Synthesis and antimicrobial activity of some condensed [4-(2,4,6- trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic acid hydrazide

Article abstract of DOI:10.1002/cjoc.201100256

Some new 1,2,4-triazolo-, 1,3,4-oxadiazolo-, 1,3,4-thiadiazol-, and pyrazolo-2,4,6-trimethylphenyl-1(2H)-oxo-phthalazine derivatives were synthesized and identified by IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The new compounds were synthesized with the objective of studying their antimicrobial activity.

Full text of DOI:10.1002/cjoc.201100256

FULL PAPER
DOI: 10.1002/cjoc.201100256
Synthesis and Antimicrobial Activity of Some Condensed
[4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic
Acid Hydrazide
El-Hashash, Maher A.a
El-Kady, Ahmed Y.b
El-Shamy, Ibrahim E.*,b
Taha, Mamdouh A.b
a Chemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
b Chemistry Department, Faculty of Science, Fayoum University, Fayoum, Egypt
Some new 1,2,4-triazolo-, 1,3,4-oxadiazolo-, 1,3,4-thiadiazol-, and pyrazolo-2,4,6-trimethylphenyl-1(2H)-oxo-
phthalazine derivatives were synthesized and identified by IR, 1H NMR, 13C NMR, MS and elemental analysis. The
new compounds were synthesized with the objective of studying their antimicrobial activity.
Keywords 1(2H)-oxo-phthalazine, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, antimicrobial activity
Introduction
yields the o-aroylbenzoic acid.[19,20] Thus, reaction of
mesitylene with phthalic anhydride in the presence of
anhydrous aluminium chloride, was carried out to pro-
duce 2-(2,4,6-trimethyl benzoyl) benzoic acid (2). Mer-
chant et al.[21] prepared phthalazin-l-ones via the con-
densation of the aroyl benzoic acid with hydrazine hy-
drate in boiling ethanol. Accordingly, adopting the
Merchant et al. procedure, condensation of benzoic acid
derivative 2 with hydrazine hydrate in boiling ethanol
afforded the 4-(2,4,6-trimethyl phenyl)-2H-phthalazin-l-
one (3) in 65% yield. The IR spectrum showed a char-
Nitrogen containing heterocyclic compounds have
received much attention as shown by the numerous
studies published on their applicability in different areas,
especially as drugs.[1,2] Phthalazines are examples of
nitrogen heterocycles that possess exciting biological
properties.[3-5] They form the structural profile for sev-
eral biologically active compounds and hence they are
considered as important key elements. Several reports in
the literature have focused on the pharmacology of
phthalazine derivatives. These reports have resulted in a
great number of contributions in diverse area of inter-
est.[6-11] Phthalazines have been reported to possess an-
ticonvulsant,[12] cardiotonic[13] and vasorelaxant activi-
ties.[14,15] Additionally, phthalazines have recently been
reported to potentially inhibit serotonin reuptake and
considered as anti-depression agents.[16] Several ap-
proaches have been reported in the literature for synthe-
sis of phthalazinone.[12,17] Generally, phthalazines are
synthesized from either phthalic anhydride derivatves,
2-aryl-3-hydroxyindene-1-ones, or β-diketones via con-
densation with hydrazine hydrate by either heating[18] or
applying microwave irradiation.[15] In view of the
aforementioned facts, it seemed most interesting to
synthesize some condensed [4-(2,4,6-trimethyl phenyl)-
1(2H)-oxo-phthalazin-2-yl] acetic acid hydrazide with
the aim to evaluate their antimicrobial activities.
acteristic absorption bands at ν 1654 cm－ correspond-
1
ing to CO group. The 1H NMR spectrum of compound 3
showed NH at δ 11.17. Compound 3 was treated with
ethyl bromoacetate to afford the corresponding phtha-
lazine acetic acid ethyl ester 4 (Scheme 1). The structure
of compound 4 was confirmed on the basis of their ele-
mental analysis and spectral data. The IR spectrum
showed a characteristic absorption band at ν＝1731
cm－ corresponding to CO of ester, CO of cyclic amide
1
at ν＝1659 cm－ and devoid any band for NH. The H
NMR spectrum of compound 4 showed a triplet signal
at δ 1.48 assigned for CH3CH2, a quartet signal at δ 4.18
assigned for CH2CH3, a singlet at δ 4.79 assigned for
CH2CO, beside 3 CH3 and aromatic protons. The phtha-
lazine acetic acid ethyl ester 4 was converted to the cor-
responding hydrazide 5 in high yield by the reaction
with hydrazine hydrate (Scheme 1). The hydrazide de-
rivative 5 revealed absorption bands at ν＝1650, 3162
1
1
Results and Discussion
and 3301 cm－ corresponding to CO and NHNH2
1
1
groups. The H NMR spectrum of compound 5 showed
Aroylation of an aromatic system by reaction with
phthalic anhydride under Friedel Craft’s conditions
δ 4.40 (s, 2H, NH2 exchangeable with D2O), 4.71 (s, 2H,
*
E-mail: iei00@fayoum.edu.eg
Received August 18, 2011; accepted September 24, 2011; published online January 19, 2012.
616
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Chin. J. Chem. 2012, 30, 616—626

Some Condensed [4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic Acid Hydrazide
4.93 for assigned N—CH2 and 5.6 for assigned NH2
CH2CO), 9.3 (s, 1H, NH exchangeable with D2O) and
aromatic protons. Whereas, the hydrazide derivatives
constitute a class of compounds that have served as
useful intermediates towards construction of different
heterocyclic compounds.[22]
(exchangeable with D2O). On the other hand condensa-
tion of compound 8 with aromatic aldehydes, namely,
benzaldehyde and p-nitrobenzaldehyde in absolute
ethanol afforded the corresponding Schiff’s bases 10a,
10b respectively. The IR spectra of compounds 10a,
10b showed a characteristic absorption band at ν 1621
Scheme 1
and 1630 cm－ corresponding to C＝N group. The H
NMR spectrum of compound 10a showed the presence
of NH and azomethin (CH＝N) at δ 13.8 and 9.5 re-
spectively. The mass spectrum of 10b showed a peak
corresponding to its molecular ion at m/z 525. Cycliza-
tion of hydrazide 5 with acetyl acetone, diethylmalonate
and/or ethylacetoacetate afforded the corresponding
pyrazole derivatives 11—13 respectively according to
reported methods[23] (Scheme 2). The IR spectra of
1
1
Ar
Ar
O
NH2NH2
O
N
O
NH
AlCl3
COOH
O
O
2
1
3
CH3
compounds 11—13 showed the presence of absorption
Ar =
－
1
1
Ar
O
band s for CO groups at 1661—1723 cm . The H
NMR of compound 11 showed signals at δ 2.01 (s, 3H,
CH3), 2.15 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.30 (s, 6H,
2CH3), 4.80 (s, 2H, CH2) and 6.40 (s, 1H, CH pyrazole).
The mass spectrum of 12 showed a peak corresponding
CH3
H3C
NH2NH2
N
N CH2COOC2H5
BrCH2COOC2H5
4
1
Ar
to its molecular ion at m/z 404. The H NMR of com-
pound 13 showed signals at δ 1.95 assigned for CH3,
4.97 assigned for CH2, and δ 6.10 assigned for 4-CH2.
Cyclization of 13 using hydrazine hydrate in boiling
ethanol gave the corresponding pyrazolotriazolophtha-
lazine derivative 14. The structure of 14 was verified by
the spectral data where, the IR showed the absorption
bands at ν 1660 cm－1 assigned for CO group, and the 1H
NMR showed signals at δ 1.97 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 2.4 (s, 6H, 2CH3), 3.05 (s, 2H, CH2), 5.02 (s, 2H,
CH2CO) and 7.33—8.10 (m, 6H, aromatic protons). The
hydrazide derivative 5 reacted with triethylorthoformate
to afford the corresponding oxadiazolederivative 15
(Scheme 2). The IR spectrum of compound 15 showed
the presence of absorption bands for CO group at 1666
cm－1 and devoid any bands for NH group. The 13CNMR
spectrum of 15 exhibited the expected number of signals
for the aromatic carbons as well as three methyl signals
and methylene signal at δ 20.5, 22.0 and 54.2. Its mass
spectrum shows the molecular ion peak at m/z 346. The
interaction of hydrazide 5 with acetic acid in presence
of phosphorus oxychloride afforded oxadiazolophtha-
lazine derivative 16 (Scheme 3), which displayed two
N
N
CH2CONHNH2
O
5
Cyclization of 5 using carbon disulphide in alcoholic
potassium hydroxide gave the corresponding oxadia-
zolo-2-thione derivative 6. The IR spectrum of com-
pound 6 revealed the presence of CO and NH groups at
1660 and 3196 cm－ respectively. The H NMR spec-
trum of compound 6 showed δ 5.01 for assigned CH2
and 7.06 for assigned NH (exchangeable with D2O) and
aromatic protons. The 13C NMR spectrum of 6 exhibited
the expected number of signals for the aromatic carbons
as well as three methyl signals and methylene signal at δ
20.1, 23.2 and 62.5. The structure of compound 6 was
inferred chemically from (i) its reaction with methyl
iodide afforded the methyl thiooxadiazolophthalazine 7,
its IR spectrum revealed no absorption for NH group,
and the 1H NMR of compound 7 showed the absence of
NH and the signals at δ 2.58 assigned for S—CH3; (ii)
its reaction with hydrazine hydrate afforded the amino
triazolo derivative 8. The IR spectrum of compound 8
showed a characteristic absorption band at ν＝3201 and
1
1
bands at 1245 and 1080 cm－ for the C—O—C asym-
1
metric and symmetric stretching, respectively, in addi-
tion to the band at 1620 cm－ for C＝N stretching. The
1
1H NMR spectrum of compound 16 showed signals at δ
2.10 for assigned CH3 (oxadiazole moity), 4.52 for as-
signed N—CH2.
3301 cm－ corresponding to NH2 group, whereas its
1
mass spectrum showed a peak corresponding to its mo-
lecular ion at m/z 392. Reaction of compound 8 with
benzyl chloride in the presence of alcoholic potassium
hydroxide yielded 2-[(4-amino-5-(benzylthio)-4H-1,2,4-
triazolo-3-yl)methyl]-4-mesityl phthalazin-1(2H)-one
(9). In the IR spectra of compound 9 no absorption at
Refluxing of compound 17 with phosphorus pen-
tasulfide in dry xylene afforded thiadiazolo phthalazine
derivative 18, and its IR revealed no absorption for NH.
1
The H NMR spectrum of compound 18 showed δ 4.42
1300 cm－ was observed indicating the disappearance
1
(s, 2H, CH2), 6.60 (s, 1H, CH thiadiazole) and aro-
maticprotons. The hydrazide derivative 5 reacted with
acrylonitrile to afford the corresponding cyanoethylhy-
1
of the thione group. The H NMR spectrum of com-
pound 9 showed signals at δ 4.79 for assigned S—CH2,
Chin. J. Chem. 2012, 30, 616—626
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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617

El-Hashash et al.
FULL PAPER
Scheme 2
Ar
N
N
N
N
H2
C
N
N
O
14
NH2NH2
Ar
Ar
O
N
N
O
N
H2
C
C N
N
N
O
H2
N
N C
O
O
13
15
Ar
Ar
O
Ar
H
O
N
O
(CH3CO)2CH2
N
H2
C
N
N
O
CH2(COOEt)2
N
N
H2
C
N
C N
C N
N CH2CONHNH2
O
O
12
O
11
5
CS2 /KOH
Ar
O
Ar
O
N
N
N
N
H2
C
N
O
H2
NH
N
N C
O
S
SH
6
Ar
O
Ar
O
N
N
N
N
N
N
H2
C
N
O
H2
C
NH
N
S
SCH3
H2N
7
8
a, Ar' = Ph
b, Ar' =
NO2
Ar
O
Ar
O
N
N
N
H2
NH
N
N
N C
N
H2
C
N
S
N
H2N
N
SCH2Ph
CHAr'
10a, 10b
9
1
drazide derivative 19 in good yield. The structure of
compound 19 was confirmed by the 1H NMR, where the
ethyl protons appear at δ 3.11 and 3.23. Treatment of 19
with carbon disulfide in pyridine afforded the corre-
sponding oxadiazolethione derivative 20 (Scheme 3).
NHPh, exchangeable with D2O). The H NMR of com-
pound 21 showed δ 9.53 assigned for NHPh (ex-
changeable with D2O), and δ 10.33 assigned for CONH
(exchangeable with D2O). The thiocarbamate derivative
21 was cyclized to the corresponding triazole derivative
23 by treatment with sodium hydroxide, while it was
cyclized to the corresponding thiadiazolo phthalazine
derivative 24 by using conc. sulfuric acid (Scheme 3).
The required structure was verified by spectral data.
Fusion of hydrazide 5 with phthalic anhydride gave the
1
Both IR and H NMR spectra showed no signals corre-
sponding to the NH groups thus confirming the structure
of compound 20. Also, the hydrazide derivative 5 re-
acted with phenyl isothiocyanate to give the corre-
sponding thiocarbamate derivative 21. Similarly, the
hydrazide derivative 5 reacted with phenyl isocyanate to
produce the corresponding carbamate derivative 22. The
1H NMR of compound 21 showed δ 10.11 (s, 1H,
CONH, exchangeable with D2O) and 12.86 (s, 1H,
1
corresponding N-amide derivative 25. The H NMR of
compound 25 showed signals at δ 4.33 assigned for
COCH2 and δ 10.72 assigned for NH (exchangeable
with D2O). Its mass spectrum showed the molecular ion
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 616—626

Some Condensed [4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic Acid Hydrazide
Scheme 3
Ar
N
N
O
H2
C
N
N
O
16
Ar
O
Ar
O
O
N
N
N CH2CONHN
POCl3
CH3COOH
N CH2CONHNHCONHPh
O
25
22
Ar
O
Ar
O
Ar
O
N
H2C CHCN
HCOOH
N CH2CONHNHCHO
N CH2CONHNHCH2CH2CN
N
N
N
CH2CONHNH2
19
5
17
PhNCS
P2S5
CS2 /pyridine
Ar
O
Ar
O
Ar
O
N
N
N
N
S
H2
C
CN
N
CH2CONHNHCSNHPh
N
N
N
H2
C
N
N
21
O
S
18
20
Ar
O
Ar
O
N
N
N
N
N
S
H2
C
N
N
H2
C
N
NH
NHPh
S
Ph
23
24
peak at m/z 466.
oxadiazole derivative 28a. The IR spectrum of com-
pound 28a showed the presence of absorption bands for
To get a new series of expected biologically active
Schiff’s bases, it was interest to condense hydrazide 5
with different aromatic aldehydes namely benzaldehyde,
p-chlorobenzaldehyde, thiophene-2-carboxaldehyde and
furfural in ethanol to give the corresponding Schiff’s
bases 26a—26d respectively. The IR spectrum of com-
pounds 26a—26d showed stretching bands at 1615—
1629 cm－1 corresponding to C＝N group. The 1H NMR
spectra of compounds 26a—26d showed the me-
thylidene protons at δ 8.55—8.98. On other hand
N'-(4-chlorobenzylidene)-2-(4-mesityl-1-oxophthalazin-
2(1H)-yl) acetohydrazide (26b) reacted with thioglycol-
lic acid to afford the corresponding thiazolidine deriva-
CO groups at 1658 and 1720 cm－ and devoid any
1
1
bands for NH group, and its H NMR showed CH of
oxadiazole ring at δ 2.08. The reaction of hydrazide 5
with (ethoxymethylene)malononitrile gave the corre-
sponding pyrazolophthalazine derivative 29. The IR
spectrum of compound 29 showed the absorption bands
characteristic for NH2 and CN groups at 3351 and 2230
－
1
cm . The mass spectrum gave the molecular ion peak
at m/z＝412. Condensation of hydrazide 5 with
D-glucose afforded the hydrazone derivative 30. The
compound 30 revealed absorption bands for OH and NH
1
groups in IR spectra and its H NMR spectrum showed
1
the presence of the sugar protons, NH and azomethine
(CH＝N). Furthermore, when compound 5 was allowed
to react with acetyl chloride it give N'-acetyl-1-{2-[4-
(2,4,6-trimethyphenyl)-1(2H)-oxo-phthalazin-2-yl]-
tive 27b in modrate yield (Scheme 4). The H NMR of
compound 27b showed δ 3.51 for assigned SCH2, 5.62
for assigned CH, 8.84 for assigned NH, and the aro-
matic protons. Cyclization of benzylidene compound
26a by its boiling with acetic anhydride afforded the
1
aceto}hydrazide (31). The H NMR of compound 31
Chin. J. Chem. 2012, 30, 616—626
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El-Hashash et al.
FULL PAPER
University.
showed COCH3 at δ 2.05. The latter compound was
subjected to a cyclization reaction by refluxing with an
ethanolic sodium hydroxide solution to give the corre-
sponding pyrazolophthalazine derivative 32. The 1H
NMR of compound 32 showed the pyrazolo protons at δ
4.48 and 7.0. The hydrazide derivative 5 reacted with
D-glucono-1,5-lactone to afford the C-nucleoside 33.
The IR spectrum of compound 33 revealed absorption
4-(2,4,6-Trimethylphenyl)phthalazin-1(2H)-one (3)
Hydrazine hydrate (98%) 0.3 mL was added to a solu-
tion of 2.6 g 2 (0.01 mol) in 15 mL absolute ethanol.
The reaction mixture was refluxed for 2 h, after cooling
the obtained solid was filtered off and crystallized from
ethanol to give 1.72 g 3 in 65% yield as colorless crys-
tals: m.p. 235—236 ℃; 1H NMR (DMSO-d6, 300 MHz)
δ: 2.39 (s, 3H, CH3), 2.50 (s, 6H, 2CH3), 7.27—8.50 (m,
6H, ArH), 11.17 (s, 1H, NH, exchangeable with D2O);
bands at 1659 and 3440 cm－ attributable to CO and
1
OH groups. 1H NMR spectrum showed the presence of
the sugar protons.
－
1
IR (KBr) v: 3212, 1654 cm ; MS (70 eV) m/z (%): 264
(M＋, 18), 77 (100). Anal. calcd for C17H16N2O: C 77.25,
H 6.10, N 10.60; found C 77.20, H 6.13, N, 10.57.
Experimental
[4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-
2-yl]acetic acid ethyl ester (4) A mixture of 2.6 g 3
(0.01 mol), 5 g ethyl bromoacetate (0.03 mol) and 4.1 g
potassium carbonate (0.03 mol) in 30 mL dry acetone
was heated under reflux for 30 h, cooled at room tem-
perature and poured into water. The obtained solid was
filtered off and crystallized from petroleum ether (40—
60 ℃) to give 2.8 g 4 in yield 80% as colorless crystals:
Melting points were measured with a Gallenkamp
apparatus and are uncorrected. The reactions were fol-
lowed up and the purification of products was carried
out on pre-coated TLC plates (Silica gel 60 F254, Merck),
visualizing the spots in ultraviolet light. IR spectra were
recorded on a Shimadzu FT-IR 8101 PC infrared spec-
trophotometer. The 1H NMR and 13C NMR spectra were
determined in DMSO-d6 at 300 MHz on a Varian Mer-
cury VX 300 NMR spectrometer and their chemical
shifts (δ) are reported with respect to TMS as internal
standard. Mass spectra were measured on a GCMS-
QP1000 EX spectrometer at 70 eV. Elemental analyses
were carried out at the Microanalytical Center of Cairo
1
m.p. 124—125 ℃; H NMR (DMSO-d6, 300 MHz) δ:
1.48 (t, J＝10 Hz, 3H, CH3CH2), 2.39 (s, 3H, CH3),
2.51 (s, 6H, 2CH3), 4.18 (q, J＝10 Hz, 2H, CH2CH3),
4.79 (s, 2H, CH2CO), 7.10—8.0 (ArH); IR (KBr) v:
－
＋
1
1731, 1659 cm ; MS (70 eV) m/z (%): 350 (M , 15),
Scheme 4
Ar
Ar
O
O
H
EtONa
N
N
N
N
N
NH
N
NHCOCH3
O
O
32
31
CH3COCl
EtO
CN
CN
CN
Ar
O
Ar
O
Ar
H2N
O
D-glucose
CH2CONHNH2
N
N
N
N
N
H2
C
N CH2CONHN CH
C N
N
OH
29
HO
O
5
30
OH
OH
CH2OH
Ar
Ar
N
N
N
N
N
R=
R
N CH2CONHN CHAr''
O
OH
O
O
HO
33
26
OH
OH
a, Ar'' =
b, Ar'' =
c, Ar'' =
CH2OH
Cl
Ar
Ar
O
Ar''
COCH3
Ar''
N
O
N
N
O
H2
N C C N N
H2
N C
S
H
S
N
O
d, Ar'' =
O
27b
O
28a
620
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 616—626

Some Condensed [4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic Acid Hydrazide
305 (100). Anal. calcd for C21H22N2O3: C 71.98, H 6.33,
N 7.99; found C 71.93, H 6.31, N 8.03.
ethanol to give 3 g 8 in yield 76% as colorless crystals:
m.p. 260—261 ℃; 1H NMR (DMSO-d6, 300 MHz) δ:
2.36 (s, 3H, CH3), 2.49 (s, 6H, 2CH3), 4.10 (s, 2H, CH2),
5.22 (s, 2H, NH2 exchangeable with D2O), 7.16—8.12
(ArH), 13.3 (s, 1H, NH exchangeable with D2O); IR
(KBr) v: 3301, 3201, 3131, 2600, 1662, 1610, 1157
[4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-
2-yl]acetic acid hydrazide (5) A mixture of 3.5 g 4
(0.01 mol) and 2 mL hydrazine hydrate in 50 mL abso-
lute ethanol was refluxed for 2 h and cooled at room
temperature. The resultant solid was filtered and crystal-
lized from ethanol to give 2.6 g 5 in yield 77% as color-
－
＋
1
cm ; MS (70 eV) m/z (%): 392 (M , 10), 248 (100).
Anal. calcd for C20H20N6OS: C 61.20, H 5.14, N 21.41,
S 8.17; found C 61.22, H 5.12, N 21.40, S 8.16.
1
less crystals: m.p. 227—228 ℃; H NMR (DMSO-d6,
300 MHz) δ: 2.30 (s, 3H, CH3), 2.48 (s, 6H, 2CH3),
4.40 (s, 2H, NH2 exchangeable with D2O), 4.71 (s, 2H,
CH2CO), 7.30 —8.01 (ArH), 9.30 (s, 1H, NH ex-
changeable with D2O); IR (KBr) v: 3301, 3298, 3162,
1650 cm ; MS (70 eV) m/z (%): 337 (M＋1, 10), 77
(100). Anal. Calcd for C19H20N4O2: C 67.84, H 5.99, N
16.66; found C 67.79, H 6.02, N 16.67.
2-[(4-Amino-5-(benzylthio)-4H-1,2,4-triazol-3-yl)-
methyl]-4-mesitylphthalazin-1(2H)-one (9)
To a
mixture of 3.9 g 8 (0.01 mol) and 0.67 g of KOH (0.012
mol) in 50 mL absolute ethanol was added 1.52 g of
benzyl chloride (0.012 mol). The reaction mixture was
heated under reflux for 2 h, cooled and dilute with 30
mL of water. The precipitated product was dried under
vacuum and recrystallized from ethanol to give 3.2 g 9
－
1
4-(2,4,6-Trimethylphenyl)-2-[(4,5-dihydro-5-thio-
oxo-1,3,4-oxadiazol-2-yl)methyl]phthalazin-1(2H)-
one (6) 0.6 g hydrazide 5 (0.002 mol) was added to
0.28 g potassium hydroxide solution in 40 mL absolute
ethanol. Then, 6 mL carbon disulfide was added portion
wise and the reaction mixture was refluxed till no odour
of hydrogen sulfide evolved (18 h). The reaction mix-
ture was poured onto ice water and rendered acidic with
hydrochloric acid. The precipitated solid was filtered,
dried and crystallized from ethanol to give 0.4 g 6 in
1
in yield 66%: m.p. 184—185 ℃; H NMR (DMSO-d6,
300 MHz) δ: 2.28—2.46 (2s, 9H, ArCH3), 4.79 (s, 2H,
S-CH2), 4.93 (s, 2H, N-CH2), 5.6 (s, 2H, NH2, ex-
changeable with D2O) and 7.10—8.45 (m, 11H, aro-
－
1
matic protons); IR (KBr) v: 3320, 3300, 1660 cm ; MS
(70 eV) m/z (%): 482 (M＋, 7), 91 (100). Anal. calcd for
C27H26N6OS: C 67.20, H 5.43, N 17.41, S 6.64; found C
67.15, H 5.39, N 17.44, S 6.65.
1
Reaction of 2-[(4-amino-5-thioxo-4,5-dihydro-1H-
1,2,4-triazol-3-yl)methyl]-4-mesitylphthalazin-
1(2H)-one (8) with some aromatic aldehydes
yield 54% as yellow crystals: m.p. 180—181 ℃; H
NMR (DMSO-d6, 300 MHz) δ: 2.35 (s, 3H, CH3), 2.47
(s, 6H, 2CH3), 5.01 (s, 2H, CH2CO), 7.06 (s, 1H, NH
exchangeable with D2O), 7.26—7.76 (ArH); 13C NMR
(DMSO-d6, 300 MHz) δ: 20.1, 23.2, 62.5, 123.8, 126.3,
127.7, 128.0, 129.8, 130.3, 131.4, 132.5, 134.2, 138.7,
141.0, 158.4, 158.6, 191; IR (KBr) v: 3196, 1660, 1274
General procedure A mixture of 0.4 g 8 (0.001
mol) and an appropriate aromatic aldehyde, namely
benzaldehyde or p-nitrobenzaldehyde (0.001 mol) was
refluxed in 20 mL absolute ethanol for 4 h. After cool-
ing the separated solid was collected by filtration, dried
and crystallized from the proper solvent to give the title
compounds 10a and 10b, respectively.
－
＋
1
cm ; MS (70 eV) m/z (%): 277 (M －C2N2OS, 23),
103 (41), 64 (100). Anal. calcd for C20H18N4O2S: C
63.47, H 4.79, N 14.80, S 8.47; found C 63.43, H 4.77,
N 14.86, S 8.45.
2-[(4-(benzylideneamino)-5-thioxo-4,5-dihydro-
1H-1,2,4-triazol-3-yl)methyl]-4-mesitylphthalazin-
1(2H)-one (10a) 4 g 10a in yield 83%, m.p. 200—201
℃; 1H NMR (DMSO-d6, 300 MHz) δ: 2.39 (s, 3H, CH3),
2.50 (s, 6H, 2CH3), 4.43 (s, 2H, CH2), 7.16—8.12
(ArH), 9.5 (s, 1H, CH＝N), 13.8 (s, 1H, NH exchange-
1,2-Dihydro-4-(2,4,6-Trimethylphenyl)-2-[(5-
methylthio)-1,3,4-oxadiazol-2-yl]phthalazine (7) To
a mixture of 20 mL absolute ethanol containing KOH
(0.05 g, 0.001 mol), compound 6 (0.4 g, 0.001 mol) and
methyl iodide (0.001 mol) were added. The reaction
mixture was stirred overnight and poured onto water.
The precipitated solid was collected by filtration, dried
and crystallized from ethanol to give 0.26 g 7 in yield
－
1
able with D2O); IR (KBr) v: 3162, 1658, 1621 cm ; MS
(70 eV) m/z (%): 480 (M＋, 5.2), 77 (100). Anal. calcd
for C27H24N6OS: C 67.48, H 5.03, N 17.49, S 6.67;
found C 67.45, H 5.10, N 17.43, S 6.64.
1
66%: m.p. 119—120 ℃; H NMR (DMSO-d6, 300
4-Mesityl-2-[(4-(4-nitrobenzylideneamino)-5-thio-
xo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]phtha-
lazin-1(2H)-one (10b) 4.7 g 10b in yield 90%, m.p.
191—192 ℃; IR (KBr) v: 3195, 1668, 1630, 1560,
1334 cm ; MS (70 eV) m/z (%): 525 (M , 4.1), 77
(100). Anal. calcd for C27H23N7O3S: C 61.70, H 4.41, N
18.65, S 6.10; found C 61.74, H 4.40, N 18.63, S 6.06.
2-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethyl)-
4-(2,4,6-trimethylphenyl)phthalazin-1(2H)-one (11)
A mixture of 0.6 g the acetic acid hydrazide 5 (0.002
mol) and 0.30 g acetyl acetone (0.003 mol) in 20 mL
ethanol was refluxed for 10 h. After cooling the ob-
tained solid was collected, dried and crystallized from
MHz) δ: 2.32 (s, 3H, CH3), 2.46 (s, 6H, 2CH3), 2.58 (s,
3H, SCH3), 4.60 (s, 2H, CH2), 7.10—7.92 (ArH); IR
(KBr) v: 1667, 1602 cm ; MS (70 eV) m/z (%): 392
(M＋, 13), 263 (100). Anal. calcd for C21H20N4O2S: C
64.27, H 5.14, N 14.28, S 8.17; found C 64.29, H 5.16,
N 14.24, S 8.15.
2-[(4-Amino-5-thioxo-4,5-dihydro-1H-1,2,4-tria-
zol-3-yl)methyl]-4-mesitylphthalazin-1(2H)-one (8)
A mixture of 3.7 g 6 (0.01 mol) and 2 mL hydrazine
hydrate (0.03 mol) in 20 mL absolute ethanol was re-
fluxed for 2 h. The solvent and the excess hydrazine
hydrate were removed under reduced pressure, the resi-
due was washed with ether, then recrystallized from
－
1
－
＋
1
Chin. J. Chem. 2012, 30, 616—626
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
621

El-Hashash et al.
FULL PAPER
ethanol to give 0.66 g 11 in yield 82% as colorless crys-
tals: m.p. 180—181 ℃; 1H NMR (DMSO-d6, 300 MHz)
δ: 2.01 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.24 (s, 3H,
CH3), 2.30 (s, 6H, 2CH3), 4.80 (s, 2H, CH2), 6.40 (s, 1H,
CH pyrazole), 7.50—8.31 (m, 6H, ArH); IR (KBr) v:
126.8, 128.2, 129.1, 129.8, 131.0, 131.9, 132.6, 134.9,
139.1, 141.5, 155.2, 159.0, 164.3; IR (KBr) v: 1666
－
＋
1
cm ; MS (70 eV) m/z (%): 346 (M , 13.0), 263 (100).
Anal. calcd for C20H18N4O2: C 69.35, H 5.24, N 16.17;
found C 69.30, H 5.28, N 16.19.
－
1
1720, 1677 cm . Anal. calcd for C24H24N4O2: C 71.98,
H 6.04, N 13.99; found C 71.95, H 6.08, N 14.02.
4-Mesityl-2-[(5-methyl-1,3,4-oxadiazol-2-yl)meth-
yl]phthalazin-1(2H)-one (16) A solution of 3.3 g 5
(0.01 mol), and 0.6 g acetic acid (0.01 mol) in phos-
phorous oxychloride (1 mL), was refluxed for 6—8 h.
After cooling, the excess phosphorous oxychloride was
evaporated under reduced pressure. The residue ob-
tained was diluted with ice water (50 mL), neutralized
with saturated sodium bicarbonate, and extracted with
ethyl acetate (50 mL×3). The combined organic layer
was dried over anhydrous sodium sulphate. After filtra-
tion, the solvent was evaporated to get crude product,
which was purified by using CombiFlash® Companion®
flash chromatography system using ethyl acetate/hexane
as mobile phase to get 2.5 g 16 in yield 69% as colorless
1-[2-(4-Mesityl-1-oxophthalazin-2(1H)-yl)acetyl]-
pyrazolidine-3,5-dione (12) A mixture of 0.6 g the
acetic acid hydrazide 5 (0.002 mol) and 0.48 g diethyl-
malonate (0.003 mol) in 20 mL ethanol was refluxed for
10 h. After cooling the obtained solid was collected,
dried and crystallized from ethanol to give 0.61 g 12 in
1
yield 76% as colorless crystals: m.p. 290—291 ℃; H
NMR (DMSO-d6, 300 MHz) δ: 2.35 (s, 3H, CH3), 2.44
(s, 6H, 2CH3), 3.20 (s, 2H, CH2), 4.50 (s, 2H, CH2CO),
7.10—8.01 (m, 6H, ArH), 9.92 (s, 1H, NH exchange-
－
1
able with D2O); IR (KBr) v: 3179, 1690, 1661 cm ;
MS (70 eV) m/z (%): 404 (M＋, 4.1), 305 (100). Anal.
calcd for C22H20N4O4: C 65.34, H 4.98, N 13.85; found
C 65.30, H 5.01, N 13.88.
1
crystals: m.p. 188—189 ℃; H NMR (DMSO-d6, 300
MHz) δ: 2.10 (s, 3H, CH3), 2.26 (s, 6H, 2CH3), 2.74 (s,
3H, CH3), 4.52 (s, 2H, CH2), 7.09—7.91 (m, 6H, ArH);
5-Methyl-3-oxo-2-[1(2H)-oxo-4-(2,4,6-trimethyl-
phenyl)phthalazin-2-ylmethylcarbonyl]-3,4-dihydro-
pyrazol (13) A mixture of 0.6 g the acetic acid hy-
drazide 5 (0.002 mol) and 0.39 g ethylacetoacetate
(0.003 mol) in 20 mL ethanol was refluxed for 8 h. After
cooling the obtained solid was collected, dried and
crystallized from ethanol to give 0.58 g 13 in yield 75%
－
1
IR (KBr) v: 1653, 1620 cm ; MS (70 eV) m/z (%): 360
(M＋, 6.0), 263 (100). Anal. calcd for C21H20N4O2: C
69.98, H 5.59, N 15.55; found C 70.01, H 5.60, N 15.50.
N'-Formyl-2-(4-mesityl-1-oxophthalazin-2(1H)-
yl)acetohydrazide (17) A solution of 3.3 g 5 (0.01
mol) in formic acid (20 mL) was refluxed for 30 min.
The solvent was evaporated and the residue was crystal-
lized from methanol to give 3.0 g 17 in yield 83%: m.p.
1
as colorless crystals: m.p. 268—269 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 1.95 (s, 3H, CH3), 2.38 (s, 3H,
CH3), 2.46 (s, 6H, 2CH3), 4.97 (s, 2H, CH2CO), 6.10 (s,
2H, CH2), 7.21—8.30 (m, 6H, ArH); IR (KBr) v: 1723,
－
1
249—250 ℃; IR (KBr) v: 3211, 1720, 1660 cm ; MS
(70 eV) m/z (%): 364 (M＋, 11), 305 (100). Anal. calcd
for C20H20N4O3: C 65.92, H 5.53, N 15.38; found C
65.88, H 5.55, N 15.40.
－
＋
1
1650, 1613 cm ; MS (70 eV) m/z (%): 402 (M , 6.0),
305 (100). Anal. calcd for C23H22N4O3: C 68.64, H 5.51,
N 13.92; found C 68.60, H 5.53, N 13.93.
2-[(1,3,4-Thiadiazol-2-yl)methyl]-4-mesitylphtha-
lazin-1(2H)-one (18) To a solution of 3.6 g 17 (0.01
mol) in xylene (150 mL), phosphorous pentasulphide
(0.01 mol) was added. The mixture was refluxed for 1 h.
The solvent was evaporated, water (10 mL) was added
and the mixture was extracted with chloroform. The
solvent was evaporated and the residue was recrystal-
lized from benzene to give 2.9 g 18 in yield 80%: m.p.
2-[(6-Methyl-7H-pyrazolo[5,1-c][1,2,4]triazol-3-
yl)methyl]-4-(2,4,6-trimethylphenyl) phthalazin-
1(2H)-one (14) Hydrazine hydrate (98%) 0.5 mL was
added to a solution of 0.4 g 13 (0.001 mol) in 10 mL
absolute ethanol. The reaction mixture was refluxed for
8 h, after cooling the obtained solid was filtered off and
crystallized from ethanol to give 0.32 g 14 in yield 82%
as colorless crystals: m.p. 239—240 ℃; 1H NMR
(DMSO-d6, 300 MHz) δ: 1.97 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 2.40 (s, 6H, 2CH3), 3.05 (s, 2H, CH2), 5.02 (s, 2H,
CH2CO), 7.09—7.85 (m, 6H, ArH); IR (KBr) v: 1660
1
130—131 ℃; H NMR (DMSO-d6, 300 MHz) δ: 2.25
(s, 3H, CH3), 2.40 (s, 6H, 2CH3), 4.42 (s, 2H, CH2), 6.6
(s, 1H, thiadiazole), 7.11—8.06 (m, 6H, ArH); IR (KBr)
－
＋
1
v: 1665, 1610 cm ; MS (70 eV) m/z (%): 362 (M ,
13.0), 263 (100). Anal. calcd for C20H18N4OS: C 66.28,
H 5.01, N 15.46, S 8.85; found C 66.30, H 5.00, N
15.44, S 8.87.
－
＋
1
cm ; MS (70 eV) m/z (%): 398 (M , 6.0), 263 (100).
Anal. calcd for C23H22N6O: C 69.33, H 5.57, N 21.09;
found C 69.35, H 5.53, N 21.13.
2-[(1,3,4-Oxadiazol-2-yl)methyl]-4-mesitylphtha-
lazin-1(2H)-one (15) A mixture of 0.6 g the acetic
acid hydrazide 5 (0.002 mol) and 5 mL triethylortho-
formate was refluxed for 15 h on steam bath. The
formed solid was collected, dried and crystallized from
ethyl acetate to give 0.50 g 15 in yield 73%: m.p. 133—
134 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 2.10 (s, H,
CH oxadiazole), 2.37 (s, 3H, CH3), 2.46 (s, 6H, 2CH3),
5.11 (s, 2H, CH2CO), 7.33—8.51 (m, 6H, ArH); 13C
NMR (DMSO-d6, 300 MHz) δ: 20.5, 22.0, 54.2, 124.1,
N'-(2-Cyanoethyl)-2-(4-(2,4,6-trimethylphenyl)-1-
oxophthalazin-2(1H)-yl) acetohydrazide (19)
A
mixture of 0.3 g the acetic acid hydrazide 5 (0.001 mol)
and 0.1 g acrylonitrile (0.001 mol) in 20 mL pyridine
was refluxed for 13 h. After cooling, the reaction mix-
ture was poured onto ice water and HCl. The precipi-
tated solid was collected by filtration, dried and crystal-
lized from methanol to give 0.28 g 19 in yield 76% as
pale yellow crystals: m.p. 165—165 ℃; 1H NMR
(DMSO-d6, 300 MHz) δ: 2.0 (s, 1H, NHCH2, ex-
622
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 616—626

Some Condensed [4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic Acid Hydrazide
changeable with D2O), 2.21 (s, 3H, CH3), 2.35 (s, 6H,
2CH3), 3.11 (t, J＝10.0 Hz, 2H, NHCH2), 3.23 (t, J＝
10.0 Hz, 2H, CH2CN), 5.00 (s, 2H, CH2CO),
7.20—8.36 (m, 6H, ArH), 8.0 (s, 1H, CONH, ex-
changeable with D2O); IR (KBr) v: 3209, 2200, 1642
15.37; found C 68.52, H 5.56, N 15.40.
2-[(5-Mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)-
methyl]-4-(2,4,6-trimethylphenyl)phthalazin-1(2H)-
one (23) 0.001 mol of thiocarbamate derivative 21
was dissolved in sodium hydroxide solution (2 mol/L,
20 mL). The clear solution was heated on a water bath
for 3 h, filtered after cooling and neutralized with dilute
hydrochloric acid. The precipitated solid was collected
by filtration, dried and crystallized from ethanol to give
0.32 g 23 in yield 71% as colorless crystals: m.p.
－
1
cm . Anal. calcd for C22H23N5O2: C 67.85, H 5.59, N
17.98; found C 67.81, H 5.61, N 18.00.
3-[5-((4-Mesityl-1-oxophthalazin-2(1H)-yl)-
methyl)-2-thioxo-1,3,4-oxadiazol-3(2H)-yl]propane-
nitrile (20) A suspension of 19 (0.38 g, 0.001 mol)
and carbon disulfide (2 mL) in pyridine (5 mL) was
heated under reflux on water bath for 24 h. The solvent
was eliminated under reduced pressure and the residue
was triturated with ice-cold water and neutralized with
diluted HCl. The solid product obtained was filtered off
and recrystallized from petroleum ether/ethyl acetate
(2∶1) to to give 0.306 g 20 in yield 69% as buff crys-
tals: m.p. 110—111 ℃; 1H NMR (DMSO-d6, 300 MHz)
δ: 2.25 (s, 3H, CH3), 2.40 (s, 6H, 2CH3), 3.01 (t, J＝
10.0 Hz, 2H, NHCH2), 3.40 (t, J ＝10.0 Hz, 2H,
CH2CN), 4.10 (s, 2H, CH2CO), 7.02—8.05 (m, 6H,
1
297—298 ℃; H NMR (DMSO-d6, 300 MHz) δ: 2.26
(s, 3H, CH3), 2.46 (s, 6H, 2CH3), 4.55 (s, 2H, COCH2),
7.00—8.10 (m, 11H, ArH), 13.8 (s, 1H, NH, exchange-
able with D2O); IR (KBr) v: 3234, 1669 cm ; MS (70
eV) m/z (%): 453 (M＋, 9.0), 77 (100). Anal. calcd for
C26H23N5OS: C 68.85, H 5.11, N 15.44, S 7.07; found C
68.80, H 5.14, N 15.46, S 7.10.
－
1
4-(2,4,6-Trimethylphenyl)-2-[(5-phenylamino-
1,3,4-thiadiazol-2-yl)methyl]phthalazin-1-(2H)-one
(24) 0.001 mol of of thiocarbamate derivatives 21 was
mixed with conc. H2SO4 (5 mL), left overnight. The
reaction mixture was poured onto ice water, the precipi-
tated solid was collected by filtration, dried and crystal-
lized from ethanol to give 0.30 g 24 in yield 66% as
colorless crystals: m.p. 148—149 ℃ ; 1H NMR
(DMSO-d6, 300 MHz) δ: 2.29 (s, 3H, CH3), 2.48 (s, 6H,
2CH3), 5.11 (s, 2H, COCH2), 6.84—8.19 (m, 11H, ArH),
10.1 (s, 1H, NH, exchangeable with D2O); IR (KBr) v:
－
1
ArH); IR (KBr) v: 2220, 1667, 1630, 1160 cm . Anal.
calcd for C23H21N5O2S: C 64.02, H 4.91, N 16.23, S
7.43; found C 64.05, H 4.89, N 16.25, S 7.40.
1-{2-[4-(2,4,6-Trimethylphenyl)-1-oxophthalazin-
2(1H)-yl]acetyl}-4-phenyl thiosemicarbazide (21)
A
mixture of 0.6 g the acetic acid hydrazide 5 (0.002 mol)
and phenyl isothiocyanate (0.002 mol) in 20 mL dry
N,N-dimethylformamide containing few drops of
triethylamine was refluxed for 24 h. After cooling, the
reaction mixture was poured onto ice water and HCl.
The precipitated solid was collected by filtration, dried
and crystallized from toluene to give 0.68 g 21 in yield
－
＋
1
3196, 1660 cm ; MS (70 eV) m/z (%): 453 (M , 9.0),
77 (100). Anal. calcd for C26H23N5OS: C 68.85, H 5.11,
N 15.44, S 7.07; found C 68.81, H 5.13, N 15.47, S
7.09.
N'-(1,3-Dioxoisoindolin-2-yl)-2-(4-mesityl-1-
oxophthalazin-2(1H)-yl)acetamide (25) A mixture of
0.6 g the acetic acid hydrazide 5 (0.002 mol) and
phthalic anhydride (0.002 mol) in 15 mL acetic acid was
refluxed for 10 h. After cooling the obtained solid was
filtered off and crystallized from acetic acid to give 0.75
g 25 in yield 81% as colorless crystals: m.p.＞300 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 2.12 (s, 3H, CH3),
2.41 (s, 6H, 2CH3), 4.33 (s, 2H, COCH2), 6.94—8.29
(m, 11H, ArH), 10.72 (s, 1H, CONH, exchangeable with
1
72% as colorless crystals: m.p.＞300 ℃; H NMR
(DMSO-d6, 300 MHz) δ: 2.0 (s, 1H, NHCS, exchange-
able with D2O), 2.22 (s, 3H, CH3), 2.46 (s, 6H, 2CH3),
5.10 (s, 2H, COCH2), 6.81—8.19 (m, 11H, ArH), 10.11
(s, 1H, CONH, exchangeable with D2O), 12.86 (s, 1H,
NHPh, exchangeable with D2O); IR (KBr) v: 3310,
－
1
＋
3294, 3147, 1655 cm ; MS (70 eV) m/z (%): 471 (M ,
22), 77 (100). 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 6.83.
－
1
D2O); IR (KBr) v: 3187, 1793, 1744, 1684 cm ; MS
(70 eV) m/z (%): 466 (M＋, 12), 305 (100). Anal. calcd
for C27H22N4O4: C 69.52, H 4.75, N 12.01; found C
69.55, H 4.72, N 12.05.
1-{2-[4-(2,4,6-Trimethylphenyl)-1-oxophthalazin-
2(1H)-yl] acetyl}-4-phenyl semicarbazide (22)
A
mixture of 0.6 g the acetic acid hydrazide 5 (0.002 mol)
and phenyl isocyanate (0.004 mol) in 20 mL dry
N,N-dimethylformamide was refluxed for 20 h. After
cooling, the reaction mixture was poured onto ice water.
The precipitated solid was collected by filtration, dried
and crystallized from toluene to give 0.686 g 22 in yield
73% as colorless crystals: m.p. 200—201 ℃; 1H NMR
(DMSO-d6, 300 MHz) δ: 2.25 (s, 3H, CH3), 2.42 (s, 6H,
2CH3), 4.96 (s, 2H, COCH2), 6.10 (s, 1H, NHCO, ex-
changeable with D2O), 7.10—8.40 (m, 11H, ArH), 9.53
(s, 1H, NHPh, exchangeable with D2O), 10.33 (s, 1H,
CONH, exchangeable with D2O); IR (KBr) v: 3210,
Reaction of phthalazine hydrazide derivative 5 with
some aromatic aldehydes
A mixture of 0.3 g the acetic acid hydrazide 5 (0.001
mol) and an appropriate aromatic aldehyde, namely
benzaldehyde, p-chlorobenzaldehyde, thiophene-2-
carboxaldehyde or furfural (0.001 mol) was refluxed in
20 mL absolute ethanol for 4 h. After cooling the sepa-
rated solid was collected by filtration, dried and crystal-
lized from the proper solvent to give aryl methylidene
hydrazide derivatives 26a—26d.
－
＋
1
N'-Benzylidene-2-(4-mesityl-1-oxophthalazin-
2(1H)-yl)acetohydrazide (26a) 0.32 g 26a in yield
1668 cm ; MS (70 eV) m/z (%): 455 (M , 18), 77
(100). Anal. calcd for C26H25N5O3: C 68.56, H 5.53, N
Chin. J. Chem. 2012, 30, 616—626
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
623

El-Hashash et al.
FULL PAPER
76% as colorless crystals from ethanol: m.p. 195—196
℃; 1H NMR (DMSO-d6, 300 MHz) δ: 2.19 (s, 3H, CH3),
2.38 (s, 6H, 2CH3), 5.27 (s, 1H, NH, exchangeable with
D2O), 5.50 (s, 2H, CH2), 6.80—7.85 (m, 10H, ArH),
8.66 (s, 1H, CH); IR (KBr) v: 3188, 1660, 1615 cm ;
Anal. calcd for C26H24N4O2: C 73.56, H 5.70, N 13.20;
found C 73.50, H 5.73, N 13.24.
anhydride (2 mL) were heated under reflux for 5 h. The
reaction mixture was cooled, poured onto water and
allowed to stand at room temperature for 3 h. The solid
product formed was collected and recrystallized from
petroleum ether/ethyl acetate mixture to give 0.68 g 28a
in yield 73% as colorless crystals: m.p. 101—102 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 2.08 (s, 1H, CH
oxadiazole), 2.18 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.35
(s, 6H, 2CH3), 5.06 (s, 2H, CH2), 7.15—8.12 (m, 11H,
ArH); IR (KBr) v: 1720, 1658, 1612 cm ; MS (70 eV)
m/z (%): 466 (M＋, 5), 43 (100). Anal. calcd for
C28H26N4O3: C 72.09, H 5.62, N 12.01; found C 72.05,
H 5.60, N 12.05.
－
1
N'-(4-Chlorobenzylidene)-2-(4-mesityl-1-oxophth-
alazin-2(1H)-yl)acetohydrazide (26b) 0.37 g 26b in
yield 82% as colorless crystals from ethanol: m.p.
152—153 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 2.19
(s, 3H, CH3), 2.38 (s, 6H, 2CH3), 5.01 (s, 2H, CH2),
6.09 (s, 1H, NH, exchangeable with D2O), 6.75—8.00
(m, 10H, ArH), 8.98 (s, 1H, CH); IR (KBr) v: 3282,
－
1
5-Amino-1-(2-(4-mesityl-1-oxophthalazin-2(1H)-
yl)acetyl)-1H-pyrazole-4-carbonitrile (29) A mix-
ture of 0.6 g the acetic acid hydrazide 5 (0.002 mol) and
ethoxymethylene malononitrile (0.24 g, 0.002 mol) in
20 mL absolute ethanol was refluxed for 8 h. After
cooling, the solvent was removed in vacuo and the solid
residue was recrystallized from ethanol to give 0.68 g
29 in yield 82% as colorless crystals: m.p. 280—281 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 2.21 (s, 3H, CH3),
2.40 (s, 6H, 2CH3), 4.66 (s, 2H, CH2), 7.01—7.90 (m,
6H, ArH and NH2, exchangeable with D2O), 8.13 (s, 1H,
－
＋
1
1649, 1618 cm ; MS (70 eV) m/z (%): 460 (M Cl37, 1),
458 (M＋Cl35, 4), 263 (100). Anal. calcd for C26H23-
ClN4O2: C 68.04, H 5.05, N 12.21; found C 68.08, H
5.01, N 12.23.
2-(4-Mesityl-1-oxophthalazin-2(1H)-yl)-N'-(thio-
phen-2-ylmethylene)acetohydrazide (26c)
0.31 g
26c in yield 72% as faint brown crystals from toluene:
m.p. 144—145 ℃; 1H NMR (DMSO-d6, 300 MHz) δ:
2.18 (s, 3H, CH3), 2.33 (s, 6H, 2CH3), 5.05 (s, 2H, CH2),
5.70 (s, 1H, NH, exchangeable with D2O), 6.69—8.07
(m, 9H, ArH), 8.55 (s, 1H, CH); IR (KBr) v: 3188, 1651,
－
1
CH pyrazole); IR (KBr) v: 3351, 2230, 1657 cm ; MS
(70 eV) m/z (%): 412 (M＋, 19), 305 (100). Anal. calcd
for C23H20N6O2: C 66.98, H 4.89, N 20.38; found C
67.01, H 4.85, N 20.40.
－
1
1619 cm . Anal. calcd for C24H22N4O2S: C 66.96, H
5.15, N 13.01, S 7.45; found C 67.00, H 5.10, N 13.05,
S 7.47.
N'-(Furan-2-ylmethylene)-2-(4-mesityl-1-oxoph-
thalazin-2(1H)-yl)acetohydrazide (26d) 0.33 g 26d
in yield 80% as faint brown crystals from toluene: m.p.
N'-D-Aldehydoglucosyl-2-(4-mesityl-1-oxophth-
alazin-2(1H)-yl)acetohydrazide (30) A mixture of
3.0 g the acetic acid hydrazide 5 (0.01 mol), D-glucose
(1.8 g, 0.01 mol), absolute ethanol (40 mL) and a cata-
lytic amount of glacial acetic acid was heated under re-
fluxed for 2 h. After cooling the separated solid was
collected by filtration, dried and crystallized from etha-
nol to 3.5 g 30 in yield 71% as colorless crystals: m.p.
300—301 ℃; 1H NMR (DMSO-d6, 300 MHz) δ: 2.29
(s, 3H, CH3), 2.35 (s, 6H, 2CH3), 3.20—3.60 (protons of
the alditol congregated with the solvent absorption),
3.70—3.80 (m, 2H, CH2OH), 4.40—5.05 (m, 5H, 5OH,
exchangeable with D2O), 5.31 (s, 2H, CH2CO),
7.26—7.90 (m, 7H, ArH and NH, exchangeable with
D2O), 8.35 (s, 1H, N＝CH); 13C NMR (DMSO-d6, 300
MHz) δ: 20.1, 22.2, 58.2, 61.2, 70.7, 72.7, 77.1, 92.6,
124.0, 127.1, 128.0, 128.7, 129.8, 131.3, 131.9, 133.3,
135.0, 139.8, 142.1, 160.1, 162.3, 173.6; IR (KBr) v:
3353, 3220, 1661, 1613 cm － 1. Anal. calcd for
C25H30N4O7: C 60.23, H 6.07, N 11.24; found C 60.27,
H 6.11, N 11.20.
N'-Acetyl-1-{2-[4-(2,4,6-trimethylphenyl)-1(2H)-
oxo-phthalazin-2-yl]aceto}hydrazide (31) A mixture
of 0.6 g the acetic acid hydrazide 5 (0.002 mol) and
acetyl chloride (0.004 mol) in 20 mL dry N,N-dimethyl-
formamide containing few drops of triethylamine was
refluxed for 14 h. After cooling, the reaction mixture
was poured onto ice water. The precipitated solid was
collected by filtration, dried and crystallized from tolu-
ene to give 0.48 g 31 in yield 64% as colorless crystals:
1
174—175 ℃; H NMR (DMSO-d6, 300 MHz) δ: 2.26
(s, 3H, CH3), 2.43 (s, 6H, 2CH3), 5.45 (s, 2H, CH2),
5.70 (s, 1H, NH, exchangeable with D2O), 6.39—7.97
(m, 9H, ArH), 8.97 (s, 1H, CH); IR (KBr) v: 3271,1659,
－
1
1629 cm . Anal. calcd for C24H22N4O3: C 69.55, H
5.35, N 13.52; found C 69.58, H 5.37, N 13.48.
[4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-
2-yl]-N-[4-oxo-2-(4-chlorophenyl) thiazolidin-3-yl]-
acetamide (27b)
A mixture of 0.6 g chloro-
methylidene hydrazide derivative 26b (0.0013 mol), 0.1
mL thioglycolic acid (0.0013 mol), 0.5 g anhydrous zinc
chloride and few drops of piperidine was refluxed in 20
mL dry N,N-dimethylformamide for 24 h. The reaction
mixture was then poured onto water and the precipitated
solid was filtered off, washed several times with water,
dried to give 0.36 g 27b in yield 69% as yellowish
1
brown crystals from toluene: m.p. 299—300 ℃; H
NMR (DMSO-d6, 300 MHz) δ: 2.28 (s, 3H, CH3), 2.47
(s, 6H, 2CH3), 3.51 (s, 2H, SCH2), 5.00 (s, 2H, CH2),
5.62 (s, 1H, CH), 6.67—8.50 (m, 10H, ArH), 8.84 (s,
1H, NH, exchangeable with D2O); IR (KBr) v: 3172,
－
1
1719, 1662 cm . Anal. calcd for C28H25ClN4O3S: C
63.09, H 4.73, N 10.51, S 6.02; found C 63.12, H 4.70,
N 10.53, S 6.05.
2-[(4-Acetyl-5-phenyl-4,5-dihydro-1,3,4-oxadia-
zol-2-yl)methyl]-4-mesitylphthalazin-1(2H)-one (28a)
Compound 26a (0.6 g, 0.002 mol) and redistilled acetic
624
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 616—626

Some Condensed [4-(2,4,6-Trimethylphenyl)-1(2H)-oxo-phthalazin-2-yl]acetic Acid Hydrazide
1
m.p. 300—301 ℃; H NMR (DMSO-d6, 300 MHz) δ:
2.05 (s, 3H, COCH3), 2.29 (s, 3H, CH3), 2.35 (s, 6H,
2CH3), 5.31 (s, 2H, CH2), 7.26—7.74 (m, 6H, ArH),
10.10 (s, 2H, 2 NH, exchangeable with D2O); IR (KBr)
30, 32 and 33 against all bacterial and fungal strains was
determined by liquid dilution method. Stock solutions of
tested compounds with 200, 100, 50, 25, 12.5 and 6.25
μg•mL－ concentrations were prepared with DMSO
1
－
1
v: 3298, 3165, 1661 cm . Anal. calcd for C21H22N4O3:
C 66.65, H 5.86, N 14.81; found C 66.60, H 5.89, N
14.83.
solvent. The solutions of standard drugs, Amoxicillin
and Ketoconazole were prepared in the same concentra-
tions. Inoculums of the bacterial and fungal culture were
also prepared. To a series of tubes containing 1 mL each
of phthalazine compound solution with different con-
centrations, 0.2 mL of the inoculums was added. Further
3.8 mL of the sterile water was added to each of the test
tubes. These test tubes were incubated for 24 h at 37 ℃
and observed for the presence of turbidity. This method
was repeated by changing phthalazine compounds with
standard drugs Amoxicillin and Ketoconazole for com-
parison. The minimum inhibitory concentration at which
no growth was observed was taken as the MIC values
(Table 1). The comparison of the MICs (in μg/mL) of
potent compounds and standard drugs against tested
strains is presented in Table 1.
2-(4,5-Dihydro-3-methyl-5-oxo-1H-pyrazol-4-yl)-
4-(2,4,6-trimethylphenyl)phthalazin-1(2H)-one (32)
To a solution of sodium ethoxide (0.23 g Na in 20 mL
abs. ethanol), compound 31 (0.001 mol) was added. The
reaction mixture was refluxed for 5 h. After cooling, the
reaction mixture was poured onto ice/HCl. The precipi-
tated solid was collected by filtration, dried and crystal-
lized from petroleum ether (40—60 ℃) to give 0.28 g
32 in yield 77% as colorless crystals: m.p. 190—191 ℃;
1H NMR (DMSO-d6, 300 MHz) δ: 1.94 (s, 3H, CH3),
2.25 (s, 3H, CH3), 2.40 (s, 6H, 2CH3), 4.48 (s, 1H, CH),
7.0 (s, 1H, NH, exchangeable with D2O), 7.20—8.00 (m,
－
1
6H, ArH); IR (KBr) v: 3219, 1701, 1632 cm . Anal.
calcd for C21H20N4O2: C 69.98, H 5.59, N 15.55; found
C 70.01, H 6.02, N 15.50.
Table 1 Antimicrobial activity of compounds 5—16, 18, 20, 23,
24, 26b, 26c, 27b, 28a, 29, 30, 32 and 33
4-Mesityl-2-((5-(1,2,3,4,5-pentahydroxypentyl)-
1,3,4-oxadiazol-2-yl)methyl)phthalazin-1(2H)-one
(33) A mixture of 0.6 g the acetic acid hydrazide 5
(0.002 mol) and D-glucono-1,5-lactone (0.002 mol) in
20 mL pyridine was refluxed for 6 h. After cooling, the
reaction mixture was poured onto ice water. The pre-
cipitated solid was collected by filtration, dried and
crystallized from ethanol to give 0.30 g 33 in yield 61%
Minimum inhibitory concentration (MIC) in μg/mL
Compound
Bacterial strain
Fungal strain
S. aureus B. subtilis S. typhi E. coli A. niger C. albican
5
200
100
50
250
100
50
250
50
500
50
250
250
125
250
62.5
62.5
250
62.5
250
125
250
250
250
250
100
250
250
250
125
62.5
125
100
250
62.5
62.5
250
62.5
—
500
250
125
125
125
62.5
125
125
250
125
250
250
250
125
250
125
250
125
100
62.5
125
250
125
125
62.5
125
62.5
—
6
7
50
100
250
25
1
8
50
50
25
as colorless crystals: m.p. 298—299 ℃; H NMR (300
9
50
100
25
25
MHz, DMSO-d6) δ: 2.23 (s, 3H, CH3), 2.41 (s, 6H,
2CH3), 3.11—3.62 (protons of the alditol congregated
with the solvent absorption), 3.75—3.91 (m, 2H,
CH2OH), 4.55—5.05 (m, 5H, 5OH, exchangeable with
D2O), 5.20 (s, 2H, CH2CO), 7.33—8.06 (m, 6H, ArH);
IR (KBr) v: 3440, 3165, 1659 cm . Anal. calcd for
C25H28N4O7: C 60.48, H 5.68, N 11.28; found C 60.50,
H 5.71, N 11.26.
10a
25
50
50
10b
25
25
25
250
250
200
200
100
50
11
50
100
200
200
250
100
50
100
250
100
200
100
100
50
12
200
200
100
100
50
－
1
13
14
15
16
100
100
100
250
250
50
Antimicrobial assay
18
50
50
The antimicrobial activity of the newly synthesized
compounds 5—16, 18, 20, 23, 24, 26b, 26c, 27b, 28a,
29, 30, 32 and 33 were evaluated against Escherichia
coli (E. coli), Staphylococcus aureus (S. aureus), Bacil-
lus subtilis (B. subtilis), Salmonella typhi (S. typhi),
bacterial stains and Aspergillums niger (A. niger), Can-
dida albicans (C. albicans), fungal strains by disc diffu-
sion method. Amoxicillin and Ketoconazole were used
as standard drugs for bacteria and fungi respectively.
Preliminary screening of phthalazine-derivatives and
standard drugs were performed at fixed concentrations
of 500 μg/mL. Inhibition was recorded by measuring the
diameter of the inhibition zone at the end of 24 h for
bacteria and 72 h for fungi. Each experiment was re-
peated twice. Based on the results of zone of inhibition,
the minimum inhibitory concentration (MIC) of com-
pounds 5—16, 18, 20, 23, 24, 26b, 26c, 27b, 28a, 29,
20
50
50
50
23
25
50
25
24
50
50
25
26a
50
50
25
26b
50
25
25
100
50
26c
25
25
50
26d
25
100
50
25
50
27b
50
50
50
28a
100
100
25
100
100
25
50
50
29
100
25
200
100
250
50
30
32
100
50
200
50
200
50
33
Amoxicillin
Ketaconazole
6.25
—
6.25
—
6.25 6.25
—
—
31.25
31.25
Investigation on antibacterial screening data (Table 1)
Chin. J. Chem. 2012, 30, 616—626
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
625

El-Hashash et al.
FULL PAPER
Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J.
J. Med. Chem. 2000, 43, 2310.
[7] Strappaghetti, G.; Brodi, C.; Giannaccini, G.; Betti, L. Bioorg. Med.
Chem. Lett. 2006, 16, 2575.
showed some of the compounds were active against four
pathogenic bacteria. Triazolo derivatives 10a, 10b, 23,
and Schiff’s bases 26c, 26d, 30 exhibited good activity
against S. aureus. Similarly Triazolo derivatives 10a,
10b, and Schiff’s bases 26b, 26c, 30 exhibited good
activity against B. subtilis. The Triazolo derivatives 8, 9,
10b, 23 and thiadiazolo derivatives 24 and Schiff’s
bases 26a, 26b, 26d, 30 exhibited good activity against
S. typhi. Also Triazolo derivative 9 exhibited good ac-
tivity against E. coli. From these results it could be gen-
eralized that triazolo derivatives and Shiff’s bases of
phthalazinone 3 show higher activity compared to
oxadiazolo, thiadiazolo and pyrazolo derivatives.
The antifungal results (Table 1) revealed that the
synthesized compounds showed variable degree of inhi-
bition against the tested fungi. Compounds 9, 10a, 11,
26c, 29, 30 and 33 possessed good antifungal activity
against A. niger and C. albican. From the results it was
conclude that the triazolophthalazinone and Schiff’s
bases of phthalazinone derivative showed better activity.
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 616—626