Synthesis of novel heterocyclic compounds with expected antibacterial activities from 4-(4-bromophenyl)-4-oxobut-2-enoic acid

Article abstract of DOI:10.1002/jhet.2182

This research describes the utility of 4-(4-bromophenyl)-4-oxobut-2-enoic acid as a key starting material for preparation of a novel series of aroylacrylic acids, pyridazinones, and furanones derivatives. These heterocyclic compounds were synthesized by r

Full text of DOI:10.1002/jhet.2182

Month 2014 Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial
Activities from 4-(4-Bromophenyl)-4-oxobut-2-enoic Acid
a
b
c
c
c
*
Maher A. El-Hashash, Ahmed Y. Soliman, Hadeer M. Bakeer, Fatehia K. Mohammed, and Haitham Hassan
aChemistry Department, Faculty of Science, Ain Shams University, Cairo, Egypt
bChemistry Department, College of Science, King Khalid University, Abha, Saudi Arabia
cChemistry Department, Faculty of Science, Fayoum University, Fayoum, Egypt
*
E-mail: hm1434@fayoum.edu.eg
Received October 20, 2012
DOI 10.1002/jhet.2182
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
This research describes the utility of 4-(4-bromophenyl)-4-oxobut-2-enoic acid as a key starting material
for preparation of a novel series of aroylacrylic acids, pyridazinones, and furanones derivatives. These
heterocyclic compounds were synthesized by reaction of 4-(4-bromophenyl)-4-oxobut-2-enoic acid with
benzimidazole, ethyl glycinate hydrochloride, anthranilic acid and o-phenylenediamine under Aza–Michael
addition conditions. Every Aza–Michael adduct was allowed to react with haydrazine hydrate and acetic
anhydride to form pyridazinones and furanones derivatives, respectively. In further step, some pyridazinones
were allowed to react with ethyl acetoacetate, acetyl acetone, acetyl chloride, and aromatic aldehydes to form
novel heterocylces. Finally, studying antibacterial activities of these compounds was performed.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
acid, and o-phenylenediamine with the aim of increasing
the synthetic potential of β-aroylacrylic acids and studying
the antibacterial activity of synthesized compounds.
Recently, β–aroylacrylic acid derivatives showed high
biological activity and exhibited a broad spectrum of physio-
logical [1] (fungicidal, antitumor, hypotensive, hypolipedemic,
and antibacterial) activities and in recovery of Alzheimer’s
disease. [2] Beside that, β-aroylacrylic acids were consid-
ered as inhibitors for phospholipase [3,4] and they have
antiproliferative activity against human cervix carcinoma
(Hela cells) [5,6]. In another side, β-aroylacrylic esters are
important intermediates in field of medical science and
agrochemicals [1]. Chemically, due to their electrophilicity,
β-aroylacrylic acid reacts with nucleophiles including pri-
mary and secondary amines [7]. β-aroylacrylic acids also
are convenient polyelectrophilic reagents in the synthesis
of heterocyclic rings, for which the addition reaction of
N-, S-, P-, or C-nucleophiles occurs exclusively at the
α-carbonyl electrophilic position of the molecule [8–20].
In view of aforementioned facts, it seems most interesting to
use 4-(4-bromophenyl)-4-oxobut-2-enoic acid to react with
benzimidazole, ethyl glycinate hydrochloride, anthranilic
RESULTS AND DISCUSSION
The target compound 4-(4-bromophenyl)-4-oxobut-2-
enoic acid 1 in the present study was readily obtained
by Friedel–Crafts reaction of maleic anhydride with
bromobenzene in the presence of anhydrous aluminum
chloride. The interaction of 4-(4-bromophenyl)-4-oxobut-
2-enoic acid (1) with benzimidazole in boiling ethanol and
with addition of three drops of piperidine yielded the Aza–
Michael adduct 2-(1H-benzimidazole-1-yl)-4-(4-bromophenyl)-
4-oxo-butanioc acid (2). The structure of the product 2
agrees well with its spectroscopic parameters. Hence, the
IR spectrum of compound 2 shows υmax of two carbonyl
groups at 1686, 1732, and broad peak for υOH centered at
1
3300 cmÀ1. The H-NMR spectrum shows two double of
doublets at δ ppm 3.97, 4.02 assigned for (CH2 group)
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M. A. El-Hashasha, A. Y. Solimanb, H. M. Bakeer, F. K. Mohammed, and H. Hassan
Vol 000
protons, double of doublet δ ppm 4.13, 4.19 assigned for
(CH group) proton, 7.17–7.95 (m, 8H, ArH), 8.14 (s, 1H,
CH in imidazole ring), and 8.36 (s, 1H, OH exchangeable
with D2O). The reaction takes place via nucleophilic attack
of nitrogen nucleophile derived from benzimidazole on
α-carbon of the acid (1,4-addition) to give the desired product.
When acid 1 was allowed to react with anthranilic acid in
boiling ethanol and with catalytic drops of piperidine, it
yielded 2-((3-(4-bromophenyl)-1-carbox-3-oxopropyl)amino)
benzoic acid (3) (Scheme 1). The structure of compound 3
was inferred from correct micro analytical data. Its IR spec-
trum revealed strong absorption bands at 1677, 3359, and
studied. The presence of different kinds of electrophilic posi-
tions in the acid leads to suggest that six or seven membered
annulated, nitrogen-containing heterocyclic compound may
be formed. However, actually the only product reported is
3-(2-(4-bromophenyl)-2-oxoethyl)-3,4-dihydroquinoxalin-
2-(1H)-one (4) [28] (Scheme 2). The IR spectrum of com-
pound 4 shows two bands at 1679 and 1728 cmÀ1, which
are assigned to the vibrations of the carbonyl groups [highly
value by about 25 cmÀ1 due to mutual induction between
two carbonyl groups] and also a band for the stretching vi-
brations of secondary amide group at 3190 and 3300 cmÀ1
for secondary amino group. The 1H-NMR spectrum
compound 4 showed singlet signal at δ ppm 5.69 assigned
to (NH) and singlet at 8.87 for (NH–CO), which were
exchangeable in D2O.
3431 cmÀ1 attributable to
and υNH bonded and non-
υC═O
bonded. The bonded hydroxyl appears as a very broad band
centered around 2800 cmÀ1. The 1H-NMR spectrum shows
the expected number of protons. The reaction proceeds
regioselectively at the 2-postion of the oxobutenoic acid
moiety and yielded of non-proteinogenic unnatural amino
acid 3.
In a continuation of our investigation of the reactivity of
enone systems towards nitrogen-containing binucleophiles
[15–17], the reaction of acid 1 with o-phenylenediamine was
Furthermore, the reaction between ethyl glycinate hy-
drochloride with β-aroyl acrylic acid 1 in boiling ethanol
in the presence of sodium acetate afforded ester 5 via
Aza–Michael addition.
1
The H-NMR spectrum of compound 5 showed δ ppm
1.18 (t, 3H, CH3 of ester), 4.09 (q, 2H, CH2 of ester),
8.16 (d, 1H, NH exchangeable with D2O). The structure
Scheme 1
Scheme 2
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Month 2014
Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities
from 4-(4-Bromophenyl)-4-oxobut-2-enoic Acid
of compound 5 also was inferred chemically via (i) Interac-
tion of compound 5 with acetic anhydride yielded furanone
derivative (6). The IR spectrum of compound 6 exhibits
strong absorption bands at 1745, 1782, 2982. 3439 cmÀ1
(basic peak) attributable to υmax of two carbonyl groups
compound 10 showed signals at δ ppm 1.92 (s, 3H, CH3,
oxadiazole ring). Interaction of the compound 7 with 4-
nitrobenzaldehyde in boiling ethanol afforded 2-((6-(4-
bromophenyl)-3-oxa-2,3,4,5-tetrahydropyridazin-4-yl) amino)-
(4-nitrobenzalidene)acetohydrazide (11) (Scheme 4). The
structure of compound 11 was confirmed from IR spec-
trum that exhibits absorption at 1648, 3313, 3424 cmÀ1
due to υC═O and υNH bonded and non-bonded. The
1H-NMR spectrum of compound 11 showed methylidene
proton at δ ppm 8.06. The 13C-NMR spectrum of
compound 11 exhibited the expected number of signals
for the aromatic carbons as well as carbonyl signals at
163.6 and 160.2 ppm.
1
υC═O, υCH, and υNH, respectively. The H-NMR spectrum
compound 6 showed signals δ ppm 1.19 (t, 3H CH3, of es-
ter), 4.11 (q, 2H, CH2 of ester) and devoid any signal for
OH group.
(ii) Hydrazinolysis of compound 5 by using hydrazine
hydrate in boiling ethanol yielded hydrazide derivative 7
(Scheme 3). The IR spectrum of compound 7 exhibits
strong absorption bands at 3224 and 3386 cmÀ1 attribut-
1
able to NH and NH2 groups. The H-NMR spectrum of
Due to their common occurrence in nature and the fact
that 2-(3H) furanone exhibit rich photochemistry [24],
oxygen-containing heterocycles are frequent and important
targets for synthesis either as final products or as useful
synthetic intermediates. Besides that, synthetic 3-(2H)-
pyridazinones are important intermediates in drug
discovery, with many of their analogs being in the
treatment of various human pathological states. They were
described as non-steroidal anti-inflammatory drugs [25].
From the previous two facts, authors planned to synthesize
furanones and pyridazinones derivatives through reacting
acids 2, 3 with acetic anhydride and hydrazine hydrate, re-
spectively. Thus, when acids 2, 3 were allowed to react
with acetic anhydride they gave furanone derivatives 12a,
b respectively. The IR spectrum of compounds 12a,b
exhibits strong absorption bands at 1782 and 1785 cmÀ1
compound 7 showed signals at δ ppm 4.86 (br, s, 2H,
NH2 exchangeable with D2O) and 8.55 (d, 2H, NH ex-
changeable with D2O).
The second stage of synthesizing heterocyclic com-
pounds is designing of the new prepared compounds based
structurally on containing other biologically active hetero-
cycles on side chains reported in the field of cancer therapy
such as pyrazoles [21] and oxadiazoles [22,23]. This aim
pushes authors to synthesize some interesting heterocyclic
compounds, for example, pyrazole and/or oxadiazole de-
rivatives incorporated with pyridazinone nucleus. From
this point of view, compound 7 was allowed to react with
ethyl acetoacetate (EAA) in boiling ethanol yielded
1
pyrazole derivative (8). The H-NMR spectrum of com-
pound 8 showed singlet signals at δ ppm 1.92 assigned
for CH3 and 2.32 assigned for CH2 (pyrazole moiety). Cy-
clization of compound 7 with acetylacetone afforded
pyrazole derivative 9. The 13C-NMR spectrum of com-
pound 9 exhibited the expected number of signals for the
aromatic carbons as well as carbonyl signals and two
methyl carbons at 26.3 and 16.8 ppm. Reaction of com-
pound 7 with acetyl chloride gave the corresponding
oxadiazole derivative 10. The 1H-NMR spectrum of
1
attributable to υC═O of γ-lactone, respectively. The H-
NMR spectrum of compound 12b showed signals at δ
ppm 3.98 (d, 1H, CH–N), 5.23 (d, 1H, CH in furanone
ring), and 6.48 (s, 1H, NH exchangeable in D2O).
When carboxylic acid derivatives 2, 3 were allowed to
react with hydrazine hydrate in boiling ethanol, afforded
pyridazinone derivatives 13a,b respectively (Scheme 5).
The IR spectrum of compound 13a showed a characteristic
Scheme 3
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M. A. El-Hashasha, A. Y. Solimanb, H. M. Bakeer, F. K. Mohammed, and H. Hassan
Vol 000
Scheme 4
Scheme 5
absorption bands at υ 1660 cmÀ1 corresponding to CO
group. The H-NMR spectrum of compound 13b showed
NH (pyridazinone moiety) at δ 9.21 ppm, which was ex-
changeable in D2O.
When carboxylic acid derivative 2 was allowed to react
with hydroxylamine hydrochloride in boiling pyridine with
the aim of obtaining the oxazinone derivative, but with an
unexpected manner [26], 2-amino-4-(4-bromophenyl)-4-
oxobut-2-enioc acid (14) is obtained. The reaction occurs
via addition of (NH2OH) after loss of benzimidazole moi-
ety to the double bond to give the fleeting intermediate
A, dehydration, and isomerisation of the resulting imine
into enamine 14 was performed (Scheme 6). The structure
of enamine 14 was inferred from correct micro analytical
data, its IR spectrum revealed strong absorption bands at
3387 and 1610 cmÀ1 attributable to υNH and υC═C, respec-
tively. The H-NMR spectrum compound 14 showed sin-
glet signal at δ ppm 11.74 assigned to (NH2).
Furthermore, compound 4 reacted with acetic anhydride
in boiling water bath, hydroxyl amine hydrochloride in
pyridine and hydrazine hydrate in ethanol to afford 4-ace-
tyl-3-(2-(4-bromophenyl)-2-oxoethyl)-3,4-
1
1
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Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities
from 4-(4-Bromophenyl)-4-oxobut-2-enoic Acid
Scheme 6
dihydroquinoxalin-2-yl acetate (15) and 3-(2-(4-bro
mophenyl)-2-(hydroxyimino)ethyl-3,4-dihydroquino
xalin-2(1H)-one (16) and 3-(2-(4-bromo phenyl)-2-
hydrazonoethyl)-3,4-dihydroquinoxalin-2(1H)-one (17),
respectively (Scheme 7).
D2O), and 11.07 (S, 1H, OH exchanged with D2O). The
IR spectrum of compound 17 showed strong absorption
bands at 1603 and 3372 attributable to υC═N and υNH2
groups, respectively. The 13C-NMR spectrum of compound
17 exhibited the expected number of signals for the aro-
matic carbons as well as carbonyl signal.
The behavior of the pyridazinone derivative 13a towards
carbon electrophiles was studied. Interaction of pyridazinone
13a with 1,5-[d]-gluconic acid lactone in boiling
The IR spectrum of compound 15 revealed strong ab-
sorption bands at 1685 and 1778 cmÀ1 attributed to υmax
of two carbonyl groups and devoid any band for υNH, its
1H-NMR spectrum showed two singlet signals at δ ppm
1
1.24, 2.08 ppm attributable to two CH3 groups. The H-
ethanol afforded a cyclo N-nucleoside 18. When
NMR spectrum of compound 16 exhibited signals at δ
ppm 3.30 (dd, 1H of methylene proton), 3.69 (dd, 1H for
other methylene proton, diastereotopic proton), 4.20 (dd,
1H, methine proton, stereogenic proton), 6.65–8.51 (m,
8H, ArH), 8.87 (s, 2H for NH protons exchanged with
pyridazinone 13a interact with acetic anhydride, yielded
2-acetyl-4-(1H-benzo[d]imidazol-1-yl)-6-(4-bromophe-
nyl)-4,5-dihydropyridazin-3-(2H)-one (19).
Furthermore, pyridazinone 13a reacted with ethyl
chloroacetate in boiling acetone and in the presence of
Scheme 7
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M. A. El-Hashasha, A. Y. Solimanb, H. M. Bakeer, F. K. Mohammed, and H. Hassan
Vol 000
potassium carbonate to afford ethyl ester 20 (Scheme 8). The
IR spectrum of compound 18 revealed strong absorption broad
159.4 ppm. The 1H-NMR spectra of compound 24 showed
the methylidene protons at δ ppm = 8.55.
band 3436 cmÀ1 attributable υOH and devoid any band for υNH
.
When the hydrazide derivative 21 was submitted to react
with EAA in boiling ethanol it yielded pyrazole derivative
26 that was reported in 2008 [27]. But in this reaction, the
ester 25 was isolated. IR spectrum of compound 25 exhibits
strong absorption bands at 1666, 1751, and a basin peak
centered at 3424 cmÀ1 attributable to υmax of two carbonyl
groups and υNH, respectively while the 1H-NMR spectrum
exhibit signals at δ ppm 1.21 (t, 3H, CH3 of ester), 1.87
(s, 3H, CH3), 2.29 (s, 2H, CH2), 4.15 (q, 2H, CH2 of ester),
and 8.46 (s, 1H, NH exchangeable in D2O) (Scheme 10).
While compound 19 was confirmed from its IR spectrum
that exhibits characteristic absorption band at 1647 cmÀ1 and
devoid any bands for υNH. The 13C-NMR spectrum of com-
pound 19 exhibited the expected number of signals for the
aromatic carbons as well as methyl signal at 19.6 ppm. The
1H-NMR spectrum of compound 20 exhibited signals at δ
ppm 1.17 (t, 3H, CH3 of ethyl ester) and 4.13 (q, 2H, CH2
of ethyl ester). The reaction of pyridazinone derivative 13a
with ethyl chloroacetate possibly takes place via N-alkylation
followed by elimination of benzimidazole. Compound 20
was allowed to react with hydrazine hydrate in refluxing
ethanol to afford the hydrazide 21. [27] (Scheme 8).
Compound 21 was allowed to react with acetyl acetone,
acetyl chloride, and 4-nitrobenzaldehyde to give pyrazole
derivative 22, oxadiazole derivative 23 Schiff’s base
derivative 24 (Scheme 9).
APPLICATION
β-aroyl acrylic acid and its derivatives represent one of
the most active classes of compounds possess a wide
spectrum of biological activity. Many of these compounds
have been used for the treatment of various diseases,
such as Alzheimer’s disease [2] and exhibit a broad spec-
trum of physiological (fungicidal, antitumor, hypotensive,
hypolipidemic, and antibacterial) activities [1]. In the
present work, synthesis of some β-aroyl acrylic acid and their
derivatives were reported. Some of the new synthesized
compounds have been evaluated for their antibacterial ac-
tivity. The antibacterial activity of each compound under
investigation was evaluated by the disk diffusion method
against Gram-positive bacteria (Streptococci) and Gram-
The structure of compound 22 was confirmed from its
IR spectrum that exhibits strong absorption band at
1
1666 cmÀ1 due to υC═O. The H-NMR spectrum of com-
pound 22 exhibit signals at δ ppm 2.39 (s, 3H, CH3 in
pyrazole ring) and 2.45 (s, 3H, CH3 in pyrazole ring). IR
spectrum of compound 23 showed strong absorption bands
at 1666 cmÀ1 due to υC═O. The 13C-NMR spectrum of
compound 23 exhibited the expected number of signals
for the aromatic carbons as well as carbonyl signal at
Scheme 8
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Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities
from 4-(4-Bromophenyl)-4-oxobut-2-enoic Acid
Scheme 9
Table 1
Scheme 10
Antibacterial activity of synthesized compounds.
Antibacterial activity
Gram-positive bacteria
Gram-negative bacteria
Compound
Streptococci
Escherichia coli
2
3
4
À
À
À
+
+
À
8
+
+
9
+++
+++
+++
À
À
+
+
10
11
12a
12b
13a
13b
14
15
16
17
21
22
23
24
26
++
À
++
+
À
À
À
++
À
À
À
À
À
À
À
++
À
negative bacteria (Escherichia coli) by using sterile
whatman-No5 filter paper disks (11 mm diameter). Each
compound was dissolved in ethanol. Filter paper disks
(11 mm) were loaded with certain amount of the tested ma-
terial (50 μL) then left with care under hot air to complete
dryness. Test plates were prepared by pouring 10 mL
Muller–Hinton agar medium seeded with the test organ-
ism. The disks were deposited on the surface of agar plates
along with control disk, which loaded only with used sol-
vent. The disks were incubated at 5°C for 1 h, to permit
good diffusion. All the plates were then incubated for
24 h at 37°C. The zones of inhibition were measured then
the following results were reported (cf. Table 1).
+
+
+++
À
À
À
À
À
À, no activity; +, weak activity; ++, moderate activity; +++, strong
activity.
of these compounds. Chemically, and as an application of
important and widely used reaction in organic chemistry,
Aza–Michael addition was investigated with different
types of amines. Furthermore, Aza–Michael adducts were
used as key starting materials to generate different hetero-
cycles that have biological potentiality. Biologically, it was
CONCLUSION
In this research, novel heterocyclic compounds were
synthesized followed by studying the antibacterial activities
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Vol 000
Synthesis of 2-((3-(4-bromophenyl)-1-carboxy-3-oxopropyl)
amino)benzoic acid (3). A mixture of 4-(4-bromophenyl)-4-
found that 3-(1H-benzimidazol-1-yl)-5-(4-bromophenyl)
furan-2(3H)-one (12a) and 4-(1H-benzimidazol-1-yl)-6-
(4-bromophenyl)-4,5-dihydropyridazin-3(2H)-one (13a)
exhibited moderate activity against Gram-negative bacteria,
which may be due to the furanone and pyridazinone
moiety. While 3-(2-(4-bromophenyl)-2-hydrazonoethyl)-
3,4-dihydroquinoxalin-2(1H)-one (17) showed strong activity
against Gram-positive bacteria, which may be due to hydrazone
group. In another side, compound 6-(4-bromophenyl)-4-
((2-(3,5-dimethyl-1H-pyrazol-1-yl)-2-oxoethyl)amino)-4,5-
dihydropyridazin-3(2H)-one (9) showed the highest activity
against Gram-positive bacteria, which may be due to the
pyrazole and pyridazinone moiety. Also, compounds 6-(4-
bromophenyl)-4-(((5-methyl-1,2,4-oxadiazol-2-yl)methyl)
amino)-4,5-dihydropyridazin-3(2H)-one (10) and 2-((6-(4-
bromophenyl)-3-oxa-2,3,4,5-tetrahydropyridazin-4-yl)amino)-
N′-(4-nitrobenzalidene)acetohydrazide (11) showed strong
activity against Gram-positive bacteria, which may be
due to pyridazinone ring that contain amino group and
oxadiazole moiety or 4-nitrobenzaldehyde.
oxobut-2-enoic acid (1) (3 g; 0.01mol) and anthranilic acid
(1.37 g; 0.01mol) in ethanol (20mL) and (4 drops) of acetic acid
glacial was refluxed for 2 h. The reaction mixture was allowed to
cool and the separated product was filtered. Crystallization of the
crude product from toluene then drying, afforded 3 (faint yellow
powder, 2.9g (75%) yield, mp 230°C). IR (cmÀ1): 3431, 3359
1
(NH bonded and non-bonded), 2800 (OH) and 1677 (C═O). H-
NMR: δ, ppm (DMSO-d6); 3.60, 3.67 (dd, J = 6 Hz, 2H,
methylene proton), 4.30, 4.27 (dd, J = 6 Hz, 1H, methine proton),
4.66 (s, 1H, NH exchangeable with D2O), 7.17–8.36 (m, 8H,
ArH), 9.13, 9.21 (s, 2H, 2 OH exchangeable with D2O). 13C-
NMR: δ, ppm (DMSO-d6); 197.7 (C═O adjacent to aroyl
moiety), 175.8 (C═O of acid), 169.9 (C═O of anthranilic acid),
135.1, 130.7, 129.3, 128.5 (phenyl carbons), 150.1, 131.4, 127.6,
126.8, 120.2, 117.1 (anthranilic benzene ring), 67.9 (CH–N), 40.5
(CH2). Anal. Calcd (%): C17H14BrNO5. C, 52.06; H, 3.60; N,
3.57. Found (%): C, 52.50; H, 3.16; N, 3.68.
Synthesis of 3-(2-(4-bromophenyl)-2-oxoethyl)-3,4-dihydro
quinoxalin-2-(1H)-one (4). A mixture of 4-(4-bromophenyl)-
4-oxobut-2-enoic acid (1) (3 g; 0.01mol) and o-phenylenediamine
(1.08 g; 0.01mol) in ethanol (20mL) and (4 drops) of acetic acid
glacial was refluxed for 2 h. The reaction mixture was allowed to
cool and the separated product was filtered and dried.
Crystallization of the crude product from toluene then drying,
afforded 4 (dark brown powder, 2.58g (75%) yield, mp 190°C).
IR (cmÀ1): 3300 (NH2), 3190 (NH) and 1728, 1679 (2C═O). 1H-
NMR: δ, ppm (DMSO-d6): 3.25 (dd, J = 6 Hz, 1H, methylene
proton), 3.00 (dd, J = 6 Hz, 1H, other methylene proton), 4.10,
4.12 (dd, J = 6 Hz, 1H, methine proton), 5.69 (s, 1H, NH
exchangeable in D2O), 6.65–8.51 (m, 8H, aromatic protons), 8.87
(S, 1H, NH–CO exchangeable in D2O). 13C-NMR: δ, ppm
(DMSO-d6); 198.4 (C═O adjacent to aroyl moiety), 172.3 (C═O
of quinoxalinone), 135.4, 132.1, 129.4, 128.6 (phenyl carbons),
140.3, 130.7, 128.2, 125.6, 119.1, 117.8 (quinoxalinone), 64.8
(CH2–H–N), 45.3 (CH2). Anal. Calcd (%): C16H13BrN2O2 C,
55.67; H, 3.80; N, 8.12. Found (%): C, 55.54; H, 3.74; N, 7.98.
Synthesis of 4-(4-bromophenyl)-2-((2-ethoxy-2-oxoethyl)amino)-
EXPERIMENTAL
Melting points were determined on STUART scientific melting
point apparatus and were uncorrected. The reaction times were
determined using the thin-layer chromatography (TLC) technique
which was performed using plates of aluminum oxide sheets
coated with silica gel (E. Merk) 60 F 254 neutral type. The IR
spectra were recorded on Bruker FTIR spectrophotometer as po-
tassium bromide disks. Mass spectra (EIMS) were performed at
70 eV with Shimadzu GCMS, QP1000 EX using the Electron
Ionization Technique (EI). The proton nuclear magnetic resonance
1H-NMR and 13C-NMR spectra were recorded in (DMSO-d6)
on Varian Gemini spectrophotometer at 200 MHz and Varian
Mercury spectrophotometer at 300 MHz, using tetra methyl silan
(TMS) as an internal reference and the chemical shift values (δ)
are given in part per million (ppm). Elemental analyses were car-
ried out at the Micro Analytical Center, National Research Center,
Cairo, Egypt.
4-oxobutanoic acid (5).
A mixture of 4-(4-bromophenyl)-4-
oxobut-2-enoic (1) (3 g; 0.01 mol) and ethyl glycinate
hydrochloride (1.39 g; 0.01 mol) in ethanol (30mL) and (4 drops)
of acetic acid glacial and sodium acetate anhydrous (0.82g;
0.01mol) was refluxed for 2 h. The reaction mixture was allowed
to cool, and the separated product was filtered. Crystallization of
the crude product from acetic acid then drying, afforded 5 (white
powder, 3.22g (90%) yield, mp 160°C). IR (cmÀ1): (OH), 3174
(NH) and 1742, 1685 (2C═O). 1H-NMR: δ, ppm (DMSO-d6);
1.18 (t, J = 9 Hz, 3H, CH3 of ester), 4.09 (q, J = 9 Hz, 2H, CH2 of
ester), 3.64, 3.67 (dd, 2H, methylene proton), 4.30, 4.27 (dd,
J = 9 Hz 1H, methine proton) 3.64 (dd, J = 9 Hz 2H, CH2–N),
7.72–7.94 (m, 4H, ArH), 8.16 (s, 1H, NH exchangeable with
D2O), and 9.21 (s, 1H, OH exchangeable with D2O). 13C-NMR:
δ, ppm (DMSO-d6); 195.4 (C═O adjacent to aroyl moiety), 174.8
(C═O of acid), 171.5 (C═O of ester), 135.2, 130.5, 128.7, 123.2
(phenyl carbons), 60.3 (CH–NH), 56.2 (CH2 in acrylic system),
52.4 (CH2 in amino system), 49.2(CH2 of ester), 14.6 (CH3 of
ester). Anal. Calcd (%): C14H16BrNO5. C, 46.92; H, 4.46; N,
3.91. Found (%): C, 46.57; H, 4.33; N, 3.73.
Synthesis of 2-(1H-benzimidazol-1-yl)-4-(4-bromophenyl)-
4-oxobutanoic acid (2).
A mixture of 4-(4-bromophenyl)-4-
oxobut-2-enoic acid (1) (2.55 g; 0.01 mol) and benzimidazole
(1.18 g; 0.01 mol) in ethanol (50 mL) and (4 drops) of piperidine
was refluxed for 2 h. The reaction mixture was allowed to
cool and the separated product was filtered. Crystallization
of the crude product from dioxane then drying, afforded 2
(brown powder, 2.7 g (75%) yield, mp 186°C). IR (cmÀ1): 3300
(OH) and 1732, 1686 (2C═O).1H-NMR: δ, ppm (DMSO-d6);
3.94, 3.97, 4.00, 4.03 (dd, J = 6 Hz, 2H, CH2); 4.12, 4.14,
4.18, 4.20 (dd, J = 4 Hz, 1H, CH); 7.17–7.95 (m, 8H, ArH),
8.14 (s, 1H, CH in imidazole ring) and 8.36 (s, 1H for one
OH exchangeable with D2O).13C-NMR: δ, ppm (DMSO-d6);
199.1 (C═O adjacent to aroyl moiety), 170.3 (C═O of acid),
143.8 (carbon of imidazole), 135.7, 132.3, 130.1, 129.4,
127.6, 128.1 (phenyl carbons), 144.9, 135.1, 125.8, 120.7,
(benzimidazole carbons), 65.9 (CH–N), 39.3 (CH2). Anal. Calcd
(%): C17H13Br N2O3 C, 54.71; H, 3.51; N, 7.51. Found (%): C,
54.55; H, 3.32; N, 7.42.
Synthesis of ethyl-2-((5-(4-bromophenyl)-2-oxo-2, 3-dihydrofur
an-3-yl)amino) acetate (6). A mixture of acid 5 (3.58 g, 0.01 mol)
and acetic anhydride (9.42 mL, 0.1 mol) was refluxed on boiling
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities
from 4-(4-Bromophenyl)-4-oxobut-2-enoic Acid
water bath for 1 h. The reaction mixture was allowed to cool then
poured into ice-water and the separated product was filtered.
Crystallization of the crude product from toluene then drying,
afforded 6 (dark brown powder, 2.38 g (70%) yield, mp 120°C). IR
(cmÀ1): 3439 (NH), 2982 (CH), and 1782, 1745 (2C═O, bonded
and non-bonded). 1H-NMR: δ, ppm (DMSO-d6); 1.19 (t, 3H,
J=9Hz, CH3 of ester), 3.51 (s, 2H, CH2CO), 4.11 (q, J=9Hz,
2H, CH2 of ester), 4,22 (d, J= 9 Hz, 1H, CH–NH in furanone ring),
5.48 (d, J= 9 Hz, 1H, CH in furanone ring ) 7.71–7.79 (m, 4H, ArH),
8.54 (s, 1H, NH exchangeable with D2O). 13C-NMR: δ, ppm
(DMSO-d6); 171.7 (C═O of ester), 167.9(C═O of furanone ring),
135.3, 130.7, 128.4, 123.9 (phenyl carbons), 145.3 (C–Ar), 97.8 (CH2
in furanone ring), 60.1 (CH–N), 46.2 (CH2 in amino system), 49.1
(CH2 of ester), 14.5 (CH3 of ester) Anal. Calcd (%): C14H14BrNO4 C,
49.43; H, 4.15; N, 4.12. Found (%): C, 49.33; H, 3.95; N, 4.00.
Synthesis of 2-((6-(4-bromophenyl)-3-oxo-2,3,4,5-tetrahydro
pyridazin-4-yl)amino) acetohydrazide (7). A mixture of acid 5
(3.58 g; 0.01 mol) and hydrazine hydrate 98% (1.5 mL; 0.04 mol)
in ethanol (50 mL) was refluxed for 2 h. The reaction mixture was
allowed to cool, and the separated product was filtered.
Crystallization of the crude product from ethanol then drying,
afforded 7 (yellow powder, 1.87 g (55%) yield, mp 258°C). IR
(cmÀ1): 3386, 3224 (NH bonded and non-bonded), 2962, 2846
(CH), 1635 (C═O). 1H-NMR: δ, ppm (DMSO-d6); 1.43, 1.45 (dd,
J=6Hz 2H, CH2 in pyridazinone moiety), 3.44 (s, 2H, CH2CO),
4.32 (dd, J= 6 Hz 1H, CH in pyridazinone moiety), 4.86 (br, s, 2H,
NH2 exchangeable with D2O) 7.70,7.78, 7.81, 7.83 (m, 4H, ArH),
8.55, 8.71 (s, 2H, NH exchangeable with D2O). 13C-NMR: δ, ppm
(DMSO-d6); 171.4(C═O of hydrazide), 160.3(C═O of pyridazinone),
143.7 (C═N in pyridazinone ring) 134.3, 132.5, 128.7, 123.2 (phenyl
carbons), 99.4 (CH–N in pyridazinone ring) 53.8 (CH2 in amino
system), 40.3 (CH2 in pyridazinone ring). EIMS: m/z (%) = (338,
0.19%), (339, 2.20%), and (340, 1.79%) (M+). Anal. Calcd (%):
C12H14BrN5O2. C, 42.37; H, 4.15; N, 20.59. Found (%): C, 42.02;
H, 3.93; N, 20.21.
Synthesis of 6-(4-bromophenyl)-4-((2-(3-methyl-5-oxo-4,5-
dihydro-1H-pyrazol-1-yl)-2-oxoethyl)amino)-4,5-dihydropyridazin-
3-(2H)-one (8). A mixture of the hydrazide 7 (3.4 g; 0.01 mol)
and EAA (1.2 mL; 0.01 mol) and few drops of piperidine in
ethanol (30 mL) were refluxed for 4 h. The reaction mixture
was allowed to cool, and the separated product was filtered.
Crystallization of the crude product from ethanol then drying,
afforded 8 (white powder, 2.31 g (57%) yield, mp 244°C). IR
(cmÀ1): 3300 (NH), 3124, 2923, 2854 (CH) and 1650 (C═O).
1H-NMR: δ, ppm (DMSO-d6); 1.92 (s, 3H, CH3 in pyrazole
ring) 1.45 (dd, J = 6 Hz, 2H, CH2 in pyridazinone moiety), 2.32
(s, 2H, CH2 in pyrazole moiety), 3.44 (s, 2H, CH2CO), 4.32 (dd,
J= 6 Hz 1H, CH in pyridazinone moiety), 5.57(s, 1H, NH–CH)
7.70–7.83 (m, 4H, ArH), 8.55 (s,1H, NH–CO). 13C-NMR: δ, ppm
(DMSO-d6); 163.2(C═O adjacent to pyrazole ring), 162.1 (C═O in
pyrazole ring), 160.3(C═O of pyridazinone ring), 155.6 (C in
pyrazole ring), 143.2 (C═N in pyridazinone ring) 134.3, 130.4,128.7,
123.2 (phenyl carbons), 91.1 (CH–NH), 73.8 (CH2 in pyrazole ring),
54.9 (CH2 in amino system), 40.3 (CH2 in pyridazinone ring), 16.0
(CH3 in pyrazole ring). Anal. Calcd (%): C16H16BrN5O3. C,
47.31; H, 3.97; N, 17.24. Found (%): C, 47.08; H, 3.65; N, 16.95.
Synthesis of 6-(4-bromophenyl)-4-((2-(3,5-dimethyl-1H-
pyrazol-1-yl)-2-oxoethyl)amino)-4,5-dihydropyridazin-3(2H)-
Crystallization of the crude product from ethanol then drying,
afforded 9 (faint yellow powder, 2.14 g (53%) yield, mp 250°C).
IR (cmÀ1): 3300, 3200 (NH), 2931, 2874 (CH) and 1658 (C═O).
1H-NMR: δ, ppm (DMSO-d6): 2.52, 2.14 (s, 6H, 2 CH3 groups in
pyrazole ring) 1.44, 1.43 (dd, J= 6 Hz, 2H, CH2 in pyridazinone
moiety), 2.32 (s, 1H, CH in pyrazole moiety), 3.41 (s, 2H, CH2CO),
4.32, 4.28 (dd, J= 6 Hz, 1H, CH in pyridazinone moiety), 7.70–7.83
(m, 4H, ArH), 8.55 (s,1H, NH–CO exchangeable with D2O).
13C-NMR: δ, ppm (DMSO-d6); 163.6(C═O adjacent to pyrazole
ring), 159.7 (C═O of pyridazinone ring), 156.9,155.3 (2 C in
pyrazole ring), 142.1 (C═N in pyridazinone ring) 133.1, 131.7,
128.9, 123.5 (phenyl carbons), 91.6 (CH–NH), 73.8 (CH in
pyrazole ring), 54.2 (CH2 in amino system), 40.6 (CH2 in
pyridazinone ring), 26.3, 16.8 (2 CH3 in pyrazole ring). EIMS:
m/e (%): 404(M+) (0.43%), 405 (M+1) (0.37%), 406 (M+2
)
(0.21%). Anal. Calcd (%): C17H18BrN5O2. C, 50.51; H, 4.49; N,
17.32. Found (%): C, 50.22; H, 4.32; N, 17.11.
Synthesis of 6-(4-bromophenyl)-4-(((5-methyl-1,2,4-oxadiazol-
2-yl)methyl)amino)-4,5-dihydropyridazin-3(2H)-one (10). A
mixture of the hydrazide 7 (3.4 g; 0.01 mol) and acetyl chloride
(2.1 mL; 0.03 mol) in pyridine (20 mL) was refluxed for 3 h. The
reaction mixture was allowed to cool then poured into ice and
HCl, and the separated product was filtered. Crystallization of
the crude product from dioxane, afforded 10 (dark brown
powder, 2.00 g (55%) yield, mp >360°C). IR (cmÀ1): 3432
(NH), 2923, 2869 (CH) and 1650 (C═O). 1H-NMR: δ, ppm
(DMSO-d6): 1.92 (s, 3H, CH3 in oxadiazole ring) 1.44, 1.42
(dd, J = 6 Hz, 2H, CH2 in pyridazinone moiety), 3.67 (s, 2H,
CH2 in amino system), 4.32, 4.28 (dd, J = 6 Hz, 1H, CH in
pyridazinone moiety), 7.70–7.83 (m, 4H, ArH), 8.57 (s,1H,
NH–CO). 13C-NMR: δ, ppm (DMSO-d6); 162.3(C═O of
pyridazinone ring), 157.1, 154.8 (2C in oxadizole ring), 143.7
(C═N in pyridazinone ring) 132.1, 129.4, 124.2, 123.8 (phenyl
carbons), 91.7 (CH–NH), 54.5 (CH2 in amino system), 40.2
(CH2 in pyridazinone ring), 27.1 (CH3 in oxadiazole ring). Anal.
Calcd (%): C14H14BrN5O2. C, 46.17; H, 3.87; N, 19.23. Found
(%): C, 45.87; H, 3.32; N, 18.98.
Synthesis of (Z)-2-(6-(4-bromophenyl)-3-oxo-2,3,4, 5-tetrahydro
pyridazin-4-ylamino)-N′-(4-nitrobenzylidene)acetohydrazide. (11).
A mixture of hydrazide 7 (3.4 g; 0.01 mol) and 4-nitrobenzaldehyde
(1.5 g; 0.01 mol) and few drops of piperidine in ethanol (20 mL) were
refluxed for 4 h. The reaction mixture was allowed to cool and the
separated product was filtered. Crystallization of the crude product
from toluene then drying, afforded 11 (yellow powder, 4.48 g (95%)
yield, mp 266°C). IR (cmÀ1): 3424, 3313(NH bonded and non-
bonded), 1648(C═O). 1H-NMR: δ, ppm (DMSO-d6): 1.43(dd,
J= 6 Hz, 2H, CH2 in pyridazinone moiety), 3.46 (s, 2H, CH2CO),
4.31, 4.26 (dd, J= 6 Hz, 1H, CH in pyridazinone moiety), 7.70–7.91
(dd, 8H, ArH), 8.06 (d, J= 6 Hz, 1H, CH═N) 8.51, 8.55 (s, 2H, for 2
NH groups exchangeable in D2O). 13C-NMR: δ, ppm (DMSO-d6);
163.6 (C═O adjacent to hydrazide), 160.2 (C═O of pyridazinone
ring), 143.1, 142.3 (C═N in pyridazinone ring and C═N in
hydrazide), 142.9, 135.5, 132.1, 131.6, 129.7, 128.5, 123.2, 121.9 (of
2 phenyl rings carbons), 90.3 (CH–NH), 54.1 (CH2 in amino
system), 38.9 (CH2 in pyridazinone ring), Anal. Calcd (%):
C19H17BrN6O4. C, 48.22; H, 3.62; N, 17.76. Found (%): C, 48.04;
H, 3.00; N, 17.54.
General procedure for the reaction of acid (2, 3) with acetic
one (9).
A mixture of the hydrazide 7 (3.4 g; 0.01 mol) and
anhydride.
A mixture of the acid (0.01 mol) and acetic
acetyl acetone (1 mL; 0.01 mol) and few drops of piperidine in
ethanol (20 mL) were refluxed for 4 h. The reaction mixture was
allowed to cool and the separated product was filtered.
anhydride (9.43 mL, 0.1 mol) was refluxed on boiling water bath
for 1 h. The reaction mixture was allowed to cool then poured
into ice-water and the separated product was filtered.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. El-Hashasha, A. Y. Solimanb, H. M. Bakeer, F. K. Mohammed, and H. Hassan
Vol 000
3-(1H-benzimidazol-1-yl)-5-(4-bromophenyl)furan-2(3H)-one
(12a). This compound was obtained as dark brown powder in
2.2 g (62%) yield, mp 125°C (toluene). IR (cmÀ1): 1773 (C═O).
1H-NMR: δ, ppm (DMSO-d6): 5.19 (d, J= 6 Hz, 1H, CH–N), 5.48
(d, 1H, CH in furanone ring), 7.11–8.39 (m, 8H, 2 ArH protons),
8.16 (s, 1H, CH═N in imidazole ring). 13C-NMR: δ, ppm
(DMSO-d6); 168.4 (C═O of furanone ring), 145.3 (C–Ar), 143.5
(carbon of imidazole), 135.9, 130.2, 129.8, 127.2, (phenyl carbons),
144.3, 135.2, 125.6, 123.1, 120.5, 119.8 (benzimidazole carbons),
93.3 (CH in furanone ring), 65.5 (CH–N). EIMS: m/z (%) = (15%
355, M+1) and (5% 356, M+2). Anal. Calcd (%): C17H11BrN2O2. C,
57.46; H, 3.09; N, 7.88. Found (%): C, 57.30; H, 2.94; N, 7.65.
2-((5-(4-bromophenyl)-2-oxo-2,3-dihydrofuran-3-yl)amino)
benzoic acid (12b). This compound was obtained as yellow
powder (toluene), 2.61 g (70%) yield, mp 210°C. IR (cmÀ1):
3435 (OH), 3100 (NH) and 1782, 1721 (2C═O).1H-NMR: δ,
ppm (DMSO-d6) 3.98 (d, 1H, CH–N), 5.23 (d, J=6Hz, 1H, CH in
furanone ring), 6.48 (s, 1H, NH), 7.39–7.98 (m, 8H, 2 ArH protons),
13.08 (s, 1H, OH).13C-NMR: δ, ppm (DMSO-d6); 169.3 (C═O of
anthranilic acid moiety), 167.8 (C═O of furanone ring), 146.7 (C–
Ar), 135.2, 132.2, 129.7,127.2 (phenyl carbons), 150.5, 131.4,
127.5, 126.9, 120.3, 117.4 (anthranilic benzene ring), 93.6 (CH in
furanone ring), 65.9 (CH–N). Anal. Calcd (%): C17H12BrNO4. C,
54.57; H, 3.23; N, 3.74. Found (%): C, 54.66; H, 2.92; N, 3.39.
General procedure for the reaction of acid (2, 3) with
poured into ice and HCl. and the separated product was filtered.
Crystallization of the crude product from toluene then drying,
afforded 14 (faint brown, 1.72 g (64%) yield, mp 198°C). IR
(cmÀ1): 3387 (NH) and 1704, 1670 (2C═O). 1H-NMR: δ, ppm
(DMSO-d6): 6.19 (s, 1H, CH–CO), 6.98 – 8.06 (m – 4H, ArH),
11.74 (s, 2H, NH exchangeable with D2O) and 12.32 (singlet 1H for
one OH exchangeable with D2O). 13C-NMR: δ, ppm (DMSO-d6);
167.3 (C═O adjacent to aroyl moiety), 165.8 (C═O of acid), 154.6
(C-NH2), 135.4, 132.6, 130.5, 128.9 (phenyl carbons), 99.4 (CH).
Anal. Calcd (%): C10H8BrNO3. C, 44.47; H, 2.99; N, 5.19. Found
(%): C, 44.25; H, 2.45; N, 5.07.
Synthesis of 4-acetyl-3-(2-(4-bromophenyl)-2-oxoethyl)-3,4-
dihydroquinoxalin-2-yl acetate (15). A mixture of compound
4 (3.45 g, 0.01 mol) and acetic anhydride (9.42 mL, 0.1 mol) was
refluxed on water bath for 1 h. The reaction mixture was allowed
to cool then poured into ice-water and the separated product was
filtered. Crystallization of the crude product from toluene and
drying, afforded 15 (brown powder, 1.71 g (40%) yield, mp
130°C). IR (cmÀ1): 1778, 1685 (2C═O). 1H-NMR: δ, ppm
(DMSO-d6): 1.24, 2.08 (s, 6H, 2 CH3), 2.25, 2.30 (dd, J=6Hz,
2H, CH2), 3.56 (t, J = 6 Hz, 1H, CH), 7.02–7.77(m, 8H, ArH). 13C-
NMR: δ, ppm (DMSO-d6); 198.4 (C═O adjacent to aroyl moiety),
177.9(O–C═O), 160.9 (N–C═O), 160.2 (C═N of quinoxalinone),
142.6, 133.9, 132.4, 130.1, 129.5, 127.2, 128.7, 125.2, 122.4,
119.8, (2 benzene ring carbons), 50.3(CH–N), 39.5 (CH2), 21.4,
19.8 (2 CH3). Anal. Calcd (%): C20H17BrN2O4. C, 55.96; H, 3.99;
hydrazine hydrate.
A mixture of the acid (0.01 mol) and
hydrazine hydrate 98% (1.5 mL; 0.04 mol) in ethanol (50 mL)
was refluxed for 2 h. The reaction mixture was allowed to cool
and the separated product was filtered.
N, 6.53. Found (%): C, 55.48; H, 4.02; N, 6.36.
Synthesis of 3-(2-(4-bromophenyl)-2-(hydroxyimin o)ethyl)-
3,4-dihydroquinoxalin-(1H)-one (16). A mixture of compound 4
(3.45 g; 0.01 mol) and hydroxyl amine hydrochloride (0.69 g;
0.01mol) in pyridine (40 mL) was refluxed for 3 h. The reaction
mixture was allowed to cool then poured into ice and HCl. and
the separated product was filtered. Crystallization of the crude
product from toluene then drying, afforded 16 (yellow powder,
2.59g (72%) yield, mp 210°C). IR (cmÀ1): 3431, 3323 (OH
bonded and non-bonded), 3186, 3133 (NH bonded and non-
4-(1H-benzimidazol-1-yl)-6-(4-bromophenyl)-4,5-dihydropy
ridazin-3(2H)-one (13a). This compound was obtained as faint
brown (ethyl acetate) in 1.84 g (50%) yield, mp 236°C. IR (cmÀ1):
3196, 3311(NH – bonded and non-bonded) and 1660 (C═O).1H-NMR:
δ, ppm (DMSO-d6): 1.94, 2.09 (dd, J= 6 Hz, 2H, CH2 in pyridazinone
ring), 4.19, 4.22 (dd, J = 6 Hz, 1H, CH in pyridazinone ring), 6.98
(singlet 1H for one NH exchangeable with D2O), 7.67–8.06
(m, 8H, ArH), 8.14 (s, 1H, CH in imidazole ring).13C-NMR: δ,
ppm (DMSO-d6); 160.1 (C═O), 144.5 (N–C═N in imidazole
moiety), 143.7 (C═N in pyridazinone ring), 134.3, 131.1, 128.9,
123.2, (benzene ring carbons) 144.3, 135.2, 125.6, 123.1, 120.5,
119.8 (benzene ring carbons of benzimidazole), 70.3 (CH–N),
40.8 (CH2 in pyridazinone). EIMS: m/z (%) = (369, 1.45% M+1)
and (371, 0.5% M+2). Anal. Calcd (%): C17H13BrN4O C, 55.30;
1
bonded), 1702 (C═O for δ-lactam) and 1612 (C═N). H-NMR:
δ, ppm (DMSO-d6): 3.30 (dd, J = 6 Hz, 1H, methylene proton),
3.69 (dd, J= 6 Hz, 1H, other methylene proton), 4.20 (dd, J=6Hz,
1H, methine proton) 6.65-8.51 (m, 8H, aromatic protons), 8.87 (s,
2H, for 2 NH which exchanged with D2O) and 11.07 (s, 1H, OH
exchanged with D2O). 13C-NMR: δ, ppm (DMSO-d6); 172.8 (C═O
of quinoxalinone), 155.3 (C═N adjacent to aroyl moiety), 139.4,
135.9, 132.6, 130.2, 129.8, 128.6, 125.8, 123.7, 119.1, 117.9
(2 benzene ring carbons), 64.6 (CH2–CH–NH), 39.5 (CH2). Anal.
Calcd (%): C16H14BrN3O2. C, 53.35; H, 3.92; N, 11.67. Found
H, 3.55; N, 15.17. Found (%): C, 55.10; H, 3.50; N, 15.10.
2-(6-(4-bromophenyl)-3-oxo-2,3,4,5-tetrahydropyridazin-4-
ylamino)benzoic acid. (13b). This compound was obtained as
faint brown (ethyl toluene) in 2.91 g (75%) yield, mp 200°C. IR
(cmÀ1): 3241 (NH), 1669 (C═O) and 1609 (C═N).1H-NMR: δ,
ppm (DMSO-d6) 2.46 (dd, J = 6 Hz, 1H, CH2), 3.38 (dd,
J = 6 Hz, 1H, CH2), 3.31(dd, J = 6 Hz, 1H, CH), 6.48–7.80 (m,
8H, aromatic protons), 9.19, 9.21 (2 s, 2H, for 2 NH which
exchanged with D2O), 11.17 (s, 1H, OH exchangeable with D2O).
13C-NMR: δ, ppm (DMSO-d6); 172.9 (C═O of anthranilic acid),
167.3 (C═O of pyridazinone ring), 149.3 (C═N of pyridazinone
ring), 135.1, 133.4, 130.4, 131.2, 123.4, 119.5, 116.9, 115.4,
113.7, 111.2 (2 benzene ring carbons), 47.4 (CH–NH), 29.9 (CH2
in pyridazinone ring) Anal. Calcd (%): C17H14BrN3O3. C, 52.57;
(%): C, 53.02; H, 3.63; N, 11.22.
Synthesis of 3-(2-(4-bromophenyl)-2-hydrazonoethyl )-3,4-
dihydroquinoxalin-2(1H)-one (17). A mixture of compound
4 (3.45 g; 0.01 mol) and hydrazine hydrate 98% (1.5 mL;
0.04 mol) in ethanol (50 mL) was refluxed for 2 h. The reaction
mixture was allowed to cool and the separated product was
filtered. Crystallization of the crude product from toluene then
drying, afforded 17 (yellow powder, 2.80 g (78%) yield, mp
290°C). IR (cmÀ1): 3372, 3308 (NH), 3053(CH aromatic), 2896
(CH aliphatic), 1679 (C═O) and 1603 (C═N). 1H-NMR: δ,
ppm (DMSO-d6): 3.04 (dd, J= 6 Hz, 1H, methylene proton), 2.75
(dd, J= 6 Hz, 1H, other methylene proton), 4.20 (dd, J=6Hz, 1H,
methine proton) 6.65-8.51 (m, 8H, aromatic protons), 8.02 (s, 2H,
for – NH groups), 8.87 (s, 2H, for NH2). 13C-NMR: δ, ppm
(DMSO-d6); 172.7 (C═O of quinoxalinone), 161.4 (C═N adjacent
to aroyl moiety), 135.8, 134.1, 130.5, 128.6, 127.2, 125.9, 123.5,
H, 3.60; N, 10.82. Found (%): C, 52.30; H, 3.44; N, 10.51.
Synthesis of (E)-2-amino-4-(4-bromophenyl)-4-oxobut-2-enoic
acid (14). A mixture of acid 2 (3.73 g; 0.01 mol) and hydroxyl
amine hydrochloride (0.69 g; 0.01 mol) in pyridine (40 mL) was
refluxed for 3 h. The reaction mixture was allowed to cool then
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis of Novel Heterocyclic Compounds with Expected Antibacterial Activities
from 4-(4-Bromophenyl)-4-oxobut-2-enoic Acid
122.1, 119.1, 117.6 (2 benzene ring carbons), 64.7 (CH2–CH–NH),
35.3 (CH2). Anal. Calcd (%): C16H15BrN4O. C, 53.50; H, 4.21; N,
15.60. Found (%): C, 53.22; H, 3.96; N, 15.32.
Synthesis of 4-(1H-benzo[d]imidazol-1-yl)-6-(4-bromophenyl)-
crude product from dioxane then drying, afforded 21 (white
powder, 2.58 g (80%) yield, mp 232°C). IR (cmÀ1): 3483, 3382,
1
3252, 3125 (NH and NH2), and1652 (C═O). H-NMR: δ, ppm
(DMSO-d6): 4.29(s, 2H, N–CH2CO), 4.72 (d, J = 6 Hz 2H, NH2
exchangeable with D2O), 5.41, 5.07 (2d, 2H, olefinic protons in
pyridazinone moiety), 7.06–7.85 (m, 4H, ArH), 9.31 (s, 1H, NH
exchangeable with D2O) 13C-NMR: δ, ppm (DMSO-d6); 166.8
(C═O of hydrazide), 159.0 (C═O in pyridazinone ring), 143.3
(C═N in pyridazinone ring), 133.9, 130.4, 128.7, 123.1 (benzene
ring carbons), 130.6, 132.8 (2 CH in pyridazinone ring), 53.4
(CH2–N). EIMS: m/z (%) = 323, 0.9% (M + 1). Anal. Calcd (%):
C12H11BrN6O2. C, 44.60; H, 3.43; N, 17.34. Found (%): C,
2-(2,3,4,5,6-pentahydroxyhexanoyl)-4, 5-dihydropyridazin-3(2H)-
one (18).
A mixture of pyridazinone 13a (3.7 g; 0.01 mol) and
1,5-[d]-gluconic acid lactone (1.7 g; 0.01 mol) in pyridine (40 mL)
was refluxed for 2 h. The reaction mixture was allowed to cool then
poured into ice-water. The collected solid was filtered off, washed
well with water. Crystallization from ethanol then drying, afforded
18 (white powder, 3.88 g 71% yield, mp 248°C). IR (cmÀ1): (OH),
1
2932, 2864 (CH), 1676, 1652 (2C═O). H-NMR: δ, ppm (DMSO-
d6) 1.87, 1.96 (dd, 2H, CH2C═N), 2.29 (S, 1H, CH–CO), 3.54–4.35
(m, CH, 6H, in gluconic chain), 7.67–8.06 (m – 8H, ArH), 8.75 (5 s,
5H, OH groups). 13C-NMR: δ, ppm (DMSO-d6); 175.8, 160.3
(2C═O), 144.5 (N–C═N in imidazole moiety), 143.7 (C═N in
pyridazinone ring), 134.3, 132.9, 132.5, 130.2, 128.6, 125.7, 123.1,
122.5, 119.8, 117.4(2 benzene ring carbons), 70.5 (CH–N), 40.2
(CH2 in pyridazinone).63–36 (5 carbons in gluconic chain). Anal.
Calcd (%): C23H23BrN4O7. C, 50.47; H, 4.24; N, 10.24. Found (%):
44.95; H, 3.30; N, 17.46.
Synthesis of 6-(4-bromophenyl)-2-(2-(3,5-dimethyl-1H-pyrazol-
1-yl)-2-oxoethyl)pyridazin-3(2H)-one (22). A mixture of the
hydrazide 21 (3.23 g; 0.01 mol) and acetyl acetone (1 mL;
0.01 mol) and few drops of piperidine in ethanol (20 mL) were
refluxed for 4 h. The reaction mixture was allowed to cool, and
the separated product was filtered. Crystallization of the crude
product from ethanol then drying, afforded 22 (faint yellow
powder, 2.43 g (63%) yield, mp 220°C). IR (cmÀ1): 1666
(C═O).1H-NMR: δ, ppm (DMSO-d6): 2.39 (s, 3H, CH3 in pyrazole
ring), 2.45 (s, 3H, CH3 in pyrazole ring), 4.12 (s, 2H, CH2), 6.08 (s,
1H, CH in pyrazole ring), 6.60 (d, J= 6 Hz 1H, CH in pyridazinone
moiety), 6.39 (d, 1H, CH in pyridazinone moiety), 7.67–8.08 (m,
4H, ArH). 13C-NMR: δ, ppm (DMSO-d6); 163.8 (C═O in side
chain), 159.6 (C═O in pyridazinone ring), 151.8, 145.3, 142.87
(carbons in pyrazole ring), 143.2 (C═N in pyridazinone ring),
133.1, 131.7, 128.2, 123.5(benzene ring carbons), 130.4, 132.6 (2
CH in pyridazinone ring), 52.5 (CH2–N), 26.2, 16.5 (2 CH3 in
pyrazole ring). Anal. Calcd (%): C17H15BrN4O2. C, 52.73; H, 3.90;
C, 50.25; H, 4.01; N, 10.11.
Synthesis of 2-acetyl-4-(1H-benzo[d]imidazol-1-yl)-6-(4-
bromophenyl)-4,5-dihydropyridazin-3(2H)-one (19). A mixture
of pyridazinone 13a (3.7 g, 0.01 mol) and acetic anhydride
(9.42mL; 0.1mol) was refluxed on boiling water bath for 2 h. The
reaction mixture was allowed to cool and the separated product
was filtered. Crystallization of the crude product from ethyl acetate
then drying, afforded 19 (faint brown powder, 3.08 g (75%) yield,
mp 270°C). IR (cmÀ1): 1647 (C═O). 1H-NMR: δ, ppm (DMSO-d6):
1.92, 2.02 (dd, 2H, CH2 in pyridazinone ring), 2.31 (s, 3H, CH3),
4.16, 4.21 (dd, 1H, CH in pyridazinone ring), 7.67–8.06 (m, 8H,
ArH), 8.14 (s, 1H, CH in imidazole ring).13C-NMR: δ, ppm
(DMSO-d6); 170.5, 162.2 (2C═O), 143.6 (N–C═N in imidazole
moiety), 141.2 (C═N in pyridazinone ring), 134.4, 132.6, 131.2,
130.4, 128.9, 126.4, 124.1, 122.5, 119.6, 117.2 (2 benzene ring
carbons), 68.7 (CH–N), 40.3 (CH2 in pyridazinone), 19.6 (CH3).
Anal. Calcd (%): C19H15BrN4O2. C, 55.49; H, 3.68; N, 13.62.
N, 14.47. Found (%): C, 52.52; H, 3.44; N, 14.11.
Synthesis of 6-(4-bromophenyl)-2-((5-methyl-1,3,4-oxadiazol-
2-yl)methyl)pyridazin-3(2H)-one (23).
A mixture of the
hydrazide 21 (3.23 g; 0.01 mol) and acetyl chloride (2.1 mL;
0.03 mol) in pyridine (30 mL) was refluxed for 3 h. The reaction
mixture was allowed to cool then poured into ice and HCl, and
the separated product was filtered. Crystallization of the crude
product from a suitable solvent then drying, afforded 23 (dark
brown, 2.01 g (58%) yield, mp >360°C). IR (cmÀ1): 1666
(C═O). 1H-NMR: δ, ppm (DMSO-d6): 2.65 (s, 3H, CH3 in
oxadiazole ring), 4.25 (s, 2H, CH2), 6.60 (d, J= 6 Hz, 1H, CH in
pyridazinone moiety), 6.39 (d, 1H, CH in pyridazinone moiety), 7.67–
8.08 (m, 4H, ArH). 13C-NMR: δ, ppm (DMSO-d6); 159.4 (C═O in
pyridazinone ring), 148.7, 145.2 (carbons in oxadiazole ring), 143.5
(C═N in pyridazinone ring), 133.4, 130.2, 128.7, 123.9 (benzene ring
carbons), 130.5, 132.3 (2 CH in pyridazinone ring), 52 (CH2–N) 20.4
(CH3 in oxadiazole ring). Anal. Calcd (%): C14H11BrN4O2. C, 48.43;
Found (%): C, 55.36; H, 3.40; N, 13.43.
Synthesis of ethyl-2-(3-(4-bromophenyl)-6-oxopyridazin-1
(6H)-yl) acetate (20). A mixture of pyridazinone 13a (3.7 g,
0.01 mol) and ethyl chloroacetate (5 mL; 0.03 mol) and
anhydrous potassium carbonate (4.1 g; 0.03 mol) in (50 mL)
acetone were refluxed on water bath for 24 h. The excess
solvent was distilled under reduced pressure. The residue was
treated with water, filtered, washed with water, and crystallized
from ethanol then drying, afforded 20 (colorless needles, 2.62 g
(78%) yield, mp170°C). IR (cmÀ1): 2983 (CH), 1754, and 1670
(2C═O). 1H-NMR: δ, ppm (DMSO-d6): 1.17 (t, J = 6 Hz, 3H,
CH3 of ethyl ester), 4.13 (q, J = 6 Hz, 2H, CH2 of ester), 4.92(s,
2H, N–CH2CO), 6.91, 7.09 (2d, 2H, olefinic protons in
pyridazinone moiety), 7.66–7.81 (dd, 4H, ArH). 13C-NMR: δ,
ppm (DMSO-d6); 167.3 (C═O of ester), 159.7 (C═O in
pyridazinone ring), 143.4 (C═N in pyridazinone ring), 135.2,
131.5, 128.2, 123.3 (benzene ring carbons), 130.3, 132.6 (2 CH
in pyridazinone ring), 61.5 (CH2 of ester), 54.6 (CH2-N), 14.5
(CH3 of ester). Anal. Calcd (%): C14H13BrN2O3. C, 49.87; H,
H, 3.19; N, 16.14. Found (%): C, 48.34; H, 2.95; N, 16.04.
Synthesis of 2-(3-(4-bromophenyl)-6-oxopyridazin-1(6H)-
yl)-N′-(4-nitrobenzylidene) acetohydrazide (24). A mixture
of the hydrazide 21 (4.1 g; 0.01 mol) and 4-nitrobenzaldehyde
(1.51 g; 0.01 mol) and few drops of piperidine in ethanol
(20 mL) were refluxed for 4 h. The reaction mixture was
allowed to cool, and the separated product was filtered.
Crystallization of the crude product from acetic acid then
drying, afforded 24 (yellow powder, 2.87 g (63%) yield, mp
3.89; N, 8.31. Found (%): C, 49.53; H, 3.61; N, 8.07.
Synthesis of 2-(3-(4-bromophenyl)-6-oxopyridazin-1(6H)-yl)
278°C). IR (cmÀ1): 3201 (NH), and 1673 (C═O). H-NMR: δ,
1
acetohydrazide (21).
A mixture of the ester 20 (3.37 g,
ppm (DMSO-d6): 4.33 (s, 2H, CH2), 6.54 (d, J = 6 Hz, 1H, CH
in pyridazinone moiety), 6.42 (d, J = 6 Hz 1H, CH in
pyridazinone moiety), 7.67–7.84 (m, 8H, 2 ArH), 8.8 (d, J=6Hz
1H, CH═N) 8.12 (s, 1H, NH exchangeable with D2O) 13C-NMR:
0.01 mol) and hydrazine hydrate (1.5 mL; 0.03mol) in ethanol
(50 mL) was refluxed for 2 h. The reaction mixture was allowed to
cool and the separated product was filtered. Crystallization of the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. El-Hashasha, A. Y. Solimanb, H. M. Bakeer, F. K. Mohammed, and H. Hassan
Vol 000
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δ, ppm (DMSO-d6); 166.1 (C═O of hydrazide), 159.8 (C═O in
pyridazinone ring), 143.6 (C═N in pyridazinone ring), 142.3 (C═N
in hydrazide) 148.5, 138.7, 135.3, 133.8, 132.5, 130.9, 123.3, 119.2
(2 benzene ring carbons), 130.4, 132.9 (2 CH in pyridazinone ring),
53.3 (CH2–N). Anal. Calcd (%): C19H14BrN5O4. C, 50.02; H, 3.09;
N, 15.35. Found (%): C, 49.82; H, 2.89; N, 15.06.
Synthesis of (E)-ethyl 3-(2-(2-(3-(4-bromophenyl)-6-
oxopyridazin-1(6H)-yl)acetyl)hydrazono)butanoate. (25).
A mixture of the hydrazide 20 (3.23 g; 0.01 mol) and EAA
(1.2 mL; 0.01 mol) and few drops of piperidine in ethanol
(30 mL) were refluxed for 4 h. The reaction mixture was allowed to
cool, and the separated product was filtered. After that the mother
liquor was allowed to evaporate, the formed compound was
separated. It was 25 (white crystals, 0.43 g (10%) yield, mp 160°C).
1
IR (cmÀ1): 3424(NH), 1751and 1666(2C═O). H-NMR: δ, ppm
(DMSO-d6): 1.21 (t, J=6Hz, 3H, CH3 of ester), 1.87 (s, 3H, CH3),
2.29 (s, 2H, CH2 ), 4.15 (q, J= 6 Hz, 2H, CH2 of ester), 4.95 (s, 2H,
N–CH2CO), 7.12, 7.16 (m, 2H, olefinic proton in pyridazinone
moiety), 7.67–8.08 (m, 4H, ArH), 8.46 (s, 1H, NH). 13C-NMR: δ,
ppm (DMSO-d6); 166.3 (C═O of hydrazide), 163.7(C═O of ester),
159.6 (C═O in pyridazinone ring), 143.2 (C═N in pyridazinone
ring), 153.6(C═N in hydrazide), 133.1, 131.2, 128.5, 123.9
(benzene ring carbons), 130.4, 132.2 (2 CH in pyridazinone ring),
60.6 (CH2 of ester), 53.5 (CH2–N), 42.7(C–CH2–CO), 14.3 (CH3
in ester), 12.1 (N═C–CH3). Anal. Calcd (%): C18H19BrN4O4. C,
49.67; H, 4.40; N, 12.87. Found (%): C, 49.33; H, 3.98; N, 12.55.
[16] Youssef, A. S. A.; Marzouk, M. I.; Madkour, H. M. F.; El-Soll,
A. M. A.; Elhashash, M. A. Can J Chem, 2003, 83, 251.
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[19] Nesmeyanov, A. N.; Rybinskaya, M. I.; Rybin, A. I. USP
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[20] Khachikyan, R. D.; Karamyan, N. V.; Panosyan, G. A.; Ind-
zhikyan, M. G. IZV Akad Nauk Ser Khim 2005, 1923.
[21] Abadi, A. H.; Eissa, A. A. H.; Hassan, G. S. Chem Pharm Bull
2003, 51, 838.
[22] Boiani, M.; Cerecetto, H.; Gonalez, M.; Risso, M.; Olea–Azar,
C.; Piro, O. E.; Castellano, E. E.; de Cerain, A. L.; Ezpeleta, O.; A.
Monge-Vega, Eur J Med Chem 2001, 36, 771.
[23] Somani, R. R., Shirodkar, P. Y.; Kadom, V. J. Drug Des
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[24] Jacob, A. M. Thumpakkara, R. K.; Prathapan, S.; Jose, B.
Tetrahedron 2005, 61, 4601.
Acknowledgment. Authors want to express about their deep
thanking to Prof. Klaus Zangger, Institute of Chemistry, Organic/
Bioorganic Chemistry Department, University of Graz, Austria for
1
his cooperation in scanning H-NMR and 13C-NMR for some of
synthesized compounds in his laboratory. Deep thanking also
goes to Ms. Asmaa Salah, Theodor bilharz research institute –
Cairo, Egypt, for her cooperation in antibacterial evaluation for
synthesized compounds.
[25] Piaz, V. D.; Vergelli, C.; Giovannoni, M. P.; Scheideler, M.
A.; Petrane, G.; Zaratin, P. Farmaco 2003, 58, 1063.
[26] Khachikyan, R. D.; Karamyan, N. V.; Panosyan, H. A.;
Injikyana, M. H.; Russ Chem Bull Int Ed 2005, 54(8), 1982.
[27] El-Hashash, M. A.; El-Sayed, G. A.; El-Kady, S. S.;
Mohamed, S. A. Egypt J Chem 2008, 51(1), 103.
[28] EL-Hashash, M. A.; Rizk, S. A.; El-Badry, Y. A. IJBMSP
2012, 2(1), 28.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet