Synthesis, reactions, and antimicrobial activity of 2-cyano-N′-(4-(2-oxo-2-phenylethoxy)benzylidene)acetohydrazide derivatives

Article abstract of DOI:10.1002/jhet.4084

Kn?venagel condensation of the starting 2-cyano-N′-(4-(2-oxo-2-phenylethoxy)-benzylidene)acetohydrazide with different aromatic aldehydes produced the comparable arylidenes derivatives. Else way, 2-cyano-N′-(4-(2-oxo-2-phenylethoxy)-benzylidene)-acetohydr

Full text of DOI:10.1002/jhet.4084

Synthesis, Reactions and Antimicrobial Activity of 2-Cyano-N'-(4-(2-oxo-2-
phenylethoxy)benzylidene)acetohydrazide Derivatives
Nadia Hanafy Metwally,*1 Fathy Mohamed Abdelrazek1, and Salwa Magdy Eldaly1
1Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
*E-mail: nhmmohamed@yahoo.com
ABSTRACT
Knӧvenagel condensation of the starting 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)-
benzylidene)acetohydrazide with different aromatic aldehydes produced the comparable
arylidenes derivatives. Else way, 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)-benzylidene)-
acetohydrazide condensed with o-hydroxybenzaldehydes affording the respective chromenes
which latter underwent acid hydrolysis giving the oxo-chromenes analogues. Moreover, the
reaction of 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)acetohydrazide
yielded the respective indeno[2,1-b]furan derivative that was converted to its oxo-analogue
through acid hydrolysis. The treatment of 2-cyano-N'-(4-(2-oxo-2-
phenylethoxy)benzylidene)acetohydrazide with α-halocompounds produced the relevant
thiazoles. The enamine 2-cyano-3-(dimethylamino)-N'-(4-(2-oxo-2-
with istain
phenylethoxy)benzylidene)acrylohydrazide underwent nucleophilic substitution reaction with
guanidine hydrochloride followed by heterocyclization to get the relative aminopyrimidine.
Contrarily, the reaction with various 4-arylazo-3,5-diaminopyrazoles provided the relative
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pyrazolo[1,5-a]pyrimidines. The antimicrobial investigation was carried out for some of the
newly synthesized compounds using agar well diffusion method.
KEYWORDS: Cyanoacetic hydrazide, Chromenes, Aminopyrazoles, Aminopyrimidines,
Pyrazolo[1,5-a]pyrimidines.
INTRODUCTION
In the last recent ten years, the research programs are aiming to develop new simple
procedures and mechanisms for synthesis of some new heterocyclic ring systems with biological
applications from available raw starting materials. Derivatives of cyanoacetic acid hydrazide are
considered important intermediates and starting materials in the synthesis of many remarkable
heterocyclic ring systems as they are highly reactive and polyfunctional compounds owing to
having both nucleophilic and electrophilic. Additionally, they have received an excellent
attention as pharmaceutical drugs [1,2] and as antibacterial agents [3]. Also, they are applicable
within the industrial field in the production of dyes [4,5] and herbicides [6]. Moreover, a lot of
heterocyclic ring systems were prepared through cyanoacetic acid hydrazide like pyrazoles [7,8],
thiophenes [9-11], thiazoles [12,13], pyrazolopyrimidines [14], pyrimidines [15,16], pyridines
[17-20], and others [21-23].
In the view of these observations and as a part of our ongoing research program aimed to
the synthesis of biologically active heterocycles [24-35], we report herein the synthesis of some
new heterocyclic compounds depending on 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)-
benzylidene)acetohydrazide 2 as a starting compound that underwent reactions with usual
chemical reagents delivering various species of heterocyclic compounds besides that
antimicrobial activity assessment has been performed for some selected compounds as a
biological application.
RESULTS AND DISCSSION
Chemistry. The synthesis of 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)-benzylidene)acetohydrazide
2 was achieved through the reaction of cyanoacetic acid hydrazide with 4-(2-oxo-2-
phenylethoxy)benzaldehyde 1 [which is prepared by the reaction of phenacyl bromide with p-
hydroxybenzaldehyde in refluxing dry acetone in the presence of potassium carbonate (Scheme
1)]. The structural formula of compound 2 was approved through spectroscopic data and
2
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elemental analyses. In IR spectrum of 2, absorption bands appeared at νmax at 3436, 2261, 1712
1
and 1675 cm-1 for the amide, cyano and carbonyl groups, respectively. Its H-NMR spectrum
showed singlet signals at δ = 4.16 and 5.65 ppm attributed to two CH2 protons in additionally a
13
D2O exchangeable signal at δ = 11.65 ppm due to –NH- proton. Also, the C-NMR spectrum
showed characteristic signals at δ = 194.1, 164.5 and 126.6 for two CO and CN groups besides
other expected signals. The mass spectrum of compound 2 showed a peak at m/z = 321 (M+,
13.7%) which is constituent to a molecular formula C18H15N3O3. The elemental analysis was in
agreement with the supposed structure of 2.
Scheme 1. Synthesis of 4-(2-oxo-2-phenylethoxy)benzaldehyde 1 and 2-cyano-N'-(4-(2-oxo-2-
phenylethoxy)-benzylidene)acetohydrazide 2
Knӧvenagel condensation reaction between compound 2 and the aromatic aldehydes 3a-g
gave the corresponding arymethylene derivatives 4a-g. The structural formula of these
arylmethylenes 4a-g was affirmed through the data obtained from the elemental and spectral
analyses (Scheme 2). The IR spectrum of 4a displayed bands at νmax = 3423, 2200 and 1689 cm-1
1
due to the NH, CN and CO groups, respectively. In H-NMR spectrum of 4a, a D2O
exchangeable singlet appeared at δ = 10.45 ppm owing to NH group along with expecting signals
for vinylic and aryl protons. Also, characteristic signals at δ (ppm) = 116.6 (CN), 171.1 (CO) and
185.5 (CO) besides other expected signals appeared in the 13C-NMR spectrum for 4a. The MS of
4a demonstrated peak at m/z = 409 (M+, 2.8%) for the molecular formula C25H19N3O3 besides
other peaks. The IR, 1H-NMR, 13C-NMR and MS data with the elemental analyses supported the
proposed structures 4a-g.
3
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Scheme 2. Synthesis of arylmethylene derivatives 4a-g of 2-cyano-N'-(4-(2-oxo-2-
phenylethoxy)-benzylidene)acetohydrazide 2
Under the same conditions, brown colored products 7a,b were obtained through refluxing
compound 2 with o-hydroxybenzaldehydes 5a,b in a mixture of absolute ethanol and few drops
of piperidine. The imino chromenes 7a,b were prepared through the non- isolable intermediate 6
that in turn underwent in situ heterocyclization to provide the final products (Scheme 3 and see
exp.). The IR spectra of 7 revealed the absence of a band near νmax ~ 2180-2300 cm-1 ascribed to
a CN function instead it showed the appearance of a band near νmax ~ 3400 cm-1 as a result, of the
generation of a new imino group. Also, the IR spectrum of 7a displayed bands at νmax = 3338 and
1658 cm-1 equivalent to the NH and CO functions, consequently. The 1H-NMR spectrum of 7a
showed two D2O exchangeable signals at δ = 9.98 and 12.28 ppm assignable to the NH protons
alongside another singlet signal at δ = 5.56 ppm assigned to CH2 group. In addition to, another
expected signals for aryl protons were appeared. The supposed structure of the novel products
was determined by the spectroscopic and elemental analyses. The acid hydrolysis of imino
chromenes 7a,b in dioxine/hydrochloric acid solution produced the oxo-analogues 8a,b. The
structure of the newly prepared series were approved by ways of physical properties (TLC and
m.p) together with spectroscopic data (1H-NMR, IR and MS).
4
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Scheme 3. Preparation of chromene derivatives 7a,b and oxo-chromene analogues 8a,b
Furthermore, 2-imino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-furo[2,3-b]indole-
3-carbohydrazide 11 was produced from the treatment of compound 2 with isatin under the same
reaction conditions (Scheme 4). The expected mechanism was proceeded through initial
tautomerism step in the intermediate 9 affording the intermediate 10 that in turn underwent in
situ heterocyclization to form the final product 11. Also, the acid hydrolysis of compound 11 in
dioxane/ hydrochloric acid gave the oxo-analogues 12. The suggested structures of compound 11
1
and 12 were confirmed by spectroscopic tools (IR, H-NMR and MS). As example, the IR
spectrum of 11 displayed absorption bands at νmax = 3428 and 1668 cm-1 due to imino (NH) and
carbonyl (CO) functions while the absorption bands for NH and CO functions in compound 12
1
appeared bands at νmax = 3405, 1690 and 1634 cm-1. Also, as compared between the H-NMR
1
spectra of 11 and 12, it had been observed that in H-NMR spectrum of 11, two D2O
exchangeable signals were found at chemical shift (δ) = 10.54 and 11.83 ppm for NH protons,
1
while the H-NMR spectrum of 12 showed a D2O exchangeable signal at δ = 10.74 ppm for of
NH proton. The elemental data is in agreement with the proposed structures 11 and 12.
5
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Scheme 4. 2-imino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-furo[2,3-b]indole-3-carbo-
hydrazide 11 and its oxo-analogous 12
The reaction of 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)-benzylidene)acetohydrazide 2
with phenyl isothiocyanate in a mixture of dry N,N-dimethylformamide and solid potassium
hydroxide at room temperature afforded the non-isolable potassium salt 13 followed by the
addition of ethyl bromoacetate 14a giving thiazole derivative 16a instead of the expected
thiophene 15. The structure of 16a was confirmed through spectroscopic and elemental tools.
The IR spectrum of 16a showed absorption bands at νmax 3425, 2203, 1695 and 1666 cm-1
1
corresponding to the NH, CN and CO functional groups, respectively. Moreover, its H-Nuclear
magnetic resonance spectrum deduced signals at δ = 11.28 and 4.10 ppm relative to NH and CH2
protons of thiazole ring besides signals for aryl protons. In MS spectrum of 16a, a peak was
identified at m/z = 496 (M+, 67.7%) that was found to be consistent with the molecular formula
C27H20N4O4S of the compound 16a (Scheme 5).
6
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Also, under the same conditions of the above reaction, compound 2 reacted with phenacyl
chlorides 14b,c to get the corresponding thiazoles 16b,c rather than expected thiophenes 15. The
IR spectrum of 16c revealed bands at νmax 3426, 2197 and 1688 cm-1 referred to NH, CN and CO
groups, respectively. It`s 1H NMR displayed a D2O exchangeable signal at δ = 11.26 ppm due to
the presence of NH proton and another signal at δ = 5.61 ppm relative to CH2 protons besides
signals for aryl and CH protons. The representative spectroscopic data with elemental analysis
together indicated the formation of thiazole 16 and ruled out the formation of thiophene 15
(Scheme 5 and see exp.).
Scheme 5. Synthesis of thiazoles derivatives 16a-c
7
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Compound 2 reacted with N,N-dimethylformamide/dimethylacetal (DMF/DMA) to
the respective enamine 2-cyano-3-(dimethylamino)-N'-(4-(2-oxo-2-
afford
phenylethoxy)benzylidene) acrylohydrazide 17 (Scheme 6). The IR spectrum of 17 exhibited
absorption bands at νmax 3294, 2184, 1702 and 1658 cm-1 assignable to NH, CN and CO groups,
respectively. Its 1H-NMR spectrum showed two new singlet signals at δ = 3.21 and 3.30 ppm for
two methyl protons of the amino group, additionally, it appeared signals at δ = 5.65 ppm for CH2
protons and multiplet signals at δ = 7.54 – 7.72 ppm for aryl protons besides a D2O exchangeable
singlet signal at δ = 10.76 ppm for amide proton. Additionally, it revealed signals at δ = 7.00 and
8.01 ppm as doublet signal with J = 8.4 and 7.2 Hz, respectively for aryl protons. The reaction of
compound 17 with guanidine hydrochloride gave the corresponding diaminopyrimidine 18. The
structure of compound 18 was established by elemental analysis and spectroscopic data (Scheme
6). The IR spectrum of 18 showed disappearance of absorption band at νmax = 2254 cm-1 for CN
group, instead it showed a broad band at νmax 3442 cm-1 equivalent to NH2 and NH groups. Also,
its 1H-NMR spectrum revealed absence of two singlet signals at δ = 3.21 ppm of the two methyl
protons of dimethylamino function in addition to three D2O exchangeable signals at δ = 10.49,
6.79 and 6.82 ppm respective to NH and two NH2 protons. The suggested reaction mechanism
was assumed to start out with initial displacement of dimethylamine moiety followed by
nucleophilic addition of the NH2 nitrogen atom to the nitrile function then tautomeric conversion
of imino (=NH) group to the amino (NH2) group to develop the target product 18 (Scheme 6 and
see exp.).
8
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Scheme 6
Scheme 6. Synthetic route of 2,4-diamino pyrimidine derivative 18
The reaction of compound 17 with 4-arylazo-3,5-diaminopyrazoles 19a-c afforded the
relative pyrazolo[1,5-a]pyrimidine derivatives 22a-c. The presumed structure for the products
was proved by spectral and elemental data. The IR spectrum of compound 22a, as a typical
example of the prepared series, revealed absence of an absorption band at νmax = 2254 cm-1
relative to a cyano group and appearance of a broad absorption band at νmax = 3400 cm-1 for NH2
and NH groups besides other bands for carbonyl groups at νmax = 1668 and 1658 cm-1. The H1-
NMR spectrum of compound 22a revealed two D2O exchangeable broad signals for amino
protons at δ = 6.35 and 6.77 ppm, besides a D2O exchangeable signal at δ = 10.89 ppm for NH
proton. The suggested structure of the newly obtained products 22a-c was affirmed by their
elemental analysis and physical properties (m.p. and TLC) together with the spectroscopic data.
The suggested mechanism for the synthesis of 22 was proceeded through initial substitution of
NMe2 by a nucleophilic addition achieved by the amino group of the substrate 19 to yield non-
isolable intermediate 20, then followed by intramolecular heterocyclization producing the non-
9
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isolable intermediate 21. Finally, a tautomeric step was occurred giving the final product 22
(Scheme 7 and see exp.).
Scheme 7. Reaction pathway to afford the relative pyrazolo[1,5-a]pyrimidines 22a-c
10
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ANTIMICROBIAL ACTIVITY INVESTIGATION
The antimicrobial activity of some of the newly synthesized products was investigated against
fungal strain (Candida albicans), Gram positive bacterial strain (Staphylococcus aureus) and
Gram negative bacterial strain (Escherichia coli and Klebsiella pneumonia) using nutrient agar
medium diffusion method [36]. Nystatin was used as a standard antifungal drug for Candida
albicans, while Ampicilin and Gentamicin are used as standard antibiotics for Gram positive and
Gram negative bacterial strains. The investigation`s results varied form no antimicrobial activity
for the tested compounds in most of the microbial strains to moderate or even very strong
antimicrobial activity in specific microbial strains while most of the tested compounds showed
no antifungal activity except few of them showed very strong activity (Table 1).
For Antifungal Activity: Most of the tested compounds have no activity against Candida
albicans except compound 4b which showed weak antifungal activity with the mean inhibition
zone = 10.3 ± 0.5 mm while compounds 22c and 4c showed moderate activity with the mean
inhibition zone = 16.3 ± 0.5 mm. The presence of 4-methoxyphenyl moiety in 4b, 4-
chlorophenyl moiety in 4c and 4-phenyl azo pyrazolo[1,5-a]pyrimidine moiety in 22c enhanced
the antifungal activity for these compounds and the presence of electron withdrawing group in 4c
and 22c increased the antifungal activity more than the presence of electron donating group in
4b. In comparison with Nystatin, compounds 18 and 4d showed very strong antifungal activity
relative to that of nystatin with mean inhibition zone = 20.6 ± 0.6 and 20.3 ± 0.5 mm,
respectively while that of nystatin = 21.0 ± 0.5 mm. The presence of aminopyrimidine moiety
and 4-nitrophenyl moiety in compounds 18 and 4d respectively, improved the antifungal activity
against the Candida albicans.
For Antibacterial Activity:
In Staphylococcus aureus: all the tested compounds have no antibacterial activity against that
strain.
In Escherichia coli: compounds 4f and 7b showed moderate activity with mean inhibition zone
= 12.3 ± 0.5 mm hence the standard drug gentamicin showed 27 ± 0.6 mm. The Antibacterial
11
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activity for these compounds may be due to the presence of pipronyl moiety and
hydroxychromene rings in 4f and 7b, respectively.
In Klebsiella pneumonia: the starting compounds 1 and 2 have moderate antibacterial activity
with mean inhibition zone = 14.3 ± 0.5 mm compared with that of gentamicin = 25 ± 0.5 mm.
Introducing indeno[2,1-b]furan and 4-chlorophenylthiazole moieties in compounds 11 and 16c,
respectively quietly decreased the antibacterial activity with mean inhibition zone = 10.3 ± 0.5
and 11.3 ± 0.5 mm, respectively.
Table 1: The antimicrobial results for the tested selected compounds against different strains
Antimicrobial Staphylococcus
Escherichia
coli
Klebsiella
Candida
albican
strains
aureus
pneumonia
St.
Ampicillin
Gentamicin
27 ± 0.6 mm
Gentamicin
25 ± 0.5 mm
Nystatin
Drug
22 ± 0.5 mm
21 ± 0.5 mm
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
14.3 ± 0.5
14.3 ± 0.5
NA
NA
NA
1
2
NA
10.3 ± 0.5
16.3 ± 0.5
20.3 ± 0.5
NA
4b
4c
4d
4f
NA
NA
NA
NA
12.3 ± 0.5
NA
NA
NA
NA
7a
7b
11
12.3 ± 0.5
NA
NA
NA
10.3 ± 0.5
NA
12
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NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
16a
16b
16c
18
11.3 ± 0.5
NA
NA
20.6 ± 0.6
16.3 ± 0.5
NA
22c
EXPERIMENTAL SECTION
I.
General chemistry.
Melting points were determined in (oC) on an electrothermal (9100) apparatus (Kleinfled,
Gehrden, Germany) and are uncorrected. IR spectra were recorded as KBr pellets on a Nicolet
205 spectrophotometer (Nicolet, Madison, WI, USA). The 1H-NMR (300 MHz) spectra and 13C-
NMR spectra (75 MHz) were obtained on a Varian EM-300 MHz spectrometer and DMSO-d6 is
used to dissolve the tested compounds besides, tetramethylsilane as an internal standard sand the
results are obtained as δ value (Varian Inc., Palo Alto, CA, USA). Mass spectra were taken on a
Shimadzu GCMS-GB 1000 PX (Shimadzu, Kyoto, Japan; 70 eV). Elemental analyses and
spectral measurements were carried out by the microanalytic center at Cairo University. The
procedure for the synthesis of cyanoacetic acid hydrazide and 3g were prepared according to
literature [37, 38].
Synthesis of 4-(2-oxo-2-phenylethoxy)benzaldehyde (1).
4-Hydroxybenzaldehyde (10 mmol) was added to phenacyl bromide (10 mmol) and potassium
carbonate (10 mmol) in dry acetone (10 ml). The reaction mixture was heated to refluxing for 12
o
hrs in water bath at 30 C. Yellowish brown solid was formed, filtered off, washed well with
water, dried and recrystallized from ethanol.
13
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o
Yellowish brown crystals, yield (60%), m.p 129-130 C; IR (KBr) ν/cm-1: 2980 (HC=O), 1745
1
(C=O) and 1698 (C=O); H NMR (DMSO-d6); δ = 5.76 (s, 2H, CH2), 7.16 (d, 2H, J = 8.7 Hz,
Ar), 7.56 (d, 2H, J = 7.2 Hz, Ar), 7.68 (d, 2H, J = 7.2 Hz, Ar), 7.85-8.05 (m, 3H, Ar), 9.87 (s,
1H, aldehydic H). 13C NMR (DMSO-d6) δ = 70.3, 115.1 (2C), 127.8 (2C), 128.8 (2C), 129.9
(2C), 131.6 (2C), 133.8, 134.1, 162.9, 191.2, 193.7. Anal. Calcd. for C15H12O3: C, 74.99; H,
5.03. Found: C, 75.16; H, 5.22%.
Synthesis of 2-cyano-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)acetohydrazide (2)
Compound 1 (10 mmol) and cyanoacetic acid hydrazide (10 mmol) was heated in absolute
ethanol (10 ml) for 4 hrs. The product was collected, filtered off and recrystallized from an
ethanol/dioxane.
o
Yellowish brown crystals, yield (96%), m.p 215-217 C; IR (KBr) ν/cm-1: 3436 (NH), 2261
1
(CN), 1712 (C=O) and 1675 (C=O); H NMR (DMSO-d6); δ = 4.16 (s, 2H, CH2), 5.65 (s, 2H,
CH2), 7.01 (d, 2H, J = 8.7 Hz, Ar), 7.55 (d, 2H, J = 7.2 Hz, Ar), 7.61-7.64 (m, 3H, Ar), 7.67 (d,
13
2H, J = 7.5 Hz, Ar), 7.94 (s, 1H, CH), 11.65 (s, 1H, NH); C NMR (DMSO-d6) δ = 66.3, 70.1,
114.9 (2C), 116.1, 126.6, 127.8 (2C), 128.5 (2C), 128.7, 128.8, 133.8, 134.2, 144.1, 159.5, 164.5,
194.1; MS: m/z = 322 (M++1, 2.9%), 321 (M+, 13.7%), 313 (0.1%), 299 (0.1%), 281 (0.1%), 278
(0.1%), 254 (0.7%), 238 (0.8%), 224 (0.35%), 213 (0.23%), 203 (0.26%), 185 (0.27%), 167
(0.2%), 152 (0.4%), 133 (0.68%), 105 (100%), 91 (12.8%), 83 (3.4%), 77 (31.5%). Anal. Calcd.
for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08. Found: C, 67.47; H, 4.89; N, 13.32 %.
Synthesis of compounds 4a-g.
A mixture of compound 2 (10 mmol) and aromatic aldehydes 3a-g (10 mmol) was heated in
ethanol (10 ml) containing drops of piperdine for 4 hrs. The products 4a-g was collected by
filtration and recrystallized from acetic acid.
2-Cyano-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-3-phenylacrylohydrazide (4a)
Yellow crystals, yield (89%), m.p 253-255 oC; IR (KBr) ν/cm-1: 3423 (NH), 2200 (CN) and 1689
1
(C=O); H NMR (DMSO-d6); δ = 5.48 (s, 2H, CH2), 6.91- 8.02 (m, 15H, Ar and CH), 8.45 (s,
1H, CH), 10.45 (s, 1H, NH); MS: m/z = 409 (M+, 2.8%), 395 (0.9%), 393 (1.5%), 367 (2.7%),
353 (1.4%), 342 (2.9%), 321 (8%), 304 (2.6%), 287 (35%), 275 (13%), 258 (3.3%), 239 (4.1%),
14
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230 (10.1%), 207 (4%), 187 (23.2%), 172 (3%), 146 (5.7%), 119 (15.1%), 105 (91%), 91
(99.7%), 77 (100%), 73 (16.7%), 69 (34.6%). Anal. Calcd. for C25H19N3O3 : C, 73.34; H, 4.68;
N, 10.26. Found: C, 73.52; H, 4.85; N, 10.49 %.
2-Cyano-3-(4-methoxyphenyl)-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)acrylohydrazide (4b)
Yellowish brown crystals, yield (76%), m.p 238-240 oC; IR (KBr) ν/cm-1: 3438 (NH), 2180 (CN)
and 1688 (CO); 1H NMR (DMSO-d6); δ = 3.86 (s, 3H, OCH3), 5.42 (s, 2H, CH2), 6.96 - 8.00 (m,
14H, Ar & CH), 8.43 (s, 1H, CH), 10.34 (s, 1H, NH). Anal. Calcd. for C26H21N3O4: C, 71.06; H,
4.82; N, 9.56. Found: C, 71.23; H, 5.01; N, 9.79 %.
3-(4-Chlorophenyl)-2-cyano-N'-(4-(2-oxo-2-phenylethoxy) benzylidene)acrylohydrazide (4c)
Yellowish brown crystals, yield (90%), m.p 260-261 oC; IR (KBr) ν/cm-1: 3423 (NH), 2361 (CN)
and 1696 (CO); 1H NMR (DMSO-d6); δ = 5.61 (s, 2H, CH2), 7.43 – 8.33 (m, 15H, Ar and 2CH),
10.67 (s, 1H, NH); MS: m/z = 444 (M++1, 24.5%), 443 (M+, 39.8%), 431 (12.5%), 429 (19.5%),
411 (10.7%), 402 (6.6%), 394 (6.1%), 376 (15.4%), 350 (6.1%), 344 (35.4%), 336 (12.5%), 321
(28.2%), 320 (97.8%), 303 (20.5%), 280 (3.5%), 263 (7.6%), 242 (3.3%), 224 (6.1%), 124
(6.4%), 88 (22.7%), 76 (100%), 68 (20.5%). Anal. Calcd. for C25H18ClN3O3: C, 67.65; H, 4.09;
Cl, 7.99; N, 9.47. Found: C, 67.81; H, 4.26; N, 9.70 %.
2-Cyano-3-(4-nitrophenyl)-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)acrylohydrazide (4d)
Brown crystals, yield (87%), m.p 266-270 oC; IR (KBr) ν/cm-1: 3423 (NH), 2197 (CN) and 1678
(C=O); 1H NMR (DMSO-d6); δ = 5.34 (s, 2H, CH2), 7.42-8.38 (m, 15H, Ar and 2CH), 10.81 (s,
1H, NH); MS: m/z = 454 (M+, 0.4%), 416 (0.7%), 395 (0.8%), 368 (7.4%), 353 (2.5%), 339
(1.33%), 313 (2.8%), 299 (1.5%), 285 (1.9%), 271 (2.1%), 261 (5.4%), 251 (6.8%), 236 (2.5%),
213 (3.1%), 183 (4.9%), 161 (3.4%), 139 (3.6%), 129 (7.9%), 111 (13.4%), 97 (25.0%), 84
(45.9%), 71 (40.1%), 67 (25.2%), 57 (100%), 55 (81.2%). Anal. Calcd. for C25H18N4O5: C,
66.08; H, 3.99; N, 12.33. Found: C, 66.25; H, 4.18; N, 12.56 %.
2-Cyano-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-3-(thiophen-2-yl)acrylohydrazide (4e)
Brown crystals, yield (96%), m.p 240-242 oC; IR (KBr) ν/cm-1: 3417 (NH), 2223 (CN) and 1670
(C=O); 1H NMR (DMSO-d6); δ = 5.55 (s, 2H, CH2), 7.21-8.40 (m, 14H, Ar and 2CH), 10.73 (s,
15
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1H, NH); MS: m/z = 415 (M+, 18.3%), 410 (9.05%), 399 (16.8%), 388 (14.07%), 381 (10.7%),
373 (26.9%), 360 (23.1%), 337 (7.7%), 321 (10.3%), 308 (11.1%), 303 (11.3%), 292 (100%),
280 (10.7%), 270 (8.9%), 240 (1.8%), 106 (9.9%), 104 (36.4%), 90 (13.1%), 83 (19.5%), 76
(79%). Anal. Calcd. for C23H17N3O3S: C, 66.49; H, 4.12; N, 10.11; S, 7.72. Found: C, 66.67; H,
4.28; N, 10.34; S, 7.90 %.
3-(Benzo[d][1,3]dioxol-5-yl)-2-cyano-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)acrylo-
hydrazide (4f)
Brown crystals, yield (89%), m.p 279-280 oC; IR (KBr) ν/cm-1: 3406 (NH), 2204 (CN) and 1696
1
(C=O); H NMR (DMSO-d6); δ = 5.49 (s, 2H, CH2), 6.27 (s, 2H, CH2), 7.67-8.21 (m, 13H, Ar
and CH), 8.46 (s, 1H, CH), 10.48 (s, 1H, NH). Anal. Calcd. for C26H19N3O5: C, 68.87; H, 4.22;
N, 9.27. Found: C, 69.25; H, 4.39; N, 9.48%.
3-(4-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-2-cyano-N'-(4-(2-oxo-2-phenyl-ethoxy)-
benzylidene)acrylohydrazide (4g)
Yellow crystals, yield (59%), m.p 266-268 oC; IR (KBr) ν/cm-1: 3424 (NH), 2300 (CN) and 1648
(C=O); 1H NMR (DMSO-d6); δ = 5.58 (s, 2H, CH2), 7.33-7.87 (m, 19H, Ar and CH), 8.62 (s, 1H,
CH), 9.28 (s, 1H, CH), 10.52 (s, 1H, NH). Anal. Calcd. for C34H24ClN5O3: C, 69.68; H, 4.13; Cl,
6.05; N, 11.95. Found: C, 69.84; H, 4.31; N, 12.18 %.
Synthesis of compounds 7a,b.
Compound 2 (10 mmol) was reacted with o-hydroybenzaldehyde derivatives 5a,b (10 mmol) in
ethanol (10 ml) containing few drops of piperdine for 4 hrs. The products 7a,b were collected by
filtration, dried and recrystallized from N,N-dimethylformamide.
2-Imino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-chromene-3-carbohydrazide (7a)
o
Brown crystals, yield (67%), m.p 248-250 C; IR (KBr) ν/cm-1: 3338 (NH) and 1658 (C=O); 1H
NMR (DMSO-d6); δ = 5.56 (s, 2H, CH2), 6.95-8.01 (m, 13H, Ar), 8.44 (s, 1H, CH), 8.64 (s, 1H,
CH), 9.98 (s, 1H, NH), 12.28 (s, 1H, NH); MS: m/z = 425 (M+, 16.4%), 421 (24.4%), 410
(17.3%), 395 (9.6%), 393 (10.8%), 369 (10.1%), 358 (41.9%), 355 (15.9%), 342 (10.2%), 341
(26.1%), 328 (21.5%), 313 (21.72%), 303 (46.6%), 287 (10.6%), 246 (7.74%), 104 (47.4%), 83
16
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(46.1%), 76 (100%), 71 (41.6%). Anal. Calcd. for C25H19N3O4: C, 70.58; H, 4.50; N, 9.88.
Found: C, 70.71; H, 4.65; N, 10.12 %.
7-Hydroxy-2-imino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-chromene-3-
carbohydrazide (7b)
o
Brown crystals, yield (75%), m.p > 300 C; IR (KBr) ν/cm-1: 3422 (OH and NH) and 1653
1
(C=O); H NMR (DMSO-d6); δ = 5.27 (s, 2H, CH2), 6.93-8.01 (m, 12H, Ar), 8.41 (s, 1H, CH),
8.62 (s, 1H, CH), 10.48 (s, 1H, NH), 10.56 (s, 1H, OH), 11.78 (s, 1H, NH); MS: m/z = 442
(M++1, 0.25%), 441 (M+, 0.3%), 431 (0.37%), 411 (0.35%), 401 (1.75%), 368 (1.8%), 353
(0.7%), 331 (0.57%), 316 (1.1%), 305 (0.8%), 291 (0.8%), 271 (1.1%), 256 (1.26%), 237
(1.45%), 221 (1.0%), 213 (1.59%), 193 (1.44%), 165 (2.58%), 149 (4.3%), 137 (5.0%), 111
(17.8%), 95 (21.4%), 83 (36.2%), 69 (52.3%), 57 (100%), 55 (66.4%). Anal. Calcd. for
C25H19N3O5: C, 68.02; H, 4.34; N, 9.52. Found: C, 68.18; H, 4.53; N, 9.75 %.
Synthesis of ompounds 8a,b.
Compounds 7a,b (10 mmol) were heated for 3 hrs in a mixture of dioxane (5 ml) and
concentrated hydrochloric acid (5 drops) (1:1). The formed solids were collected, filtrated off,
dried and recrystallized from N,N-dimethylformamide.
2-Oxo-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-chromene-3-carbohydrazide (8a)
o
Brown crystals, yield (56%), m.p 270-275 C; IR (KBr) ν/cm-1: 3277 (NH) 1700 (C=O) and
1
1645 (C=O); H NMR (DMSO-d6); δ = 5.44 (s, 2H, CH2), 7.38-8.47 (m, 14H, Ar and CH), 8.54
(s, 1H, CH), 10.67 (s, 1H, NH); MS: m/z = 426 (M+, 6.33%), 425 (16.47%), 421(24.49%), 409
(17.72%), 393 (10.86%), 369 (10.12%), 358 (41.98%), 341 (26.15%), 328 (21.50%), 313
(21.72%), 303 (46.67%), 287 (10.66%), 246 (7.74%), 104 (47.47%), 83 (46.19%), 76 (100%).
Anal. Calcd. for C25H18N2O5: C, 70.42; H, 4.25; N, 6.57. Found: C, 70.63; H, 4.44; N, 6.79 %.
7-Hydroxy-2-oxo-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-chromene-3-carbohydrazide
(8b)
o
Brown crystals, yield (70%), m.p > 300 C; IR (KBr) ν/cm-1: 3389 (OH and NH), 1679 (C=O)
and 1643 (C=O); 1H NMR (DMSO-d6); δ = 5.56 (s, 2H, CH2), 7.48 – 8.45 (m, 13H, Ar and CH),
17
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9.07 (s, 1H, CH), 10.53 (s, 1H, OH), 10.73 (s, 1H, NH). Anal. Calcd. for C25H18N2O6: C, 67.87;
H, 4.10; N, 6.33. Found: C, 68.04; H, 4.26; N, 6.56 %.
Synthesis
of
2-imino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-furo[2,3-b]indole-3-
carbohydrazide (11)
Compound 2 (10 mmol) was heated with isatin (10 mmol) in absolute ethanol (10 ml) in
presence of few drops of piperidine for 3 hrs. The solid product was collected by filtration and
recrystallized from N,N-dimethylformamide.
o
1
Brown crystals, yield (54%), m.p > 300 C; IR (KBr) ν/cm-1: 3428 (NH) and 1668 (C=O); H
NMR (DMSO-d6); δ = 5.66 (s, 2H, CH2), 7.68-8.42 (m, 13H, Ar and CH), 8.60 (s, 1H, CH),
10.54 (s, 1H, NH), 11.83 (s, 1H, NH). Anal. Calcd. for C26H18N4O4 : C, 69.33; H, 4.03; N, 12.44.
Found: C, 69.48; H, 4.20; N, 12.62 %.
Synthesis of 2-oxo-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-2H-furo[2,3-b]indole-3-carbo-
hydrazide (12) the same procedure for synthesis of (8a,b)
Compounds 7a,b (10 mmol) were heated for 3 hrs in a mixture of dioxane (5 ml) and
concentrated hydrochloric acid (5 drops) (1:1). The formed solids were collected, filtrated off,
dried and recrystallized from N,N-dimethylformamide.
o
Brown crystals, yield (60%), m.p > 300 C; IR (KBr) ν/cm-1: 3405 (NH), 1690 (CO) and 1634
1
(C=O); H NMR (DMSO-d6); δ = 5.41 (s, 2H, CH2), 7.16-7.69 (m, 12H, Ar), 8.48 (s, 1H, CH),
8.52 (s, 1H, CH), 10.74 (s, 1H, NH). Anal. Calcd. for C26H17N3O5: C, 69.18; H, 3.80; N, 9.31.
Found: C, 69.34; H, 3.97; N, 9.54 %.
Synthesis of compounds 16a-c.
Dissolved compound 2 (10 mmol) in N,N'-dimethylformamide (DMF) (10 ml), then add
potassium hydroxide (10 mmol). The mixture was stirred at room temperature till complete
dissolution of potassium hydroxide then phenyl isothiocyanate (10 mmol) was added with
completing the stirring for 3 hrs. The α-haloketones 14a-c (10 mmol) were added with stirring
for overnight. Then, it was quenched into water and acidified with 10% hydrochloric acid and
obtained products 16a-c were collected by filtration and recrystallized from acetic acid.
18
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2-oxo-2-phenylethoxy)benzylidene)-2-(4-oxo-3-phenylthiazolidin-2-ylidene)acetohydrazide
(16a)
o
Brown crystals, yield (89%), m.p 258-260 C; IR (KBr) ν/cm-1: 3425 (NH), 2203 (CN), 1695
(C=O) and 1666 (C=O); 1H NMR (DMSO-d6); δ = 4.10 (s, 2H, CH2), 5.66 (s, 2H, CH2), 7.05 (d,
2H, J = 7.2 Hz, Ar), 7.38 – 7.70 (m, 12H, Ar), 8.62 (s, 1H, CH), 11.28 (s, 1H, NH); MS: m/z =
496 (M+, 67.7%), 416 (59%), 410 (57.9%), 374 (100%), 300 (61.7%), 238 (100%), 236 (83.6%),
203 (96.7%), 198 (60.1%), 173 (97.2%), 121 (70.4%), 61 (100%). Anal. Calcd. for
C27H20N4O4S: C, 65.31; H, 4.06; N, 11.28; S, 6.46. Found: C, 65.49; H, 4.23; N, 11.49; S, 6.64
%.
2-Cyano-2-(3,4-diphenylthiazol-2(3H)-ylidene)-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-
acetohydrazide (16b)
Brown crystals, yield (52%), m.p 276-278 oC; IR (KBr) ν/cm-1: 3418 (NH), 2226 (CN) and 1675
(C=O); 1H NMR (DMSO-d6); δ = 5.67 (s, 2H, CH2), 7.04-8.03 (m, 20H, Ar and CH), 8.50 (s, 1H,
CH), 11.76 (s, 1H, NH). Anal. Calcd. for C33H24N4O3S: C, 71.21; H, 4.35; N, 10.07; S, 5.76.
Found: C, 71.44; H, 4.54; N, 10.31; S, 5.93 %.
2-(4-(4-Chlorophenyl)-3-phenylthiazol-2(3H)-ylidene)-2-cyano-N'-(4-(2-oxo-2-phenylethoxy)-
benzylidene)acetohydrazide (16c)
Yellowish brown crystals, yield (55%), m.p 278-280 oC; IR (KBr) ν/cm-1: 3426 (NH), 2197 (CN)
1
and 1688 (C=O); H NMR (DMSO-d6); δ = 5.61 (s, 2H, CH2), 6.64-8.01 (m, 19H, Ar and CH),
8.58 (s, 1H, CH), 11.26 (s, 1H, NH). Anal. Calcd. for C33H23ClN4O3S: C, 67.06; H, 3.92; Cl,
6.00; N, 9.48; S, 5.42. Found: C, 67.22; H, 4.06; N, 9.70; S, 5.61%.
Synthesis of 2-cyano-3-(dimethylamino)-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)acrylo-
hydrazide (17)
Compound 2 (10 mmol) was reacted with (DMF-DMA) (10 mmol) in dry dioxane (10 ml) for 6
hrs. The product was collected by filtration, dried and recrystallized from an ethanol/dioxane.
o
Brown crystals, yield (86%), m.p 224-226 C; IR (KBr) ν/cm-1: 3294 (NH), 2184 (CN), 1702
(C= O) and 1658 (C=O); 1H NMR (DMSO-d6); δ = 3.21 (s, 3H, CH3), 3.30 (s, 3H, CH3), 5.65 (s,
19
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2H, CH2), 7.00 (d, 2H, J = 8.4 Hz, Ar), 7.54-7.72 (m, 5H, Ar), 7.81 (s, 1H, CH), 8.01 (d, 2H, J =
7.2 Hz, Ar), 8.27 (s, 1H, CH), 10.76 (s, 1H, NH). Anal. Calcd. for C21H20N4O3 : C, 67.01; H,
5.36; N, 14.88. Found: C, 67.24; H, 5.54; N, 15.12 %.
Synthesis
of
2,4-diamino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)pyrimidine-5-carbo-
hydrazide (18)
Compound 17 (10 mmol) was mixed with guanidine hydrochloride (10 mmol) and sodium
carbonate (10 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was heated for 6
hrs. The product was collected by filtration, washed off with water and ethanol and recrystallized
from N,N-dimethylformamide.
Brown crystals, yield (53%), m.p < 300 oC; IR (KBr) ν/cm-1: 3442 (NH2 and NH), 1681 (C=O)
1
and 1642 (C=O); H NMR (DMSO-d6); δ = 5.47 (s, 2H, CH2), 6.79 (broad, 2H, NH2), 6.82
(broad, 2H, NH2), 7.41-8.17 (m, 9H, Ar), 8.46 (s, 1H, CH), 9.23 (s, 1H, CH), 10.49 (s, 1H, NH).
Anal. Calcd. for C20H18N6O3: C, 61.53; H, 4.65; N, 21.53. Found: C, 61.68; H, 4.81; N, 21.77%.
Synthesis of compounds 22a-c.
Compound 17 (10 mmol) was reacted with compounds 22a-c (10 mmol) in N,N-
dimethylformamide (10 ml) containing few drops of piperidine (3 drops), and heated for 6 hrs.
The solid products 17a-c were collected by filletration, washed with ethanol, dried and
recrystallized from N,N-dimethylformamide.
2,7-Diamino-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-3-(phenyldiazenyl)pyrazolo[1,5-a]-
pyrimidine-6-carbohydrazide (22a)
o
Brownish orange crystals, yield (56%), m.p > 300 C; IR (KBr) ν/cm-1: 3400 (NH), 1668 (C=O)
1
and 1658 (C=O); H NMR (DMSO-d6); δ = 5.60 (s, 2H, CH2), 6.35 (broad, 2H, NH2), 6.77
(broad, 2H, NH2), 7.34-8.26 (m, 15H, Ar and CH), 8.54 (s, 1H, CH), 10.89 (s, 1H, NH). Anal.
Calcd. for C28H23N9O3: C, 63.03; H, 4.35; N, 23.63. Found: C, 63.15; H, 4.53; N, 23.87 %.
2,7-Diamino-3-((4-methoxyphenyl)diazenyl)-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-
pyrazolo[1,5-a]pyrimidine-6-carb-hydrazide (22b)
20
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o
Brown crystals, yield (56%), m.p > 300 C; IR (KBr) ν/cm-1: 3412 (NH2 and NH), 1670 (C=O)
1
and 1644 (C=O); H NMR (DMSO-d6); δ = 3.86 (s, 3H, OCH3), 5.68 (s, 2H, CH2), 6.73 (broad,
2H, NH2), 7.24 (broad, 2H, NH2), 7.33-8.18 (m, 13H, Ar), 8.44 (s, 1H, CH), 8.50 (s, 1H, CH),
10.58 (s, 1H, NH). Anal. Calcd. for C29H25N9O4: C, 61.80; H, 4.47; N, 22.37. Found: C, 61.96;
H, 4.64; N, 22.62 %.
2,7-Diamino-3-((2-chlorophenyl)diazenyl)-N'-(4-(2-oxo-2-phenylethoxy)benzylidene)-
pyrazolo[1,5-a]pyrimidine-6-carbohydrazide (22c)
o
Brown crystals, yield (89%), m.p > 300 C; IR (KBr) ν/cm-1: 3396 (NH), 1676 (C=O) and 1638
1
(C=O); H NMR (DMSO-d6); δ = 5.62 (s, 2H, CH2), 6.72 (broad, 2H, NH2), 6.99 (broad, 2H,
NH2), 7.19-8.03 (m, 13H, Ar), 8.16 (s, 1H, CH), 8.35 (s, 1H, CH), 11.05 (s, 1H, NH). Calcd.
Anal. for C28H22ClN9O3: C, 59.21; H, 3.90; Cl, 6.24; N, 22.19. Found: C, 59.39; H, 4.06; N,
22.42%.
Antimicrobial activity investigation:
Agar well diffusion method
The sterilized media were poured into the sterilized petri dishes (20-25 ml, each petri dish) and
allowed to solidify at room temperature. The microbial suspension was prepared in sterilized
saline equivalent to McFarland 0.5 standard solution (1.5 x 105 CFU ml-1) and its turbidity was
adjusted to OD = 0.13 using spectrophotometer at 625 nm. After 15 min, a sterile cotton swab
was dipped into the adjusted suspension and was flooded on the dried agar surface then allowed
to dry for 15 min with lid in place. With a sterile borer, wells of 6 mm diameter were made in the
solidified media. 100 µl of the solution of the tested compound was added to each well with the
o
help of micropipette. The plates were incubated at 37 C for 24 hrs in case of antibacterial
activity and the experiment was carried out three times and the inhibition zones were measured
in mm scale.
Supporting information:
Supplementary file
REFERENCES
21
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[1] Gilman, A. G.; Goodman, L. S. Pharmaceutical Basis of Therapeutics. Macmillan: New
York. 1985, 1109.
[2] Shaker, S. A.; Marzouk, M. I. Molecules, 2016, 21(2), 155.
[3] De Marinis, R. M.; Hoover,J. R. E.; Dunn, G. L.; Actor, P.; Uri, J. V. ; Weisbach, J. A. J.
Antibiot. 1975, 28, 463.
[4] Fahmy, S. M.; Badran, A. H.; Elnagdi, M. H. Chem. Tech. 1980, 30, 390.
[5] Fahmy, S. M.; El-Hosami, M.; Elgamal, S.; Elnagdi, M. H. J. Chem. Technol. Biotechnol.
1982, 32, 1042.
[6] Cosales, M. J.; Kleschick, W. A.; Her, R. J.; Wiemer, M. R. US Patent. 1998, 792, 587;
Chem. Abstr. 1998, 128, 67792k.
[7] Vosrova, L. M.; Grenad`orova, M. V.; Klad`ko, L. G. UK. Khim. Zh. 2004, 70, 115; Chem.
Abstr., 2004, 142, 392328.
[8] Gorolets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O. Tetrahedron 2004, 60, 8633.
[9] Nitsche, C.; Steuer, C.; Klein, C. D.Bioorg. & Med. Chem.. 2011, 19,7318 .
[10] Khalil, M. A.; Sayed, S. M.; Raslan, M. A. Am. J. Org. Chem.. 2012, 2, 161.
[11] Behbehani, H.; Ibrahim, H. M.; Makhseed, S.; Mahmoud, H. Eur. J. Med. Chem.. 2011, 46,
[12] Mohareb, R. M.; Aziz, S. I.; Abdel-Sayed, N. I.; El-Banna, A. H. J. Chem. Res. Synop..
1999, 10.
[13] Fahmy, H. T. Y.; Rostom, S. A. F.; Bekhit, A. A. Arch. Pharm. Med. Chem.. 2002, 5,
213.1813.
[14] Mohareb, R. M.; Sherif, S. M. Sulfur Lett., 1992, 15, 91; Chem. Abstr., 1993, 118, 80892k.
[15] Elgemeie, G. E. H.; El-Ezbawy, S. R.; Ali, H. A. Synth. Commun.. 2001, 31, 3459.
[16] Metwally, N. H.; Abdelrazek, F. M. J. Prakt. Chem. Chem-Ztg., 1998, 340, 676; Chem.
Abstr.. 1999, 130, 13960r.
22
This article is protected by copyright. All rights reserved.

[17] El-gemeie, G. H.; El-Ezbawy, S. R.; Ramiz, M. M.; Mansour, O. A. Org. Prep. Proced. Int.,
1991, 23, 654.
[18] Baliciki, R. Pol. J. Chem., 1984, 58, 85.
[19] Abdelrazek, F. M.; Metwally, N. H. Afindad. 2003, 61, 134.
[20] El-Rady, E. A.; Khalil, M. A. J. Chin. Chem. Soc.. 2004, 51, 799; Chem. Abstr.. 2004, 142,
219224.
[21] Mekheimer, R. A.; Shaker, R. M. J. Chem. Res. Synop., 1999, 76.
[22] Demirbas, N.; Demirbas, A.; Sancak, K. Turk. J. Chem., 2002, 26, 801.
[23] Golovko, T. V.; Solov`eva, N. P.; Anisimova, O. S.; Granik, V. G. Chem.
Heterocycl. Compound., 2003, 39, 344.
[24] Elgemeie, G. E. H.; Mansour, O. A.; Metwally, N. H. Nucleosides and
Nucleotides. 1999, 18, 113-123.
[25] Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mahrouky, S. F. Arch. Pharm Chem Life
Sci.. 2006, 339, 456-460.
[26] Metwally, N. H. Phosphorus, Sulfur, Silicon and Related Elements. 2008, 183, 34-43.
[27] Abdelrazek, F. M.; Metwally, N. H.; Sobhy, N. A. Afinidad. 2008, 63, 522-525.
[28] Mosselhi, M. A.; Abdallah, M. A.; Metwally, N. H.; El-Desoky, I. A.; Break, L. M.
Arkivoc. 2009, xiv, 53-63.
[29] Metwally, N. H.; Abdallah, M. A.; Mosselhi, M. A.; El-Desoky, E. A. Carbohydrate
Research. 2010, 345, 1135–1141.
[30] Metwally, N. H.; Badway, M. A.; Okpy, D. S. Chem Pharm Bull. 2015, 63, 495-503.
[31] Metwally, N. H.; Abdelrazek, F. M.; Eldaly, S. M. Res Chem Intemed., 2016, 42, 1071-
1089.
[32] Metwally, N. H.; Deeb, E. A. Bioorg. Chem., 2018, 77, 203-214.
23
This article is protected by copyright. All rights reserved.

[33] Metwally, N. H.; Abdelrazek, F. M.; Eldaly, S. M. J. Heter. Chem., 2018, 45, 2668-2682.
[34] Metwally, N. H.; Radwan, El-Serwy, W. S.; Mohamed, M. A. Bioorg. Chem. 2019, 84, 456-
467.
[35] Metwally, N. H.; Mohamed, M. S.; Ragab, E. A. Bioorg. Chem., 2019, 88, 102929.
[36] Aspelund, H.; Sjoblom, L. Acta Acad. Aboensis, Math. Phys., 1964, 24(2), 22, (Ger.),
Chem.Abstr., 1966, 64, p. 6634.
[37] Gorolets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. Tetrahedron, 2004, 60, 8633.
[38] Kira, M. A.; Abdel-Rahman, M. O.; Gadalla, K. Z., Tetrahedron Letters, 1969, 10(2), 109-
110.
24
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