzoyl)benzoic acid
(2) to react with hydrazine hydrate gave 4-(4-isopropyl
phenyl)phthalazin-1(2H)-one 4 (Scheme 2). Compound 4
Encouraged by the above-mentioned facts, and in our
endeavor to develop novel synthetic approaches to construct
new valuable heterocycles for biological screening,30,31 we
report herein the synthesis of novel and diverse phthala-
zine, 1,3,4-oxadiazole, and pyrazole derivatives from read-
ily available and inexpensive scaffolds utilizing short and
straightforward synthetic routes.
Results and discussion
Owing to the aforementioned therapeutic properties of
phthalazines, aroylation of cumene by phthalic anhydride
Scheme 2. Compounds 2 and 3 as precursors for various phthalazines.

Mourad et al.
3
was identified through its spectral and analytical data in revealed two absorption bands at 3212 and 3444 cm−1
which the IR spectrum showed the disappearance of the corresponding to 2NH and an NH2 group, respectively. The
hydroxy group absorption and the appearance of a cyclic mass spectrum showed the molecular ion peak at m/z=353
amide carbonyl absorption band at 1664cm−1 in addition to (24%), which was equivalent to the molecular formula
a characteristic signal for the NH group at 3155cm−1. In C18H19N5OS.
addition, the mass spectrum of 4 exhibited the molecular
ion peak at m/z=264 (99%), which was in accordance with reaction of benzoxazinone derivative 3 with thiocarbonohy-
the molecular formula C17H16N2O. drazide in refluxing dioxane instead of refluxing pyridine
Interestingly, changing the solvent and performing the
It is noteworthy that 1-oxophthalazine derivatives 5 and gave access to a new fused tricyclic system containing a
6 were obtained via the reaction of 2-(4-isopropylbenzoyl) triazine moiety; namely, 7-(4-isopropylphenyl)-2H-[1,2,4,5]
benzoic acid (2) with thiosemicarbazide or thiocarbonohy- tetrazino[6,1-a]phthalazine-3(4H)-thione (10) (Scheme 2).
drazide, respectively, in refluxing pyridine (Scheme 2). The The IR spectrum of compound 10 was devoid of any absorp-
structure of compound 5 was substantiated through the IR tion band for a carbonyl group, but new frequencies at
spectrum which was devoid of the characteristic hydroxy 1284cm−1 corresponding to C=S and at 3212 and 3270cm−1
group absorption and revealed strong absorption bands at corresponding to 2NH groups were recorded and the molec-
3178 and 3367cm−1 characteristic for an NH2 group, an ular ion peak equivalent to the molecular formula C18H17N5S
intense absorption band at 1643cm−1 for the amide car- was detected in the mass spectrum at m/z=335 (11%).
bonyl group, and at 1284cm−1 due to the C=S group. The Another piece of evidence was acquired from the 1H NMR
1H NMR spectrum exhibited the amino group signal at δ spectrum in which two new slightly broad singlet peaks
6.90, while the mass spectrum revealed the molecular ion were revealed at 7.68 and 8.91ppm and were characteristic
peak at m/z=323 (5%), which was in accordance with the of two new NH groups.
molecular formula of C18H17N3OS. Likewise, the IR spec-
In addition, dihydroisoquinoline derivative 11 was
trum of compound 6 showed the disappearance of the readily obtained through the reaction between benzox-
hydroxy group band and the appearance of strong absorp- azinone 3 and acetylacetone as a carbon nucleophile
tion bands at 3440 and 3155cm−1 due to NH and NH2 (Scheme 2).36,37 The structure of compound 11 was con-
groups, respectively, a sharp absorption band at 1666cm−1 firmed by spectroscopic analysis. The IR spectrum exhib-
for the amide carbonyl group, and an absorption band at ited strong absorption bands at 1735 and 1666 cm−1
1423cm−1 for the C=S. The mass spectrum showed the attributed to three carbonyl groups, and at 1600 cm−1 cor-
1
molecular ion peak at m/z=338 (10%) which was equiva- responding to a cyclic imine C=N. Also, the H NMR
lent to the molecular formula C18H18N4OS.
spectrum supported the proposed structure of compound
In the same context, investigation of the behavior of 11 by revealing a new characteristic methyl group singlet
benzoxazinone 3 toward nitrogen nucleophiles was appeal- signal integrating for six protons at δ 2.50. Finally, the
ing. Interestingly, phthalazinone 4 was obtainable not only mass spectrum showed the molecular ion peak at
from o-aroylbenzoic acid derivative 2, as illustrated before, m/z = 347 (26%) equivalent to the molecular formula
but also from benzoxazinone derivative 3 through its C22H21NO3.
ammonolysis by fusing it with ammonium acetate at 150°C
In our attempts to build up additional fused heterocycles,
(Scheme 2).33,34 The formation of phthalazinone 4 was con- phthalazin-1-one derivative 4 was allowed to react with more
1
firmed from its IR spectrum, mass spectrum, H NMR, diversified carbon nucleophiles such as ethyl bromoacetate
melting and mixed melting points.
and benzoyl chloride (Scheme 2). Accordingly, 4-(4-isopro-
Another convenient approach for the preparation of pylphenyl)phthalazin-1(2H)-one (4) was allowed to react
phthalazinone derivatives was achieved via the reaction of with ethyl bromoacetate and anhydrous K2CO3 in dry ace-
benzoxazinone derivative 3 with benzyl amine in ethanol to tone to afford the corresponding N-alkyl derivatives 12.
afford 2-benzyl-4-(4-isopropylphenyl)phthalazin-1(2H)-
one (7) (Scheme 2).35,36
It is worthwhile to mention that no O-alkylation product
was isolated and the reaction most probably took place via
2
Moreover, 1-oxophthalazine derivatives 8 and 9 were SN reaction mechanism and this may be attributed to the
synthesized through the reactions of benzoxazinone deriv- fact that the nitrogen atom is more nucleophilic than oxygen
ative 3 with thiosemicarbazide or thiocarbonohydrazide, and therefore the N-alkylation product was the sole product.
respectively, in refluxing pyridine (Scheme 2). The struc- The structure of compound 12 was confirmed on the basis of
ture of 1-(4-(4-isopropylphenyl)-1-oxophthalazin-2(1H)- its elemental analysis and spectral data. The IR spectrum
yl)thiourea (8) was substantiated via its spectroscopic data. showed characteristic absorption bands at 1742cm−1 corre-
The IR spectrum exhibited intense absorption bands at 3178 sponding to the C=O of the ester and at 1657cm−1 corre-
and 3367cm−1 due to the NH and NH2 groups, respectively, sponding to the cyclic amide C=O, while it was devoid of
along with an amide carbonyl group at 1643cm−1. Also, the any absorption bands for NH. Also, the 1H NMR spectrum
1H NMR spectrum of compound 8 revealed signals at δ of 12 exhibited the distinctive ethyl group triplet–quartet
4.50 and 8.63 due to NH2 and NH, respectively. The mass splitting pattern at δ 1.20 and 4.15. Also, it confirmed the
spectrum showed the molecular ion peak at m/z=338 introduction of a new methylene group (CH2CO) at 4.98.
(21%) equivalent to the molecular formula C18H18N4OS. The mass spectrum of compound 12 revealed the molecular
Similarly, the IR spectrum of N-(4-(4-isopropylphenyl)- ion peak at m/z=350 (0.02%) equivalent to the molecular
1-oxophthalazin-2(1H)-yl)hydrazinecarbothioamide (9) formula C21H22N2O3.

4
Journal of Chemical Research 00(0)
Scheme 3. Reactions of acetic acid hydrazide derivative 13.
In addition, the chemical structure of the latter com- hydrazide 13 and different aromatic aldehydes; namely,
pound 12 was confirmed chemically via its interaction with benzaldehyde, p-chlorobenzaldehyde, and p-nitrobenzalde-
hydrazine hydrate to afford 2-(4-(4-isopropylphenyl)-1-ox- hyde in ethanol (Scheme 3). The IR spectra of compounds
ophthalazin-2(1H)-yl)acetohydrazide (13). The IR spectrum 15a–c showed stretching bands around 1579–1584cm−1
of 13 revealed absorption bands at 1662cm−1 correspond- corresponding to the imine group C=N. The 1H NMR spec-
ing to the C=O groups, and at 3329 and 3444cm−1 corre- trum of compound 15a, as a representative example,
sponding to the NH and NH2 groups, respectively, while 1H showed signals for NH at δ 4.95 and for CH at δ 8.72,
NMR spectrum revealed NH2 and NH signals at δ 4.28 and while the mass spectrum revealed the molecular ion peak at
9.29, respectively. The mass spectrum of compound 13 m/z=424 (100%) equivalent to the molecular formula
showed the molecular ion peak at m/z=336 (15%) equiva- C26H24N4O2. Subsequent cyclization of aryl methylidene
lent to the molecular formula C19H20N4O2.
hydrazide derivatives 15a–c to oxadiazole derivatives 16a–c
Refluxing phthalazinone derivative 4 with benzoyl was achieved through boiling in acetic anhydride (Scheme
chloride on a steam bath gave access to 2-benzoyl-4-(4- 3). The IR spectra of compounds 16a–c revealed absorption
isopropylphenyl)phthalazin-1(2H)-one (14). The IR spec- bands around 1661cm−1 corresponding to C=O groups and
1
trum of 14 was devoid of any NH absorption bands, but were devoid of any bands for NH groups. Also, the H
showed an intense absorption band at 1692cm−1 attributed NMR spectrum of compound 16a, as a representative
to the two C=O groups. The mass spectrum showed a peak example, showed the oxadiazole singlet signal at δ 7.03 and
corresponding to the molecular ion at m/z=368 (53%). the new methyl singlet signal at δ 2.04, while the mass
Interestingly, hydrazinolysis of phthalazin-1-one deriva- spectrum showed the molecular ion peak at m/z=466
tive 14 with hydrazine hydrate in ethanol afforded a mix- (100%) equivalent to the molecular formula C28H26N4O3.
ture of benzoyl hydrazine and phthalazinone derivative 4.
In addition, a cyclization reaction took place when ace-
Driven by the high functionality of the side chain of tic acid hydrazide derivative 13 was allowed to react with
oxophthalazine acetohydrazide derivative 13, the effect of carbon disulfide in alcoholic potassium hydroxide to afford
various carbon nucleophiles was explored. For instance, the corresponding oxadiazolo-2-thione derivative 17
reactions of compound 13 with aromatic aldehydes to (Scheme 3). The IR spectrum of compound 17 revealed the
1
obtain a new series of biologically active Schiff’s bases is introduction of a C=S group at 1423cm−1. Also, the H
described, in which the corresponding Schiff bases 15a–c NMR spectrum of compound 17 showed a methylene
were obtained through a condensation reaction between bridge singlet signal at δ 5.51 and an NH group signal at

Mourad et al.
5
14.6, whereas the mass spectrum showed a peak corre- absorption bands for the four C=O groups at 1662, 1737,
sponding to the molecular ion at m/z=378 (4%) equivalent and 1792cm−1, while the 1H NMR spectrum showed a sin-
to the molecular formula C20H18N4O2S.
gle signal for the methylene bridge at δ 5.11 and revealed
A new approach was adopted to synthesize more oxadia- an NH signal at δ 11.05. Finally, the mass spectrum showed
zole rings attached to the phthalazine moiety in which the molecular ion peak at m/z=466 (0.05%) equivalent to
hydrazide derivative 13 was allowed to reflux with triethy- the molecular formula C27H22N4O4.
lorthoformate for 15h to afford 2-((1,3,4-oxadiazol-2-yl)
methyl]-4-(4-isopropylphenyl)phthalazin-1(2H)-one (18)
(Scheme 3). The IR spectrum of compound 18 was devoid
Antimicrobial assay
of any absorption bands for NH groups, while the 1H NMR Phthalazine and phthalazine hybrid structures, in which a
spectrum of compound 18 exhibited the methylene bridge phthalazine moiety is attached to another heterocycle, are
singlet signal at δ 4.88 and the oxadiazole CH singlet signal considered to be of immense importance owing to their wide
at δ 9.63. The mass spectrum showed the molecular ion spectrum of biological activities.1,2,10 Accordingly, the in
peak at m/z=346 (17%) equivalent to the molecular for- vitro antimicrobial activity of the newly synthesized hetero-
mula C20H18N4O2.
cycles was appraised against two Gram-positive bacteria,
Likewise, an oxadiazole ring could be attached to our namely, Bacillus subtilis and Staphylococcus aureus, in addi-
phthalazinone heterocycle by the reaction of hydrazide 13 tion to two Gram-negative bacteria, namely, Pseudomonas
with acetic acid in presence of phosphorus oxychloride to aeruginosa and Escherichia coli.
afford oxadiazolophthalazine derivative 19 (Scheme 3).
In the current in vitro antimicrobial assay, Amoxicillin
The IR spectrum of compound 19 showed the disappear- was employed as a standard and the antibacterial activities of
1
ance of the NH and NH2 absorption bands, while the H the compounds under investigation were recorded as inhibi-
NMR spectrum showed the presence of a new singlet sig- tion diameter zones (IZ) in millimeters (mm) (Table 1).
nal integrating for three protons at δ 2.51, and the mass
spectrum showed the molecular ion peak at m/z=360 revealed a wide range of variation in their biological
(32%). activities.
Moreover, 2-{2-[4-(4-isopropylphenyl)-1-oxophthala- Compound 4 was inactive against the two tested Gram-
As shown in Table 1, the compounds under investigation
zin-2(1H)-yl]acetyl}-N-phenylhydrazine-1-carbothioam- positive bacterial strains while compound 11 was inactive
ide (20) was accessible through the reaction of hydrazide against the two Gram-negative bacteria used in this test
derivative 13 with phenyl isothiocyanate in pyridine (Table 1, entries 3 and 10). Moreover, of all the tested
(Scheme 3). The IR spectrum of compound 20 showed the compounds, 14 showed the highest activity against B. sub-
presence of a new absorption band for the C=S group at tilis (Table 1, entry 13). Likewise, compound 15a exhib-
1427cm−1, while the mass spectrum showed the molecular ited very promising inhibition effects against S. aureus
ion peak at m/z=471 (7%) equivalent to the molecular for- bacteria (Table 1, entry 14) followed by compounds 5, 23,
mula C26H25N5O2S.
and 17 (Table 1, entries 4, 26, and 20). In addition, com-
Interestingly, a pyrazole ring could be attached to the pounds 2, 10, and 16a showed exactly the same high activ-
phthalazine moiety through the reaction of the hydrazide ity value against S. aureus (Table 1, entries 1, 9, and 17).
derivative 13 with various activated reagents such as acetyl However, and with respect to Gram-negative bacteria, the
acetone, diethyl malonate, or malononitrile. Accordingly, highest activity index in the case of Pseudomonas aerugi-
refluxing the key starting compound 13 with the aforemen- nosa was observed for compounds 10 and 19 (Table 1,
tioned reagents in boiling ethanol afforded the correspond- entries 9 and 22). Contrarily, compounds 3, 4, and 15c
ing pyrazole derivatives 21–23. The 1H NMR spectrum of were inactive against the above-mentioned pathogen.
compound 21 showed new singlet signals at δ 2.25 and 2.46 Finally, the highest activity against E. coli was recorded in
integrating to three protons each and attributed to the intro- the case of tested compound 5 (Table 1, entry 4). However,
duction of two new methyl groups, in addition to a singlet compounds 7–9, 15b, and 19–25 were totally inactive
signal at δ 6.29 attributed to the CH of the pyrazole.
A new pyrazole ring attached to the phthalazine ring was
obtained through the reaction of hydrazide derivative 13
with acrylonitrile to yield 2-[2-(5-amino-2,3-dihydro-
against E. coli (Table 1, entries 6–8, 15, and 22–28).
Conclusion
1H-pyrazol-1-yl)-2-oxoethyl]-4-(4-isopropylphenyl) In summary, o-aroylbenzoic acid derivative 2, benzox-
phthalazin-1(2H)-one (24) (Scheme 3). The IR spectrum of azinone derivative 3, and acetic acid hydrazide derivative
compound 24 showed the presence of the two C=O groups 13 were utilized as precursors to construct novel and valu-
with an absorption band at 1673cm−1 and NH and NH2 able phthalazine derivatives via simple and straightforward
absorptions at 3266 and 3440cm−1, respectively. The mass synthetic routes. Subsequently, carbon and nitrogen nucle-
spectrum showed the molecular ion peak at m/z=389 ophiles were exploited to give access to plentiful and
(91%), equivalent to the molecular formula C22H23N5O2.
diverse 1,3,4-oxadiazole and pyrazole rings attached to the
Furthermore, acetic acid hydrazide derivative 13 reacted phthalazine moiety. Finally, the in vitro antimicrobial activ-
with phthalic anhydride, as a dicarbonyl compound in a ity of the newly synthesized heterocyclic compounds was
cyclic structure, to afford N-(1,3-dioxoisoindolin-2-yl)-2- tested against assorted pathological strains. Interestingly,
[4-(4-isopropylphenyl)-1-oxophthalazin-2(1H)-yl]aceta- many of the products revealed excellent inhibition effi-
mide (25). The IR spectrum of compound 25 exhibited ciency against the tested pathogens.

6
Journal of Chemical Research 00(0)
Table 1. In vitro antimicrobial activity of the synthesized compounds.
Entry
Compound
Gram-positive bacteria
Staphylococcus aureus
Gram-negative bacteria
Bacillus subtilis
Pseudomonas aeruginosa
Escherichia coli
IZ±SDa
Activity
index (%)
IZ±SDa
Activity
index (%)
IZ±SDa
Activity
index (%)
IZ±SDa
Activity
index (%)
1
2
3
4
5
6
7
8
2
3
4
5
6
7
8
9
5±0.29
3±0.29
NA
5±0.15
4±0.50
3±0.76
5±0.36
NA
5±0.20
4±0.15
4±0.12
2±0.58
9±0.20
NA
2.5±0.36
NA
6±0.12
6±0.29
NA
6±0.20
4±0.50
7±0.36
5±0.12
NA
6±0.15
3±0.50
7±0.20
4±0.50
8
62.5
37.5
–
62.5
50.0
37.5
62.5
–
62.5
50.0
50.0
25.0
112.5
–
31.3
–
75.0
75.0
–
75.0
50.0
87.5
62.5
–
75.0
37.5
87.5
50.0
100
9±0.15
NA
NA
112.5
–
–
12±0.29
NA
NA
60.0
–
–
8±0.50
6±0.78
3±0.76
9±0.12
6±0.20
NA
NA
NA
4±0.20
NA
3±0.29
6±0.12
8±0.29
3±0.20
NA
2±0.50
5±0.58
3±0.29
3±0.12
6±0.20
7±0.15
NA
80.0
60.0
30.0
90.0
60.0
–
–
–
40.0
–
30.0
60.0
80.0
30.0
–
20.0
50.0
30.0
30.0
60.0
70.0
–
13±0.87 162.5
12±0.36
12±0.29
8±0.20
14±0.58
6±0.15
15±0.12
NA
10±0.29
12±0.58
14±0.36
2±0.87
5±0.50
NA
13±0.15
12±0.20
13±0.12
4±0.76
10±0.58
15±0.15
11±0.36
14±0.20
9±0.36
5±0.76
10±0.36
6±0.29
20
60.0
60.0
40.0
70.0
30.0
75.0
–
50.0
60.0
70.0
10.0
25.0
–
65.5
60.0
65.5
20.0
50.0
75.0
55.0
70.0
45.0
25.0
50.0
30.0
100
6±0.20
3±0.29
NA
8±0.50
9±0.15
2±0.5
3±0.20
6±0.29
8±0.36
75.0
37.5
–
100
112.5
25.0
37.5
75.0
100
9
10
11
12
13
14
15a
15b
15c
16a
16b
16c
17
18
19
20
21
22
23
24
25
Amoxicillin
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
15±0.87 187.5
2±0.29
6±0.12
9±0.12
2±0.50
5±0.20
10±0.87 125.0
4±0.36
NA
25.0
75.5
112.5
25.0
50.0
50.0
–
50.0
62.5
50.0
4±0.20
5±0.12
4±0.29
NA
NA
NA
NA
NA
NA
10
–
–
–
–
–
–
100
11±0.15 137.5
2±0.50
7±0.12
8
25.0
87.5
100
NA: No antimicrobial activity detected; SD: standard deviation.
aInhibition diameter zones expressed in millimeters (mm).
2-(4-Isopropylbenzoyl)benzoic acid (2). In a 1000mL three-
necked flask equipped with a condenser, a mixture of
phthalic anhydride (14.8g, 0.1mol) and cumene (15mL)
was treated with then anhydrous aluminum chloride (20.0g,
0.15mol) gradually during stirring over a period of half an
hour.32 The reaction mixture was refluxed in a water bath
for 2h and then the mixture was allowed to stand at room
temperature overnight. Ice-HCl was added to the mixture
and the excess cumene was removed by steam distillation.
The collected solid was filtered off, washed well with
water, and dried. Recrystallization from ethanol afforded 2
in 65% yield as beige crystals; m.p. 230–231°C, IR (cm−1):
1656, 1709 (2CO), 2955 (CH aliphatic), 3293–3455 (OH).
Anal. calcd for C17H16O3: C, 76.10; H, 6.01; found: C,
76.06; H, 5.97%.
Experiment
General
Melting points were determined with an electrothermal
melting point apparatus and are uncorrected. The reaction
times were determined using thin-layer chromatography
(TLC) which was performed with fluorescent silica gel
plates HF245 (Merck) and the plates were viewed with
iodine. Merck silica gel (230–400 mesh) was used for flash
chromatography separations. The Microanalytical Center
of Cairo University performed the microanalyses. IR (KBr)
spectra were recorded on a Pye-Unicam IR spectropho-
tometer SP 2000 (Faculty of Science, Fayoum University).
The mass spectra were run using a Shimadzu-GC-MS-GP
1000 EX instrument by employing the direct inlet system.
Nuclear magnetic resonance (NMR) spectra were recorded
on a Varian Mercury 300-MHz spectrometer using tetra-
methylsilane (TMS) as the internal standard at the National
Research Center. Chemical shifts (δ) and coupling con-
stants (J) are recorded in parts per million (ppm) and Hertz
(Hz), respectively.
4-(4-Isopropylphenyl)-1H-benzo[d][1,2]oxazin-1-one (3). A mix-
ture of compound 2 (2.6g, 0.01mol) and hydroxylamine
hydrochloride (0.01mol) in dry pyridine (15mL) was re-
fluxed for 15h. On cooling, the reaction mixture was poured
onto ice-cold water acidified with HCl and the produced

Mourad et al.
7
solid was filtered off, washed with water, and recrystal- ArH), 7.61 (d, J=7.5Hz, 2H, ArH), 7.75–7.92 (m, 4H,
lized from ethanol as colorless crystals in 71% yield; m.p. ArH), 8.21 (s, 1H, NH); 13C NMR (DMSO-d6, 75MHz,
110–111°C, IR (KBr): 1596cm−1 (C=N), 1731cm−1 (CO), ppm) δ 23.3, 34.2, 126.1, 126.5, 126.8, 127.5, 128.1, 129.1,
2962cm−1 (CH aliphatic).1H NMR (dimethyl sulphoxide 129.9, 132.7, 134.5, 150.6, 168.8, 170.7, 172.1. Anal. calcd
(DMSO)-d6, 300MHz, ppm) δ 1.24 (d, J=6.4Hz, 6H, 2CH3), for C18H18N4OS: C, 63.88; H, 5.36; N, 16.56; S, 9.47;
2.90–3.03 (m, 1H, CH), 7.33–8.20 (m, 8H, ArH); 13C NMR found: C, 63.86; H, 5.26; N, 16.50; S, 9.50%. MS (70eV)
(DMSO-d6, 75MHz, ppm) δ 23.2, 34.2, 125.7, 126.6, 126.9, m/z (%): 338 (10) (M+), 307 (8), 265 (100).
127.6, 128.1, 129.7, 130.4, 133.0, 134.8, 148.4, 152.3, 158.6.
Anal. calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28; 2-Benzyl-4-(4-isopropylphenyl)phthalazin-1(2H)-one (7). A mix-
found: C, 76.93; H, 5.68; N, 5.30%. MS (70eV) m/z (%): ture of benzooxazine 3 (2.65g, 0.01mol) and benzyl amine
265 (50) (M+), 106 (100).
(1.10mL, 0.01mol) in ethanol (20mL) was heated at reflux
temperature for 20h and left to cool. The solid product was
4-(4-Isopropyl phenyl)phthalazin-1(2H)-one (4). Method A: To collected, dried, and recrystallized from ethanol to afford 7
a solution of 2 (2.6g, 0.01mol) in absolute ethanol (15mL), in 63% yield as colorless crystals; m.p. >300°C, IR (KBr):
98% hydrazine hydrate (0.3mL) was added.32 The reaction 1581cm−1 (C=N), 1662cm−1 (CO), 2954cm−1 (CH aliphatic).
mixture was refluxed for 4h and after cooling the obtained 1H NMR (DMSO-d6, 300MHz, ppm) δ 1.29 (d, J=6.4Hz,
solid was filtered off and recrystallized from ethanol to 6H, 2CH3), 2.98–3.19 (m, 1H, CH), 4.84 (s, 2H, CH2),
give 4 in 57% yield as colorless crystals.
7.10–7.54 (m, 5H, ArH), 7.62 (d, J=7.5Hz, 2H, ArH), 7.78
Method B: A mixture of benzoxazine 3 (2.65g, 0.01mol) (m, 2H, ArH), 7.93–8.02 (m, 4H, ArH); 13C NMR (DMSO-d6,
and ammonium acetate (0.77g, 0.01mol) was fused for 2h 75MHz, ppm) δ 23.2, 34.2, 53.3, 126.3, 126.5, 126.7, 127.6,
in an oil bath at 150°C. After cooling, the obtained solid 127.8, 127.9, 128.6, 128.9, 129.3, 130.6, 132.7, 134.3,
was washed with water, filtered off, and recrystallized from 135.8, 143.9, 150.5, 158.2. Anal. calcd for C24H22N2O: C,
ethanol to give 4 in 57% yield as colorless crystals; m.p. 81.33; H, 6.26; N, 7.90; found: C, 81.31; H, 6.21; N: 7.88%.
260–261°C, IR (KBr): 1606cm−1 (C=N), 1664cm−1 (CO), MS (70eV) m/z (%): 354 (1) (M+), 275 (10), 250 (100).
2956 (CH aliphatic), 3155cm−1 (NH). Anal. calcd for
C17H16N2O: C, 77.25; H, 6.10; N, 10.60; found: C, 77.20; 1-[4-(4-Isopropylphenyl)-1-oxophthalazin-2(1H)-yl]thiourea (8).
H, 6.12; N, 10.58%. MS (70eV) m/z (%): 264 (99) (M+), A mixture of benzooxazine 3 (2.65g, 0.01mol) and thios-
249 (100).
emicarbazide (0.91g, 0.01mol) was refluxed in pyridine
(20mL) for 8h. On cooling, the reaction mixture was poured
4-(4-Isopropylphenyl)-1-oxophthalazine-2(1H)-carbothioamide (5). onto ice-cold water acidified with HCl and the solid prod-
A mixture of 2 (2.6g, 0.01mol) and thiosemicarbazide uct was filtered off, washed with water, and recrystallized
(0.01mol) was refluxed in pyridine (20mL) for 8h. On from ethanol to afford 8 in 69% yield as beige crystals;
cooling, the reaction mixture was poured onto ice-cold m.p. 168–169°C, IR (KBr): 1284cm−1 (C=S), 1619cm−1
water acidified with HCl and the solid produced was filtered (C=N), 1643cm−1 (CO), 2966cm−1 (CH aliphatic), 3178 and
off, washed with water, and crystallized from ethanol to 3367cm−1 (NH) and (NH2), respectively. 1H NMR (DMSO-d6,
give 5 in 69% yield as colorless crystals; m.p. 278–279°C, 300MHz, ppm) δ 1.28 (d, J=6.3Hz, 6H, 2CH3), 2.95–3.03
IR (KBr): 1284cm−1 (C=S), 1619cm−1 (C=N), 1643cm−1 (m, 1H, CH), 4.50 (s, 2H, NH2), 7.19–7.56 (m, 8H, ArH),
1
(CO), 3178 and 3367cm−1 (NH2). H NMR (DMSO-d6, 8.63 (s, 1H, NH);13C NMR (DMSO-d6, 75 MHz, ppm) δ
300MHz, ppm) δ 1.04 (d, J=6.3Hz, 6H, 2CH3), 3.18–3.21 23.2, 34.1, 126.3, 126.7, 127.2, 127.6, 129.2, 129.8, 130.1,
(m, 1H, CH), 6.90 (s, 2H, NH2), 7.10 (d, J=7.5Hz, 2H, 132.5, 134.5, 146.4, 150.5, 161.4, 179.3. Anal. calcd for
ArH), 7.17 (d, J=7.5Hz, 2H, ArH), and 7.26–8.11 (m, 4H, C18H18N4OS: C, 63.88; H, 5.36; N, 16.56; S, 9.47; found:
ArH); 13C NMR (DMSO-d6, 75MHz, ppm) δ 23.2, 34.2, C, 63.85; H, 5.32; N, 16.50; S, 9.43%. MS (70eV) m/z (%):
125.8, 126.3, 126.9, 127.5, 127.8, 128.6, 129.9, 132.6, 338 (21) (M+), 279 (11), 236 (13), 57 (100).
134.3, 149.6, 167.1, 168.35, 172.1. Anal. calcd for
C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91; found: N-[4-(4-isopropylphenyl)-1-oxophthalazin-2(1H)-yl]hydrazine-
C, 66.81; H, 5.27; N, 12.86; S, 9.89%. MS (70eV) m/z (%): carbothioamide (9). A mixture of benzooxazine 3 (2.65g,
323 (5) (M+), 205 (11), 77 (100).
0.01mol) and thiocarbonohydrazide (1.06g, 0.01mol) was
refluxed in pyridine (20mL) for 8h. On cooling, the reaction
4-(4-Isopropylphenyl)-1-oxophthalazine-2(1H)-carbothiohydra- mixture was poured onto ice-cold water acidified with HCl
zide (6). A mixture of 2 (2.6g, 0.01mol) and thiocarbono- and the solid product was filtered off, washed with water,
hydrazide (1.06g, 0.01mol) was refluxed in pyridine and crystallized from ethanol to furnish 9 in 63% yield as
(20mL) for 8h. On cooling, the reaction mixture was beige crystal; m.p. 296–297°C, IR (KBr): 1425cm−1 (C=S),
poured onto ice-cold water acidified with HCl and the pro- 1604cm−1 (C=N), 1668cm−1 (CO), 2960cm−1 (CH aliphatic),
1
duced solid was filtered off, washed with water, and recrys- 3212 and 3444cm−1 (2NH) and (NH2), respectively. H
tallized from ethanol to give 6 in 63% yield as colorless NMR (DMSO-d6, 300MHz, ppm) δ 1.26 (d, J=6.4Hz, 6H,
crystals; m.p. >300°C, IR (KBr): 1423cm−1 (C=S), 1604 cm−1 2CH3), 3.00–3.22 (m, 1H, CH), 4.86 (s, 2H, NH2), 7.24
(C=N), 1666cm−1 (CO), 2958cm−1 (CH aliphatic), 3155 and (d, J=7.5Hz, 2H, ArH), 7.38 (d, J=7.4Hz, 2H, ArH), 7.89–
3440cm−1 (NH) and (NH2), respectively. 1H NMR (DMSO- 8.14 (m, 4H, ArH), 8.43 (s,2H, 2NH); 13C NMR (DMSO-d6,
d6, 300MHz, ppm) δ 1.28 (d, J=6.4Hz, 6H, 2CH3), 3.12–3.31 75MHz, ppm) δ 23.2, 34.2, 126.5, 126.7, 127.2, 127.7, 129.1,
(m, 1H, CH), 4.65 (s, 2H, NH2), 7.22 (d, J=7.5Hz, 2H, 129.8, 130.2, 132.3, 134.5, 146.2, 150.6, 160.9, 179.3. Anal.

8
Journal of Chemical Research 00(0)
calcd for C18H19N5OS: C, 61.17; H, 5.42; N, 19.82; S: 9.07; 2-[4-(4-Isopropylphenyl)-1-oxophthalazin-2(1H)-yl]acetohydra-
found: C, 61.15; H, 5.40; N: 19.79; S, 9.04%. MS (70eV) zide (13). A mixture of 12 (3.5g, 0.01mol) and hydrazine
m/z (%): 353 (24) (M+), 322 (7), 264 (52), 76 (100).
hydrate (2mL) in absolute ethanol (30mL) was refluxed
for 6 h. The reaction mixture was allowed to cool down
7-(4-Isopropylphenyl)-2H-[1,2,4,5]tetrazino[6,1-a]phthala- and the separated solid product was filtered off and dried.
zine-3(4H)-thione (10). A mixture of benzooxazine 3 Recrystallization of the crude product with ethanol afforded
(2.65g, 0.01mol) and thiocarbonohydrazide (1.06g, 13 in 78% yield as colorless crystals; m.p. 158–159°C, IR
0.01mol) in dioxane (20mL) was heated at reflux for 8h (KBr): 1662cm−1 (2CO), 2955cm−1 (CH aliphatic), 3329
1
and then left to cool. The precipitated solid was collected, and 3444cm−1 (NH) and (NH2), respectively. H NMR
dried, and recrystallized from ethanol to afford 10 in 69% (DMSO-d6, 300MHz, ppm) δ 1.27 (d, J=6.4Hz, 6H, 2CH3),
yield as yellow crystals; m.p. 160–161°C, IR (KBr): 2.97–3.04 (m, 1H, CH), 4.28 (s, 2H, NH2), 4.77 (s, 2H,
1284cm−1 (C=S), 1639cm−1 (C=N), 2958cm−1 (CH ali- CH2CO), 7.43 (d, J=7.5Hz, 2H, ArH), 7.51 (d, J=7.5Hz,
phatic), 3212 and 3270 cm−1 (2NH). 1H NMR (DMSO-d6, 2H, ArH), 7.74–8.37 (m, 4H, ArH), 9.29 (s, 1H, NH);
300 MHz, ppm) δ 1.30 (d, J=6.4Hz, 6H, 2CH3), 2.98–3.21 13C NMR (DMSO-d6, 75MHz, ppm) δ 23.2, 34.1, 53.9,
(m, 1H, CH), 7.38 (d, J=7.5Hz, 2H, ArH), 7.49 (d, 126.3, 126.7, 126.9, 127.4, 127.7, 129.1, 130.8, 132.7, 134.5,
J=7.5Hz, 2H, ArH), 7.68 (s, 1H, NH), 7.87–8.25 (m, 4H, 145.8, 150.5, 159.6, 172.6. Anal. calcd for C19H20N4O2:
ArH), 8.91 (s, 1H, NH); 13C NMR (DMSO-d6, 75MHz, ppm) C, 67.84; H, 5.99; N, 16.66; found: C, 67.79; H, 6.02;
δ 23.2, 34.2, 120.7, 126.3, 126.5, 127.1, 127.4, 127.9, 128.5, N, 16.67%. MS (70eV) m/z (%):336 (15) (M+), 264 (13),
129.1, 129.9, 134.5, 150.5, 148.8, 167.8. Anal. calcd for 249 (100).
C18H17N5S: C, 64.45; H, 5.11; N, 20.88; S, 9.56; found: C,
64.41; H, 4.81; N, 20.68; S, 9.53%. MS (70eV) m/z (%): 2-Benzoyl-4-(4-isopropylphenyl)phthalazin-1(2H)-one (14). A
335 (11) (M+), 320 (23), 287 (40), 261 (100).
mixture of phthalazine 4 (2.60g, 0.01mol) and excess ben-
zoyl chloride (5mL) was refluxed for 3h on a steam bath.
1,1′-[1-(4-Isopropylphenyl)-4-oxo-3,4-dihydroisoquinoline- The reaction mixture was poured into ice-cold water and
3,3-diyl]bis(ethan-1-one) (11). To a solution of benzooxazine the separated solid was filtered off, washed well with
3 (2.65g, 0.01mol) in ethanol (20mL) and a few drops of water, and dried. Recrystallization from ethanol afforded
piperidine, acetylacetone (1.0mL, 0.01mol) was added 14 in 58% yield as colorless crystals; m.p. 134–135°C, IR
and the mixture was refluxed for 30h and left to cool. The (KBr): 1591cm−1 (C=N), 1692cm−1 (2CO), 2935cm−1
1
precipitated solid was collected, dried, and recrystallized (CH aliphatic). H NMR (DMSO-d6, 300MHz, ppm) δ
from ethanol to give 11 in 62% yield as yellow crystals; 1.28 (d, J=6.4Hz, 6H, 2CH3), 3.00–3.19 (m, 1H, CH),
m.p. 140–141°C, IR (KBr): 1600cm−1 (C=N), 1666cm−1, 7.23–7.47 (m, 7H, ArH), 7.69–8.30 (m, 6H, ArH); 13C NMR
1735cm−1 (3CO), 2958cm−1 (CH aliphatic). 1H NMR (DMSO-d6, 75MHz, ppm) δ 23.2, 34.2, 126.2, 126.6, 127.4,
(DMSO-d6, 300MHz, ppm) δ 1.28 (d, J=6.3Hz, 6H, 2CH3), 127.7, 127.8, 128.8, 129.2, 129.5, 129.9, 132.5, 132.8,
2.50 (s, 6H, 2CH3), 2.92–3.04 (m, 1H, CH), 7.36 (d, J=7.5Hz, 132.9, 134.4, 150.5, 154.9, 156.8, 163.3. Anal. calcd for
2H, ArH), 7.48 (d, J=7.5Hz, 2H, ArH), 7.53–8.37 (m, 4H, C24H20N2O2: C, 78.24; H, 5.47; N, 7.60; found: C, 78.31;
ArH); 13C NMR (DMSO-d6, 75MHz, ppm) δ 23.1, 29.6, H, 5.40; N, 7.57%. MS (70eV) m/z (%): 368 (53) (M+),
34.2, 125.4, 126.3, 126.5, 128.9, 130.2, 131.1, 132.3, 134.8, 305 (100), 263 (6).
135.7, 151.3, 162.2, 176.2, 182.5, 187.4. Anal. calcd for
C22H21NO3: C, 76.06; H, 6.09; N, 4.03; found: C, 75.96; H,
Reactions of phthalazine hydrazide
derivative 13 with aromatic
aldehydes 15a–c
6.03; N, 3.83%. MS (70eV) m/z (%): 347 (26) (M+), 262
(11), 234 (9), 76 (100).
Ethyl 2-[4-(4-isopropylphenyl)-1-oxophthalazin-2(1H)-yl]ace-
tate (12). A mixture of 4 (2.6g, 0.01mol), ethyl bromoac-
General procedure
etate (0.03mol), and potassium carbonate (4.1g, 0.03mol) A mixture of acetic acid hydrazide 13 (0.30g, 0.001mol),
in dry acetone (30mL) was heated under reflux for 30h, the appropriate aromatic aldehyde; namely, benzaldehyde,
cooled to room temperature, and poured into ice-cold water. p-chlorobenzaldehyde, or p-nitrobenzaldehyde (0.001mol)
The obtained solid was filtered off and recrystallized from and a few drops of piperidine was refluxed in boiling etha-
ethanol to give 12 in 85% yield as colorless crystals; nol (20mL) for 6h. After cooling, the separated solid was
m.p. 162–163°C, IR (KBr): 1606cm−1 (C=N), 1657cm−1 collected by filtration, dried, and recrystallized from etha-
(amide CO), 1742cm−1 (ester CO), 2959cm−1 (CH aliphatic). nol to give aryl methylidene hydrazide derivatives 15a–c.
1H NMR (DMSO-d6, 300MHz, ppm) δ 1.20 (t, J=6Hz,
3H, CH3), 1.26 (d, J = 6.4 Hz, 6H, 2CH3), 2.95–3.02 N′-Benzylidene-2-[4-(4-isopropylphenyl)-1-oxophthalazin-
(m, 1H, CH), 4.15 (q, J=6Hz, 2H, CH2), 4.98 (s, 2H, 2(1H)-yl]acetohydrazide (15a). Colorless crystals were iso-
CH2CO), 7.42 (d, J=7.5Hz, 2H, ArH), 7.51 (d, J=7.5Hz, lated in 76% yield; m.p. 228–229°C, IR (KBr): 1579cm−1
2H, ArH), 7.74–8.38 (m, 4H, ArH); 13C NMR (DMSO-d6, (C=N), 1659cm−1 (2CO), 2958cm−1 (CH aliphatic),
1
75MHz, ppm) δ 14.8, 23.2, 34.2, 48.6, 60.9, 126.3, 126.5, 3217 cm−1 (NH). H NMR (DMSO-d6, 300 MHz, ppm)
127.2, 127.7, 127.9, 129.1, 130.9, 132.5, 134.6, 146.3, 150.5, δ 1.27 (d, J=6.4Hz, 6H, 2CH3), 2.98–3.02 (m, 1H, CH),
159.3, 167.1. Anal. calcd for C21H22N2O3: C, 71.98; H, 6.33; 4.95 (s, 1H, NH), 5.35 (s, 2H, CH2), 7.44 (d, J=7.5Hz, 2H,
N, 7.99; found: C, 71.93; H, 6.31; N, 8.03%. MS (70eV) ArH), 7.51 (d, J=7.5Hz, 2H, ArH), 7.70–8.40 (m, 9H, ArH),
m/z (%): 350 (0.02) (M+), 263 (0.33), 71 (100).
8.72 (s, 1H, CH); 13C NMR (DMSO-d6, 75MHz, ppm) δ

Mourad et al.
9
23.2, 34.1, 54.1, 126.3, 126.6, 127.5, 127.7, 128.9, 129.1, 2-[(4-Acetyl-5-(4-chlorophenyl)-4,5-dihydro-1,3,4-oxadiazol-
129.3, 130.9, 132.6, 134.5, 134.8, 145.7, 146.8, 150.5, 152.9, 2-yl)methyl]-4-(4-isopropylphenyl)phthalazin-1(2H)-one
155.4, 158.6, 163.3. Anal. calcd for C26H24N4O2: C, 73.56; (16b). Colorless crystals were isolated in 79% yield; m.p.
H, 5.70; N, 13.20; found: C, 73.50; H, 5.73; N, 13.24%. MS 140–141°C, IR (KBr): 1583cm−1 (C=N), 1661cm−1 (2 CO),
1
(70eV) m/z (%): 424 (100) (M+), 305 (94), 76 (2).
2959cm−1 (CH aliphatic). H NMR (DMSO-d6, 300MHz,
ppm) δ 1.25 (d, J=6.4Hz, 6H, 2CH3), 2.07 (s, 3H, CH3),
N′-(4-Chlorobenzylidene)-2-(4-(4-isopropylphenyl)-1-oxopht- 2.98–3.05 (m, 1H, CH), 5.28 (s, 2H, CH2), 7.11 (s, 1H, CH
halazin-2(1H)-yl)acetohydrazide (15b). Colorless crystals were oxadiazole), 7.27 (d, J=7.5Hz, 2H, ArH), 7.32 (d, J=7.5Hz,
isolated in 82% yield; m.p. 270–271°C, IR (KBr): 1580cm−1 2H, ArH), 7.49–7.73 (m, 4H, ArH), 7.98–8.38 (m, 4H, ArH);
(C=N), 1676cm−1 (2CO), 2958cm−1 (CH aliphatic), 3068 cm−1 13C NMR (DMSO-d6, 75MHz, ppm) δ 23.2, 23.4, 34.2,
1
(CH aromatic), 3205 cm−1 (NH). H NMR (DMSO-d6, 46.3, 99.3, 126.3, 126.5, 127.3, 127.5, 127.8, 128.8, 129.2,
300MHz, ppm) δ 1.28 (d, J=6.4Hz, 6H, 2CH3), 3.03–3.21 129.6, 130.1, 132.7, 134.0, 134.5, 136.4, 146.2, 150.5,
(m, 1H, CH), 5.41 (s, 2H, CH2), 7.22–7.35 (m, 4H, ArH), 154.1, 158.2, 159.6. Anal. calcd for C28H25 ClN4O3: C, 67.13;
7.42–8.05 (m, 8H, ArH), 8.21 (s,1H, NH), 8.79 (s, 1H, CH); H, 5.03; N, 11.18; Cl, 7.08; found: C, 67.15; H, 5.00; N, 11.22;
13C NMR (DMSO-d6, 75MHz, ppm) δ 23.37, 34.20, 54.2, Cl, 6.88%. MS (70eV) m/z (%): 500 (3) (M+), 73 (100).
126.3, 126.5, 127.2, 127.6, 127.9, 128.9, 129.2, 129.7,
130.2, 132.4, 134.3, 134.7, 135.1, 144.5, 146.8, 150.5, 159.1, 2-[(4-Acetyl-5-(4-nitrophenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)
164.1. Anal. calcd for C26H23ClN4O2: C, 68.04; H, 5.05; methyl]-4-(4-isopropylphenyl)phthalazin-1(2H)-one (16c).
N, 12.21; found: C, 68.08; H, 5.01; N, 12.23%. MS (70eV) Beige crystals were isolated in 72% yield; m.p. 216–217°C,
m/z (%): 458 (82) (M+), 305 (100).
IR (KBr): 1581cm−1 (C=N), 1662cm−1 (2 CO), 2962cm−1
(CH aliphatic). H NMR (DMSO-d6, 300MHz, ppm) δ
1
2-[4-(4-Isopropylphenyl)-1-oxophthalazin-2(1H)-yl]-N′-(4- 1.26 (d, J=6.4Hz, 6H, 2CH3), 2.05 (s, 3H, CH3), 2.98–3.05
nitrobenzylidene)aceto-hydrazide (15c). Beige crystals were (m, 1H, CH), 5.34 (s, 2H, CH2), 7.08 (s, 1H, CH oxadia-
isolated in 72% yield; m.p. 298–299°C, IR (KBr): 1584cm−1 zole), 7.22 (d, J=7.5Hz, 2H, ArH), 7.30 (d, J=7.5Hz, 2H,
(C=N), 1694cm−1 (2CO), 2959cm−1 (CH aliphatic), 3068 cm−1 ArH), 7.41–7.68 (m, 4H, ArH), 7.88–8.27 (m, 4H, ArH);
(CH aromatic), 3446cm−1 (NH). H NMR (DMSO-d6, 13C NMR (DMSO-d6, 75MHz, ppm) δ 23.3, 23.4, 34.2,
1
300MHz, ppm) δ 1.28 (d, J=6.4Hz, 6H, 2CH3), 2.99–3.05 46.4, 99.2, 124.6, 126.4, 126.7, 126.9, 127.2, 127.5, 127.7,
(m, 1H, CH), 5.70 (s, 2H, CH2), 7.30–7.48 (m, 5H, ArH), 129.3, 130.8, 132.6, 134.5, 142.1, 145.8, 148.1, 150.5,
7.60 (s, 1H, NH), 7.65–8.12 (m, 7H, ArH), 8.61 (s,1H, CH); 154.0, 157.9, 159.7. Anal. calcd for C28H25 N5O5: C, 65.74;
13C NMR (DMSO-d6, 75MHz, ppm) δ 23.2, 34.2, 54.2, H, 4.93; N, 13.69; found: C, 65.71; H, 4.97; N, 13.65%. MS
124.6, 126.3, 126.6, 127.1, 127.6, 127.9, 128.2, 129.1, 131.2, (70eV) m/z (%): 511 (52) (M+), 469 (100), 277 (1).
132.7, 134.5, 138.9, 145.6, 147.9, 148.7, 150.5, 159.3,
164.2. Anal. calcd for C26H23N5O4: C, 66.51; H, 4.94; N, 4-(4-Isopropylphenyl)-2-[(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-
14.9; found: C, 66.00; H, 5.10; N, 14.6%. MS (70eV) m/z 2-yl)methyl]phthalazin-1(2H)-one (17). A mixture of the ace-
(%): 469 (2) (M+), 305 (100).
tic acid hydrazide 13 (0.6g, 0.002mol) was added to
potassium hydroxide (0.28g, 0.005mol) solution in abso-
lute ethanol (40mL) and then carbon disulfide (6mL) was
added portionwise and the reaction mixture was refluxed
until no odor of hydrogen sulfide evolved (18h). The reac-
Cyclization of Schiff’s bases 15a–c: general
procedure
Compounds 15a–c (0.002mol) and acetic anhydride (2mL) tion mixture was poured onto ice-cold water and rendered
were heated under reflux for 5h. The reaction mixture was acidic with HCl. The precipitated solid was filtered off,
cooled, poured onto water, and allowed to stand at room dried, and recrystallized from ethanol to give 17 in 54%
temperature for 3h. The solid product formed was collected yield as yellow crystals; m.p. 210–211°C, IR (KBr): 1423cm−1
and recrystallized from ethanol to afford 16a–c.
(C=S), 1581cm−1 (C=N), 1663cm−1 (CO), 2958 cm−1 (CH
aliphatic). H NMR (DMSO-d6, 300 MHz, ppm) δ 1.27
1
2-[(4-Acetyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]- (d, J = 6.4 Hz, 6H, 2CH3), 2.98–3.02 (m, 1H, CH), 5.51
4-(4-isopropylphenyl)phthalazin-1(2H)-one (16a). Colorless (s, 2H, CH2), 7.43 (d, J=7.5Hz, 2H, ArH), 7.52 (d, J=7.5Hz,
crystals were isolated in 73% yield; m.p. 130–131°C, IR 2H, ArH), 7.76–8.4 (m, 4H, ArH), 14.6 (s, 1H, NH); 13C NMR
(KBr): 1581cm−1 (C=N), 1662cm−1 (2 CO), 2958cm−1 (DMSO-d6, 75MHz, ppm) δ 23.2, 34.2, 46.4, 126.3, 126.5,
1
(CH aliphatic). H NMR (DMSO-d6, 300MHz, ppm) δ 127.3, 127.6, 127.8, 129.1, 131.0, 132.7, 134.5, 146.4, 150.5,
1.22 (d, J=6.4Hz, 6H, 2CH3), 2.04 (s, 3H, CH3), 2.98–3.02 155.7, 159.4, 178.9. Anal. calcd for C20H18N4O2S: C, 63.47;
(m, 1H, CH), 5.01 (s, 2H, CH2), 7.03 (s, 1H, CH oxadia- H, 4.79; N, 14.80; S, 8.47; found: C, 63.43; H, 4.77; N, 14.86;
zole), 7.21–7.51 (m, 5H, ArH), 7.52–8.38 (m, 8H, ArH); S: 8.45%. MS (70eV) m/z (%): 378 (4) (M+), 304 (100),
13C NMR (DMSO-d6, 75MHz, ppm) δ 23.1, 23.5, 34.2, 277 (69).
46.4, 98.9, 126.3, 126.6, 126.9, 127.1, 127.6, 127.8, 128.9,
129.3, 130.1, 130.9, 132.7, 134.3, 134.6, 145.7, 150.5, 2-[(1,3,4-Oxadiazol-2-yl)methyl]-4-(4-isopropylphenyl)phthala-
153.7, 157.7, 159.3. Anal. calcd for C28H26N4O3: C, 72.09; zin-1(2H)-one (18). A mixture of acetic acid hydrazide 13
H, 5.62; N, 12.01; found: C, 72.05; H, 5.60; N, 12.05%. MS (0.6g, 0.002mol) and triethylorthoformate (5mL) was
(70eV) m/z (%): 466 (100) (M+), 424 (91), 277 (3).
heated under reflux for 15h. After cooling, the formed solid

10
Journal of Chemical Research 00(0)
was collected, dried, and recrystallized from ethanol to 2-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethyl]-4-(4-isopropyl-
yield 18 in 73% yield as colorless crystals; m.p. 292–293°C, phenyl)phthalazin-1(2H)-one (21). A mixture of acetic acid
IR (KBr): 1582cm−1 (C=N), 1663cm−1 (CO), 2959cm−1 hydrazide 13 (0.6g, 0.002mol) and acetyl acetone (0.2mL,
(CH aliphatic). 1H NMR (DMSO-d6, 300MHz, ppm) δ 1.26 0.002mol) in ethanol (20mL) was refluxed for 10h. The
(d, J = 6.4 Hz, 6H, 2CH3), 2.97–3.01 (m, 1H, CH), 4.88 (s, resulting solid was filtered and crystallized from ethanol
2H, CH2), 7.41 (d, J=7.5Hz, 2H, ArH), 7.50 (d, J=7.5Hz, to afford 21 in 82% yield as colorless crystals; m.p.
2H, ArH), 7.70–8.37 (m, 4H, ArH), 9.63 (s, 1H, CH oxadia- 180–181°C, IR (KBr): 1581cm−1 (C=N), 1659cm−1 (2CO),
1
zole); 13C NMR (DMSO-d6, 75MHz, ppm) δ 23.3, 34.2, 2957cm−1 (CH aliphatic). H NMR (DMSO-d6, 300MHz,
45.7, 126.3, 126.6, 127.2, 127.5, 127.7, 129.2, 131.1, 132.7, ppm) δ 1.25 (d, J=6.4Hz, 6H, 2CH3), 2.25 (s, 3H, CH3),
134.5, 145.9, 150.5, 158.7, 160.4, 162.8. Anal. calcd for 2.46 (s, 3H, CH3), 2.95–3.03 (m, 1H, CH), 5.69 (s, 2H, CH2),
C20H18N4O2: C, 69.35; H, 5.24; N, 16.17; found: C, 69.30; 6.29 (s, 1H, CH pyrazole), 7.41 (d, J=7.5Hz, 2H, ArH),
H, 5.28; N, 16.19%. MS (70eV) m/z (%): 346 (17) (M+), 7.51 (d, J = 7.5 Hz, 2H, ArH), 7.70–8.39 (m, 4H, ArH);
277 (26), 76 (9), 48 (100).
13C NMR (DMSO-d6, 75MHz, ppm) δ 13.4, 14.7, 23.2,
34.1, 52.8, 112.6, 126.5, 126.8, 127.2, 127.49, 127.7, 129.3,
4-(4-Isopropylphenyl)-2-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl] 130.8, 132.6, 134.5, 140.7, 145.6, 150.5, 151.8, 158.3, 167.9.
phthalazin-1(2H)-one (19). A mixture of acetic acid hydra- Anal. calcd for C24H24N4O2: C, 71.98; H, 6.04; N, 13.99;
zide 13 (0.6g, 0.002mol) and acetic acid (0.12mL, found: C, 71.95; H, 6.08; N, 14.02%. MS (70eV) m/z (%):
0.002mol) in phosphorous oxychloride (1mL) was heated 396 (0.2) (M+–4), 305 (0.05), 263 (2), 73 (100).
under reflux for 6h. After cooling, the excess phosphorous
oxychloride was removed under reduced pressure. The 2-[2-(3,5-Diamino-1H-pyrazol-1-yl)-2-oxoethyl]-4-(4-isopropyl-
obtained solid was poured on ice-cold water (50mL) and phenyl)phthalazin-1(2H)-one (22). A mixture of acetic acid
neutralized with saturated sodium bicarbonate, The obtained hydrazide 13 (0.6g, 0.002mol) and malononitrile (0.002mol)
solid was collected by filtration and then recrystallized in ethanol (20mL) was refluxed for 8h. On cooling, the
from ethyl acetate to give 19 in 70% yield as beige crystals; separated solid was filtered off and recrystallized from
m.p. 220–221°C, IR (KBr): 1581cm−1 (C=N), 1658cm−1 ethanol to give 22 in 75% yield as beige crystals; m.p.
(CO), 2958cm−1 (CH aliphatic). 1H NMR (DMSO-d6, 246–247°C, IR (KBr): 1583cm−1 (C=N), 1666cm−1 (2CO),
300 MHz, ppm) δ 1.26 (d, J = 6.4 Hz, 6H, 2CH3), 2.51 2958 cm−1 (CH aliphatic), 3158 and 3442 cm−1 (2NH2).
(s, 3H, CH3), 2.97–3.02 (m, 1H, CH), 5.32 (s, 2H, CH2), 1H NMR (DMSO-d6, 300MHz, ppm) δ 1.28 (d, J=6.4Hz,
7.39–7.35 (m, 5H, ArH), 7.72–8.35 (m, 3H, ArH); 13C 6H, 2CH3), 3.00–3.17 (m, 1H, CH), 4.92 (s, 1H, CH pyr-
NMR (DMSO-d6, 75MHz, ppm) δ 11.2, 23.1, 34.2, 45.6, azole), 5.65 (s, 2H, CH2), 5.98 (s, 2H, NH2), 6.30 (s, 2H,
126.4, 126.7, 127.3, 127.5, 127.8, 129.4, 131.2, 132.7, NH2), 7.28 (d, J=7.5Hz, 2H, ArH), 7.54 (d, J=7.5Hz, 2H,
134.5, 145.6, 150.5, 156.7, 157.2, 158.6. Anal. calcd for ArH), 7.78–8.32 (m, 4H, ArH); 13C NMR (DMSO-d6,
C21H20N4O2: C, 69.98; H, 5.59; N, 15.55; found: C, 70.01; 75MHz, ppm) δ 23.2, 34.2, 51.9, 87.6, 126.3, 126.5, 127.1,
H, 5.60; N, 15.50%. MS (70eV) m/z (%): 360 (32) (M+), 127.7, 127.9, 129.3, 131.2, 132.7, 134.4, 138.6, 145.8, 150.5,
345 (8), 277 (22), 249 (100).
158.7, 163.6, 167.4. Anal. calcd for C22H22N6O2: C, 65.66;
H, 5.51; N: 20.88; found: C, 65.60; H, 5.53; N, 20.85%.
2-{2-[4-(4-Isopropylphenyl)-1-oxophthalazin-2(1H)-yl]acetyl}- MS (70eV) m/z (%):402 (3) (M+), 305 (75), 277 (100).
N-phenylhydrazine-1-carbothioamide (20). A mixture of ace-
tic acid hydrazide 13 (0.6g, 0.002mol) and phenyl 1-{2-[4-(4-Isopropylphenyl)-1-oxophthalazin-2(1H)-yl]acetyl}
isothiocyanate (0.2mL, 0.002mol) in pyridine (20mL) was pyrazolidine-3,5-dione (23). A mixture of acetic acid hydra-
refluxed for 8h. After cooling, the reaction mixture was zide 13 (0.6g, 0.002mol) and diethyl malonate (0.002mol)
poured on ice-cold water acidified with HCl. The precipi- was refluxed in ethanol (20mL) for 10h. On cooling, the
tated solid was collected by filtration, dried, and crystal- separated solid was filtered off and crystallized from etha-
lized from ethanol to afford 20 in 72% yield as colorless nol gave 23 in 73% yield as colorless crystals; m.p. >300°C,
crystals; m.p. 200–201°C, IR (KBr): 1427cm−1 (C=S), IR of (KBr): 1581 (C=N), 1631 (4CO), 2923 (CH aliphatic),
1
1576 cm−1 (C=N), 1656 cm−1 (2CO), 2959 cm−1 (CH ali- 3421 cm−1 (NH). H NMR (DMSO-d6, 300 MHz, ppm) δ
1
phatic), 3258cm−1 (NH). H NMR (DMSO-d6, 300MHz, 1.29 (d, J=6.4Hz, 6H, 2CH3), 3.03–3.15 (m, 1H, CH), 4.51
ppm) δ 1.28 (d, J=6.4Hz, 6H, 2CH3), 3.05–3.18 (m, 1H, (s, 2H, CH2 pyrazole), 5.70 (s, 2H, CH2), 7.37 (d, J=7.5Hz,
CH), 5.62 (s, 2H, CH2), 7.10–7.32 (m, 5H, ArH), 7.41 2H, ArH), 7.58 (d, J=7.5Hz, 2H, ArH), 7.68–8.35 (m, 4H,
(d, J=7.5Hz, 2H, ArH), 7.58 (d, J=7.5Hz, 2H, ArH), ArH), 8.97 (s, 1H, NH); 13C NMR (DMSO-d6, 75MHz,
7.73 (m, 2H, ArH), 7.91 (s, 1H, NH), 8.16 (s, 1H, NH), ppm) δ 23.2, 34.1, 37.5, 51.3, 126.3, 126.5, 127.1, 127.5,
8.22–8.39 (m, 2H, ArH), 8.64 (s, 1H, NH); 13C NMR 127.7, 129.2, 131.1, 132.6, 134.5, 146.0, 150.5, 158.5,
(DMSO-d6, 75MHz, ppm) δ 23.2, 34.2, 53.4, 120.7, 164.2, 171.2, 174.7. Anal. calcd for C22H20N4O4: C, 65.34;
124.6, 126.3, 126.6, 127.3, 127.5, 127.9, 128.8, 129.3, H, 4.98; N, 13.85; found: C, 65.30; H, 5.01; N, 13.88%. MS
131.1, 132.6, 134.5, 138.7, 146.2, 150.6, 158.5, 168.9, (70eV) m/z (%): 404 (15) (M+), 305 (5),263 (11), 57 (100).
176.4. Anal. calcd for C26H25N5O2S: C, 66.22; H, 5.34; N,
14.85; S, 6.80; found: C, 66.25; H, 5.33; N, 14.83; S, 2-[2-(5-Amino-2,3-dihydro-1H-pyrazol-1-yl)-2-oxoethyl]-4-(4-
6.83%. MS (70eV) m/z (%): 471 (7) (M+), 379 (34), 305 isopropylphenyl)phthalazin-1(2H)-one (24). A mixture of
(78), 277 (100).
acetic acid hydrazide 13 (0.3g, 0.001mol) and acrylonitrile

Mourad et al.
11
(0.001mol) in boiling pyridine (20mL) was refluxed for activity. Importantly, the average growth of microbes was
10 h. On cooling, the reaction mixture was poured into calculated after the plates were done in triplicate. The
ice-cold water acidified with HCl and the solid produced observed clear zone size is directly proportional to the
was filtered off, washed several times with water, and crys- inhibitory effect of the investigated compound. In each
tallized from ethanol to afford 24 in 76% yield as color- experiment, a negative control was incorporated by using a
less crystals; m.p. 290–291°C, IR (KBr): 1581cm−1 (C=N), pure solvent disk. For comparison, a disk with Amoxicillin
1673cm−1 (2CO), 2958cm−1 (CH aliphatic), 3266cm−1 (standard drug) was screened for antimicrobial activity
1
(NH), 3440cm−1 (NH2). H NMR (DMSO-d6, 300MHz, using the same conditions.
ppm) δ 1.25 (d, J=6.4Hz, 6H, 2CH3), 2.98–3.12 (m, 1H, CH),
3.95 (d, J=6.2Hz, 2H, CH2 pyrazole), 4.57 (t, J=6.2Hz, Declaration of conflicting interests
1H, CH pyrazole), 5.58 (s, 2H, CH2), 6.36 (s, 2H, NH2),
The author(s) declared no potential conflicts of interest with
7.35 (d, J=7.5Hz, 2H, ArH), 7.58 (d, J=7.5Hz, 2H, ArH),
7.72–8.29 (m, 4H, ArH), 8.61 (s, 1H, NH); 13C NMR
(DMSO-d6, 75MHz, ppm) δ 23.1, 34.2, 53.4, 54.6, 93.8,
126.4, 126.7, 127.3, 127.6, 127.9, 129.2, 131.2, 132.6,
134.5, 144.3, 145.9, 150.5, 158.7, 169.8. Anal. calcd for
C22H23N5O2: C, 67.85; H, 5.95; N, 17.98; found: C, 67.81;
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
H, 5.91; N, 18.00%. MS (70eV) m/z (%): 389 (91) (M+), authors would like to extend their profound appreciation to
Fayoum University for the financial support.
388 (100), 305 (5).
ORCID iD
N-(1,3-Dioxoisoindolin-2-yl)-2-[4-(4-isopropylphenyl)-1-
oxophthalazin-2(1H)-yl]acetamide (25). A mixture of acetic
acid hydrazide 13 (0.6g, 0.002mol) and phthalic anhydride
Asmaa Kamal Mourad
https://orcid.org/0000-0002-6417-8540
(0.3g, 0.002mol) was heated under reflux in acetic acid References
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IR (KBr): 1580 cm−1 (C=N), 1662, 1737, 1792 cm−1
(4CO), 2958cm−1 (CH aliphatic), 3210cm−1 (NH). 1H
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