2-Aminothiophenes as building blocks in heterocyclic synthesis: Synthesis and antimicrobial evaluation of a new class of pyrido[1,2-a]thieno[3,2-e] pyrimidine, quinoline and pyridin-2-one derivatives

Article abstract of DOI:10.1016/j.ejmech.2012.03.004

Multisubstituted 2-aminothiophenes 1a-c can be readily cyanoacylated via reaction with cyanoacetic acid in presence of acetic anhydride under a microwave irradiation to form the corresponding cyanoacetamides 2a-c, which condensed with DMF-DMA to form the corresponding enamines 4 that reacted with hydrazine hydrate to yield the aminopyrazoles 5. Moreover the cyanoacetamides 2a-c reacted with a variety of arylidenmalononitrile to afford a novel pyrido[1,2-a] thieno[3,2-e]pyrimidine derivatives 12a-o. In addition the enamines 4a,b reacted with malononitrile to afford the pyrido[1,2-a]thieno[3,2-e]pyrimidine derivatives 19a,b. The cyanoacetamides 2a,b reacted also with salicylaldehyde to afford the quinoline derivatives 24a,b. Moreover the cyanoacetamides 2a,b reacted with the enaminones 25a-c to form the corresponding Pyridin-2-one derivatives 29a-c. Reactions of 2a,c with bezenediazonium chloride afford the arylhydrazones 30a,b that reacted with chloroacetonitrile to form the acyclic product 31 which could not be further cyclized to the corresponding 4-aminopyrazole. The X-ray crystallographic analyses of seven products could be obtained thus establishing with certainty the proposed structures in this work. Most of the synthesized compounds in this investigation were tested and evaluated as antimicrobial agents.

Full text of DOI:10.1016/j.ejmech.2012.03.004

European Journal of Medicinal Chemistry 52 (2012) 51e65
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
2-Aminothiophenes as building blocks in heterocyclic synthesis: Synthesis and
antimicrobial evaluation of a new class of pyrido[1,2-a]thieno[3,2-e]pyrimidine,
quinoline and pyridin-2-one derivatives
,
b
a
a
Haider Behbehani a , Hamada Mohamed Ibrahim , Saad Makhseed , Mohamed H. Elnagdi ,
*
Huda Mahmoud c
a Chemistry Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
b Chemistry Department, Faculty of Science, Fayoum University, Fayoum, Egypt
c Biology Department, Faculty of Science, Kuwait University, P.O. Box 5969, Safat 13060, Kuwait
a r t i c l e i n f o
a b s t r a c t
Article history:
Multisubstituted 2-aminothiophenes 1aec can be readily cyanoacylated via reaction with cyanoacetic
acid in presence of acetic anhydride under a microwave irradiation to form the corresponding cya-
noacetamides 2aec, which condensed with DMF-DMA to form the corresponding enamines 4 that
reacted with hydrazine hydrate to yield the aminopyrazoles 5. Moreover the cyanoacetamides 2aec
reacted with a variety of arylidenmalononitrile to afford a novel pyrido[1,2-a]thieno[3,2-e]pyrimidine
derivatives 12aeo. In addition the enamines 4a,b reacted with malononitrile to afford the pyrido[1,2-a]
thieno[3,2-e]pyrimidine derivatives 19a,b. The cyanoacetamides 2a,b reacted also with salicylaldehyde
to afford the quinoline derivatives 24a,b. Moreover the cyanoacetamides 2a,b reacted with the enam-
inones 25aec to form the corresponding Pyridin-2-one derivatives 29aec. Reactions of 2a,c with
bezenediazonium chloride afford the arylhydrazones 30a,b that reacted with chloroacetonitrile to form
the acyclic product 31 which could not be further cyclized to the corresponding 4-aminopyrazole. The
X-ray crystallographic analyses of seven products could be obtained thus establishing with certainty the
proposed structures in this work. Most of the synthesized compounds in this investigation were tested
and evaluated as antimicrobial agents.
Received 6 October 2011
Received in revised form
1 March 2012
Accepted 2 March 2012
Available online 16 March 2012
Keywords:
2-Aminothiophene
Cyanoacetic acid
Cyanoacetamides
Pyridin-2-one
Pyrido[1,2-a]thieno[3,2-e]pyrimidine
Antimicrobial activity
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
2-aminothiophenes are privileged structures, which attracted
considerable attention in the designing of biologically active
Multisubstituted 2-aminothiophenes and thiophene contain-
ing compounds have demonstrated a broad spectrum of uses,
including dyes, agrochemical applications [1] and they are known
to exhibit various biological and pharmaceutical activities such as
potential antioxidant and anti-inflammatory agents [2,3], anti-
HIV PR inhibitors [4], anti-breast cancer [5], anthelmintic
activity against haemonchus contortus [6], anti-avian influenza
virus (H5N1) [7], a multitargeted kinase inhibitor [8], AMPK
activators [9], antitubercular agent [10]. Multisubstituted
molecules [11e15]; the simplest and most convergent preparation
of this class of compounds is the condensation of ketones with an
activated nitriles and elemental sulfur in the presence of a base,
which was first described in 1960s by Gewald and co-workers
[16]. Although a one-pot procedure is well-established, the two-
step procedure in which an
a,b-unsaturated nitrile is first
prepared by Knoevenagel condensation of a ketone or aldehyde
with an activated nitriles [1,17], followed by base-promoted
reaction with sulfur, has generally been found to result in
higher yields (Eq. (1)). In the course of our current biological
chemistry research, the multisubstituted 2-aminothiophenes will
be utilized as building blocks in the synthesis of a new class of
heterocyclic compounds with the evaluation of their biological
activities.
* Corresponding author. Tel.: þ965 990 630 32; fax: þ965 248 164 82.
E-mail address: hidar@bahbahani.com (H. Behbehani).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2012.03.004

52
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
R1
CN
O
CN
base
Eq. 1
R
R1
S
+
+
R
NH2
S
CN
1
2. Results and discussion
In a similar manner, another class of pyrido[1,2-a]thieno[3,2-e]
pyrimidine derivatives 19a,b could be prepared by the reaction of
enaminones 4a,b with malononitrile in refluxing DMF containing
few drops of piperidine via the intermediacy of 15e18 (cf. Scheme 3).
In contrast to the above observed chemistry the cyanoaceta-
mides 2a,b reacted with 2-(4-dimethyl- aminobenzylidene)malo-
nonitrile 20 to afford the arylidene derivatives 21. Which could be
2.1. Synthetic chemistry
The amino group in the multisubstituted 2-aminothiophenes
[16] 1 is feebly basic and can only be reacted with electrophiles
by special technique and condition. Recently Slatt’s [18] cyanoa-
cetamide synthesis could be applied in our laboratories to synthesis
a variety of a novel cyanoacetamides and heterocyclic compounds
[19e22]. It appeared to us of value to investigate the reactivity of
the amino group in the 2-aminothiophenes 1 which can be cya-
noacylated to yield the corresponding cyanoacetamides via the
same methodologies. The possibility of using these cyanoaceta-
mides as precursor to a variety of novel thiophene derivatives and
dyes will be investigated. The investigation aimed at this goal began
with the reactions of 1 with a preheated mixture of acetic anhy-
dride and cyanoacetic acid under microwave irradiation conditions
to yield the corresponding cyanoacetamides 2. The structure of 2a
was established based on X-ray crystallographic analysis (cf. Table 1
and Fig. 1). The cyanoacetamides 2a,b react with dimethylforma-
mide dimethylacetal (DMF-DMA) to yield the corresponding
enamines 4a,b. Although these processes have the potential of
producing mixtures of the enamines stereoisomers 3 and 4. The fact
that only the E-isomer 4 could be formed was confirmed by using
X-ray single crystal (cf. Fig. 2). The enamines 4a,b react with
hydrazine hydrate in refluxing dioxane to yield the corresponding
aminopyrazoles 5a,b (cf. Scheme 1).
The active methylene in the cyanoacetamides 2 underwent
nucleophilic addition reaction to the double bond of a variety of
arylidenmalononitrile 6 via a Michael type addition reaction, by
refluxing in ethanol containing few drops of piperidine where
a substance its structure should be either 7 or one of the two
isomeric forms 12 or 14 was produced. The actual structure of the
product was assigned as pyrido[1,2-a]thieno[3,2-e]pyrimidine
derivatives 12 based on its 1H NMR spectroscopic data which
showed two NH signals and devoid of an amino group signal which
should be appeared if the reaction product was 7 or 14. Moreover 7
was excluded as reaction product since the 1H NMR lacked the
pyran H-4 signal which should appear at approximately
also
obtained
via
condensation
of
2
with
4-
dimethylaminobenzaldehyde in EtOH/piperidine to afford the
arylidene derivatives 21. (cf. Scheme 4, Fig. 5)
Moreover condensation of cyanoacetamides 2a,b with salicy-
laldehyde afforded the quinoline derivatives 24a,b through the
intermediacy of 22 and 23. The structure of the products was
confirmed by X-ray single crystal determination of 24a (cf. Scheme
5, Fig. 6) (Table 2).
The addition of a variety of enaminones 25aec to cyanoaceta-
mide 2a gave intermediate adduct 26, which readily eliminates
dimethylamine group to give 27 that cyclized to 28 before rear-
rangement to the final pyridine derivatives 29aec. The pyridone
structure was confirmed via the 1H-NMR spectra of the product
which showed two NH signals one for the amide NH and the another
one for the pyridone NH. Also the IR and 13C-NMR spectra illustrate
the presence of two CO and only one CN group (cf. Scheme 6).
The cyanoacetamides 2a,c also coupled with the bezenediazo-
nium chloride to yield the aryl hydrazones 30a,b. It was found that
the cyanoacetamides 2a underwent coupling reaction with beze-
nediazonium chloride in pyridine while 2c in EtOH/AcONa to form
the corresponding arylhydrazones 30a,b. The E conformation of the
arylhydrazones was established via the X-ray structure determi-
nation of 30b. In accordance with the literature reports [29,30]
compound 30b react with chloroacetonitriles in triethylamine to
yield the acyclic product 31. Trials to affect the cyclization of 31 into
the corresponding 4-aminopyrazole 32 under variety of conditions
was failed (cf. Scheme 7, Fig. 7) (Table 3).
3. Pharmacology
3.1. Methodology
d
¼ 4e5 ppm. In addition the X-ray crystallographic analysis of this
The antimicrobial activities of 32 different chemical compounds
were tested using Agar-well diffusion technique (Isaacson and
product demonstrated that it has the structure represented by 12
which is believed to be formed, most likely, via the intermediacy of
8e11 through the Dimroth rearrangement and aromatization of the
latter to 12 (cf. Scheme 2, Figs. 3 and 4).
Table 1
Selected bond lengths and bond angles for 2a.
Bond
Bond length(Å)
Bond
Bond angle(ꢀ)
C1eC2
C2eC9
C9eC10
S1eC10
S1eC1
1.359
1.438
1.379
1.716
1.715
1.394
C1eS1eC10
S1eC1eC2
C1eC2eC9
C2eC9eC10
S1eC10eC9
N2eC10eC9
90.77
114.44
110.00
113.04
111.74
124.78
Fig. 1. ORTEP plot of the X-ray crystallographic data determined for 2a. Crystallo-
graphic data have been deposited with the Cambridge crystallographic data Center as
supplementary publication number CCDC 841496 [23].
C10eN2

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
53
Fig. 2. ORTEP plot of the X-ray crystallographic data determined for 4a. Crystallo- graphic data have been deposited with the Cambridge crystallographic data Center as
supplementary publication number CCDC 841636 [24].
Kirchbaum, 1986) against 7 different microbial cultures obtained
from Carolina Biological Supply (USA). Pure cultures of Escherichia
coli (#124300), Pseudomonas aeruginosa (#155250A) and Serratia
marcescens (#155449) (Gram negative bacteria), Bacillus subtilis
(#154921) and Staphylococcus aureus (#155554A) (Gram positive
bacteria) and Candida albicans (#155965) and Saccharomyces cer-
evisiae (#156250) (Yeast) were involved in the test. An aliquot of
0.1 ml of each bacterial strain was inoculated and spread on
nutrient agar while 0.1 ml of the yeast was spread on potato
dextrose agar (PDA). Agar-Well diffusion test was applied where
4 mm wells were produced by sterile cork borer and each well was
inhibition of glycoprotein wall formation in these organisms [34].
Therefore, both penicillin and cycloheximide were utilized in the
current study as reference compounds to compare the strength and
the significance of the antimicrobial activities of the synthesized
chemicals in comparison to established and utilized antimicrobial
compounds .
3.2. Antimicrobial evaluation
The tested chemical compounds in this study showed variation
in their antimicrobial activities, the results depicted in Table 4,
show strong activities against Gram positive and Gram negative
bacteria as well as against yeast. In addition, most of the chemical
compounds in Table 5 showed moderate to week inhibition ability
against most of the tested microorganisms as revealed by the
diameters of their inhibition zones. The tested chemicals 1a, 24a
and 24b displayed strong inhibitory effects on the growth of E. coli
and B. subtilis which showed inhibition zones exceeding 10 mm
compared to the reference chemotherapeutic penicillin. Also
compounds 1a, 4b, 19a and 21a exhibit strong activities against S.
marcescens in comparison with the reference drug. Moreover
compounds 1b, 2c, 5b and 30b revealed interesting high activities
against the Gram positive bacteria B. subtilis with respect to the
used reference drug. It’s worth noticing that compounds 1a, 12l and
24a strongly inhibited the growth of C. albicans when the cyclo-
heximide failed to do. This microbe is known for its ability to cause
diseases, either because it acts as primary pathogen or as an
inoculated with 100 ml of each of the tested chemicals with a final
concentration of 1 mg mlꢁ1. Nutrient agar plates were incubated at
37 ꢀC for 24 h while PDA plates were incubated at 25 ꢀC for 48 h.
The inhibition zones around the wells were measured and the
average based on 3 replicas was recorded. For reference drugs
100 mg mlꢁ1 of penicillin (Sigma) and cycloheximide (Sigma) were
used as antibacterial and antifungal drugs respectively. The meth-
odology shows the rational of using the two reference compounds
i.e. the penicillin and the cycloheximide. The former is an active
antibacterial agent because it works on the peptidoglycan that
found only in the cell wall of bacteria and inhibit the bacterial cell
wall synthesis by preventing the cross linking of peptides between
the N-acetyl muramic acid and N-acetyl glucose amine [32]. On the
other hand, the cycloheximide is an antifungal drug which works
only on the eukaryotic cells and affects the RNA synthesis inhibiting
the protein synthesis in yeasts [33] which subsequently leads to the
R1
CN
O
CN
R1
CN
R1
CN
R
N
S
H
O
Me2N
NCCH2CO2H
DMF-DMA
3
CN
CN
R
NH2
R
N
S
1
AC O,
S
MW
250 W
2
H
R1
CN
2
O
CN
NMe2
R
N
H
S
4
R1
O
R
R
2, 4, 5
NH2
NH
NH2NH2.H2O
R
N
a
b
c
C6H5
H
H
S
H
4-ClC6H4
CH3
N
5
COOEt
Scheme 1. Synthesis of 5-amiopyrazole 5.

54
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
CN
NC
H
Ar
N
R1
O
S
CN
R
NH2
7
R1
CN
R1
CN
NC
CN
Ar
O
EtOH
O
CN
Ar
+
CN
piperidine
R
N
S
R
N
H
S
H
NC
2
6
8
CN
R1
CN
N
R1
CN
NH2
CN
O
CN
Ar
CN
R
S
R
N
S
O
Ar
HN
CN
OH
CN
9
13
aromatization
R
Ar
12
R
R1
CN
NH2
a
b
c
H
C6H5
C6H5
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
C4H3S
C6H5
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
C4H3S
C6H5
R1
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
COOEt
COOEt
CN
Ar
H
H
H
H
H
H
H
H
H
H
N
CN
Ar
R
N
S
d
e
N
R
HN
S
f
O
14
10
CN
g
h
i
HN
O
j
R1
k
l
R1
O
NH
CN
Ar
CN
Ar
H
rearrangement
aromatization
m
CH3
CH3
CH3
N
N
R
R
S
S
n
o
4-MeC6H4
COOEt 4-ClC6H4
HN
HN
CN
CN
12
11
Scheme 2. Synthesis of pyrido[1,2-a]thieno[3,2-e]pyrimidine derivatives 12.
opportunistic pathogen in humans with weak immune system.
Inhibition zones for the Gram positive bacteria S. aureus were
stronger than those recorded for B. subtilis in case of 1a, 24a and
30b. Regarding the structureeactivity relationship of the thio-
phenes against the microorganisms it was found that
transformation of the aminothiophenes 1 into the corresponding
cyanoacetamides 2 generally decrease the inhibitory effects while
transformation of the latter into the corresponding enamines 4
caused slight increase in the biological effect like 4a and not 4b
which have moderate growth inhibitory activities against
Fig. 3. ORTEP plot of the X-ray crystallographic data determined for 12j. Crystallo- graphic data have been deposited with the Cambridge crystallographic data Center as
supplementary publication number CCDC 841890[25].

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
55
moderate antimicrobial activity. Finally the conversion of the cya-
noacetamides 2c to the corresponding arylhydrazone 30b dis-
played a broad spectrum antibacterial profile only against B. subtilis
and S. aureus (Gram positive bacteria).
The results obtained for the synthesized compounds in this
study support the findings of the other researchers who showed
that chemicals with aminothiophenes building blocks and pyrido-
thieno-pyrimidine core have various biological activities. Amino-
thiophenes were proved by many researchers for possessing bio-
logical effects including antimicrobial (bacterial, fungal, protozaol
and viral) activities as well as for having antitumor and anti-
inflammatory activities [35,36]. Where it has been reported that
thiophenes derivatives act as allosteric enhancers of A1-adenosine
receptor [37]. On the other hand, the synthesized chemical
compounds with pyrido-thieno-pyrimidine core may act against
cancer cells by acting as inhibitors for Cdc7 kinase which play
critical roles in regulation of DNA replication in eukaryote cells [38].
Therefore, the new synthesized classes showed promising results
for possessing the potentials to be utilized for medicinal purposes.
Finally it is worth mention that despite the Cycloheximide, is strong
antifungal compound the Candida albicans showed strong resis-
tance to it in our study, which is compatible with the findings by
many researchers [39e42].
Fig. 4. ORTEP plot of the X-ray crystallographic data determined for 12o containing
a DMF molecule. Crystallographic data have been deposited with the Cambridge
crystallographic data Center as supplementary publication number CCDC 847262 [26].
P. aeruginosa (Gram negative bacteria) as revealed by the diameters
of their inhibition zones. In contrast, attachment of a pyrazole to
the thiophene nucleus at position 2 via a carboxamide linker,
exemplified by compounds 5a,b unfortunately leads to a moderate
antimicrobial effect. On other hand fusing the thiophene ring into
the tricyclic system pyrido[1,2-a]thieno[3,2-e]pyrimidine deriva-
tives 12aeo and 19a,b slightly enhance the antimicrobial activity
since the majority of these compounds having moderate growth
inhibitory activities against the tested organisms except
compounds 12c,f,i and 19a,b which displayed a broad spectrum
antibacterial profile only against the Gram negative bacteria Pseu-
domonas aeruginosa, while 12l showed strong activity on both the
Gram negative bacteria P. aeruginosa and the C. albicans (Yeast). It
worth mentioning that the substances 24a,b, possessing a quino-
line ring appended to the C2 position of the thiophene nucleus via
a carboxamide linker showed a high antimicrobial activity against
the Gram negative bacteria (Pseudomonas aeruginosa), Gram posi-
tive bacteria (B. subtilis and S. aureus) and especially against Yeast
(C. albicans and S. cerevisiae). In contrast linking a pyridine ring to
the thiophene nucleus via a carboxamide linker in 29a,b leads to
4. Experimental
4.1. General
Melting points were recorded on a Griffin melting point appa-
ratus and are reported uncorrected. IR spectra were recorded using
KBr disks using a PerkineElmer System 2000 FTeIR spectropho-
tometer. 1H NMR (400 MHz) or (600 MHz) and 13C NMR (100 MHz)
or (150 MHz) spectra were recorded at 25 ꢀC or as reported in CDCl3
or DMSO-d6 as solvent with TMS as internal standard on a Bruker
DPX 400 or 600 super-conducting NMR spectrometer. Chemical
shifts are reported in ppm. Mass spectra were measured using
a high resolution GCeMS (DFS) thermo spectrometers with EI
(70 EV). Microanalyses were performed on a LECO CHNS-932
Elemental Analyzer. Follow up of the reactions and checking
homogeneity of the prepared compounds was made by thin layer
chromatography (TLC). Reactions were conducted under micro-
wave irradiation in heavy-walled Pyrex tubes (capacity 10 mL)
fitted with PCS caps. Microwave heating was carried out with
R1
CN
R1
CN
R1
CN
O
O
O
CN
CN
- NHMe2
R
N
DMF
piperidine
R
N
CN NC
CN
S
S
H
R
N
+
S
H
HN
NC
NC
15
NMe2
NMe2
CN
H
4a,b
16
O
R1
CN
HN
R1
R1
NH
CN
OH
CN
O
rearrangement
CN
CN
CN
N
R
R
N
S
S
N
R
S
HN
HN
CN
R
R
19
a
HN
18
C6H5
4-ClC6H4
H
19
17
H
b
Scheme 3. Reaction of enamines 4a,b with malononitrile.

56
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
R1
CN
R1
CN
NC
CN
O
H
O
CN
EtOH
piperidine
R
N
CN
+
S
H
R
N
S
H
Me
NC
N
20
2a,b
CN
Me
Me
N
Me
NC
CN
R1
CN
Me
Me
O
N
CHO
CN
R
N
S
2
H
piperidine
EtOH/
21
Me
N
R
R
21
Me
a
C6H5
H
H
b
4-ClC6H4
Scheme 4. Reaction of 2a,b with 2-(4-dimethylaminobenzylidene)malononitrile.
a
single mode cavity Explorer Microwave synthesizer (CEM
were added and the reaction mixture was heated for further 30 min
at 100 ꢀC. The reaction mixture was allowed to cool to room
temperature and the formed crystalline solid was separated by
filtration and washed with ethanol in case of 2a,b and with water in
case of 2c.
Corporation, 3100 Smith Farm Road, Matthews, NC, USA). The
crystal structures were determined by a Rigaku R-AXIS RAPID
diffractometer and Bruker X8 Prospector at Kuwait University.
Compounds 1aec were prepared using literature procedures [16].
Also the enaminones 25aec were prepared according to the liter-
ature procedure [43].
4.2.3. 2-Cyano-N-(3-cyano-4-phenylthiophen-2-yl)acetamide (2a)
Recrystallized from EtOH as creamy white crystals, yield: ther-
mally (72%), by microwave (94%), m.p.: 233e234 ꢀC; IR (KBr):
4.2. General procedure for the preparation of cyanoacetamides
2aec
n
d
cmꢁ1 3225 (NH), 2215 (br, 2CN), 1668 (CO); 1H NMR (DMSO-d6):
¼ 4.19 (s, 2H, CH2), 7.33 (s, 1H, thiophene H-5), 7.43 (t, J ¼ 7.6 Hz,
1H, AreH), 7.49 (t, J ¼ 7.6 Hz, 2H, AreH), 7.60 (d, J ¼ 7.6 Hz, 2H,
4.2.1. Method A (mw)
AreH) and 12.12 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
¼ 26.13
A solution of cyanoacetic acid (0.425 g, 5 mmol) in Ac2O (5 mL)
was heated in a microwave oven at a power of 250 W and 85 ꢀC for
10 s then compounds 1a-c (5 mmol) were added and the reaction
mixture was heated for further 20 s at 100 ꢀC. The reaction mixture
was allowed to cool to room temperature and the formed crystal-
line solid was separated by filtration and washed with ethanol in
case of 2a,b and with water in case of 2c.
(CH2), 92.99 (thiophene C-3), 114.57 (CN), 115.32 (CN), 115.94,
127.54, 128.36, 128.86, 133.48, 138.02, 150.41 and 162.11 ppm (AreC
and CO); MS (EI): m/z (%) 267 (Mþ, 46.35), 268 (Mþþ1, 9.75). Anal.
calcd. for C14H9N3OS (267.31): C, 62.91; H, 3.39; N, 15.72; S, 12.00.
Found: C, 62.85; H, 3.36; N, 15.79; S, 11.97.
4.2.4. Crystallographic analysis for 2a
The crystals were mounted on a glass fiber. All measurements
were performed on a Rigaku R-AXIS RAPID diffractometer using
filtered Mo-Ka radiation. The data were collected at a temperature
4.2.2. Method B (thermally)
A solution of cyanoacetic acid (0.425 g, 5 mmol) in Ac2O (10 mL)
was heated at 100 ꢀC for 5 min then compounds 1aec (5 mmol)
Fig. 5. ORTEP plot of the X-ray crystallographic data determined for 21a. Crystallographic data have been deposited in the Cambridge crystallographic data Center as supplementary
publication number CCDC 843132 [27].

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
57
R1
CN
R1
CN
O
CHO
O
CN
OH
OH
EtOH
piperidine
CN
N
H
R
S
+
R
N
S
R
H
2a,b
22
R1
CN
R1
CN
O
O
NH
O
NH
N
rearrangement
S
H
O
N
R
S
1
H
R
R
24
a
C6H5
4-ClC6H4
H
H
b
24
23
Scheme 5. Reaction of cyanoacetamides 2a,b with salicylaldehyde.
of 20 ꢂ 1 ꢀC to a maximum 2
q
value of 55.0ꢀ using the
u
scanning
4.2.7. Ethyl-4-cyano-5-(2-cyanoacetamido)-3-methylthiophene-2-
carboxylate (2c)
technique. The structure was solved by charge flipping method and
expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using the
riding model.
Recrystallized from EtOH as creamy white crystals, yield: ther-
mally (68%), by microwave (89%), m.p.: 209e210 ꢀC; IR (KBr):
n
cmꢁ1 3214 (NH), 2225 (br, 2CN), 1713, 1685 (2CO); 1H NMR
(DMSO-d6):
d
¼ 1.30 (t, 3H, J ¼ 7.2 Hz, CH3CH2), 2.51 (s, 3H, CH3),
4.2.5. Crystal data
4.18 (s, 2H, CH2), 4.27 (q, 2H, J ¼ 7.2 Hz, CH3CH2) and 12.51 ppm (s,
1H, NH); MS (EI): m/z (%) 277 (Mþ, 42.75), 278 (Mþþ1, 8.12). Anal.
calcd. for C12H11N3O3S (277.30): C, 51.98; H, 4.00; N, 15.15; S, 11.56.
Found: C, 52.05; H, 3.98; N, 15.19; S, 11.50.
C14H9N3OS,
M
¼
267.31, monoclinic,
a
¼
9.4297(7) Å,
b ¼ 14.1478(6) Å, c ¼ 9.4854(7) Å, V ¼ 1261.7(2) Å3,
a
¼
g
¼ 90.00ꢀ,
b
¼ 94.402(7)ꢀ, space group: P21/c, Z ¼ 4, Dcalc ¼ 1.407 g cmꢁ3, No.
of reflection measured 2879, 2qmax ¼ 54.9ꢀ, R1 ¼ 0.036. Fig. 1
illustrates the structure as determined. Full data can be obtained
on request from the CCDC [23].
4.3. General procedure for the preparation of enamines 4a,b
Mixtures of 2a,b (5 mmol), N,N-dimethylformamide dimethy-
lacetal (DMF-DMA) (0.6 mL, 5 mmol) in dioxane (20 mL) were
stirred at reflux for 2 h. The separated solid product obtained on
standing at room temperature was collected by filtration, washed
by EtOH and recrystallized from dioxane to afford the corre-
sponding enamines 4a,b.
4.2.6. N-[4-(4-Chlorophenyl)-3-cyanothiophen-2-yl]-2-
cyanoacetamide (2b)
Recrystallized from an EtOH/dioxane (1:1) mixture as white
crystals, yield: thermally (75%), by microwave (90%), m.p.:
226e228 ꢀC; IR (KBr):
1H NMR (DMSO-d6):
5), 7.56 (d, J ¼ 8.0 Hz, 2H, AreH), 7.61 (d, J ¼ 8.0 Hz, 2H, AreH) and
12.16 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
n
cmꢁ1 3231 (NH), 2218 (br, 2CN), 1697 (CO);
d
¼ 4.19 (s, 2H, CH2), 7.39 (s, 1H, thiophene H-
4.3.1. (E)-2-cyano-N-(3-cyano-4-phenylthiophen-2-yl)-3-
dimethylaminoacrylamide (4a)
d
¼ 26.13 (CH2), 92.67
yellowish white crystals, yield: 93%, m.p.: 218e219 ꢀC; IR (KBr):
(thiophene C-3), 114.41 (CN), 115.28 (CN), 116.49, 128.86, 129.30,
132.27, 133.14, 136.59, 150.49 and 162.16 ppm (AreC and CO); MS
(EI): m/z (%) 301 (Mþ, 45.17), 302 (Mþþ1, 8.90). Anal. calcd. for
C14H8ClN3OS (301.76): C, 55.73; H, 2.67; N, 13.93; S, 10.63. Found: C,
55.66; H, 2.74; N, 13.92; S, 10.65.
n
d
cmꢁ1 3364 (NH), 2191 (br, 2CN), 1675 (CO); 1H NMR (DMSO-d6):
¼ 3.28 (s, 3H, CH3), 3.33 (s, 3H, CH3), 7.26 (s, 1H, thiophene H-5),
7.41 (t, J ¼ 7.6 Hz, 1H, AreH), 7.49 (t, J ¼ 7.6 Hz, 2H, AreH), 7.60 (d,
J ¼ 7.6 Hz, 2H, AreH), 7.94 (s. 1H, olefinic CH) and 10.40 ppm (s, 1H,
Fig. 6. ORTEP plot of the X-ray crystallographic data determined for 24a. Crystallographic data have been deposited in the Cambridge crystallographic data Center as supplementary
publication number CCDC 845670 [28].

58
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
Table 2
4.3.4. (E)-N-[4-(4-Chlorophenyl)-3-cyanothiophen-2-yl]-2-cyano-
Selected bond lengths and bond angles for 24a.
3-dimethylaminoacrylamide (4b)
Bond
Bond length(Å)
Bond
Bond angle(ꢀ)
yellowish white crystals, yield: 91%, m.p.: 266e267 ꢀC; IR (KBr):
n
cmꢁ1 3379 (NH), 2205, 2190 (2CN), 1672 (CO); 1H NMR (DMSO-
N3eC15
N3eC14
O2eC14
C13eC14
C13eC21
S1eC10
S1eC9
1.388
1.367
1.273
1.465
1.354
1.708
1.721
1.226
C14eN3eC15
N3eC14eC13
N3eC15eC20
C13eC21eC20
C14eC13eC21
C15eC20eC21
C9eS1eC10
123.0
117.6
119.9
122.2
118.9
118.3
90.9
d6):
d
¼ 3.28 (s, 3H, CH3), 3.33 (s, 3H, CH3), 7.30 (s, 1H, thiophene H-
5), 7.55 (d, J ¼ 7.6 Hz, 2H, AreH), 7.62 (d, J ¼ 7.6 Hz, 2H, AreH), 7.94
(s. 1H, olefinic CH) and 10.46 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
¼ 38.45(CH3), 47.35(CH3), 69.30 (C-2), 93.01 (thiophene C-3),
114.92 (CN), 116.20 (CN), 118.63, 128.91, 129.11, 132.54, 133.00,
136.19,152.02,157.53 and 163.62 ppm (AreC, olefinic C and CO); MS
(EI): m/z (%) 356 (Mþ, 14.20), 357 (Mþþ1, 4.15). Anal. calcd. for
C17H13ClN4OS (356.84): C, 57.22; H, 3.67; N, 15.70; S, 8.99. Found: C,
57.18; H, 3.65; N, 15.76; S, 9.03.
O1eC12
C9eN2eC12
124.7
NH); 13C NMR (DMSO-d6):
d
¼ 38.36(CH3), 47.25(CH3), 69.27 (C-2),
93.20 (thiophene C-3), 114.96 (CN), 115.52 (CN), 118.54, 127.25,
128.11, 128.77, 133.65, 137.49, 151.75, 157.40 and 163.39 ppm (AreC,
olefinic C and CO); MS (EI): m/z (%) 322 (Mþ, 29.00), 323 (Mþþ1,
6.95). Anal. calcd. for C17H14N4OS (322.39): C, 63.34; H, 4.38; N,
17.38; S, 9.95. Found: C, 63.30; H, 4.37; N, 17.35; S, 9.99.
4.4. General procedure for the preparation of 5-amiopyrazole 5a,b
Solutions of the enaminonitrile 4a,b (5 mmol) and hydrazine
hydrate (80%, 0.35 mL) in dioxane (20 mL) were stirred at reflux for
5 h. The reaction mixtures were cooled to room temperature and
poured into ice cold water containing a few drops of hydrochloric
acid (2N). The formed solid products were collected by filtration,
washed with water then ethanol and crystallized from EtOH/
dioxane (2:1) mixture to afford the corresponding 5-amiopyrazole
5a,b.
4.3.2. Crystallographic analysis for 4a
The crystals were mounted on a glass fiber. All measurements
were performed on a Rigaku R-AXIS RAPID diffractometer using
filtered Mo-Ka radiation. The data were collected at a temperature
of 20 ꢂ 1 ꢀC to a maximum 2
q u scanning
value of 55.0ꢀ using the
technique. The structure was solved by charge flipping method and
expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using the
riding model.
4.4.1. 5-Amino-N-(3-cyano-4-phenylthiophen-2-yl)-1H-pyrazole-
4-carboxamide (5a)
yellow crystals, yield: 70%, m.p.: 244e245 ꢀC; IR (KBr): cmꢁ1
n
4.3.3. Crystal data
3465, 3362, 3257, 3198 (NH2 and 2NH), 2215 (CN), 1649 (CO); 1H
NMR (DMSO-d6):
C17H14N4OS, M ¼ 322.39, triclinic, a ¼ 7.451(8) Å, b ¼ 10.282(1)
d
¼ 6.30 (br, 2H, NH2), 7.28 (s, 1H, thiophene H-5),
Å, c ¼ 11.389(1) Å, V ¼ 767.9(2) Å3,
a
¼ 102.987(8)ꢀ,
b
¼ 100.048(7)ꢀ,
7.42 (t, J ¼ 7.2 Hz, 1H, AreH), 7.50 (t, J ¼ 7.2 Hz, 2H, AreH), 7.61 (d,
J ¼ 7.2 Hz, 2H, AreH), 7.94 (s, 1H, pyrazole H-3), 11.03 (s, 1H, NH)
and 11.94 ppm (s, 1H, NH); MS (EI): m/z (%) 309 (Mþ, 14.80), 310
(Mþþ1, 3.95). Anal. calcd. for C15H11N5OS (309.35): C, 58.24; H,
3.58; N, 22.64; S, 10.36. Found: C, 58.18; H, 3.61; N, 22.58; S, 10.40.
g
¼ 110.056(8)ꢀ, space group: P-1, Z ¼ 2, Dcalc ¼ 1.394 g cmꢁ3, No. of
reflection measured 3499, 2qmax ¼ 54.9ꢀ, R1 ¼ 0.041. Fig. 2 illus-
trates the structure as determined. Full data can be obtained on
request from the CCDC [24].
R1
CN
R1
CN
O
H
O
CN
O
R
N
S
O
AcOH
AcONa
CN
H
Ar
NMe2
+
R
N
S
H
Ar
Me2N
2a
25a-c
26
- NHMe2
R1
CN
R1
CN
O
NH
O
CN
R
N
S
OH
R
N
O
H
S
H
Ar
Ar
27
28
R1
CN
R
Ar
29
R
O
O
C6H5
a
b
c
H
C6H5
R
N
NH
S
H
C6H5
C6H5
H
H
S
N
Ar
H C
29
Scheme 6. Reaction of cyanoacetamides 2a with the enaminones 25aec.

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
R1
59
R1
CN
CN
R1
CN
O
O
-
O
+
ClCH2CN
TEA
CN
Ph N N Cl
CN
CN
R
N
R
N
S
R
N
H
S
S
pyridine
or
H
H
N
N
CN
N
NH
Ph
31
EtOH/AcONa
30
2
Ph
R1
CN
O
R
R
30
a
NH2
R
N
H
H
C6H5
CH3
S
N
b
COOEt
CN
N
32
Ph
Scheme 7. Reaction of cyanoacetamides 2 with bezenediazonium chloride.
4.4.2. 5-Amino-N-[4-(4-Chlorophenyl)-3-cyanothiophen-2-yl]-1H-
pyrazole-4-carboxamide (5b)
4.5.1. 9-Imino-4-oxo-3,7-diphenyl-5,9-dihydro-4H-pyrido[1,2-a]
thieno[3,2-e]pyrimidine-6,8-dicarbo- nitrile (12a)
pale yellow crystals, yield: 68%, m.p.: 250e252 ꢀC; IR (KBr):
Recrystallized from an EtOH/DMF (1:3) mixture as pale yellow
crystals, yield: 94%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3445, 3307
(2NH), 2214 (br, 2CN),1651, 1628 (CO and C]N); 1H NMR (DMSO-d6
at 120 ꢀC):
¼ 6.01 (s, 1H, thiophene H-2), 7.54e7.56 (m, 2H, AreH),
7.57e7.60 (m, 8H, AreH), 7.74 (s, 1H, NH) and 8.92 ppm (s, 1H, NH);
13C NMR (DMSO-d6 at 120 ꢀC):
n
cmꢁ1 3465, 3404, 3368, 3325 (NH2 and 2NH), 2218 (CN), 1655
n
(CO); 1H-NMR (DMSO-d6):
d
¼ 6.35 (br, 2H, NH2), 7.33 (s, 1H,
thiophene H-5), 7.56 (d, J ¼ 7.2 Hz, 2H, Are-H), 7.63 (d, J ¼ 7.2 Hz,
2H, AreH), 8.03 (s, 1H, pyrazole H-3), 11.08 (s, 1H, NH) and
12.00 ppm (s, 1H, NH); MS (EI): m/z (%) 343 (Mþ, 13.18), 344 (Mþþ1,
3.20). Anal. calcd. for C15H10ClN5OS (343.80): C, 52.41; H, 2.93; N,
20.37; S, 9.33. Found: C, 52.49; H, 2.98; N, 20.44; S, 9.30.
d
d
¼ 85.35, 86.58, 113.85, 115.12 (CN),
115.15 (CN), 125.78, 127.61, 127.91, 128.50, 128.61, 128.73, 129.55,
133.42, 133.62,134.30,144.81, 150.67, 156.37, 157.15 and 158.81 ppm
(AreC and CO); MS (EI): m/z (%) 419 (Mþ, 100), 420 (Mþþ1, 29.75).
Anal. calcd. for C24H13N5OS (419.47): C, 68.72; H, 3.12; N, 16.70; S,
7.64. Found: C, 68.76; H, 3.09; N, 16.75; S, 7.66.
4.5. General procedure for synthesis of pyrido[1,2-a]thieno[3,2-e]
pyrimidine derivatives 12aeo
4.5.2. 9-Imino-4-oxo-3-phenyl-7-p-tolyl-5,9-dihydro-4H-pyrido
[1,2-a]thieno[3,2-e]pyrimidine-6,8-di- carbonitrile (12b)
Independent mixtures of cyanoacetamides 2a-c (5 mmol) and
the appropriate arylidenmalononitrile 6 (5 mmol) in ethanol
(30 mL) containing few drops of piperidine (5 drops) were stirred at
reflux for 1 h then, the reaction mixtures were cooled to room
temperature. The solid which formed was collected by filtration,
washed with hot ethanol, and recrystallized from the indicated
solvent to afford 12a-o respectively, as pure substances.
Recrystallized from an EtOH/DMF (1:4) mixture as pale yellow
crystals, yield: 91%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3447, 3301
n
(2NH), 2214 (br, 2CN), 1653, 1629 (CO and C]N); 1H NMR (DMSO-
d6 at 120 ꢀC):
¼ 2.45 (s, 3H, CH3), 6.12 (s, 1H, thiophene H-2), 7.40
(d, J ¼ 7.6 Hz, 2H, AreH), 7.49 (d, J ¼ 7.6 Hz, 2H, AreH), 7.54e7.60
d
Fig. 7. ORTEP plot of the x-ray crystallographic data determined for 30b containing one DMF molecule. Crystallographic data have been deposited in the Cambridge crystallographic
data Center as supplementary publication number CCDC 841962 [31].

60
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
Table 3
4.5.5. 7-(4-Chlorophenyl)-9-imino-4-oxo-3-phenyl-5,9-dihydro-
4H-pyrido[1,2-a]thieno[3,2-e]pyramid- ine-6,8-dicarbonitrile (12e)
Selected bond lengths and bond angles for 30b.
Bond
Bond length(Å)
Bond
Bond angle(ꢀ)
Recrystallized from an EtOH/DMF (1:3) mixture as yellow
crystals, yield: 90%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3443, 3304
n
C12eC13
C12eC11
C13eC10
S1eC10
S1eC11
N1eN2
1.423
1.371
1.364
1.715
1.733
1.310
C10eS1eC11
C12eC11eS1
C13eC10eS1
C10eC13eC12
C11eC12eC13
C7eN2eN1
90.4
113.4
112.2
113.8
110.2
122.6
(2NH), 2214 (br, 2CN), 1650, 1628 (CO and C]N); 1H NMR (DMSO-
d6):
¼ 6.28 (s, 1H, thiophene H-2), 7.53e7.61 (m, 5H, AreH), 7.63
(d, J ¼ 7.6 Hz, 2H, AreH), 7.71 (d, J ¼ 7.6 Hz, 2H, AreH), 7.81 (s, 1H,
NH) and 9.45 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
d
¼ 85.22,
86.34, 113.77, 115.05 (CN), 115.18 (CN), 125.94, 128.17, 128.51, 128.61,
128.73, 129.61, 132.97, 133.31, 133.60, 134.72, 144.72, 150.56, 156.31,
157.07 and 157.46 ppm (AreC and CO); MS (EI): m/z (%) 453 (Mþ,
100), 454 (Mþþ1, 33.54). Anal. calcd. for C24H12ClN5OS (453.91): C,
63.51; H, 2.66; N, 15.43; S, 7.06. Found: C, 63.55; H, 2.60; N, 15.44; S,
7.11.
(m, 5H, AreH), 7.73 (s, 1H, NH) and 9.03 ppm (s, 1H, NH); 13C NMR
(DMSO-d6 at 120 ꢀC):
(CN), 115.28 (CN), 125.76, 127.65, 128.49, 128.50, 128.61, 128.75,
131.38, 133.45, 133.62, 139.54, 144.80, 150.69, 156.35, 157.18 and
158.88 ppm (AreC and CO); MS (EI): m/z (%) 433 (Mþ, 100), 434
(Mþþ1, 26.80). Anal. calcd. for C25H15N5OS (433.50): C, 69.27; H,
3.49; N, 16.16; S, 7.40. Found: C, 69.21; H, 3.52; N, 16.20; S, 7.37.
d
¼ 20.30 (CH3), 85.34, 86.57, 113.83, 115.24
4.5.6. 9-Imino-4-oxo-3-phenyl-7-(thiophen-2-yl)-5,9-dihydro-4H-
pyrido[1,2-a]thieno[3,2-e]pyrimidine -6,8-dicarbonitrile (12f)
Recrystallized from an EtOH/DMF (1:2) mixture as pale yellow
crystals, yield: 81%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3474, 3362
n
(2NH), 2213 (br, 2CN), 1651, 1610 (CO and C]N); 1H NMR (DMSO-d6
at 90 ꢀC):
4.5.3. 9-Imino-7-(4-methoxyphenyl)-4-oxo-3-phenyl-5,9-dihydro-
4H-pyrido[1,2-a]thieno[3,2-e]pyrim- idine-6,8-dicarbonitrile (12c)
Recrystallized from an EtOH/DMF (1:2) mixture as yellow
d
¼ 6.22 (s, 1H, H-2), 7.32 (t, J ¼ 5.4 Hz, 1H, thiophene H),
7.52e7.59 (m, 5H, AreH), 7.63 (d, J ¼ 5.4 Hz, 1H, thiophene H), 7.79
(s,1H, NH), 8.00 (d, J ¼ 5.4 Hz,1H, thiophene H) and 9.40 ppm (s,1H,
crystals, yield: 88%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3444, 3301
n
NH); 13C NMR (DMSO-d6 at 90 ꢀC):
d
¼ 85.55, 86.57, 113.99, 115.45
(2NH), 2222, 2210 (2CN), 1648, 1630 (CO and C]N); 1H NMR
(DMSO-d6):
(CN), 115.53 (CN), 126.04, 127.19, 128.70, 128.80, 128.88, 129.99,
130.55, 133.25, 133.51, 133.79, 144.99, 150.87, 151.17, 156.53 and
157.30 ppm (AreC and CO); MS (EI): m/z (%) 425 (Mþ, 100), 426
(Mþþ1, 26.95). Anal. calcd. for C22H11N5OS2 (425.49): C, 62.10; H,
2.61; N, 16.46; S, 15.07. Found: C, 62.03; H, 2.58; N, 16.50; S, 15.11.
d
¼ 3.87 (s, 3H, CH3), 6.17 (s, 1H, thiophene H-2), 7.15 (d,
J ¼ 7.6 Hz, 2H, AreH), 7.52 (d, J ¼ 7.6 Hz, 2H, AreH), 7.55e7.59 (m,
5H, AreH), 7.77 (s, 1H, NH) and 9.36 ppm (s, 1H, NH); 13C NMR
(DMSO-d6):
d
¼ 55.35 (CH3), 85.58, 86.57,113.97,114.02,116.41 (CN),
116.44 (CN), 126.37, 126.47, 129.01, 129.19, 129.28, 130.19, 133.80,
134.03, 145.23, 151.16, 156.66, 157.89, 158.76 and 160.83 ppm (AreC
and CO); MS (EI): m/z (%) 449 (Mþ, 100), 450 (Mþþ1, 30.30). Anal.
calcd. for C25H15N5O2S (449.49): C, 66.80; H, 3.36; N, 15.58; S, 7.13.
Found: C, 66.77; H, 3.41; N, 15.52; S, 7.17.
4.5.7. 3-(4-Chlorophenyl)-9-imino-4-oxo-7-phenyl-5,9-dihydro-
4H-pyrido[1,2-a]thieno[3,2-e]pyramid- ine-6,8–dicarbonitrile (12g)
Recrystallized from DMF as canary yellow crystals, yield: 89%,
m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3442, 3301 (2NH), 2211 (br,
n
2CN), 1657, 1630 (CO and C]N); 1H NMR (DMSO-d6 at 85 ꢀC):
¼ 6.64 (s,1H, thiophene H-2), 7.52e7.62 (m, 9H, AreH), 7.80 (s,1H,
NH) and 9.33 ppm (s, 1H, NH); 13C NMR (DMSO-d6 at 85 ꢀC):
4.5.4. 9-Imino-7-(4-nitrophenyl)-4-oxo-3-phenyl-5,9-dihydro-4H-
pyrido[1,2-a]thieno[3,2-e]pyramid- ine-6,8-dicarbonitrile (12d)
Recrystallized from an EtOH/DMF (1:2) mixture as yellow
d
crystals, yield: 84%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3435, 3302
n
d
¼ 85.35, 86.47, 113.71, 115.33 (CN), 115.36 (CN), 126.42, 127.72,
(2NH), 2214 (br, 2CN), 1658, 1631 (CO and C]N); 1H NMR (DMSO-
d6):
¼ 6.31 (s, 1H, thiophene H-2), 7.54e7.57 (m, 5H, AreH), 7.80
(s, 1H, NH), 7.92 (d, J ¼ 7.6 Hz, 2H, AreH), 8.47 (d, J ¼ 7.6 Hz, 2H,
AreH) and 9.51 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
128.05, 128.67, 129.69, 130.60, 132.19, 132.56, 133.56, 134.36, 145.07,
150.67, 156.32, 157.29 and 158.89 ppm (AreC and CO); MS (EI): m/z
(%) 453 (Mþ, 100), 454 (Mþþ1, 33.05). Anal. calcd. for C24H12ClN5OS
(453.91): C, 63.51; H, 2.66; N,15.43; S, 7.06. Found: C, 63.48; H, 2.70;
N, 15.44; S, 7.00.
d
d
¼ 85.48,
86.41,114.17,115.80 (CN),115.87 (CN),123.89,126.88,129.07,129.22,
129.31, 130.09, 133.66, 134.15, 140.80, 148.54, 150.90, 156.74, 156.95,
157.59 and 157.70 ppm (AreC and CO); MS (EI): m/z (%) 464 (Mþ,
100), 465 (Mþþ1, 31.70). Anal. calcd. for C24H12N6O3S (464.47): C,
62.06; H, 2.60; N, 18.09; S, 6.90. Found: C, 62.10; H, 2.55; N, 18.07; S,
6.94.
4.5.8. 3-(4-Chlorophenyl)-9-imino-4-oxo-7-p-tolyl-5,9-dihydro-
4H-pyrido[1,2-a]thieno[3,2-e]pyramid- ine-6,8–dicarbonitrile (12h)
Recrystallized from an EtOH/DMF (1:3) mixture as yellow
crystals, yield: 85%, m.p.: above 300 ꢀC; IR (KBr):
n
cmꢁ1 3447, 3299
Table 4
Inhibition zone diameter of the tested chemicals that showed strong antimicrobial activities against the tested microorganisms.
Compound no.
Inhibition zone diameter (Nearest mm) Average(ꢂstandard deviation)
E.coli
P . aeruginosa
S. marcescens
B.subtilis
S. aureus
C. albicans
S. cerevisiae
1a
1b
10.6(1.1)
4(0)
10.6(1.1)
5(1.1)
11.3(1.1)
0
14.6(1.1)
11(0)
21(2)
6.6 (1.1)
18(2)
2.6 (1.1)
16(0)
7 (1.1)
4a
4(0)
3.3(1.1)
4(0)
4(0)
4(0)
4(0)
2(0)
8.6(2.3)
8(0)
0
10.8(0)
14(0)
11.3(0)
13.1(1.1)
10.6(1.1)
9(2)
3.3(1.1)
2(0)
0
1.6(0.5)
2(0)
3.3(2.3)
2(0)
2(0)
2(0)
6(2)
11(0)
10.5(0.15)
13(0.2)
0
0
0
0
0
0
4(4)
0
0
0
12(0)
2.6(4)
0
16(0)
e
1.3(1.1)
0
0
0
12c
12f
12i
12 l
19a
19b
24a
24b
30b
4(0)
2.6(1.1)
6.6(1.1)
3.3(1.1)
6(0)
0
1.3(1.1)
0
14(2)
e
8(0)
2.6(2.3)
12(0)
8(0.06)
14 (0.5)
10(3.4)
11(0.5)
6(0)
e
2.6(1.1)
0
0

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
61
Table 5
Inhibition zone diameter of the tested chemicals that showed moderate to week antimicrobial activities against the tested microorganisms.
Chemical name
Inhibition zone diameter (Nearest mm) Average(ꢂstandard deviation)
E.coli
P.aeuroginas
S. marcescens
B.subtilus
S. aureus
C.albicans
S. cerevisiae
2a
2b
2c
4b
5a
5b
12a
12b
12d
12e
12g
12h
12j
12k
12o
21a
4(0)
4(0)
7(0.02)
4(0)
2.6(2.3)
0
6.3(1.1)
2.6(1.1)
4(0)
4.6(1.1)
4(0)
3.3(1.1)
5.3(1.1)
4(0)
8(0.1)
2(0)
4(0)
4(0)
e
2(0)
1.3 (1.1)
e
2(0)
0
0
4(0)
0
0
0
4(2)
6.6(1.1)
2(0)
0
0
0
0
0
2.6(1.1)
3 (1.3)
0
1.3(1.1)
2.6(2)
4(0)
2.6(1.1)
0.7(1.1)
0
1.3(1.1)
4(0)
2(0)
1.3(1.1)
0.7(1)
0
4.6 (1.1)
7(0.02)
1(0)
2(0)
7.3(1.1)
4(0)
2(0)
2(0)
1.6(0.5)
2(0)
2(0)
e
4(0)
6.6(1.1)
3.3(1)
4(0)
6(0)
6.6(1.1)
4.3(2.3)
6(0)
6(0)
6(0)
7(0)
6(0)
4(0)
6(0)
5.3(1.1)
4(2)
4(2)
0
7(1.1)
0.7(1)
2(0)
4.6(1.1)
3.3(1)
4.6(1.1)
3.3(1.1)
4(0)
4(0)
4(2)
2.6(1.1)
4.6(2.3)
7.3(1.1)
2(0)
2(0)
2(0)
0
0
7(1.1)
e
0
0
2(0)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
4(0)
3.3(1.1)
2(0)
2.6(2)
0
0
0
0
0
0
0
0
e
0
0
0
0
21b
29a
29b
29c
2(0)
3.3(1.1)
2(0)
0
0
3.6(0.5)
1.6(0.5)
2(0)
0
0
1.3(1)
2(0)
0
0
e
DMSO (solvent)a
Penicillinb
Cycloheximidec
0
8.6(1.1)
e
30(0)
e
4.6(1.1)
e
40(0)
e
40(0)
ꢁ not tested.
a
DMSO ¼ Dimethyl sulfoxide.
b
c
Antibacterial drug.
Antifungal drug.
(2NH), 2212 (br, 2CN), 1643, 1629 (CO and C]N); 1H NMR (DMSO-
d6 at 110 ꢀC):
d6):
d
¼ 85.36, 86.16, 113.96, 115.86 (CN), 115.92 (CN), 123.90, 127.21,
d
¼ 2.33 (s, 3H, CH3), 6.63 (s, 1H, thiophene H-2), 7.42
129.12, 130.02, 131.05, 132.39, 133.09, 133.75, 140.84, 145.43, 148.53,
150.88, 156.63, 157.00, and 157.69 ppm (AreC and CO); MS (EI): m/z
(%) 498 (Mþ,100), 499 (Mþþ1, 29.15). Anal. calcd. for C24H11ClN6O3S
(498.91): C, 57.78; H, 2.22; N, 16.84; S, 6.43. Found: C, 57.75; H, 2.18;
N, 16.79; S, 6.37.
(d, J ¼ 7.2 Hz, 2H, AreH), 7.49 (d, J ¼ 7.2 Hz, 2H, AreH), 7.54 (d,
J ¼ 7.6 Hz, 2H, AreH), 7.61 (d, J ¼ 7.6 Hz, 2H, AreH), 7.80 (s, 1H, NH)
and 9.30 ppm (s, 1H, NH); 13C NMR (DMSO-d6 at 110 ꢀC):
d
¼ 20.33
(CH3), 85.29, 86.46, 113.67, 115.35 (CN), 115.39 (CN), 126.29, 127.66,
128.53, 128.62, 130.54, 131.41, 132.17, 132.50, 133.55, 139.57, 145.03,
150.58, 156.27, 157.25 and 158.94 ppm (AreC and CO); MS (EI): m/z
(%) 467 (Mþ, 100), 468 (Mþþ1, 32.80). Anal. calcd. for C25H14ClN5OS
(467.94): C, 64.17; H, 3.02; N,14.97; S, 6.85. Found: C, 64.20; H, 2.98;
N, 14.99; S, 6.91.
4.5.11. Crystallographic analysis for 12j
The crystals were mounted on a glass fiber. All measurements
were performed on a Rigaku R-AXIS RAPID diffractometer using
filtered Mo-Ka radiation. The data were collected at a temperature
of 20 ꢂ 1 ꢀC to a maximum 2
q u scanning
value of 55.0ꢀ using the
4.5.9. 9-Imino-7-(4-methoxyphenyl)-4-oxo-3-phenyl-5,9-dihydro-
4H-pyrido[1,2-a]thieno[3,2-e]pyri- midine-6,8-dicarbonitrile (12i)
Recrystallized from an EtOH/DMF (1:2) mixture as pale yellow
technique. The structure was solved by charge flipping method and
expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using the
riding model.
crystals, yield: 89%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3475, 3373
n
(2NH), 2222 (br, 2CN), 1664, 1623 (CO and C]N); 1H NMR (DMSO-
d6):
¼ 3.87 (s, 3H, CH3), 6.58 (s, 1H, thiophene H-2), 7.16 (d,
J ¼ 7.6 Hz, 2H, AreH), 7.52e7.62 (m, 6H, AreH), 7.78 (s, 1H, NH) and
9.27 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
4.5.12. Crystal data
C24H11ClN6O3S,
M
¼
498.91, triclinic,
a
¼
9.8993(7) Å,
d
¼ 55.94 (CH3), 86.26,
b ¼ 15.558(2) Å, c ¼ 17.974(2) Å, V ¼ 2661.2(4) Å3,
a
¼ 91.591(7)ꢀ,
87.38, 114.62, 116.49 (CN), 116.54 (CN), 127.26, 129.61, 130.53, 131.14,
131.53, 132.52, 133.17, 133.49, 134.51, 146.01, 151.67, 157.24, 158.29,
159.59 and 161.52 ppm (AreC and CO); MS (EI): m/z (%) 483 (Mþ,
100), 484 (Mþþ1, 27.00). Anal. calcd. for C25H14ClN5O2S (483.94): C,
62.05; H, 2.92; N, 14.47; S, 6.63. Found: C, 62.03; H, 2.89; N, 14.53; S,
6.60.
b
¼ 102.724(8)ꢀ,
g
¼ 99.035(7)ꢀ, space group: P-1, Z ¼ 2,
Dcalc
¼
1.425 g , No. of reflection measured 11953,
cmꢁ3
2
qmax ¼ 54.9ꢀ, R1 ¼ 0.088. Fig. 3 illustrates the structure as deter-
mined. Full data can be obtained on request from the CCDC [25].
4.5.13. 3,7-Bis(4-chlorophenyl)-9-imino-4-oxo-5,9-dihydro-4H-
pyrido[1,2-a]thieno[3,2-e]pyrimidine-6,8-dicarbonitrile (12k)
Recrystallized from an EtOH/DMF (1:2) mixture as yellow
4.5.10. 3-(4-Chlorophenyl)-9-imino-7-(4-nitrophenyl)-4-oxo-3-
phenyl-5,9-dihydro-4H-pyrido[1,2-a]- thieno[3,2-e]pyrimidine-6,8-
dicarbonitrile (12j)
crystals, yield: 88%, m.p.: above 300 ꢀC; IR (KBr): cmꢁ1 3439, 3301
n
(2NH), 2215 (br, 2CN), 1658, 1631 (CO and C]N); 1H NMR (DMSO-
d6):
¼ 6.74 (s, 1H, thiophene H-2), 7.54 (d, J ¼ 8.0 Hz, 2H, AreH),
7.61e7.64 (m, 4H, AreH), 7.71 (d, J ¼ 8.0 Hz, 2H, AreH), 7.82 (s, 1H,
NH) and 9.38 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
Recrystallized from DMSO as yellow crystals, yield: 86%, m.p.:
d
above 300 ꢀC; IR (KBr): cmꢁ1 3435, 3310 (2NH), 2219 (br, 2CN),
n
1654, 1630 (CO and C]N); 1H NMR (DMSO-d6):
d
¼ 6.78 (s, 1H,
d
¼ 85.56,
thiophene H-2), 7.53 (d, J ¼ 8.0 Hz, 2H, AreH), 7.61 (d, J ¼ 8.0 Hz, 2H,
AreH), 7.83 (s, 1H, NH) 7.89 (d, J ¼ 8.2 Hz, 2H, AreH), 8.46 (d,
J ¼ 8.2 Hz, 2H, AreH), and 9.41 ppm (s, 1H, NH); 13C NMR (DMSO-
86.41, 113.92, 116.16 (CN), 116.19 (CN), 127.15, 128.88, 129.15, 130.33,
131.10, 132.48, 133.08, 133.40, 133.77, 135.30, 145.45, 150.95, 156.61,
157.81 and 157.91 ppm (AreC and CO); MS (EI): m/z (%) 487 (Mþ,

62
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
100), 488 (Mþþ1, 34.70). Anal. calcd. for C24H11Cl2N5OS (488.36): C,
59.03; H, 2.27; N, 14.34; S, 6.57. Found: C, 58.99; H, 2.25; N, 14.40; S,
6.65.
and CO) not done; MS (EI): m/z (%) 463 (Mþ, 100), 464 (Mþþ1,
25.08). Anal. calcd. for C22H14ClN5O3S (463.91): C, 56.96; H, 3.04; N,
15.10; S, 6.91. Found: C, 57.02; H, 3.07; N, 15.14; S, 6.90.
4.5.14. 3-(4-Chlorophenyl)-9-imino-4-oxo-7-(thiophen-2-yl)-5,9-
dihydro-4H-pyrido[1,2-a]thieno[3,2-e]pyrimidine-6,8-dicarbonitrile
(12l)
4.5.18. Crystallographic analysis for 12o
The crystals were mounted on a glass fiber. All measurements
were performed on Bruker X8 Prospector. The data were collected
Recrystallized from an EtOH/DMF (1:2) mixture as pale brown
at a temperature of 20 ꢂ 1 ꢀC to a maximum
q
value of 66.61ꢀ using
crystals, yield: 85%, m.p.: above 300 ꢀC; IR (KBr):
n
cmꢁ1 3444, 3303
the u scanning technique. The structure was solved by direct
(2NH), 2209 (br, 2CN), 1649, 1628 (CO and C]N); 1H NMR (DMSO-
method using SHELXS-97 (Sheldrick, 2008) and refined by Full-
matrix least-squares on F2. The non-hydrogen atoms were refined
anisotropically. Data were corrected for absorption effects using the
multi-scan method (SADABS).
d6 at 90 ꢀC):
d
¼ 6.45 (s, 1H, H-2), 7.32 (t, J ¼ 5.0 Hz, 1H, thiophene
H), 7.63 (d, J ¼ 7.6 Hz, 2H, AreH), 7.59e7.63 (m, 3H, 2AreH and one
thiophene H), 7.78 (s, 1H, NH), 7.95 (d, J ¼ 5.0 Hz, 1H, thiophene H)
and 9.16 ppm (s, 1H, NH); 13C NMR (DMSO-d6 at 90 ꢀC):
d
¼ 85.41,
86.31, 113.73, 115.64 (CN), 115.72 (CN), 126.64, 127.28, 128.78,
130.16, 130.66, 130.69, 132.26, 132.66, 133.22, 133.60, 145.17, 150.80,
151.08, 156.38 and 157.39 ppm (Ar-C and CO); MS (EI): m/z (%) 459
(Mþ, 100), 460 (Mþþ1, 31.60). Anal. calcd. for C22H10ClN5OS2
(459.94): C, 57.45; H, 2.19; N, 15.23; S, 13.94. Found: C, 57.49; H,
2.21; N, 15.17; S, 13.98.
4.5.19. Crystal data
C22H14ClN5O3S, M ¼ 463.91, monoclinic, a ¼ 16.139(9) Å,
b ¼ 7.067(4) Å, c ¼ 26.308(19) Å, V ¼ 2964.8(3) Å3,
a
¼
g
¼ 90.00ꢀ,
b
¼ 98.862(7)ꢀ, space group: P 1 21/n 1, Z ¼ 4, Dcalc ¼ 1.367 g cmꢁ3
,
No. of reflection measured 5415, qmax ¼ 25.34ꢀ, R1 ¼ 0.0599. Fig. 4
illustrates the structure as determined. Full data can be obtained on
request from the CCDC [26].
4.5.15. 6.8-Dicyano-9-imino-3-methyl-4-oxo-7-phenyl-5,9-
dihydro-4H-pyrido[1,2-a]thieno[3,2-e]pyri- midine-2-carboxylic
acid ethyl ester (12m)
4.6. General procedure for synthesis of pyrido[1,2-a]thieno[3,2-e]
pyrimidine derivatives 19a,b
Recrystallized from DMF as yellow crystals, yield: 90%, m.p.:
above 300 ꢀC; IR (KBr):
n
cmꢁ1 3489, 3313 (2NH), 2225 (br, 2CN),
Independent mixtures of the enaminones 4a,b (5 mmol) and the
malononitrile (0.33 g, 5 mmol) in DMF (20 mL) containing few
drops of piperidine (10 drops) were stirred at reflux for 4 h then, the
reaction mixtures were cooled to room temperature. The solid
which formed was collected by filtration, washed with hot ethanol,
and recrystallized from DMF to afford 19a,b respectively.
1718 (CO ester), 1661, 1643 (CO and C]N); 1H NMR (DMSO-d6):
¼ 1.35 (t, 3H, J ¼ 7.2 Hz, CH3CH2), 2.92 (s, 3H, CH3), 4.36 (q, 2H,
J ¼ 7.2 Hz, CH3CH2), 7.58e7.62 (m, 5H, AreH), 8.19 (s, 1H, NH) and
9.55 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
d
¼ 13.99 (CH3), 14.34
(CH3), 61.59 (CH2), 85.64, 86.67, 115.73 (CN), 115.78 (CN), 116.95,
125.16, 128.32, 128.61, 130.49, 134.30, 138.22, 145.57, 151.06, 156.92,
157.70, 159.70, and 161.54 ppm (Ar-C and CO); MS (EI): m/z (%) 429
(Mþ, 100), 430 (Mþþ1, 24.89). Anal. calcd. for C22H15N5O3S
(429.46): C, 61.53; H, 3.52; N, 16.31; S, 7.47. Found: C, 61.59; H, 3.55;
N, 16.37; S, 7.49.
4.6.1. 9-Imino-4-oxo-3-phenyl-5,9-dihydro-4H-pyrido[1,2-a]thieno
[3,2-e]pyrimidine-6,8-dicarbo- nitrile (19a)
yellowish white crystals, yield: 73%, above 300 ꢀC; IR (KBr):
n
cmꢁ1 3433, 3302 (2NH), 2219 (br, 2CN), 1658, 1633 (CO and C]N);
1H NMR (DMSO-d6 at 110 ꢀC):
thiophene H-2), 7.76 (s, 1H, H-7), 7.95 (s, 1H, NH) and 8.56 ppm (s,
1H, NH); 13C NMR (DMSO-d6 at 110 ꢀC):
d
¼ 7.51e7.58 (m, 6H, 5AreH and
4.5.16. 6.8-Dicyano-9-imino-3-methyl-4-oxo-7-p-tolyl-5,9-
dihydro-4H-pyrido[1,2-a]thieno[3,2-e]pyri- midine-2-carboxylic
acid ethyl ester (12n)
d
¼ 83.99, 85.41, 113.85,
115.50 (CN), 115.59 (CN), 125.70, 128.48, 128.57, 128.72, 133.41,
133.56, 144.87, 146.66, 151.12, 156.10 and 157.33 ppm (Ar-C and CO);
MS (EI): m/z (%) 343 (Mþ, 100), 344 (Mþþ1, 24.43). Anal. calcd. for
C18H9N5OS (343.37): C, 62.96; H, 2.64; N, 20.40; S, 9.34. Found: C,
62.93; H, 2.70; N, 20.35; S, 9.33.
Recrystallized from DMF as yellow crystals, yield: 81%, above
300 ꢀC; IR (KBr): cmꢁ1 3433, 3272 (2NH), 2220 (br, 2CN), 1704 (CO
n
ester), 1657, 1639 (CO and C]N); 1H NMR (DMSO-d6):
d
¼ 1.36 (t,
3H, J ¼ 7.2 Hz, CH3CH2), 2.43 (s, 3H, CH3), 2.95 (s, 3H, CH3), 4.37 (q,
2H, J ¼ 7.2 Hz, CH3CH2), 7.41 (d, J ¼ 8.0 Hz, 2H, AreH), 7.47 (d,
J ¼ 8.0 Hz, 2H, AreH), 8.20 (s, 1H, NH) and 9.53 ppm (s, 1H, NH); 13C
4.6.2. 3-(4-Chlorophenyl)-9-imino-4-oxo-5,9-dihydro-4H-pyrido
NMR (DMSO-d6):
d
¼ 13.50 (CH3), 13.87 (CH3), 20.39 (CH3), 60.95
[1,2-a]thieno[3,2-e]pyrimidine-6,8-dicarbonitrile (19b)
(CH2), 85.30, 86.53, 115.17 (CN), 115.19 (CN), 116.78, 125.58, 127.67,
128.57, 131.30, 137.31, 139.72, 145.75, 150.95, 156.99, 157.42, 159.51
and 161.37 ppm (Ar-C and CO); MS (EI): m/z (%) 443 (Mþ, 100), 444
(Mþþ1, 27.80). Anal. calcd. for C23H17N5O3S (433.49): C, 62.29; H,
3.86; N, 15.79; S, 7.23. Found: 62.33; H, 3.90; N, 15.84; S, 7.20.
pale yellow crystals, yield: 75%, above 300 ꢀC; IR (KBr): cmꢁ1
n
3443, 3303 (2NH), 2219 (br, 2CN), 1661, 1634 (CO and C]N); 1H
NMR (DMSO-d6 at 120 ꢀC):
d
¼ 6.66 (s, 1H, thiophene H-2), 7.52 (d,
J ¼ 8.0 Hz, 2H, AreH), 7.61 (d, J ¼ 8.0 Hz, 2H, AreH), 7.78 (s,1H, H-7),
8.57 (s, 1H, NH) and 9.20 ppm (s, 1H, NH); 13C NMR (DMSO-d6 at
120 ꢀC):
d
¼ 84.98, 86.35, 114.75, 116.58 (CN), 116.67 (CN), 120.56,
4.5.17. 7-(4-Chlorophenyl)-6.8-dicyano-9-imino-3-methyl-4-oxo-
5,9-dihydro-4H-pyrido[1,2-a]thieno- [3,2-e]pyrimidine-2-
carboxylic acid ethyl ester (12o)
127.26, 129.61, 131.52, 133.17, 133.45, 134.56, 138.38, 147.79, 157.06
and 158.42 ppm (Ar-C and CO); MS (EI): m/z (%) 377 (Mþ, 100), 378
(Mþþ1, 33.90). Anal. calcd. for C18H8ClN5OS (377.81): C, 57.22; H,
2.13; N, 18.54; S, 8.49. Found: C, 57.18; H, 2.15; N, 18.48; S, 8.55.
Recrystallized from DMF as yellow crystals, yield: 85%, above
300 ꢀC; IR (KBr): cmꢁ1 3490, 3337 (2NH), 2220 (br, 2CN), 1711 (CO
n
ester), 1659, 1640 (CO and C]N); 1H NMR (DMSO-d6):
d
¼ 1.34 (t,
4.7. General procedure for synthesis of the arylidene derivatives
21a,b
3H, J ¼ 7.2 Hz, CH3CH2), 2.84 (s, 3H, CH3), 4.33 (q, 2H, J ¼ 7.2 Hz,
CH3CH2), 7.63 (d, J ¼ 8.0 Hz, 2H, AreH), 7.70 (d, J ¼ 8.0 Hz, 2H,
AreH), 8.21 (s, 1H, NH) and 9.60 ppm (s, 1H, NH); 13C NMR (DMSO-
4.7.1. Method A
d6):
d
¼ 14.04 (CH3), 14.40 (CH3), 61.51 (CH2), 85.56, 86.55, 115.80
A mixture of cyanoacetamides 2a,b (5 mmol) and 2-(4-
dimethylaminobenzylidene)malononitrile 20 (1.0 g, 5 mmol) was
refluxed in EtOH (20 mL) in the presence of piperidine (5 drops) for
(CN), 115.84 (CN), 117.15, 125.42, 128.84, 130.17, 133.21, 135.33,
138.17, 146.00, 151.30, 157.21, 157.88, 158.48 and 161.75 ppm (Ar-C

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
63
1 h. Then, the reaction mixture was allowed to cool to room
temperature, the formed crude product was collected by filtration
washed with water and recrystallized from the proper solvent.
of piperidine (7 drops) for 2 h. Then, the reaction mixture was
allowed to cool to room temperature, the formed crude product
was collected by filtration washed with EtOH and recrystallized
from DMF to afford 24a,b respectively.
4.7.2. Method B
A
mixture of cyanoacetamides 2a,b (5 mmol) and 4-
4.8.1. N-(3-cyano-4-phenylthiophen-2-yl)-2-oxo-1,2-
dimethylaminobenzaldehyde (0.75 g, 5 mmol) in EtOH (20 mL) in
the presence of piperidine (5 drops) were refluxed for 2 h with
continuous stirring. The solid product which formed was collected
by filtration, washed EtOH recrystallized from the proper solvent.
dihydroquinoline-3-carboxamide (24a)
yellow crystals, yield: 80%, m.p.: 258e259 ꢀC; IR (KBr): cmꢁ1
n
3436, 3327 (2NH), 2214 (CN), 1712, 1677 (2CO); 1H NMR (DMSO-
d6):
¼ 7.26 (s, 1H, thiophene H-5), 7.33e7.87 (m, 9H, AreH), 8.68
(s. 1H, quinoline H-4), 10.12 (s, 1H, NH) and 14.60 ppm (s, 1H, NH);
13C NMR (DMSO-d6):
d
4.7.3. (E)-2-cyano-N-(3-cyano-4-phenylthiophen-2-yl)-3-[4-
(dimethylamino)phenyl]acrylamide (21a)
d
¼ 83.55, 105.08, 115.41 (CN), 116.43, 116.73,
125.42, 126.83, 127.18, 127.25, 127.74, 128.58, 128.79, 128.89, 129.85,
135.39, 138.66, 153.42, 154.08 and 166.30 ppm (Ar-C and CO); MS
(EI): m/z (%) 371 (Mþ, 43.56), 372 (Mþþ1, 17.25). Anal. calcd. for
C21H13N3O2S (371.42): C, 67.91; H, 3.53; N, 11.31; S, 8.63. Found: C,
67.87; H, 3.59; N, 11.35; S, 8.57.
Recrystallized from an EtOH/DMF (1:2) mixture as orange
crystals, yield: 85%, m.p.: 278e280 ꢀC; IR (KBr): cmꢁ1 3373 (NH),
n
2212, 2198 (2CN), 1671 (CO); 1H NMR (DMSO-d6 at 90 ꢀC):
d
¼ 3.14
(s, 6H, 2CH3), 6.87 (d, J ¼ 8.6 Hz, 2H, AreH), 7.34 (s, 1H, thiophene
H-5), 7.42 (t, J ¼ 7.8 Hz,1H, AreH), 7.49 (t, J ¼ 7.8 Hz, 2H, AreH), 7.63
(d, J ¼ 7.8 Hz, 2H, AreH), 7.96 (d, J ¼ 8.6 Hz, 2H, AreH), 8.15 (s. 1H,
olefinic CH) and 10.92 ppm (s, 1H, NH); 13C NMR (DMSO-d6 at
4.8.2. Crystallographic analysis for 24a
The crystals were mounted on a glass fiber. All measurements
were performed on a Rigaku R-AXIS RAPID diffractometer using
90 ꢀC):
d
¼ 39.48 (2CH3), 94.80 (C-2), 96.06 (thiophene C-3), 111.86,
114.38 (CN), 116.64 (CN), 117.42, 118.77, 127.37, 128.17, 128.70,
133.46, 133.68, 138.35, 155.65, 152.74, 153.90 and 161.58 ppm (Ar-C,
olefinic C and CO); MS (EI): m/z (%) 398 (Mþ, 20.15), 399 (Mþþ1,
5.09). Anal. calcd. for C23H18N4OS (398.49): C, 69.33; H, 4.55; N,
14.06; S, 8.05. Found: C, 69.27; H, 4.59; N, 14.12; S, 8.01.
filtered Mo-Ka radiation. The data were collected at a temperature
of 20 ꢂ 1 ꢀC to a maximum 2
q u scanning
value of 55.0ꢀ using the
technique. The structure was solved by charge flipping method and
expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using the
riding model.
4.7.4. Crystallographic analysis for 21a
The crystals were mounted on a glass fiber. All measurements
were performed on a Rigaku R-AXIS RAPID diffractometer using
4.8.3. Crystal data
C21H13N3O2S,
M
¼
371.42, triclinic,
a
¼
3.8641(3) Å,
filtered Mo-K
a
radiation. The data were collected at a temperature
b ¼ 12.0951(9) Å, c ¼ 17.999(2) Å, V ¼ 833.0(1) Å3,
a
¼ 86.818(6)ꢀ,
of 20 ꢂ 1 ꢀC to a maximum 2
q
value of 55.0ꢀ using the
u
scanning
b
¼
86.151(6)ꢀ,
g
¼
83.561(6)ꢀ, space group: P-1,
Z
¼
2,
technique. The structure was solved by charge flipping method and
expanded using Fourier techniques. The non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were refined using the
riding model.
Dcalc ¼ 1.481 g cmꢁ3, No. of reflection measured 3701, 2qmax ¼ 55.0ꢀ,
R1 ¼ 0.099. Fig. 6 illustrates the structure as determined. Full data
can be obtained on request from the CCDC [28].
4.8.4. N-[4-(4-Chlorophenyl)-3-cyanothiophen-2-yl]-2-oxo-1,2-
4.7.5. Crystal data
dihydroquinoline-3-carboxamide(24b)
C23H18N4OS,
M
¼
322.39, triclinic,
a
¼
7.4449(4) Å,
yellow crystals, yield: 80%, m.p.: 265e266 ꢀC; IR (KBr): cmꢁ1
n
b ¼ 12.8268(8) Å, c ¼ 20.887(2) Å, V ¼ 1960.4(2) Å3,
a
¼ 85.238(6)ꢀ,
3423, 3329 (2NH), 2217 (CN), 1712, 1678 (2CO); 1H NMR (DMSO-
d6):
b
¼
83.849(6)ꢀ,
g
¼
82.276(6)ꢀ, space group: P-1,
Z
¼
4,
d
¼ 7.31 (s, 1H, thiophene H-5), 7.38e7.42 (m, 2H, AreH), 7.56
Dcalc ¼ 1.35 g cmꢁ3, No. of reflection measured 8891, 2qmax ¼ 54.9ꢀ,
R1 ¼ 0.060. Fig. 5 illustrates the structure as determined. Full data
can be obtained on request from the CCDC [27].
(d, J ¼ 8.0 Hz, 2H, AreH), 7.66e7.72 (m, 3H, AreH), 7.93 (d,
J ¼ 9.2 Hz, 1H, AreH), 8.76 (s. 1H, quinoline H-4), 10.18 (s, 1H, NH)
and 14.74 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
¼ 83.04, 105.54,
115.25 (CN), 115.69, 116.55, 124.68, 125.23, 128.37, 128.44, 128.63,
128.71, 129.77, 130.26, 133.87, 135.20, 136.07, 152.90, 153.24 and
166.27 ppm (Ar-C and CO); MS (EI): m/z (%) 405 (Mþ, 52.66), 406
(Mþþ1, 18.93). Anal. calcd. for C21H12ClN3O2S (405.87): C, 62.15; H,
2.98; N, 10.35; S, 7.90. Found: C, 62.11; H, 2.92; N, 10.41; S, 7.88.
4.7.6. (E)-N-[4-(4-Chlorophenyl)-3-cyanothiophen-2-yl]-2-cyano-
3-[4-(dimethylamino)phenyl]acryl- amide (21b)
Recrystallized from an EtOH/DMF (1:2) mixture as orange crys-
tals, yield: 79%, m.p.: 297e298 ꢀC; IR (KBr): cmꢁ1 3373 (NH), 2210,
n
2195 (2CN), 1673 (CO); 1H NMR (DMSO-d6):
d
¼ 3.11 (s, 6H, 2CH3),
6.87 (d, J ¼ 9.0 Hz, 2H, AreH), 7.40 (s, 1H, thiophene H-5), 7.55 (d,
J ¼ 8.0 Hz, 2H, AreH), 7.65 (d, J ¼ 8.0 Hz, 2H, AreH), 7.96 (d, J ¼ 9.0 Hz,
2H, AreH), 8.15 (s. 1H, olefinic CH) and 11.16 ppm (s, 1H, NH); 13C
4.9. General procedure for the preparation of pyridone 29a-c
Independent solutions of cyanoacetamides 2a (2.67 g, 10 mmol)
and enaminones 4aec (10 mmol) in AcOH (20 mL) containing
anhydrous sodium acetate (1.5 g) were stirred at reflux for 4 h.
Then, the reaction mixtures were cooled to room temperature and
poured onto ice cold water. The crude products were collected by
filtration, washed with water and recrystallized from the appro-
priate solvent to afford the pyridine derivatives 29aec.
NMR (DMSO-d6):
d
¼ 39.09 (2CH3), 94.85 (C-2), 96.93 (thiophene C-
3), 111.46, 116.80 (CN), 117.21 (CN), 118.31, 127.41, 128.40, 128.74,
132.08,132.79,133.11,135.10,136.52,152.46,153.46 and 161.42 ppm
(Ar-C, olefinic C and CO); MS (EI): m/z (%) 432 (Mþ, 20.15), 433
(Mþþ1, 4.09). Anal. calcd. for C23H17ClN4OS (432.94): C, 63.81; H,
3.96; N, 12.94; S, 7.41. Found: C, 63.85; H, 3.94; N, 12.88; S, 7.45.
4.8. General procedure for synthesis of the quinoline derivatives
24a,b
4.9.1. N-(3-cyano-4-phenylthiophen-2-yl)-2-oxo-6-phenyl-1,2-
dihydropyridine-3-carboxamide(29a)
Recrystallized from an EtOH/DMF (1:1) mixture as orange
A mixture of cyanoacetamides 2a,b (5 mmol) and salicylalde-
hyde (0.61 g, 5 mmol) was refluxed in EtOH (25 mL) in the presence
crystals, yield: 70%, m.p.: 289e290 ꢀC; IR (KBr): cmꢁ1 3445, 3331
n
(2NH), 2214 (CN), 1674, 1655 (2CO); 1H NMR (DMSO-d6):
d
¼ 6.97

64
H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
(d, J ¼ 7.8 Hz, 1H, H-5), 7.30 (s, 1H, thiophene H), 7.42 (t, J ¼ 7.8 Hz,
1H, AreH), 7.50 (t, J ¼ 7.8 Hz, 2H, AreH), 7.56e7.59 (m, 3H, AreH),
7.67 (d, J ¼ 7.8 Hz, 2H, AreH), 7.87 (d, J ¼ 7.8 Hz, 2H, Ar-eH), 8.53 (d,
J ¼ 7.8 Hz, 1H, H-4), 12.97 (s, 1H, NH) and 13.90 ppm (s, 1H, NH); 13C
(DMSO-d6):
d
¼ 7.19 (t, J ¼ 7.6 Hz, 1H, AreH), 7.41 (s, 1H, thiophene
H-5), 7.42e7.45 (m, 3H, AreH), 7.51 (t, J ¼ 7.6 Hz, 2H, AreH), 7.63 (d,
J ¼ 7.6 Hz, 2H, AreH), 7.70 (d, J ¼ 7.6 Hz, 2H, AreH),10.98 (s, 1H, NH)
and 12.44 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
¼ 95.96, 105.10,
NMR (DMSO-d6 at 100 ꢀC):
d
¼ 93.26, 106.59, 114.93, 115.88 (CN),
110.80, 114.68, 116.45 (CN), 116.53 (CN), 125.08, 127.29, 128.36,
128.91, 129.26, 133.36, 137.95, 141.74, 150.24 and 159.47 ppm (Ar-C
and CO); MS (EI): m/z (%) 371 (Mþ, 43.98), 372 (Mþþ1, 10.70). Anal.
calcd. for C20H13N5OS (371.42): C, 64.68; H, 3.53; N, 18.86; S, 8.63.
Found: C, 64.74; H, 3.55; N, 18.90; S, 8.69.
116.21, 127.72, 128.08, 128.67, 129.25, 129.46, 131.62, 132.39, 134.12,
138.07, 145.66, 151.68, 152.53, 161.69 and 163.94 ppm (Ar-C and
CO); MS (EI): m/z (%) 397 (Mþ, 22.10), 398 (Mþþ1, 6.98). Anal. calcd.
for C23H15N3O2S (397.46): C, 69.51; H, 3.80; N, 10.57; S, 8.07. Found:
C, 69.48; H, 3.85; N, 10.58; S, 8.13.
4.10.2. (E)-4-cyano-5-[2-cyano-2-(phenylhydrazono)acetylamino]-
4.9.2. N-(3-cyano-4-phenylthiophen-2-yl)-2-oxo-6-(thiophen-
2yl)-1,2-dihydropyridine-3-carboxamide(29b)
3-methylthiophene-2-carboxylic acid ethyl ester (30b)
yellow crystals, yield: 73%, m.p.: 249e250 ꢀC; IR (KBr): cmꢁ1
n
Recrystallized from an EtOH/DMF (1:1) mixture as orange
3367, 3227 (2NH), 2215 (br, 2CN), 1688 (CO); 1H NMR (DMSO-d6):
crystals, yield: 68%, m.p.: 223e225 ꢀC; IR (KBr):
n
cmꢁ1 3421, 3265
d
¼ 1.29 (t, 3H, J ¼ 7.2 Hz, CH3CH2), 2.51 (s, 3H, CH3), 4.26 (q, 2H,
(2NH), 2215 (CN), 1674, 1659 (2CO); 1H NMR (DMSO-d6):
d
¼ 6.92
J ¼ 7.2 Hz, CH3CH2), 7.20 (t, J ¼ 7.6 Hz, 1H, AreH), 7.42 (t, J ¼ 7.6 Hz,
2H, AreH), 7.66 (d, J ¼ 7.6 Hz, 2H, AreH), 11.22 (s, 1H, NH) and
(d, J ¼ 8.4 Hz, 1H, H-5), 7.29 (t, J ¼ 4.8 Hz, 1H, thiophene H), 7.33 (s,
1H, thiophene H), 7.50e7.64 (m, 5H, AreH), 7.94 (d, J ¼ 4.8 Hz, 1H,
thiophene H), 8.09 (d, J ¼ 4.8 Hz, 1H, thiophene H), 8.56 (d,
J ¼ 8.4 Hz, 1H, H-4), 13.24 (s, 1H, NH) and 13.92 ppm (s, 1H, NH); 13C
12.53 ppm (s, 1H, NH); 13C NMR (DMSO-d6):
d
¼ 14.09 (CH3), 14.32
(CH3), 60.91 (CH2), 98.83, 104.67, 110.60, 113.30, 116.59, 117.72,
125.32, 129.29, 141.66, 143.45, 150.80, 159.76 and 161.32 ppm (2 CN,
Ar-C and CO); MS (EI): m/z (%) 381 (Mþ, 27.75), 382 (Mþþ1, 7.90).
Anal. calcd. for C18H15N5O3S (381.42): C, 56.68; H, 3.96; N, 18.36; S,
8.41. Found: C, 56.71; H, 3.92; N, 18.41; S, 8.35.
NMR (DMSO-d6 at 100 ꢀC):
d
¼ 92.97, 105.06, 115.50 (CN), 116.02,
127.20, 128.38, 128.87, 128.92, 129.21, 129.64, 131.05, 133.31, 134.04,
137.41,145.32,150.34,159.24,160.33 and 161.47 ppm (Ar-C and CO);
MS (EI): m/z (%) 403 (Mþ, 50.08), 404 (Mþþ1, 24.50). Anal. calcd. for
C21H13N3O2S2 (403.48): C, 62.51; H, 3.25; N, 10.41; S, 15.89. Found:
C, 62.43; H, 3.32; N, 10.34; S, 15.98.
4.10.3. Crystallographic analysis for 30b
The crystals were mounted on a glass fiber. All measurements
were performed on Bruker X8 Prospector. The data were collected
4.9.3. N-(3-cyano-4-phenylthiophen-2-yl)-6-(6-methylpyridin-
2yl)-2-oxo-1,2-dihydropyridine-3-carbox- amide(29c)
at a temperature of 20 ꢂ 1 ꢀC to a maximum
q
value of 66.61ꢀ using
u scanning technique. The structure was solved by direct
the
Recrystallized from an EtOH/DMF (1:1) mixture as green crystals,
method using SHELXS-97 (Sheldrick, 2008) and refined by Full-
matrix least-squares on F2. The non-hydrogen atoms were refined
anisotropically. Data were corrected for absorption effects using the
multi-scan method (SADABS).
yield: 63%, m.p.: 274e275 ꢀC; IR (KBr): cmꢁ1 3429, 3287 (2NH),
n
2214 (CN), 1677, 1663 (2CO); 1H NMR (DMSO-d6):
d
¼ 2.61 (s, 3H,
CH3), 7.26 (s,1H, thiophene H), 7.37 (d, J ¼ 7.2 Hz,1H, H-5), 7.40e7.44
(m, 2H, AreH), 7.48 (t, J ¼ 7.8 Hz, 2H, AreH), 7.64 (d, J ¼ 7.8 Hz, 2H,
AreH), 7.89 (t, J ¼ 7.8 Hz, 1H, AreH), 8.01 (d, J ¼ 7.8 Hz, 1H, AreH),
8.58 (d, J ¼ 7.2 Hz, 1H, H-4), 12.46 (s, 1H, NH) and 13.91 ppm (s,
4.10.4. Crystal data
C18H15N5O3S,
M
¼
381.42, monoclinic,
a
V
¼
8.0336(4) Å,
2312.6(2) Å3,
1H, NH); 13C NMR (DMSO-d6 at 90 ꢀC):
d
¼ 23.38 (CH3), 92.66,104.90,
b
a
¼
14.2787(7) Å,
c
¼
20.2833(10) Å,
¼
113.99, 115.15 (CN), 117.41, 118.83, 125.18, 126.86, 127.85, 128.40,
133.22, 137.31, 137.75, 145.22, 145.99, 147.53, 150.59, 158.34, 160.56
and 161.96 ppm (Ar-C and CO); MS (EI): m/z (%) 412 (Mþ, 27.85), 413
(Mþþ1, 8.25). Anal. calcd. for C23H16N4O2S (412.47): C, 66.98; H,
3.91; N, 13.58; S, 7.77. Found: C, 66.96; H, 3.87; N, 13.64; S, 7.69.
¼
g
¼ 90.00ꢀ,
b
¼ 96.305(3)ꢀ, space group: P 1 21/n 1, Z ¼ 4,
Dcalc ¼ 1.305 g cmꢁ3, No. of reflection measured 3987, qmax ¼ 66.61ꢀ,
R1 ¼ 0.06. Fig. 7 illustrates the structure as determined. Full data
can be obtained on request from the CCDC [31].
4.10. General procedure for the preparation of 30a,b
4.11. 4-Cyano-5-[2-cyano-2-(cyanomethylphenylhydrazono)
acetylamino]-3-methylthiophene-2-carbo- xylic acid ethyl ester
(31)
A cold solution of benzenediazonium chloride (10 mmol) was
prepared by adding a solution of sodium nitrite (1.4 g dissolved in
10 mL water) to cold solution of aniline hydrochloride (0.93 g of
aniline in 10 mL, 6M HCl) with stirring. The resulting solution of
benzenediazonium chloride was then added to a cold solution of
cyanoacetamide 2a (2.67 g, 10 mmol) in pyridine or to a solution of
the cyanoacetamide 2c (2.77 g, 10 mmol) in ethanol (50 mL) in the
presence of sodium acetate trihydrate (4.2 g, 30 mmol). The reaction
mixture was stirred at room temperature for 1 h. In case of 30a the
mixture was poured into ice cold water and neutralized with HCl, the
formed solid product was collected by filtration and washed with
water then EtOH. While in case of 30b the product was collected
directly from the reaction mixture by filtration and washed with
water then EtOH. Finally the obtained products were recrystallized
from an EtOH/DMF (1:2) mixture to afford 30a,b respectively.
To a solution of 30b (1.9 g, 5 mmol) in a mixture of DMF (2 ml)
and triethylamine (15 ml) was added the chloroacetonitrile
(0.45g, 6 mmol) with external cooling. The reaction mixture was
refluxed for 4 h and left to cool to room temperature. The
obtained residual product was triturated with ethanol to give
a solid product that was collected by filtration, washed with
water and recrystallized from ethanol giving yellow, yield: 78%,
m.p.: 188e189 ꢀC; IR (KBr):
n
cmꢁ1 3446 (NH), 2208 (br, 3CN),
¼ 1.28 (t, 3H, J ¼ 7.2 Hz,
1678 (CO); 1H NMR (DMSO-d6):
d
CH3CH2), 2.51 (s, 3H, CH3), 4.21 (q, 2H, J ¼ 7.2 Hz, CH3CH2), 4.85 (s,
2H, CH2), 7.07 (t, J ¼ 7.6 Hz, 1H, AreH), 7.37 (t, J ¼ 7.6 Hz, 2H,
AreH), 7.45 (d, J ¼ 7.6 Hz, 2H, AreH) and 15.32 ppm (s, 1H, NH);
13C NMR (DMSO-d6):
d
¼ 14.33 (CH3), 14.56 (CH3), 45.57(CH2),
59.88 (CH2), 98.13, 112.23, 113.86, 114.25, 114.37, 117.16, 118.15,
123.50, 129.55, 142.28, 143.28, 162.33, 164.32 and 164.90 ppm (2
CN, Ar-C and CO); MS (EI): m/z (%) 420 (Mþ, 25.75), 421 (Mþþ1,
6.85). Anal. calcd. for C20H16N6O3S (420.45): C, 57.13; H, 3.84; N,
19.99; S, 7.63. Found: C, 57.15; H, 3.79; N, 20.03; S, 7.69.
4.10.1. (E)-2-cyano-N-(3-cyano-4-phenylthiophen-2-yl)-2-
(phenylhydrazono)acetamide (30a)
reddish browncrystals, yield: 65%, m.p.: 218e220 ꢀC; IR (KBr):
n
cmꢁ1 3377, 3227 (2NH), 2222, 2207 (2CN), 1685 (CO); 1H NMR

H. Behbehani et al. / European Journal of Medicinal Chemistry 52 (2012) 51e65
65
[14] W. Kemnitzer, N. Sirisoma, C. May, B. Tseng, J. Drewe, S.X. Cai, Bioorg. Med.
Chem. Lett. 19 (2009) 3536e3540.
5. Conclusions
[15] J. Katada, K. Iijima, M. Muramatsu, M. Takami, E. Yasuda, M. Hayashi,
M. Hattori, Y. Hayashi, Bioorg. Med. Chem. Lett. 9 (1999) 797e802.
[16] K. Gewald, E. Schinke, H. Böttcher, Chem. Ber. 99 (1966) 94e100.
[17] P. Milart, J. Wilamowski, J.J. Sepiol, Tetrahedron 54 (1998) 15643e15656.
[18] J. Slatt, I. Romero, J. Bergman, Synthesis 16 (2004) 2760e2765.
[19] H.M. Ibrahim, S. Makhseed, R.M. Abdel-Motaleb, A.A. Makhloof, M.H. Elnagdi,
Heterocycles 71 (2007) 1951e1966.
[20] H. Behbehani, H.M. Ibrahim, S. Makhseed, ARKIVOC ii (2010) 267e282.
[21] H. Behbehani, H.M. Ibrahim, S. Makhseed, H. Mahmoud, Eur. J. Med. Chem. 46
(2011) 1813e1820.
[22] H.M. Ibrahim, H. Behbehani, S. Makhseed, M.H. Elnagdi, Molecules 16 (2011)
3723e3739.
[23] Crystallographic data for 2a (ref. CCDC 841496) can be obtained on request
from the director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EW, UK.
[24] Crystallographic data for 4a (ref. CCDC 841636) can be obtained on request
from the director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EW, UK.
[25] Crystallographic data for 12j (ref. CCDC 841890) can be obtained on request
from the director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EW, UK.
[26] Crystallographic data for 12o (ref. CCDC 847262) can be obtained on request
from the director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EW, UK.
[27] Crystallographic data for 21a (ref. CCDC 843132) can be obtained on request
from the director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EW, UK.
In this investigation the cyanoacetamides, of the multi-
substituted 2-aminothiophenes were used as key synthons for the
preparation of wide variety of a novel, pyrido[1,2-a]thieno[3,2-e]
pyrimidine derivatives. In addition it was also used for the
synthesis of a new class of quinoline and pyridine derivatives. The
objective of this study was verified by synthesizing the above class
of compounds and investigating the antimicrobial activities for
these new compounds with the hope of discovering new structure
leads serving as potent antibacterial and antifungal agents, the
results of biological evaluations demonstrate that members from
these compounds have promising antimicrobial activities against
Gram negative bacteria, Gram positive bacteria and Yeast.
Acknowledgments
Support of this work was provided by the University of Kuwait
through a research grant (SC03/07). The facilities of Analab/SAF
supported by research grants GS01/01, GS01/05, GS01/03 and GS03/
08 are gratefully acknowledged.
[28] Crystallographic data for 24a (ref. CCDC 845670) can be obtained on request
from the director, Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EW, UK.
[29] R.M. Abdel-Motaleb, A.A. Makhloof, H.M. Ibrahim, M.H. Elnagdi, J. Heterocycl.
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