Synthesis and Antimicrobial Activity of Novel Heterocycles Utilizing 3-(1,4-Dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile as Precursors

Article abstract of DOI:10.1002/jhet.3463

The reaction of 3-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile 1 and salicyladehyde furnished coumarin derivatives 4 and 5. Coupling reaction of 1 with aryl diazonium chlorides and benzene-1,4-bis (diazonium) chloride gave the corresponding hydrazones 6a,b and bishydrazone 9, respectively. Hydrazones 6 underwent intramolecular cyclization upon treating with hydrazine hydrate to give 3-aminopyrazoles 7. Pyranyl phthalazine 13 was prepared from the reaction of 1 with ethyl 2-cyano-3-ethoxyacrylate 10. Enaminonitrile 14 was reacted with hydrazine hydrate/phenylhydrazine and hydroxylamine to afford the corresponding pyrazoles 16 and oxime 17. The antimicrobial evaluation revealed pyrazole derivatives 7a,b and 16a,b displayed a broad spectrum activity against most strains. 3-Aminopyrazole derivative 7b showed potent antibacterial activity against all tested microorganisms.

Full text of DOI:10.1002/jhet.3463

Month 2019
Synthesis and Antimicrobial Activity of Novel Heterocycles Utilizing
3-(1,4-Dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile as
Precursors
Rizk E. Khidrea,b
and Ibrahim Ali M. Radinib
*
aChemical Industries Division, National Research Centre, Giza, Dokki 12622, Egypt
bChemistry Department, Faculty of Science, Jazan University, Jazan, Saudi Arabia
*E-mail: rizkkhidre@yahoo.com
Received September 3, 2018
DOI 10.1002/jhet.3463
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
The reaction of 3-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile 1 and salicyladehyde
furnished coumarin derivatives 4 and 5. Coupling reaction of 1 with aryl diazonium chlorides and
benzene-1,4-bis (diazonium) chloride gave the corresponding hydrazones 6a,b and bishydrazone 9, respec-
tively. Hydrazones 6 underwent intramolecular cyclization upon treating with hydrazine hydrate to give
3-aminopyrazoles 7. Pyranyl phthalazine 13 was prepared from the reaction of 1 with ethyl 2-cyano-3-
ethoxyacrylate 10. Enaminonitrile 14 was reacted with hydrazine hydrate/phenylhydrazine and hydroxyl-
amine to afford the corresponding pyrazoles 16 and oxime 17. The antimicrobial evaluation revealed
pyrazole derivatives 7a,b and 16a,b displayed a broad spectrum activity against most strains.
3-Aminopyrazole derivative 7b showed potent antibacterial activity against all tested microorganisms.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
reported one-pot synthesis of pyrazolo[1,2-b]phthalazine-
5,10-diones as antimicrobial, antituberculosis, and
antioxidant agents.
In addition, coumarin derivatives occupied significant
site either in natural products or in organic synthesis due
to their exhibit plenty pharmacological activities [25–27].
Based on the earlier information and in continuing with
our previous work [28,29], we have designed and
synthesized coumarin, pyrane, pyrazole, and hydrazone
derivatives bearing phthalazine moiety.
Phthalazines are important heterocycles that are known
to possess diverse pharmacological properties like
antimicrobial [1–3], antitumor [4], anticonvulsant [5],
cardiotonic [6], and vasorelaxant activities [7].
Subramanian et al. [8] reported the synthesis of
hydrazinyl phthalazine as anti-malaria parasite and
Plasmodium falciparum. Moreover, 1,2,4-triazolo[3,4-a]
phthalazines have been reported to have high-affinity
ligands to the a2d-1 subunit of voltage-gated calcium
channel
[9].
1,2,4-Triazolo[3,4-a]phthalazine-3-
RESULTS AND DISCUSSION
carboxamides were found to possess anti-inflammatory
activities [10]. Chromeno pyrazolo[1,2-b]phthalazines
have been reported to have antifungal activity [11]. N-
substituted phthalazin-1-amine derivatives reported to
have epidermal growth factor receptor inhibitors [12].
Furthermore, pyrazole containing heterocyclic are great
interest because they show plenty pharmacological
activities such as antidepressant [13], antioxidant [14],
anti-inflammatory [15], anticancer [16], antimicrobial
[17–19], antiviral [20,21], anticonvulsant [22], and
insecticidal activities [23]. Recently, Sangani et al. [24]
Chemistry.
The
precursor
3-(1,4-dioxo-3,4-
dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile (1) was
prepared, in a very good yield, from the reaction of
equimolar amount of phthalic anhydride with
cyanoacetohydrazide in acetic acid at room temperature
[30–32]. N-coumarinyl phthalazinyl ketones 4 and 5 were
prepared from the reaction of 1 and salicylaldehyde either
in EtOH containing piperidine at room temprature (RT)
or in AcOH containing anhydrous sodium acetate at
© 2019 Wiley Periodicals, Inc.

R. E. Khidre and I. A. M. Radini
Vol 000
reflux temperature, respectively. The IR spectrum of 4 and
5 showed the lack of nitrile absorption peak at 2258 cmÀ1
and the appearance of new peaks at 3350 and 1732 cmÀ1
attributed to C═NH (imino) and C═O, respectively. In
1
addition H NMR spectroscopy revealed increasing in the
aromatic signals intensity because of coumarin moiety,
and the disappearance of methylene protons at δ
3.35 ppm. Their 13C NMR spectrum revealed, among
others, signals resonate at δ 157.6 and 159.5 ppm owing
to C═NH and C═O carbons, respectively. The mass
spectrum of 4 and 5 gave the molecular ion peaks at m/z
333.9 and 334.1, respectively (Scheme 1).
The
coupling
reaction
of
1
with
and
4-
4-
Figure 1. Energy of E-configuration of compound 6a. [Color figure can
be viewed at wileyonlinelibrary.com]
chlorobenzenediazonium
chloride
methylbenzenediazonium chloride was performed in
EtOH/AcONa at 0–5°C to afford hydrazones 6a and 6b,
respectively. 1H NMR spectrum showed new D2O
exchangeable singlet signals at δ 10.85 and 10.91 ppm
owing to HNN═ of 6a and 6b, respectively, and the
disappearances CH2 singlet signal. The mass spectra of
6a,b gave molecular ion peaks at m/z 367.1 and 347.1,
respectively. The geometry of 6a was studied using the
quantum mechanical calculations using DFT, B3LYP,
and 6-31G** as basis set. The latter calculation showed
E-configuration is more stable than Z-configuration
(Fig. 1). Hydrazones 6a,b underwent intramolecular
cyclization upon treating with hydrazine hydrate in
ethanol to give 3-aminopyrazoles 7a,b. The IR spectrum
of 7b displayed the lack of nitrile and carbonyl
absorption peaks and the appearance three peaks in the
region 3320–3127 cmÀ1 because of NH2 and NH. Also,
1H NMR exhibited D2O exchangeable broad singlet
signal at δ 5.62 ppm owing to four exchangeable
hydrogens (NH2 and 2NH), as reported previously [33–35].
Alternatively, compounds 7a,b were prepared from
coupling reaction of 5-aminopyrazolyl phthalazine 8,
which was synthesized from the reaction of 1 with
hydrazine hydrate in EtOH at reflux temperature, with
diazotized aromatic amine. Similarly, compound 1 was
treated with benzene-1,4-bis(diazonium) chloride to give
the corresponding bishydrazone 9 (Scheme 2). The
quantum mechanical calculations of bishydrazone 9
showed that E,Z-configuration is the most stable isomer
(Fig. 2).
On the other hand, compound 1 was treated with ethyl 2-
cyano-3-ethoxyacrylate 10 in ethanol containing EtONa at
reflux temperature to furnish ethyl 2-iminopyran-3-
carboxylate 13, in a good yield (Scheme 3). The
mechanism of formation compound 13 involves Michael
addition reaction of 1 to 10 to afford intermediate 11 then
intramolecular cyclization of enol form 12 to give
product 13. The structure of 13 was elucidated using
spectral and analytical data. The IR spectrum exhibited
peaks at 3286, 2224, 1713, 1700, and 1681 because of
NH, CN, (C═O, ester), (C═O, pyranone), and (C═O,
1
amide) functions, respectively. Also, H NMR spectrum
exhibited new triplet, quartet, and singlet signals at δ
1.30, 4.22, and 8.13 ppm because of ethoxy and
pyranone protons, respectively, besides multiplet signals
at 7.20–7.34 ppm owing to phthalazine protons. 13C
NMR spectrum showed peaks at 14.4, 60, 157.6, 162.8,
163.6, and 169.2 owing to CH3, CH2O, C═O of ester,
C═O of lactone, and 2C═O of phthalazine, respectively.
Its mass spectrum revealed m/z 339 [M À Me]+ (20%),
296.77 [M À (Me+CN)]+, (45%), 172 (100%).
Treatment enaminonitrile 14, which was prepared
according to the literature procedures [32], with
hydrazine hydrate or phenylhydrazine in EtOH at reflux
temperature to afford 5-aminopyrazoles 16a and 16b,
Scheme 1. Synthesis of compounds 4 and 5.
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Month 2019
3-(1,4-Dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile Derivatives
Scheme 2. Synthesis of compounds 6, 7, 8, and 9.
Figure 2. The E,Z-configuration of bishydrazone 9. [Color figure can be viewed at wileyonlinelibrary.com]
respectively, in over 85% yields. The IR spectrum of 16b
showed the disappearance of the nitrile peak. The 1H
NMR spectrum revealed the lack of olefinic singlet and
two methyl protons of enamine moiety, in addition, NH2
and NH protons appeared at δ 5.54 and 11.49 ppm,
respectively. Moreover, the mass spectrum of 16b
displayed [M+] at m/z 374. When 14 was treated with
hydroxylamine HCl in ethanol containing potassium
carbonate at reflux temperature, gave the corresponding
oxime 17 and the expected isoxazole derivative 18 not
obtained (Scheme 4). It is compatible with the previously
reported by Al-Zaydi et al. [36]. In addition, Shawali
et al. [37] and Farag et al. [38] reported that the reaction
of enaminone and hydroxylamine firstly yield the
corresponding oxime followed by intramolecular
cyclocondensation to afford the corresponding isoxazole.
The structure of oxime 17 was elucidated using quantum
mechanical calculations and spectral data. The quantum
calculation of 17 revealed it has four stereoisomers (E,E;
E,Z; Z,E; and Z,Z). Z,Z-isomer is the most stable one
because of intramolecular hydrogen bonding (Fig. 3). The
IR spectrum of 17 showed two bands at 2229 and
2191 cmÀ1 owing to nitrile. In addition, the 1H NMR
spectrum exhibited two D2O exchangeable signals at δ
9.95 and 11.57 ppm assigned to OH and NH protons,
respectively. Moreover, the mass spectrum of 17 gave
molecular ion peaks at m/z 301.3 [M + 2]+ (2%) and
283.9 [M À 15]+ (100%).
Antimicrobial activity. In vitro antimicrobial screening
of the newly synthesized compounds was carried out using
cultures of two Gram-positive bacteria and two Gram-
negative bacteria, as well as, two fungal strains using the
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R. E. Khidre and I. A. M. Radini
Vol 000
Scheme 3. Synthesis of compound 13. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 4. Synthesis of compounds 16a, 16b, and 17.
Figure 3. Energy of Z,Z-isomers of compound 17. [Color figure can be viewed at wileyonlinelibrary.com]
agar well diffusion method [39]. Ampicillin and
Colitrimazole are antibacterial and antifungal agents,
respectively, were used as controls to evaluate the
potency of the compounds being studied under the same
conditions as shown in Table 1.
The results revealed that some compounds displayed
high antibacterial activity toward Gram-positive bacteria
than Gram-negative bacteria. However, compounds 5, 14,
and 17 were inactive with most strains. Pyrazole
derivatives 7a, 7b, 16a, and 16b displayed a broad
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3-(1,4-Dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile Derivatives
Table 1
,
In vitro antimicrobial activity of the synthesized compoundsa b
.
Gram-negative bacteria
Gram-positive bacteria
Fungi
Pseudomonas
aeuroginosa
Staphylococcus
aureus
Aspergillus
flavus
Escherichi coli
Bacillus subtilis
Candida albicans
I.
Activity
Activity
Activity
Activity
Activity
Activity
Entry
Z.
index (%)
I.Z.
index (%)
I.Z.
index (%)
I.Z.
index (%)
I.Z.
index (%)
I.Z.
index (%)
1
4
5
6b
7a
7b
8
9
6
2
24.0
8.0
—
9
6
39.1
26.1
—
7
7
29.2
29.2
—
10
11
2
14
18
19
11
12
7
17
15
3
23
NA
43.5
47.8
8.7
4
10
NA
15
17
20
7
14.8
37.0
—
5
13
NA
17
19
22
10
15
8
23
18
2
NA
25
20.0
52.0
—
NAc
NA
10
15
17
7
NA
12
20
21
9
10
6
16
14
2
6
12
13
4
9
NA
7
10
NA
25
NA
24.0
48.0
52.0
16.0
36.0
—
28.0
40.0
—
43.5
65.2
73.9
30.4
52.2
13.0
47.8
52.2
—
50.0
83.3
87.5
37.5
41.7
25.0
66.7
58.3
8.3
60.9
78.3
82.6
47.8
52.2
30.4
73.9
65.2
13.0
100
55.5
63.0
74.1
25.9
48.1
22.2
88.9
59.2
—
68.0
76.0
88.0
40.0
60.0
32.0
92.0
72.0
8.0
12
3
13
6
14
16a
16b
17
Ampicillin
Colitrimazole
11
12
NA
23
NA
24
16
NA
NA
27
100
—
100
—
24
NA
100
—
—
100
—
100
—
aAntimicrobial activity expressed as inhibition diameter zones (I.Z.) in millimeters (mm).
bThe experiment was carried out in triplicate and the average zone of inhibition was calculated.
cNA, no activity.
Table 2
Minimum inhibitory concentration in (μg/mL) for compounds 7a, 7b, 16a, and 16b.
Minimum inhibitory concentration
Escherichi
coli
Pseudomonas
aeuroginosa
Staphylococcus
aureus
Bacillus
subtilis
Candida
albicans
Aspergillus
flavus
Entry
7a
7b
16a
16b
Ampicillin
Colitrimazole
187.5
93.7
250
750
125
—
125
62.5
187.5
500
125
—
250
125
375
500
187.5
—
93.7
62.5
187.5
375
125
—
15.6
7.8
23.4
46.9
—
11.7
3.9
15.6
31.2
—
5.8
3.9
spectrum activity against most strains. Pyrazoles 7a and 7b
showed higher activity toward Pseudomonas aeuroginosa,
Staphylococcus aureus, and Bacillus subtilis than 16a and
16b. Compound 7b exhibited greater activity than 7a. The
fungal strain Candida albicans and Aspergillus flavus
showed a potent sensitivity toward compounds 7a, 7b,
16a, and 16b with activity index (63, 74.1, 88.9, 59.2),
and (76, 88, 92, 72), respectively. Also, it was observed
that compound 16a displayed higher activity than 7b.
Colitrimazole. Moreover, compound 7a displayed low
MIC value on B. subtilis than standard drug Ampicillin
and showed MIC value on P. aeuroginosa equal to
Ampicillin.
Structure–activity relationship.
The structure–activity
relationship revealed that compounds with pyrazole unit
7a,b and 16a,b showed higher activity than other
compounds. Furthermore, the presence of aryldiazene
substituents increases the activity as in 7a and 7b. The
presence of electron donating substituents on the aromatic
ring increased its antimicrobial activity as 7b.
Minimum inhibitory concentration.
Compounds that
showed greater antibacterial and antifungal activities are
further assayed for minimum inhibitory concentration
(MIC), and the values are listed in Table 2. MIC value of
compound 7b against Escherichi coli, P. aeuroginosa,
B. subtilis, and S. aureus is lower than standard
antibacterial drug Ampicillin while displaying MIC value
against A. flavus equal to standard antifungal drug
CONCLUSION
In this study, we synthesized a novel coumarins 4, and 5;
hydrazone 6; bishyrazone 9; pyrazole 7, 8, and 16;
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R. E. Khidre and I. A. M. Radini
Vol 000
pyran-2-one 13 and oxime 17 derivatives bearing
phthalazine scaffold, in good yields, utilizing phthalazinyl-
3-oxopropanenitrile 1. The new compounds are
characterized by spectral and CHN analysis. The quantum
mechanical calculations of hydarzone 6, bishydrazone 9,
and oxime 17 exhibited the most stable configuration is
E-configuration; E,Z-configuration; and Z,Z-configuration,
respectively. The antimicrobial evaluation showed
compounds 7a, 7b, 16a, and 16b have prominent
antibacterial activity against against most strains.
C18H11N3O4 (333.30): C, 64.87; H, 3.33; N, 12.61,
Found: C, 64.55; H, 3.11; N, 12.49%.
2-(2-Oxo-2H-chromene-3-carbonyl)-2,3-dihydrophthalazine-
1,4-dione (5). Method A.
To a solution of 1 (0.458 g,
2 mmol) in acetic acid (30 mL) containing 0.5 g of fused
sodium acetate, salicylaldehyde 2 (0.244 g, 2 mmol) was
added. The mixture was heated under reflux for 3 h
(TLC). After cooling, the formed product was filtered off,
washed with EtOH, dried, and crystallized from mixture
EtOH. Yellow crystals, yield 86%, mp 300°C (EtOH); IR
(νmax, cmÀ1): 3275w (NH), 1732s, 1716s, 1690s (C═O),
1
1608–1510s (C═C); H NMR (500 MHz, DMSO-d6) δH
(ppm): 7.46 (t, 1H, J 7.5 Hz, coumarin-H6), 7.55 (d, 1H,
J 9 Hz, coumarin-H8), 7.80 (t, 1H, J 7.5, coumarin-H7),
7.99 (m, 5H, phthalazine-H and coumarin-H5), 8.99 (s,
1H, coumarin-H4), 10.78 (s, D2O exchangeable, 1H,
NH); 13C NMR (125 MHz, DMSO-d6) δC (ppm): 116.3,
117, 118.2, 123.9, 125.3, 129.5, 130.7, 135, 135.4,
147.5, 149.9, 154.3 (C═O), 159.5 (C═O), 161.1 (C═O),
164.7 (C═O); MS m/z (%): 334.1 [M+] (100%), 335
(26%), 173.1 (45); Anal. Calcd for C18H10N2O5 (334.29):
C, 64.67; H, 3.02; N, 8.38, Found: C, 64.35; H, 2.92; N,
8.10%.
EXPERIMENTAL
Chemistry. General.
All melting points were
determined on digital Gallen-Kamp MFB-595 instrument
using open capillary tubes and are uncorrected. IR spectra
were recorded on Schimadzu FTIR 440 spectrometer
using KBr pellets. Mass spectra were performed at 70 eV
on an MS-50 Kratos (A.E.I.) spectrometer provided with
a data system. 1H NMR and 13C NMR spectra were
recorded on a Bruker model (500 MHz) Ultra Shield
NMR spectrometer in CDCl3 or DMSO-d6 using
tetramethylsilane as an internal standard; chemical shifts
are reported as δ ppm units. Solvents were dried by
standard techniques. The monitoring of the progress of all
reactions and homogeneity of the synthesized compounds
was carried out and was run using thin layer
chromatography (TLC) aluminum sheets silica gel
60 F254 (Merck). Compounds 1 [31,32] and 14 [32] were
Method B.
The iminochromene derivative 6 (2 mmol)
was dissolved in EtOH (30 mL) and treated with HCl
(5 mL). The reaction mixture was heated under reflux for
3 h, left to cool. The obtained product was filtered off,
washed with cold water, dried, and crystallized from
mixture EtOH.
General procedure for synthesis of hydrazones 6a, 6b, and
9. To a stirred solution of N-cyanoacetophthalazine 1
(0.458 g, 2 mmol) in ethanol (30 mL), sodium acetate
synthesized based on the reported procedures.
2-(2-Imino-2H-chromene-3-carbonyl)-2,3-
dihydrophthalazine-1,4-dione (4).
A
mixture of N-
trihydrate (0.26 g, 2 mmol) was added. After stirring for
15 min, the mixture was chilled at 0°C and treated with
cold solution of 4-chloroaniline (0.254 g, 2 mmol), 4-
methylaniline (0.214 g, 2 mmol), or 1,4-phenylene
diamine (0.108 g, 1 mmol) in 6 M hydrochloric acid
(1.5 mL) with sodium nitrite solution (0.14 g, 2 mmol) in
water (3 mL). The addition of the diazonium salt was
stirred for an additional 2 h at 0–5°C and then left for 8 h
in a refrigerator (4°C). The resulting solid was collected
by filtration, washed thoroughly with water, and dried.
cyanoacetophthalazine
1 (0.458 g, 2 mmol) and
salicylaldehyde 2 (0.244 g, 2 mmol) in EtOH (25 mL)
containing a catalytic amount of piperidine (0.5 mL) was
stirred at room temperature for 4 h (TLC). The solid
formed was filtered off, washed with EtOH, dried, and
crystallized from EtOH. Colorless powder, yield 85%,
mp 243–244°C (EtOH); IR (νmax, cmÀ1): 3350w, 3161w
(NH), 1699s, 1681s, 1668s (C═O), 1605s (C═N), 1541-
1496w (C═C); 1H NMR (500 MHz, DMSO-d6) δH
(ppm): 4.35 (s, D2O exchangeable, 1H, ═NH), 6.77 (t,
1H, J 7 Hz, coumarin-H6), 7.15 (t, 1H, J 7.5 Hz,
coumarin-H8), 7.24 (m, 1H, coumarin-H7), 7.40–7.43 (t,
1H, J 7.5 Hz, coumarin-H5), 7.54 (dd, 3H, J 7, 4.5 Hz,
phthalazine-H), 7.75 (dd, 1H, J 8, 1.5 Hz, phthalazine-
H), 8.15 (s, 1H, coumarin-H4), 9.90 (s, D2O
exchangeable, 1H, NH); 13C NMR (125 MHz,
DMSO-d6) δC (ppm): 115.7, 118.8, 124.2, 126.7, 128.1,
129.6, 129.9, 131.3, 133.3, 137.6, 153.2, 155.8 (C═O),
157.6 (C═NH), 165.3 (C═O), 168 (C═O); MS m/z (%):
333.9 [M+] (10%), 291 (30), 266.1 (100); Anal. Calcd for
The crude product was crystallized from ethanol to give
hydrazones 6a, 6b, and 9, respectively.
(E)-N-(4-chlorophenyl)-2-(1,4-dioxo-3,4-dihydrophthalazin-
2(1H)-yl)-2-oxoacetohydrazonoyl cyanide (6a).
Yellow
crystals, yield 83%, mp 259–260°C (EtOH); IR (νmax
,
cmÀ1): 3235w (NH), 2222w (CN), 1737s, 1681s (C═O),
1640–1600w (C═N), 1552–1485 m (C═C); 1H NMR
(500 MHz, CDMSO-d6) δH (ppm): 7.31 (d, 2H, J 7.5 Hz,
Ar─H), 7.43 (d, 2H, J 7 Hz, Ar─H), 7.73 (dd, 2H, J 8,
2.5 Hz, phthalazine-H), 7.93 (dd, 2H,
J 8 Hz,
phthalazine-H), 10.85 (s, D2O exchangeable, 1H, NH),
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3-(1,4-Dioxo-3,4-dihydrophthalazin-2(1H)-yl)-3-oxopropanenitrile Derivatives
12.11 (s, D2O exchangeable, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δC (ppm): 103.9, 110.8, 117.5,
123.9, 128, 128.6, 129.6, 132.3, 141, 158.6 (C═O), 161.7
(C═O), 167.3 (C═O); MS m/z (%): 367.1 [M+] (97), 368
[M + H]+ (32); Anal. Calcd for C17H10ClN5O3 (367.75):
C, 55.52; H, 2.74; N, 19.04, Found: C, 55.17; H, 2.48;
for C17H12ClN7O2 (381.78): C, 53.48; H, 3.17; N, 25.68,
Found: C, 53.29; H, 3.03; N, 25.49%.
2-(5-Amino-4-(p-tolyldiazenyl)-1H-pyrazol-3-yl)-2,3-
dihydrophthalazine-1,4-dione (7b).
Brown crystals, yield
79%, mp 255–257°C (EtOH); IR (νmax, cmÀ1): 3320–
3172 m (NH2 and NH), 1660–1643 (C═O), 1595–1556s
1
(C═N), 1495 (C═C); H NMR (500 MHz, DMSO-d6) δH
N, 18.83%.
(ppm): 2.26 (s, 3H, CH3), 5.62 (s, broad, D2O
exchangeable, 4H, NH2, and 2NH, appear together) [33–
35], 7.17 (d, 2H, J 8 Hz, Ar─H), 7.39 (d, 2H, J 7.5 Hz,
Ar─H), 7.82 (dd, 2H, J 9.5, 3.5 Hz, phthalazine-H), 8.06
(dd, 2H, J 9.5, 3.5 Hz, phthalazine-H); 13C NMR
(125 MHz, DMSO-d6) δC (ppm): 20.5 (CH3), 115.1,
125.3, 128, 129.3, 129.8, 132.1, 133.5, 139.6, 149.9,
155.7, 158.8 (C═O), 159 (C═O); MS m/z (%): 346 [M-
15]+ (2%), 217 (100%); Anal. Calcd for C18H15N7O2
(361.37): C, 59.83; H, 4.18; N, 27.13, Found: C, 59.71;
(E)-2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-2-oxo-N-
(p-tolyl) acetohydrazonoyl cyanide (6b).
Yellow crystals,
yield 82%, mp 251–252°C (EtOH); IR (νmax, cmÀ1):
3232w (NH), 2220w (CN), 1735s, 1678s (C═O), 1640–
1600w (C═N), 1552–1485
m
(C═C); 1H NMR
(500 MHz, CDMSO-d6) δH (ppm): 2.29 (s, 3H, CH3),
7.21 (d, 2H, J 8.5 Hz, Ar─H), 7.64 (d, 2H, J 8.5,
Ar─H), 7.96 (dd, 2H, J 8.5, 3 Hz, phthalazine-H), 8 (dd,
2H, J 5.5, 3 Hz, phthalazine-H), 10.91 (s, 1H, D2O
exchangeable, 1H, NH), 12.25 (s, D2O exchangeable, 1H,
NH); 13C NMR (125 MHz, DMSO-d6) δC (ppm): 20.5
(CH3), 103.9, 110.9, 116.4, 124, 129.3, 129.7, 134.3,
135.4, 139.6, 160.7(C═O), 163.3 (C═O), 165.3 (C═O);
MS m/z (%): 347.1 [M+] (97%), 348 [M + H]+ (40),
347.1 [M]+ (97), 346.5 (100); Anal. Calcd for
C18H13N5O3 (347.33): C, 62.24; H, 3.77; N, 20.16,
Found: C, 62.06; H, 3.51; N, 19.96%.
H, 4.05; N, 26.98%.
2-(5-Amino-4H-pyrazol-3-yl)-2,3-dihydrophthalazine-1,4-
dione (8). To a solution of N-cyanoacetophthalazine 1
(1.145 g, 5 mmol) in EtOH (30 mL), hydrazine hydrate
(80%, 0.5 ml) was added. The mixture was heated at
reflux 5 h and then allowed to cool. The precipitated
product was filtered, washed (EtOH), dried, and
recrystallized from EtOH. Colorless powder, (89%), mp
300°C (EtOH); IR (νmax, cmÀ1): 3320–3167 (NH2 and
NH) 1662 (C═O), 1600–1556s (C═N), 1492–1458
General procedure for synthesis 4-arylazopyrazoles 7.
Method A. To a solution of the appropriate hydrazone
6a or 6b (2 mmol) in EtOH (20 mL) was added
hydrazine hydrate (2 mmol). The reaction mixture was
refluxed for 6 h and then left to cool. The solid product
was collected, washed with EtOH, dried, and finally
recrystallized from EtOH to afford the corresponding 4-
arylazopyrazole derivatives 7a and 7b, respectively.
Method B. To a stirred cold solution of the pyrazole
derivative 8 (0.486 g, 2 mmol) in pyridine (10 mL) was
added the appropriate arenediazonium chloride (2 mmol)
portion wise over a period of 30 min at 0–5°C. After
complete addition, the reaction mixture was stirred for
further 3 h at 0–5°C. The solid product was collected,
washed with water, dried, and finally recrystallized from
EtOH afforded the corresponding 4-arylazopyrazole
1
(C═C); H NMR (500 MHz, DMSO-d6) δH (ppm): 1.78
(s, 2H, CH2), 6.30 (s, broad D2O exchangeable, 3H,
NH2, and NH, appear together) [33–35], 7.79 (m, 2H,
phthalazine-H), 8.05 (m, 2H, phthalazine-H); 13C NMR
(125 MHz, DMSO-d6) δC (ppm): 23.8 (CH2), 125.4,
125.6, 128.6, 131.9, 132.18, 156.6, 175 (C═O); MS m/z
(%): 216.9 [M-26]+ (100%), 161.6 (27%); Anal. Calcd
for C11H9N5O2 (243.23): C, 54.32; H, 3.73; N, 28.79,
Found: C, 54.06; H, 3.47; N, 28.68%.
(E)-N-(4-(2-((Z)-1-cyano-2-(1,4-dioxo-3,4-
dihydrophthalazin-2(1H)-yl)-2-oxoethylidene)hydrazineyl)
phenyl)-2-(1,4-dioxo-3,4-dihydrophthalazin-2(1H)-yl)-2-
oxoacetohydrazonoyl cyanide (9). Colorless powder, yield
81%, mp 195–196°C (EtOH); IR (νmax, cmÀ1): 3275,
3254, (NH), 2216 (CN), 1737s, 1681s (C═O), 1604
(C═N), 1546–1469s (C═C); 1H NMR (500 MHz,
DMSO-d6) δH (ppm): 7.53 (s, 4H, Ar─H), 7.79 (dd, 4H, J
8.5, 3.5 Hz, phthalazine-H), 8.11 (dd, 4H, J 8.5, 3.5 Hz,
phthalazine-H), 10.91 (s, D2O exchangeable, 2H, NH),
11.20 (s, D2O exchangeable, 2H, NH); 13C NMR
(125 MHz, DMSO-d6) δC (ppm): 104.5, 110.9, 118.6,
123.8, 129.6, 130.5, 133.3, 159.4 (C═O), 162.5 (C═O),
166.3 (C═O); MS m/z (%): 588 [M]+ (20%), 229 (100%);
Anal. Calcd for C28H16N10O6 (588.50): C, 57.15; H, 2.74;
N, 23.80, Found: C, 56.96; H, 2.52; N, 23.56%.
derivatives 7a and 7b.
2-(5-Amino-4-((4-chlorophenyl)diazenyl)-1H-pyrazol-3-yl)-
2,3-dihydrophthalazine-1,4-dione (7a).
Brown crystals,
yield 80%, 265–267°C (EtOH); IR (νmax, cmÀ1): 3325–
3165 m (NH2 and NH), 1664 (C═O), 1618–1560s
(C═N), 1500–1458 (C═C); 1H NMR (500 MHz,
DMSO-d6) δH (ppm): 5.61 (s, broad D2O exchangeable,
4H, NH2 and 2NH, appear together) [33–35], 7.13 (d,
2H, J 7.5 Hz, Ar─H), 7.45 (d, 2H, J 7 Hz, Ar─H), 7.70
(dd, 2H, J 7, 3 Hz, phthalazine-H), 8.10 (dd, 2H, J 7.5,
3 Hz, phthalazine-H); 13C NMR (125 MHz, DMSO-d6)
δC (ppm): 117.9, 124.6, 125.8, 128.5, 128.7, 131.9,
133.5, 138.2, 151.5, 154.5, 158.5 (C═O), 159 (C═O);
MS m/z (%): 381 [M]+(12%), 217 (100%); Anal. Calcd
Synthesis
of
ethyl
5-cyano-6-(1,4-dioxo-3,4-
dihydrophthalazin-2(1H)-yl)-2-oxo-2H-pyran-3-carboxylate
(13).
Sodium (0.023 g, 1 mmol) was dissolved in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. E. Khidre and I. A. M. Radini
Vol 000
absolute EtOH (30 mL), to this solution, N-
cyanoacetophthalazine 1 (0.229 g, 1 mmol) was added
and stirred for 10 min at room temperature. Ethyl 2-
cyano-3-ethoxyacrylate 10 (0.169 g, 1 mmol) was added
to this mixture and refluxed for 6 h. The solid formed
was filtered off, washed with EtOH, dried, and
crystallized from EtOH. Yellow, yield 75%, mp 300°C
(EtOH); IR (νmax, cmÀ1): 3286w (NH), 2224 m (CN),
1713s (C═O, ester), 1700s (C═O, pyrone), 1681s (C═O,
amide), 1454–1402 m (C═C); 1H NMR (500 MHz,
DMSO-d6) δH (ppm): 1.30 (t, 3H, CH3), 4.22 (q, 2H,
CH2), 7.27 (m, 4H, phthalazine-H), 8.13 (s, 1H, pyran-
H), 11.33 (s, D2O exchangeable, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δC (ppm):14.4 (CH3), 60 (CH2),
80.2, 117, 125.7, 129.1, 140.5, 144.3, 152.5, 154.2,
157.6 (CO), 162.8 (CO), 163.7 (CO), 169.2 (CO); MS
161.6 (C8H5N2O2, phthalazine, 100%); Anal. Calcd for
C18H13N5O3 (347.33): C, 62.24; H, 3.77; N, 20.16,
Found: C, 62.02; H, 3.52; N, 19.96%.
3-(Dimethylamino)-2-(1,4-dioxo-3,4-dihydrophthalazin-
2(1H)-yl)(hydroxyimino)methyl) acrylonitrile (17).
To a
solution of enaminonitrile 14 (0.568 g, 2 mmol) in
absolute ethanol (30 mL) was added hydroxylamine
hydrochloride (0.139 g, 2 mmol) in the presence of
anhydrous potassium carbonate (0.276 g, 2 mmol). The
reaction mixture was then refluxed for 5 h. The solid
formed was collected by filtration and crystallized from
ethanol. Colorless crystals, yield 88%, mp 259–260°C
(EtOH); IR (νmax, cmÀ1): 3367w (OH), 3275w (NH),
2229w, 2191w (CN), 1728s, 1662s (C═O), 1616s
1
(C═N), 1504 (C═C); H NMR (500 MHz, DMSO-d6) δH
(ppm): 3.21 (s, 3H, CH3), 3.30 (s, 3H, CH3), 7.79 (m,
5H, pthalazine-H and C═CH), 9.95 (s, D2O
exchangeable, 1H, OH), 11.57 (s, D2O exchangeable, 1H,
NH); 13C NMR (125 MHz, DMSO-d6) δC (ppm): 38.3,
47.2, 67.1, 118.5, 123.9, 129.5, 135.3, 157.6, 164.5,
165.5, 167.3; MS m/z (%): 301.3 [M + 2]+ (3%), 283.9
[M-15]+ (100%), 161.6 (87); Anal. Calcd for
C14H13N5O3 (299.29): C, 56.18; H, 4.38; N, 23.40,
Found: C, 55.97; H, 4.19; N, 23.17%.
Antimicrobial activity. The antibacterial activity of the
synthesized compounds was tested against a panel of two
Gram-positive bacteria (S. aureus, B. subtilis), two Gram-
negative bacteria (E. coli, P. aeuroginosa), and two fungi
(C. albicans, Aspergillus flavus) was determined using
agar well diffusion method as described in the literature
[39] and the result was cited in Tables 1 and 2.
m/z (%): 339 [M
À
Me]+ (20%), 296.8
[M À (Me + CN)]+, (45%), 172 (100%); Anal. Calcd for
C17H11N3O6 (353.29): C, 57.80; H, 3.14; N, 11.89,
Found: C, 57.53; H, 3.05; N, 11.69%.
General procedure for synthesis of 5-aminopyrazoles 16.
To a solution of enaminonitrile 14 (0.568 g, 2 mmol) in
EtOH (20 mL), hydrazine hydrate (80%, 0.2 mL) or
phenylhydrazine (0.2 mL, 2 mmol) was added. The
mixture was heated at reflux for 5 h (TLC) and then
allowed to cool. The precipitated product was filtered,
washed (EtOH), dried, and recrystallized from EtOH to
give 16a and 16b, respectively.
2-(5-Amino-1H-pyrazole-4-carbonyl)-2,3-
dihydrophthalazine-1,4-dione (16a). Yellow powder, yield
85%, mp 300°C (EtOH); IR (νmax, cmÀ1): 3273–3165 m
(NH2 and NH), 1700–1650 (C═O), 1600–1500 m
1
(C═N); H NMR (500 MHz, DMSO-d6) δH (ppm): 5.64
Acknowledgment. The authors are thankful to Department of
Pharmacology, Faculty of Pharmacy, Mansoura University,
Egypt for performing the antimicrobial evaluation.
(s, D2O exchangeable, 3H, NH2 and NH, appear
together), 7.96 (dd, 2H, J 8.5, 3.5 Hz, phthalazine-H),
8.21 (dd, 2H, J 8.5, 3 Hz, phthalazine-H), 8.23 (s, 1H,
pyrazole-H), 11.62 (s, D2O exchangeable, 1H, NH); 13C
NMR (125 MHz, DMSO-d6) δC (ppm):115.6, 123.2,
128.2, 130.5, 132.4, 136.4, 158.6 (CO), 166.7 (CO),
169.4 (CO); MS m/z (%): 347 [M]+(3%), 161.6
(C8H5N2O2, phthalazine, 100%); Anal. Calcd for
C12H9N5O3 (271.24): C, 53.14; H, 3.34; N, 25.82,
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet