Uses of ethyl benzoyl acetate for the synthesis of thiophene, pyran, and pyridine derivatives with antitumor activities

Article abstract of DOI:10.1002/jhet.4112

The N-(arly)propanamide derivatives 3a,b were used for a series of heterocyclization reactions to give thiophene, pyran, and pyridine derivatives. Thus, these compounds underwent the Gewald's thiophene synthesis through their reactions with either malononitrile or ethyl cyanoacetate and elemental sulfur to afford compounds 6a-f, respectively. In addition, they were subjected through a series of multicomponent reactions (MCRs) to give pyran and fused derivatives. The reactions of 3a,b with either malononitrile or ethyl cyanoacetate gave pyridine derivatives 14a-d, respectively. The latter compounds afforded arylhydrazone derivatives 15a-m through their reactions with any of the aromatic diazonium salts 15a-c. The antitumor of the synthesized compounds against A549 (nonsmall cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer), and MKN-45 (human gastric cancer cancer) cancer cell lines together with foretinib as the positive control by a MTT assay was measured, and the results obtained showed that many compounds exhibited high potency against the six cancer cell lines.

Full text of DOI:10.1002/jhet.4112

Heterocyclization of ethyl benzoylacetate
Uses of ethyl benzoyl acetate for the synthesis of thiophene, pyran and pyridine
derivatives with anti-tumor activities
Bishoy Anis Ibrahim,1* Rafat Milad Mohareb1
1Department of chemistry Faculty of Science Cairo University, Giza, Egypt
e-mail: bishoyibrahim191@yahoo.com
Abstract: The N-(arly)propanamide derivatives 3a,b were used for a series of
heterocyclization reactions to give thiophene, pyran and pyridine derivatives. Thus, these
compounds underwent the Gewald’s thiophene synthesis through their reactions with
either malononitrile or ethyl cyanoacetate and elemental sulfur to afford compounds 6a-f,
respectively. In addition, they were subjected through a series of multicomponent
reactions to give pyran and fused derivatives. The reactions of 3a,b with either
malononitrile or ethyl cyanoacetate gave pyridine derivatives 14a-d, respectively. The
latter compounds afforded arylhydrazone derivatives 15a-m through their reactions with
any of the aromatic diazonium salts 15a-c. The antitumor of the synthesized compounds
against A549 (non-small cell lung cancer), H460 (human lung cancer), HT-29 (human
colon cancer) and MKN-45 (human gastric cancer cancer) cancer cell lines together with
foretinib as the positive control by a MTT assay were measured and the results obtained
showed that many compounds exhibited high potency’s against the six cancer cell lines.
Keywords: Propanamide, thiophene, pyran, pyridine, antitumor
1. Introduction
Development of modern synthetic organic chemistry faces some complicated problems
through measuring the biological screening of the synthesized products together with the
economic path way to get such compounds [1]. Especially, atom economy [2-4], time
saving, and the rules of environmental treatment of compounds together with the lack of
reaction steps should be put into considerations during adopting such reactions [5]. All
these encourage scientists to explore modern reaction conditions and new methods to
synthesis organic target molecules [6-8]. In this context, the use of the multicomponent
reactions (MCRs) was a privilege in modern organic chemistry [9-11], with at least three
different simple reagents [12,13] reacting in a well-defined manner to form a single
compound, has emerged as a powerful strategy [14]. Especially within the field of
combinatorial chemistry where formation of several new covalent bonds in a one-pot
transformation was well adopted with many reports [15]. There were many reaction
conditions for MCRs reactions the early reported in 1850 by Strecker [16], this well-
known concept [17], also widely represented in nature, has been extensively used in
both liquid-phase [14] and solid phase [18] chemistry for the rapid assembly of
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Heterocyclization of ethyl benzoylacetate
complex heterocyclic structures of importance for pharmaceutical development [19].
Isocyanide-based reactions were used as a base of MCRs [20-24], in addition Passerini
and coworkers reported MCRs [25,26] to produce diversity of heterocyclic derivatives
[27]. Early appearing as 1882 the well-known Hantzsch’s dihydropyridine synthesis [28]
using 1,3-dicarbonyl derivatives as one of the first substrate classes involved in a MCR
such reaction received many attentions within the field of organic synthesis. 1,3-
Dicarbonyl compounds and their applications in MCRs producing biologically active
products with highly functionalized small organic molecules with biological interest [29]
was received many attentions in recent years. These reactions involving the mixing of
three substrates together or sometimes the use of two fold of substrate to produce
heterocyclic target molecules with diverse biological interest [30-35]. In the present
work, we report the uses of the N-(aryl)propanamide derivatives 3a,b as -diketone for
the synthesis thiophene, pyran and pyridine derivatives followed by their anti-tumor
evaluations.
2. Results and discussion
The N-(arly)propanamide derivatives 3a,b were obtained through the reaction of ethyl
benzoyl acetate with either of aniline or 4-chloroaniline. The reaction of either of
compound 3a or 3b with elemental sulfur and either malononitrile (4a) or ethyl
cyanoacetate (4b) in ethanol containing a catalytic amount of triethylamine gave the
thiophene derivatives 5a-d, respectively. The 2-amino group present in compounds 5a-d
showed interesting reactivity toward amide formation. Thus, the reaction of any of
compounds 5a-d with ethyl cyanoacetate in dimethylformamide under reflux conditions
gave the cyanoacetamide derivatives 6a-d, respectively.
Muti-component reactions (MCRs) involving the use of three substrates that react
together in a short reaction time and economic reaction conditions [36,37]. Specific
products might be produced through MCRs reactions which be the main aim of such
reactions [38,39]. Interestingly 4-H pyran derivatives were one of the main class of
compounds that produced through MCRs [40-44] this encouraged us to synthesis 4-H
pyran derivative through the multi-component reactions of compounds 3a and 3b. Thus,
the multi-component reaction of compound 3a with benzaldehyde (7) and malononitrile
in ethanol containing a catalytic amount of triethylamine gave the pyran derivative (8). In
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Heterocyclization of ethyl benzoylacetate
addition, the multi-component reaction of compound 3a with salicylaldehyde (9) and
malononitrile (4a) in ethanol containing a catalytic amount of triethylamine gave 4-
amino-5-imino-N,2-diphenyl-5,10b-dihydropyrano[3,4-c]chromene-1-carboxamide (10)
(Scheme 1). The analytical and spectral data of compounds 8 and 10 were consistent with
their respective structures (see experimental section).
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Heterocyclization of ethyl benzoylacetate
NH2
O
oil bath
120 oC
O
X
+
CONH
COOEt
Ph
Ph
1
3a, X = H
b, X = Cl
X
2a, X = H
b, X = Cl
CN
R
H2C
S8
EtOH
Et3N
4a, R = CN
b, R = COOEt
Ph
R
R
Ph
4a
DMF
NH2
NHCOCH2CN
X
CONH
X
CONH
S
S
5a-d
6a-d
c
Cl
d
Cl
5 & 6
b
a
H
H
X
R
CN
CN
COOEt
COOEt
Ph
PhHNOC
Ph
CN
NH2
CHO
O
4a
8
7
EtOH
Et3N
3a
CHO
4a
EtOH
Et3N
O
OH
9
PhHNOC
NH
NH2
Ph
O
10
Scheme 1. Synthesis of compounds 3a,b; 5a-d; 6a-d; 8 and 10.
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Heterocyclization of ethyl benzoylacetate
Compound 3b reacted with benzaldehyde (7) and either malononitrile (4a) or ethyl
cyanoacetate (4b) in ethanol containing a catalytic amount of triethylamine gave the
pyran derivatives 11a and 11b, respectively. On the other hand, the reaction of compound
3b with salicylaldehyde (9) and either malononitrile (4a) or ethyl cyanoacetate (4b) gave
the N,2-diphenyl-5,10b-dihydropyrano[3,4-c]chromene-1-carboxamide derivatives 12a
and 12b, respectively.
The Knoevenagel condensation reaction of either compound 3a or 3b with either
malononitrile (4a) or ethyl cyanoacetate (4b) in the presence of ammonium acetate in an
oil bath at 120 oC gave the products 13a-d, respectively (Scheme 2 ). The elemental and
spectral data of the latter products were in agreement with their respective structures.
1
Thus, the H NMR spectrum of 13a (as an example) showed a singlet at δ 5.32 ppm
equivalent to the CH2 group, a multiplet at δ 7.22-7.43 ppm indicating the two C6H5
groups, a singlet at δ 8.28 ppm (D2O exchangeable) corresponding to the NH group. In
addition, the 13C NMR spectrum revealed a signal at δ 62.6 for the CH2 group, two
signals at δ 116.1, 116.8 corresponding to the two CN groups, eight signals at δ 120.1,
121.9, 123.6, 124.3, 125.7, 126.2, 127.5, 128.8 equivalent to the two C6H5 groups, a
signal at δ 164.4 for the CO group.
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Heterocyclization of ethyl benzoylacetate
CN
CONH
Ph
H2C
Cl
R
CHO
R
4a, R = CN
b, R = COOEt
7
NH2
O
EtOH
Et3N
11a, R = CN
3b
b, R = COOEt
EtOH
Et3N
CHO
4a,b
OH
O
9
CONH
Ph
Cl
Y
NH2
O
12a, Y = NH
b, Y = O
CN
R
CN
R
CH3COONH4
H2C
3a,b
+
CONH
X
Ph
Oil bath 120 oC
4a, R = CN
b, R = COOEt
13
X
c
Cl
d
b
H
a
H
Cl
R
CN
CN
COOEt
COOEt
Scheme 2. Synthesis of compounds 11a,b; 12a,b and 13a-d
On the other hand, the reaction of either compound 3a or 3b with either malononitrile
(4a) or ethyl cyanoacetate (4b) in ethanol containing a catalytic amount of triethylamine
gave the pyridine derivatives 14a-d, respectively. The structures of the latter products
were established on the basis of analytical and spectral data. Thus, the 1H NMR spectrum
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Heterocyclization of ethyl benzoylacetate
of compound 14a showed the presence of asinglet at δ 4.82 ppm (D2O exchangeable) for
the NH2 group, a singlet at δ 6.32 ppm for the pyridine H-5, and a multiplet at δ 7.24-
13
7.40 equivalent for the two C6H5 groups. In addition, the C NMR spectrum showed a
signal at δ 116.5 for the CN group, eight signals at δ 120.4, 120.6, 122.3, 124.8, 125.0,
126.6, 127.3, 128.3 equivalent to the two C6H5 groups and a signal at δ 164.8
confirming the presence of the CO group. Finally, the reaction of any of compounds
14a-d with any of the diazonium salts 15a-c gave the corresponding arylazo derivatives
16a-m, respectively (Scheme 3).
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Heterocyclization of ethyl benzoylacetate
R'
NC
X
N
CN
EtOH
Et3N
H2C
3a,b
+
R
Ph
O
14a-d
4a, R = CN
b, R = COOEt
14
X
a
c
d
b
H
H
Cl
Cl
R
COOEt
NH2
OH
NH2
+
-
N NCl
AcONa
EtOH (0 oC)
15a, Y = H
b, Y = Cl
c, Y = OCH3
Y
R'
NC
X
N
Ph
O
N
N
Y
16a-m
g
m
16
X
c
H
e
i
b
k
l
a
d
f
h
Cl
Cl
H
H
H
Cl
Cl
H
H
Cl
Cl
OH
OH
Cl
NH2
NH2
H
OH
H
NH2
H
NH2
Cl
R’
NH2
Cl
NH2
OH
Cl
OH
OH
H
OCH3
OCH3
OCH3
Y
OCH3
Scheme 3. Synthesis of compounds 14a-d and 16a-m.
2.1. Biology section
2.1.1. Cell proliferation assay
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Heterocyclization of ethyl benzoylacetate
2.1.2. In vitro cell assays
All the synthesized compounds were assessed the inhibitory activities against A549 (non-
small cell lung cancer), H460 (human lung cancer), HT-29 (human colon cancer) and
MKN-45 (human gastric cancer cancer) cancer cell lines together with foretinib as the
positive control by a MTT assay. Furthermore, all compounds were further evaluated
against U87MG (human glioblastoma) and SMMC-7721 (human liver cancer) cell lines.
The results expressed as IC50 were summarized in Table 1. The IC50 values are the
average of at least three independent experiments. The data listed in Table 1 revealed that
the compounds possessed moderate to strong cytotoxicity against the five tested cell lines
in the single-digit lM range, and high selectivity for inhibition A549, H460 and MKN-45
cells.
Table 1. In vitro growth inhibitory effects (IC50 M) of the selected compounds against
cancer cell lines
Compound
IC50 ± SEM (M)
A549
H460
HT29
MKN-45
U87MG
SMMC-
7721
No
10.42±2.59 9.40 ± 3.53 12.63 ± 4.26 10.52 ± 2.73 9.80 ± 2.19 8.63 ± 2.42
3a
3b
5a
5b
5c
2.08 ± 0.80 1.31± 0.88 2.30 ± 0.80
8.28 ± 4.18 9.62 ± 2.70 8.39 ± 2.73
6.80 ± 1.42 8.59 ± 1.80 7.49 ± 2.73
0.70± 0.29 0.76 ± 0.38 0.65 ± 0.27
0.23 ± 0.08 0.38 ± 0.27 0.19 ± 0.08
7.59 ± 2.31 8.06 ± 3.19 6.59 ± 1.80
0.32 ± 0.20 0.49 ± 0.21 0.63 ± 0.32
1.40 ± 0.69 1.04 ± 0.73 0.86 ± 0.32
0.60 ± 0.24 0.43 ± 0.26 0.62 ± 0.30
10.28±3.57 8.47 ± 2.49 8.29 ± 2.57
0.38± 0.16 0.42 ± 0.24 0.38 ± 0.08
8.72 ± 2.37 6.93 ± 0.26 4.80 ± 1.53
1.28 ± 0.63 1.32 ± 0.92 2.42 ± 0.79
10.37±3.80 8.51 ± 2.72 8.97 ± 1.60
2.73 ± 0.92 4.52 ± 1.69 1.08 ± 0.93
7.09 ± 2.35 8.93 ± 2.73 5.09 ± 1.63
8.09 ± 2.04 7.42 ± 2.69 8.58 ± 2.68
0.42 ± 0.23 0.59 ± 0.18 0.69 ± 0.28
0.26 ± 0.11 0.39 ± 0.21 0.42 ± 0.27
9.14 ± 2.59 6.28 ± 1.49 7.93 ± 1.31
0.59 ± 0.23 0.62 ± 0.18 0.53 ± 0.27
0.59 ± 0.32 0.86 ± 0.52 0.39 ± 0.18
5d
6a
6b
6c
0.39± 0.15
0.43 ± 0.26 0.73 ± 0.31
6d
8
9.36 ± 2.53 8.29 ± 2.44 10.21 ± 2.52
0.72 ± 0.37 0.66 ± 0.26 0.72 ± 0.17
8.38 ± 2.17 9.49 ± 2.58 8.27 ± 2.69
2.29 ± 0.06 1.81 ± 0.20 1.64± 0.21
8.93 ± 2.73 9.71 ± 2.60 8.63 ± 2.59
10
11a
11b
12a
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Heterocyclization of ethyl benzoylacetate
0.35± 0.24 0.43 ± 0.19 0.65 ± 0.26
6.22 ± 2.48 7.80 ± 2.57 8.41 ± 2.39
5.60 ± 1.31 6.27 ± 1.42 5.33 ± 2.41
0.41 ± 0.28 0.84 ± 0.32 0.52 ± 0.42
0.38 ± 0.16 0.45 ± 0.18 0.39 ± 0.16
0.53 ± 0.19 0.63 ± 0.17 0.52 ± 0.28
8.29 ± 2.72 8.93± 2.58 8.36 ± 2.61
6.38 ± 2.08 5.70 ± 2.49 8.90 ± 2.37
0.63 ± 0.36 0.49 ± 0.23 0.71 ± 0.36
0.50 ± 0.24 0.72 ± 0.30 0.45 ± 0.27
9.03 ± 2.42 7.05 ± 1.62 6.99 ± 2.37
0.68 ± 0.28 0.63 ± 0.25 0.52 ± 0.26
0.30 ± 0.17 0.42 ± 0.16 0.41 ± 0.20
0.25 ± 0.08 0.29 ± 0.13 0.38 ± 0.20
12b
13a
13b
13c
13d
14a
14b
14c
6.93 ± 2.30 7.29 2.52
8.04 ± 2.17
0.38± 0.16 0.42 ± 0.27 0.38 ± 0.17
0.25 ± 0.29 0.39 ± 0.23 0.46 ± 0.27
0.31 ± 0.16 0.42 ± 0.12 0.22 ± 0.13
8.40 ± 2.25 7.84 ± 2.60 9.31 ± 2.53
2.73 ± 1.06 1.38 ± 0.87 3.51 ± 1.63
5.29 ± 2.17 6.68 ± 2.58 8.32 ± 2.70
1.02 ± 0.82 0.99 ± 0.35 0.62 ± 0.41
3.47 ± 1.02 1.40 ± 0.39 0.72 ± 0.38
1.38± 0.68 1.46 ± 0.67 1.34 ± 0.57
2.38 ± 0.89 1.29 ± 0.76 1.32 ± 0.75
1.40 ±0.57 0.80 ± 0.62 1.39 ± 0.74
2.30 ± 1.02 1.96 ± 0.88 2.70 ± 1.16
0.33 ± 0.15 0.62 ± 0.21 0.29 ± 0.18
0.42 ± 0.26 0.41 ± 0.21 0.63 ± 0.30
0.29 ± 0.12 0.35 ± 0.17 0.59 ± 0.25
14d
16a
16b
16c
8.52± 2.39
8.63 ± 2.38 8.16 ± 2.38
4.17 ± 1.27 5.02 ± 1.69 3.26 ± 1.16
4.83 ± 1.95 5.07 ± 1.26 6.95 ± 2.41
0.40 ± 0.15 0.52 ± 0.28 0.63 ± 0.27
16d
16e
0.98 ± 0.33 0.86± 0.52
0.98 ± 0.61
2.63 ± 1.59 1.93 ± 0.82 2.83 ± 0.96
2.61 ± 1.18 2.83 ± 0.83 1.63 ± 0.87
0.79 ± 0.25 1.05 ± 0.69 0.96 ± 0.34
1.97 ± 0.86 1.38 ± 0.94 4.80 ± 1.18
0.30 ± 0.13 0.52 ± 0.17 0.46 ± 0.21
0.49 ± 0.19 0.32 ± 0.11 0.63 ± 0.21
0.48 ± 0.23 0.37 ± 0.25 0.69 ± 0.32
16f
16g
16h
16i
16k
16l
16m
Foretinib
0.08 ± 0.01 0.18 ± 0.03 0.15 ± 0.023 0.03±0.0055 0.90 ± 0.13 0.44 ± 0.062
2.1.3. Structure activity relationship
It is clear from Table 1 that the most cytotoxic compounds are 5c, 5d, 6b, 6d, 10, 12b,
13c, 13d, 14b, 14c, 14d, 16d, 16k, 16l and 16m. Considering the anilide derivatives 3a
and 3b, it is clear that compound 3b (X = Cl) showed higher cytotoxicity than 3a (X =
H). For the thiophene derivatives 5a-d, compounds 5c (X = Cl, R = CN) and 5d (X = Cl,
R = COOEt) were of high cytotoxicities than 5a and 5b, this was due to the presence of
the electronegative Cl group in both compounds. On the other hand, for compounds 6a-d,
compounds 6b (X = H, R = COOEt), 6c (X = Cl, R = CN) and 6d (X = Cl, R = COOEt)
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Heterocyclization of ethyl benzoylacetate
with high cytotoxicities. The high inhibitions of compounds 6b, 6c and 6d were attributed
to the presence of the electronegative Cl group within these compounds. The pyran
derivative 8 showed low cytotoxicity while the dihydropyrano[3,4-c]chromen-1-
carboxamide 10 revealed high inhibitions. It was obvious that the existence of the fused
pyrano[3,4-c]chromen was responsible for the activity of compound 10. Surprisingly,
compound 11a (R = CN) had lower inhibitions than 11b (R = COOEt) although the CN
group is an electronegative group, therefore, it was clear that the high oxygen content of
11b was responsible for its high inhibitions. On the other hand, the dihydropyrano[3,4-
c]chromene derivative 12b (X = O) has higher cytotoxicity than 12a (X = NH), this was
attributed to the presence of the C=O group within the structure of compound 12a. In
addition, for the anilide derivatives 13a-d, it is obvious that compounds 13c (X = Cl, R =
CN) and 13d (X = Cl, R = COOEt) showed high inhibitions than 13a and 13b. Since
compounds 13c and 13b with the electronegative Cl group in their structures.
Considering the pyridine derivatives 14a-d, it is obvious that compounds 14b (X = H, R’
= OH), 14c (X = Cl, R’ = NH2) and 14d (X = Cl, R’ = OH) showed high inhibitions while
compound 14a with low inhibitions. For the pyridine derivatives 16a-m, it is clear that
compounds 16d, 16k, 16l and 16m showed high cytotoxicities than the rest of such series
of compounds. It was clear in these compounds that the existence of the OH group
together with the Cl group was the controlling factor for the high inhibitions of 16d, 16k,
16l and 16m. Comparison with the reference drug foretinib, it was clear that compounds
5c, 5d, 6b, 6c, 6d, 10, 12b, 13c, 13d, 14b, 14c, 14d, 14e, 16c, 16d, 16k, 16l and 16m
had higher inhibitions than foretinib (IC50 0.90 M) against U87MG cell line. In addition,
compounds 5d, 6c, 14c and 14d showed higher inhibitions than foretinib (IC50 0.44 M)
against SMMC-7721 cell line.
3. Conclusions
In conclusion, a new series of thiophene and pyan derivatives were developed using
ethyl benzoylacetate. The obtained compounds demonstrated great activities toward
the six cancer cell lines A549, H460 HT-29, MKN-45, U87MG and SMMC. The
results expressed that compounds 5c, 5d, 6b, 6d, 10, 12b, 13c, 13d, 14b, 14c, 14d,
16d, 16k, 16l and 16m were the most cytotoxic compounds. Some of the compounds
afforded higher inhibitions than the reference drug foretinib, especially against
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Heterocyclization of ethyl benzoylacetate
U87MG and SMMC-7721 cell lines. The results obtained encourage further work in
the future for the applications of MCRs to produce target molecules as anti-cancer
agents.
4. Experimental section
4.1. General
The obtained compounds showed their melting points using Electrothermal digital
melting point apparatus and are uncorrected. IR spectra (KBr discs) were measured
on a FTIR plus 460 or PyeUnicam SP-1000 spectrophotometer (PyeUnicam, UK,
1
Cambridge). H NMR spectra were obtained from Varian Gemini-300 (300 MHz,
Varian UK) using DMSO-d6 as a solvent and Tetraethylsilane (TMS) as internal
standard. Chemical shifts are expressed as δ ppm. The mass spectra were measured
with Hewlett Packard 5988 A GC/MS system (Hewlett Packard, Agilent, USA)
instrument.
4.1.1. Synthesis of the anilide derivatives 3a,b
Equimolar amounts of ethyl benzoylacetate (1.92 g, 0.01 mol) and either of aniline (0.93
o
g, 0.01 mol) or 4-chloroaniline (1.27 g, 001 mol) was heated in an oil bath at 120 C for
30 min then was left to cool. The solid product formed, in each case, was collected by
filtration. M.p. was close to that reported by chemical companies.
4.1.2. General procedure for the synthesis of the thiophene derivatives 5a-d
To a solution of either of compound 3a (2.39 g, 0.01 mol) or 3b (2.53 g, 0.01 mol) in
ethanol (40 mL) containing triethylamine (0.50 mL) either malononitrile (0.66 g, 0.01
mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) was added. The reaction mixture was
heated under reflux for 3 h then poured onto ice/water mixture containing a few drops of
hydrochloric acid and the formed solid product was collected by filtration.
4.1.2.1. 5-Amino-4-cyano-N,3-diphenylthiophene-2-carboxamide (5a)
Brown crystals from ethanol, yield (2.1 g, 65.8 %), m.p 84-86 °C. IR (KBr) υ max cm-1:
1
3482-3353 (NH2, NH), 3056 (CH, aromatic), 2220 (CN), 1686 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 4.75 (s, 2H, D2O exchangeable, NH2), 7.26-7.36
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Heterocyclization of ethyl benzoylacetate
(m,10H, 2C6H5), 8.26 (s, 1H, D2O exchangeable, NH); 13C NMR (DMSO- d6, 75
MHz): 116.8 (CN), 120.3, 122.5, 123.8, 124.6, 124.9, 126.2, 127.4, 129.0 (2C6H5),
166.2 (CO). Anal. Calculated for C18H13N3OS: C, 67.69; H, 4.10; N, 13.16; S, 10.04.
Found: C, 67.44; H, 3.86; N, 13.41; S, 10.29. MS: m/e 319 (M+, 36 %).
4.1.2.2. Ethyl 2-amino-4-phenyl-5-(phenylcarbamoyl)thiophene-3-carboxylate (5b)
Brown crystals from ethanol, yield (2.3 g, 62.75 %), m.p 77-80 °C. IR (KBr) υ max cm-1:
1
3475-3328 (NH2, NH), 3055 (CH, aromatic), 1689, 1686 (2CO), 1630 (C=C); H NMR
(DMSO- d6, 200 MHz): δ = 1.12 (t, 3H, J = 7.39 Hz, OCH2CH3), 4.23 (q, 2H, J = 7.39
Hz, OCH2CH3), 4.78 (s, 2H, D2O exchangeable, NH2), 7.24-7.40 (m,10H, 2C6H5), 8.28
13
(s, 1H, D2O exchangeable, NH); C NMR (DMSO- d6, 75 MHz): 16.8 (OCH2CH3),
50.8 (OCH2CH3), 120.1, 123.2, 123.8, 125.2, 125.6, 126.1, 127.8, 128.3 (2C6H5), 164.4,
166.8 (2CO). Anal. Calculated for C20H18N2O3S: C, 65.55; H, 4.95; N, 7.64; S, 8.75.
Found: C, 65.80; H, 5.18; N, 7.48; S, 8.69. MS: m/e 366 (M+, 42 %).
4.1.2.3. 5-Amino-N-(4-chlorophenyl)-4-cyano-3-phenylthiophene-2-carboxamide
(5c)
Brown crystals from ethanol, yield (2.49 g, 70.3 %), m.p 140-142 °C. IR (KBr) υ max
cm-1: 3469-3342 (NH2, NH), 3054 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 4.73 (s, 2H, D2O exchangeable, NH2), 7.22-7.46
13
(m, 9H, C6H5, C6H4), 8.24 (s, 1H, D2O exchangeable, NH); C NMR (DMSO- d6, 75
MHz): 116.3 (CN), 120.1, 122.2, 124.0, 124.5, 125.3, 126.9, 127.1, 128.3 (C6H5, C6H4),
166.8 (CO). Anal. Calculated for C18H12ClN3OS: C, 61.10; H, 3.42; N, 11.88; S, 9.06.
Found: C, 61.28; H, 3.53; N, 12.06; S, 8.93. MS: m/e 353 (M+, 28 %).
4.1.2.4. Ethyl 2-amino-5-((4-chlorophenyl)carbamoyl)-4-phenylthiophene-3-
carboxylate (5d)
Pale yellow crystals from ethanol, yield (2.22 g, 55.5 %), m.p 150-152 °C. IR (KBr) υ
max cm-1: 3476-3329 (NH2, NH), 3055 (CH, aromatic), 1689, 1687 (2CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 1.12 (t, 3H, J = 6.57 Hz, OCH2CH3), 4.23 (q, 2H, J
= 6.57 Hz, OCH2CH3), 4.74 (s, 2H, D2O exchangeable, NH2), 7.23-7.48 (m, 9H, C6H5,
13
C6H4), 8.23 (s, 1H, D2O exchangeable, NH); C NMR (DMSO- d6, 75 MHz): 16.5
(OCH2CH3), 50.3 (OCH2CH3), 120.5, 122.6, 123.2, 124.7, 125.9, 126.3, 126.8, 127.2
(C6H5, C6H4), 164.1, 166.3 (2CO). Anal. Calculated for C20H17ClN2O3S: C, 59.92; H,
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Heterocyclization of ethyl benzoylacetate
4.27; N, 6.99; S, 8.00. Found: C, 59.72; H, 4.38; N, 7.28; S, 8.23. MS: m/e 400 (M+, 36
%).
4.1.3. General procedure for the synthesis of the cyanoacetamido derivatives 6a-
d
Ethyl cyanoacetate (1.13 g, 0.01 mol) was added to a solution of either compound 5a
(3.19 g, 0.01 mol), 5b (3.66 g, 0.01 mol), 5c (3.53 g, 0.01 mol) or 5d (4.00 g, 0.01 mol)
in dimethylformamide (40 mL). The reaction mixture was heated under reflux for 3 h
then poured onto ice/water and the formed solid product, in each case, was heated under
reflux.
4.1.3.1. 4-Cyano-5-(2-cyanoacetamido)-N,3-diphenylthiophene-2-carboxamide (6a)
Yellow crystals from 1,4-dioxane, yield (1.15 g, 30 %), m.p 110-112 °C. IR (KBr) υ max
cm-1: 3473-3328 (NH), 3054 (CH, aromatic), 2256, 2220 (2CN), 1689, 1686 (2CO), 1630
1
(C=C); H NMR (DMSO- d6, 200 MHz): δ = 5.35 (s, 2H, CH2), 7.24-7.39 (m,10H,
2C6H5), 8.24, 8.31 (2s, 2H, D2O exchangeable, 2NH); 13C NMR (DMSO- d6, 75 MHz):
62.3 (CH2), 116.5, 116.9 (2CN), 120.1, 122.9, 124.2, 124.6, 125.3, 126.2, 127.4, 128.2
(2C6H5), 164.2, 166.8 (2CO). Anal. Calculated for C21H14N4O2S: C, 65.27; H, 3.65; N,
14.50; S, 8.30. Found: C, 65.39; H, 3.83; N, 14.83; S, 8.18. MS: m/e 386 (M+, 28 %).
4.1.3.2. Ethyl 2-(2-cyanoacetamido)-4-phenyl-5-(phenylcarbamoyl)thiophene-3-
carboxylate (6b)
Yellow crystals from ethanol, yield (1.68 g, 38.75 %), m.p 91-93 °C. IR (KBr) υ max
cm-1: 3480-3343 (NH), 3055 (CH, aromatic), 2254 (CN), 1689-1686 (3CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 1.13 (t, 3H, J = 7.14 Hz, OCH2CH3), 4.22 (q, 2H, J
= 7.14 Hz, OCH2CH3), 5.39 (s, 2H, CH2), 7.22-7.41 (m,10H, 2C6H5), 8.25, 8.30 (2s, 2H,
D2O exchangeable, 2NH); 13C NMR (DMSO- d6, 75 MHz): 16.6 (OCH2CH3), 50.3
(OCH2CH3), 117.0 (CN), 120.5, 122.6, 123.8, 125.7, 126.0, 126.7, 127.2, 128.0 (2C6H5),
164.6, 166.8, 167.2 (3CO). Anal. Calculated for C23H19N3O4S: C, 63.73; H, 4.42; N,
9.69; S, 8.40. Found: C, 63.52; H, 4.60; N, 9.84; S, 8.32. MS: m/e 433 (M+, 35 %).
4.1.3.3. N-(4-Chlorophenyl)-4-cyano-5-(2-cyanoacetamido)-3-phenylthiophene-2-
carboxamide (6c)
Pale brown crystals from 1,4-dioxane, yield (0.9 g, 21.4 %), m.p 88-90 °C. IR (KBr) υ
max
cm-1: 3491-3348 (NH), 3054 (CH, aromatic), 2256, 2221 (2CN), 1689, 1687
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Heterocyclization of ethyl benzoylacetate
1
(2CO), 1630 (C=C); H NMR (DMSO- d6, 200 MHz): δ = 5.36 (s, 2H, CH2), 7.24-7.46
13
(m, 9H, C6H5, C6H4), 8.23, 8.33 (2s, 2H, D2O exchangeable, 2NH); C NMR (DMSO-
d6, 75 MHz): 62.1 (CH2), 116.1, 116.8 (2CN), 120.1, 122.5, 124.3, 124.6, 125.3, 126.8,
127.1, 128.2 (2C6H5), 164.1, 166.6 (2CO). Anal. Calculated for C21H13ClN4O2S: C,
59.93; H, 3.11; N, 13.31; S, 7.62. Found: C, 59.73; H, 3.38; N, 13.48; S, 7.79. MS: m/e
420 (M+, 48 %).
4.1.3.4. Ethyl 5-((4-chlorophenyl)carbamoyl)-2-(2-cyanoacetamido)-4-phenyl-
thiophene-3-carboxylate (6d)
Brown crystals from ethanol, yield (1.2 g, 25.6 %), m.p 148-150 °C. IR (KBr) υ max
cm-1: 3469-3348 (NH), 3055 (CH, aromatic), 2253 (CN), 1689-1685 (3CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 1.12 (t, 3H, J = 6.53 Hz, OCH2CH3), 4.22 (q, 2H, J
= 6.53 Hz, OCH2CH3), 5.37 (s, 2H, CH2), 7.22-7.48 (m, 9H, C6H5, C6H4), 8.22, 8.32 (2s,
2H, D2O exchangeable, 2NH); 13C NMR (DMSO- d6, 75 MHz): 16.3 (OCH2CH3), 50.1
(OCH2CH3), 117.2 (CN), 120.3, 122.6, 123.4, 125.7, 126.2, 126.1, 127.3, 128.9 (2C6H5),
164.3, 166.6, 167.1 (3CO). Anal. Calculated for C23H18ClN3O4S: C, 59.04; H, 3.88; N,
8.98; S, 6.85. Found: C, 59.25; H, 4.69; N, 9.13; S, 6.42. MS: m/e 467 (M+, 24 %).
4.1.4. 6-Amino-5-cyano-N,2,4-triphenyl-4H-pyran-3-carboxamide (8)
A mixture of compound 3a (2.39 g, 0.01 mol), benzaldehyde (1.08 g, 0.01 mol) and
malononitrile (0.66 g, 0.01 mol) in absolute ethanol (40 mL) containing triethylamine
(1.00 mL) was heated under reflux for 2 h. The solid product obtained during heating was
collected by filtration.
Orange crystals from 1,4-dioxane, yield (3 g, 76.3 %), m.p 68-70 °C. IR (KBr) υ max
cm-1: 3484-3341 (NH2, NH), 3054 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 4.39 (s, 2H, D2O exchangeable, NH2), 6.03 (s, 1H,
13
pyran H-4), 7.28-7.49 (m, 15H, 3C6H5), 8.36 (s, 1H, D2O exchangeable, NH); C NMR
(DMSO- d6, 75 MHz): 40.1 (pyran C-4), 116.8 (CN), 119.6, 120.2, 121.8, 121.3, 121.9,
122.3, 122.6, 123.0, 123.5, 124.3, 124.6, 125.3, 130.8, 132.5, 138.2, 140.3 (3C6H5, pyran
C), 164.8 (CO). Anal. Calculated for C25H19N3O2: C, 76.32; H, 4.87; N, 10.68. Found:
C, 76.48; H, 4.69; N, 10.47. MS: m/e 393 (M+, 24 %).
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Heterocyclization of ethyl benzoylacetate
4.1.5. 4-Amino-5-imino-N,2-diphenyl-5,10b-dihydropyrano[3,4-c]chromene-1-
carboxamide (10)
A mixture of compound 3a (2.39 g, 0.01 mol), salicylaldehyde (1.22 g, 0.01 mol) and
malononitrile (0.66 g, 0.01 mol) in absolute ethanol (40 mL) containing triethylamine
(1.00 mL) was heated under reflux for 2 h. The solid product obtained during heating was
collected by filtration.
Brown crystals from 1,4-dioxane, yield (2.68 g, 65.5 %), m.p 100-103 °C. IR (KBr) υ
max cm-1: 3476-3328 (NH2, NH), 3055 (CH, aromatic), 1687 (CO), 1650 (exocyclic
1
C=N), 1630 (C=C); H NMR (DMSO- d6, 200 MHz): δ = 4.48 (s, 2H, D2O
exchangeable, NH2), 6.10 (s, 1H, pyran H-4), 7.22-7.48 (m, 14H, 2C6H5, C6H4), 8.32,
13
8.39 (2s, 2H, D2O exchangeable, 2NH); C NMR (DMSO- d6, 75 MHz): 41.8 (pyran
C-4), 119.4, 120.4, 121.8, 121.5, 122.3, 123.5, 123.8, 124.0, 124.5, 125.9, 126.2, 127.9,
133.6, 138.5, 140.8, 141.4 (2C6H5, C6H4, pyran C), 164.5 (CO), 172.6 (C=N). Anal.
Calculated for C25H19N3O3: C, 73.34; H, 4.68; N, 10.26. Found: C, 73.59; H, 4.39; N,
10.31. MS: m/e 409 (M+, 36 %).
4.1.6. General procedure for the synthesis of the pyran derivatives 11a,b
A mixture of compound 3b (3.63 g, 0.01 mol), benzaldehyde (1.08 g, 0.01 mol) and
either malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) in
absolute ethanol (40 mL) containing triethylamine (1.00 mL) was heated under reflux for
2 h. The solid product obtained during heating was collected by filtration.
3.1.6.1. 6-Amino-N-(4-chlorophenyl)-5-cyano-2,4-diphenyl-4H-pyran-3-carboxamide
(11a)
Brown crystals from ethanol, yield (3.84 g, 90 %), m.p 205-207 °C. IR (KBr) υ max
cm-1: 3484-3339 (NH2, NH), 3055 (CH, aromatic), 2220 (CN), 1688 (CO), 1650
1
(exocyclic C=N), 1630 (C=C); H NMR (DMSO- d6, 200 MHz): δ = 4.45 (s, 2H, D2O
exchangeable, NH2), 6.08 (s, 1H, pyran H-4), 7.22-7.53 (m, 14H, 2C6H5, C6H4), 8.36 (s,
1H, D2O exchangeable, NH); 13C NMR (DMSO- d6, 75 MHz): 41.8 (pyran C-4), 116.8
(CN), 119.8, 120.5, 121.3, 122.6, 122.9, 124.3, 124.8, 125.3, 125.6, 126.3, 126.7, 127.7,
132.2, 138.9, 140.3, 141.6 (2C6H5, C6H4, pyran C), 164.5 (CO), 172.6 (C=N). Anal.
Calculated for C25H18ClN3O2: C, 70.18; H, 4.24; N, 9.82. Found: C, 70.26; H, 4.39; N,
10.16. MS: m/e 427 (M+, 24 %).
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Heterocyclization of ethyl benzoylacetate
4.1.6.2. Ethyl 2-amino-5-((4-chlorophenyl)carbamoyl)-4,6-diphenyl-4H-pyran-3-
carboxylate (11b)
Yellow crystals from ethanol, yield (1.85 g, 39 %), m.p 135-138 °C., IR (KBr) υ max
cm-1: 3474-3326 (NH2, NH), 3055 (CH, aromatic), 2221 (CN), 1689, 1688 (2CO), 1630
1
(C=C); H NMR (DMSO- d6, 200 MHz): δ = 1.12 (t, 3H, J = 6.72 Hz, OCH2CH3), 4.22
(q, 2H, J = 6.72 Hz, OCH2CH3), 4.80 (s, 2H, D2O exchangeable, NH2), 6.03 (s, 1H,
13
pyran H-4), 7.23-7.39 (m, 14H, 2C6H5, C6H4), 8.28 (s, 1H, D2O exchangeable, NH); C
NMR (DMSO- d6, 75 MHz): 16.2 (OCH2CH3), 50.3 (OCH2CH3), 117.0 (CN), 120.4,
121.8, 123.4, 125.3, 126.0, 126.1, 127.4, 128.9, 130.5, 135.2, 139.6, 141.2 (2C6H5, pyran
C), 164.3, 166.8 (2CO). Anal. Calculated for C27H23ClN2O4: C, 68.28; H, 4.88; N, 5.90.
Found: C, 68.38; H, 4.72; N, 6.13. MS: m/e 474 (M+, 35 %).
4.1.7. General procedure for the synthesis of the dihydropyrano[3,4-c]chromene-
1-carboxamide derivatives 12a,b
To a solution of compound 3b (3.63 g, 0.01 mol) in absolute ethanol (40 mL) containing
triethylamine (1.00 mL) each of salicylaldehyde (1.22 g, 0.01 mol) and either
malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13g, 0.01 mol) were added. The
reaction mixture was heated under reflux for 2 h and the produced solid product during
heating was collected by filtration.
4.1.7.1.
4-Amino-N-(4-chlorophenyl)-5-imino-2-phenyl-5,10b-dihydropyrano-[3,4-
c]chromene-1-carboxamide (12a)
Brown crystals from 1,4-dioxane, yield (4 g, 90 %), m.p 128-131°C. IR (KBr) υ max
cm-1: 3492-3348 (NH2, NH), 3055 (CH, aromatic), 1687 (CO), 1650 (exocyclic C=N),
1630 (C=C); 1H NMR (DMSO- d6, 200 MHz): δ = 4.45 (s, 2H, D2O exchangeable, NH2),
6.10 (s, 1H, pyran H-4), 7.22-7.48 (m, 13H, C6H5, 2C6H4), 8.34, 8.36 (2s, 2H, D2O
13
exchangeable, 2NH); C NMR (DMSO- d6, 75 MHz): 41.3 (pyran C-4), 119.8, 120.2,
121.3, 121.9, 122.1, 123.7, 124.2, 124.4, 124.9, 125.2, 126.62, 127.8, 133.8, 138.9, 140.4,
141.2 (2C6H5, C6H4, pyran C), 164.8 (CO), 172.8 (C=N). Anal. Calculated for
C25H18ClN3O3: C, 67.65; H, 4.09; N, 9.47. Found: C, 67.80; H, 4.36; N, 9.53. MS: m/e
443 (M+, 36 %).
4.1.7.2.
4-Amino-N-(4-chlorophenyl)-5-oxo-2-phenyl-5,10b-dihydropyrano[3,4-
c]chromene-1-carboxamide (12b)
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Heterocyclization of ethyl benzoylacetate
Yellow crystals from 1,4-dioxane, yield (4.25 g, 95 %), m.p 86-88 °C. IR (KBr) υ max
cm-1: 3476-3342 (NH2, NH), 3055 (CH, aromatic), 1688, 1686 (2CO), 1650 (exocyclic
1
C=N), 1630 (C=C); H NMR (DMSO- d6, 200 MHz): δ = 4.46 (s, 2H, D2O
exchangeable, NH2), 6.08 (s, 1H, pyran H-4), 7.20-7.46 (m, 13H, C6H5, 2C6H4), 8.31, (s,
1H, D2O exchangeable, NH); 13C NMR (DMSO- d6, 75 MHz): 41.5 (pyran C-4), 119.2,
120.8, 121.1, 121.4, 122.4, 123.9, 124.0, 124.8, 125.1, 125.3, 126.8, 127.9, 133.3, 138.2,
140.6, 141.6 (2C6H5, C6H4, pyran C), 164.2, 168.3 (2CO).Anal. Calculated for
C25H17ClN2O4: C, 67.50; H, 3.85; N, 6.30. Found: C, 67.72; H, 3.59; N, 6.42. MS: m/e
444 (M+, 38 %).
4.1.8. General procedure for the synthesis of the 4-cyano-N,3-diphenylbut-3-
enamide derivatives 13a-d
To a dry solid of either compound 3a (2.39 g, 0.01 mol), or 3b (3.63 g, 0.01 mol) either
malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) was added. To
the reaction mixture, in each case, ammonium acetate (0.50 g) was added and the whole
reaction mixture was heated in an oil bath at 120 oC for 30 min then was left to cool. The
remaining product was triturated with ethanol and the formed solid product was collected
by filtration.
4.1.8.1. 4,4-Dicyano-N,3-diphenylbut-3-enamide (13a)
Brown crystals from 1,4-dioxane, yield (1.37 g, 48 %), m.p 150-152 °C. IR (KBr) υ max
cm-1: 3487-3325 (NH), 3054 (CH, aromatic), 2227, 2220 (2CN), 1688 (CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 5.32 (s, 2H, CH2), 7.22-7.43 (m, 10H, 2C6H5), 8.28,
13
(s, 1H, D2O exchangeable, NH); C NMR (DMSO- d6, 75 MHz): 62.6 (CH2), 116.1,
116.8 (2CN), 120.1, 121.9, 123.6, 124.3, 125.7, 126.2, 127.5, 128.8 (2C6H5), 164.4 (CO).
Anal. Calculated for C18H13N3O: C, 75.25; H, 4.56; N, 14.63. Found: C, 75.38; H, 4.38;
N, 14.80. MS: m/e 287 (M+, 32 %).
4.1.8.2. Ethyl 2-cyano-5-oxo-3-phenyl-5-(phenylamino)pent-2-enoate (13b)
Yellow crystals from 1,4-dioxane, yield (1.39 g, 42 %), m.p 105-107 °C. IR (KBr) υ
max cm-1: 3469-3342 (NH), 3054 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 1.12 (t, 3H, J = 6.89 Hz, OCH2CH3), 4.22 (q, 2H, J
= 6.89 Hz, OCH2CH3), 5.36 (s, 2H, CH2), 7.28-7.41 (m, 10H, 2C6H5), 8.26 (s, 1H, D2O
exchangeable, NH); 13C NMR (DMSO- d6, 75 MHz): 16.2 (OCH2CH3), 50.3
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Heterocyclization of ethyl benzoylacetate
(OCH2CH3), 62.6 (CH2), 116.5 (CN), 120.6, 121.3, 123.9, 124.9, 125.3, 126.8, 127.8,
128.3 (2C6H5), 164.8, 166.5 (2CO). Anal. Calculated for C20H18N2O3: C, 71.84; H, 5.43;
N, 8.38. Found: C, 71.69; H, 5.70; N, 8.26. MS: m/e 334 (M+, 38 %).
4.1.8.3. N-(4-Chlorophenyl)-4,4-dicyano-3-phenylbut-3-enamide (13c)
Yellow crystals from 1,4-dioxane, yield (1.30 g, 39.40 %), m.p 154-156 °C. IR (KBr) υ
max cm-1: 3464-3352 (NH), 3054 (CH, aromatic), 2223, 2220 (2CN), 1688 (CO), 1630
(C=C); 1H NMR (DMSO- d6, 200 MHz): δ = 5.38 (s, 2H, CH2), 7.24-7.40 (m, 9H, C6H5,
13
C6H4), 8.28 (s, 1H, D2O exchangeable, NH); C NMR (DMSO- d6, 75 MHz): 62.3
(CH2), 116.3, 116.9 (2CN), 120.6, 121.7, 122.4, 124.9, 125.4, 126.8, 127.3, 128.6 (C6H5,
C6H4), 164.3 (CO). Anal. Calculated for C18H21ClN3O: C, 67.19; H, 3.76; N, 13.06.
Found: C, 67.26; H, 3.80; N, 12.84. MS: m/e 330 (M+, 38 %).
4.1.8.4. Ethyl 5-((4-chlorophenyl)amino)-2-cyano-5-oxo-3-phenylpent-2-enoate
(13d)
White crystals from 1,4-dioxane, yield (2.25 g, 61%), m.p 140-143 °C. IR (KBr) υ max
1
cm1: 3485-3321 (NH), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 1.11 (t, 3H, J = 7.22 Hz, OCH2CH3), 4.22 (q, 2H, J =
7.22 Hz, OCH2CH3), 5.33 (s, 2H, CH2), (m, 9H, C6H5, C6H4), 8.23 (s, 1H, D2O
exchangeable, NH); 13C NMR (DMSO- d6, 75 MHz): 16.4 (OCH2CH3), 50.6
(OCH2CH3), 62.3 (CH2), 116.8 (CN), 120.3, 121.6, 122.5, 124.9, 125.6, 126.2, 127.7,
128.8 (C6H5, C6H4), 164.3, 166.9 (2CO). Anal. Calculated for C20H17ClN2O3: C, 65.13;
H, 4.65; N, 7.60. Found: C, 65.30; H, 4.59; N, 7.41. MS: m/e 368 (M+, 52 %).
4.1.9. General procedure for the synthesis of the pyridine derivatives 14a-d
Either malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) was
added to a solution of either compound 3a (2.39 g, 0.01 mol), or 3b (3.63 g, 0.01 mol) in
absolute ethanol (40 mL) containing triethylamine (1.0 mL). The reaction mixture, in
each case, was heated under reflux for 4h then left to cool and the formed solid product,
in each case, was collected by filtration.
4.1.9.1. 2-Amino-6-oxo-1,4-diphenyl-1,6-dihydropyridine-3-carbonitrile (14a)
Orange crystals from 1,4-dioxane, yield (1.30 g, 45 %), m.p 85-87 °C. IR (KBr) υ max
1
cm-1: 3449, 3355 (NH2), 3055 (CH, aromatic), 2221 (CN), 1689 (CO), 1630 (C=C); H
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Heterocyclization of ethyl benzoylacetate
NMR (DMSO- d6, 200 MHz): δ = 4.82 (s, 2H, D2O exchangeable NH2), 6.32 (s, 1H,
13
pyridine H-5), 7.24-7.40 (m, 10H, 2C6H5); C NMR (DMSO- d6, 75 MHz): 116.5
(CN), 120.4, 120.6, 122.3, 124.8, 125.0, 126.6, 127.3, 128.3 (2C6H5), 164.8 (CO). Anal.
Calculated for C18H13N3O: C, 75.25; H, 4.56; N, 14.63. Found: C, 75.41; H, 4.63; N,
14.59. MS: m/e 287 (M+, 44 %).
4.1.9.2. 2-Hydroxy-6-oxo-1,4-diphenyl-1,6-dihydropyridine-3-carbonitrile (14b)
Yellow crystals from 1,4-dioxane, yield (1.4 g, 48.5 %), m.p 85-87 °C., IR (KBr) υ max
1
cm-1: 3563-3337 (OH), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 6.38 (s, 1H, pyridine H-5), 7.26-7.42 (m, 10H, 2C6H5),
13
10.20 (s, 1H, D2O exchangeable, OH); C NMR (DMSO- d6, 75 MHz): 116.8 (CN),
120.2, 121.8, 122.6, 124.3, 125.6, 127.2, 127.8, 128.9 (2C6H5), 164.6 (CO). Anal.
Calculated for C18H12N2O2: C, 74.99; H, 4.20; N, 9.72. Found: C, 74.75; H, 4.43; N,
9.80. MS: m/e 288 (M+, 32 %).
4.1.9.3. 2-Amino-1-(4-chlorophenyl)-6-oxo-4-phenyl-1,6-dihydropyridine-3-
carbonitrile (14c)
Pale yellow crystals from 1,4-dioxane, yield (1.73 g, 54 %), m.p 142-144 °C. IR (KBr) υ
max cm-1: 3436, 3317 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 4.87 (s, 2H, D2O exchangeable NH2), 6.36 (s, 1H,
pyridine H-5), 7.22-7.49 (m, 9H, C6H5, C6H4); 13C NMR (DMSO- d6, 75 MHz): 116.8
(CN), 120.1, 121.8, 121.9, 123.6, 124.3, 126.2, 127.8, 128.0 (C6H5, C6H4), 164.6 (CO).
Anal. Calculated for C18H12ClN3O: C, 67.19; H, 3.76; N, 13.06. Found: C, 67.36; H,
3.93; N, 12.85. MS: m/e 321 (M+, 38 %).
4.1.9.4. 1-(4-Chlorophenyl)-2-hydroxy-6-oxo-4-phenyl-1,6-dihydropyridine-3-
carbonitrile (14d)
Pale yellow crystals from 1,4-dioxane, yield (1.75 g, 54 %), m.p 148-150 °C. IR (KBr) υ
max cm-1: 3539-3323 (OH), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1634 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 6.35 (s, 1H, pyridine H-5), 7.22-7.46 (m, 9H, C6H5,
13
C6H4), 10.23 (s, 1H, D2O exchangeable, OH); C NMR (DMSO- d6, 75 MHz): 116.9
(CN), 120.8, 121.2, 122.3, 124.5, 125.7, 127.0, 127.6, 128.5 (2C6H5), 164.9 (CO). Anal.
Calculated for C18H11ClN2O2: C, 66.99; H, 3.44; N, 8.68. Found: C, 67.25; H, 3.61; N,
8.47. MS: m/e 322 (M+, 38 %).
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Heterocyclization of ethyl benzoylacetate
4.1.10. General procedure for the synthesis of the arylazo derivatives 16a-m
Either of benzenediazonium chloride (0.01 mol), 4-chlorobenzenediazonium chloride
(0.01 mol) or 4-methoxybenzenediazonium chloride (0.01 mol) [prepared by the addition
o
of sodium nitrite (0.70 g, 0.01 mol) to a cold solution (0-5 C) of either aniline (0.93 g,
0.01 mol), 4-chloroaniline (1.27 g, 0.01 mol) or 4-methoxyaniline (1.23 g, 0.01 mol) in
concentrated hydrochloric acid (12 mL, 18 mol) with continuous stirring] was added to a
cold solution of either 14a (2.87 g, 0.01 mol), 14b (2.88 g, 0.01 mol), 14c (3.21 g, 0.01
mol) or 14d (3.22 g, 0.01 mol) with contineous stirring. The reaction mixture, each case,
was stirred at room temperature for an additional two hours and the formed solid product
was collected by filtration.
4.1.10.1.
2-Amino-6-oxo-1,4-diphenyl-5-(phenyldiazenyl)-1,6-dihydropyridine-3-
carbonitrile (16a)
Orange crystals from 1,4-dioxane, yield (0.861 g, 22 %), m.p 147-150 °C., IR (KBr) υ
max cm-1: 3459, 3328 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C);
1H NMR (DMSO- d6, 200 MHz): δ = 4.89 (s, 2H, D2O exchangeable NH2), 7.23-7.42 (m,
15H, 3C6H5); 13C NMR (DMSO- d6, 75 MHz): 116.7 (CN), 120.5, 121.3, 121.7, 122.8,
123.1, 123.7, 124.3, 125.1, 125.6, 126.6, 127.1, 128.3 (3C6H5), 166.8 (CO). Anal.
Calculated for C24H17N5O: C, 73.64; H, 4.38; N, 17.89. Found: C, 73.80; H, 4.22; N,
18.03. MS: m/e 391 (M+, 26 %).
4.1.10.2.
2-Amino-5-((4-chlorophenyl)diazenyl)-6-oxo-1,4-diphenyl-1,6-dihydro-
pyridine-3-carbonitrile (16b)
Orange crystals from ethanol, yield (1.91 g, 45 %), m.p 150-153 °C. IR (KBr) υ max
1
cm-1: 3438, 3362 (NH2), 3055 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 4.86 (s, 2H, D2O exchangeable NH2), 7.21-7.48 (m,
14H, 2C6H5, C6H4); 13C NMR (DMSO- d6, 75 MHz): 116.9 (CN), 120.2, 121.6, 121.9,
122.2, 123.4, 123.4, 124.6, 125.7, 125.9, 126.8, 127.3, 128.8 (2C6H5, C6H4), 166.2 (CO).
Anal. Calculated for C24H16ClN5O: C, 67.69; H, 3.79; N, 16.44. Found: C, 67.83; H,
4.02; N, 16.72. MS: m/e 425 (M+, 42 %).
4.1.10.3. 2-Amino-5-((4-methoxyphenyl)diazenyl)-6-oxo-1,4-diphenyl-1,6-
dihydropyridine-3-carbonitrile (16c)
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Heterocyclization of ethyl benzoylacetate
Orange crystals from ethanol, yield (2.0 g, 47 %), m.p 160-162 °C. IR (KBr) υ max cm-1:
1
3459, 3383 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); H NMR
(DMSO- d6, 200 MHz): δ = 3.67 (s, 3H, OCH3), 4.89 (s, 2H, D2O exchangeable NH2),
7.20-7.52 (m, 14H, 2C6H5, C6H4); 13C NMR (DMSO- d6, 75 MHz): 52.9 (OCH3), 116.7
(CN), 120.6, 120.8, 121.6, 122.4, 123.6, 123.8, 124.2, 124.9, 125.3, 126.2, 127.1, 128.5
(2C6H5, C6H4), 166.8 (CO). Anal. Calculated for C25H19N5O2: C, 71.25; H, 4.54; N,
16.62. Found: C, 71.09; H, 4.32; N, 16.80. MS: m/e 421 (M+, 38 %).
4.1.10.4. 2-Hydroxy-6-oxo-1,4-diphenyl-5-(phenyldiazenyl)-1,6-dihydro-
pyridine-3-carbonitrile (16d)
Orange crystals from ethanol, yield (2.66 g, 68 %), m.p 143-145 °C. IR (KBr) υ max
1
cm-1: 3468, 3331 (NH2), 3055 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 7.23-7.41 (m, 15H, 3C6H5), 9.83 (s, 1H, D2O
exchangeable); 13C NMR (DMSO- d6, 75 MHz): 116.8 (CN), 120.8, 121.3, 122.6,
122.9, 123.1, 123.6, 124.2, 125.3, 125.9, 126.8, 127.6, 128.2 (3C6H5), 166.6 (CO). Anal.
Calculated for C24H16N4O2: C, 73.46; H, 4.11; N, 14.28. Found: C, 73.26; H, 4.26; N,
14.38. MS: m/e 392 (M+, 38 %).
4.1.10.5. 5-((4-Chlorophenyl)diazenyl)-2-hydroxy-6-oxo-1,4-diphenyl-1,6-
dihydropyridine-3-carbonitrile (16e)
Orange crystals from ethanol, yield (4.0 g, 94 %), m.p 167-170 °C. IR (KBr) υ max cm-
1: 3478, 3351 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); 1H NMR
(DMSO- d6, 200 MHz): δ = 7.21-7.47 (m, 14H, 2C6H5, C6H4), 9.86 (s, 1H, D2O
exchangeable); 13C NMR (DMSO- d6, 75 MHz): 116.5 (CN), 120.2, 120.7, 121.3,
122.4, 123.8, 123.3, 124.5, 125.8, 126.1, 126.2, 127.6, 128.7 (2C6H5, C6H4), 166.9 (CO).
Anal. Calculated for C24H15ClN4O2: C, 67.53; H, 3.54; N, 13.13. Found: C, 67.48; H,
3.70; N, 13.26. MS: m/e 426 (M+, 43 %).
4.1.10.6. 2-Hydroxy-5-((4-methoxyphenyl)diazenyl)-6-oxo-1,4-diphenyl-1,6-
dihydropyridine-3-carbonitrile (16f)
Orange crystals from ethanol, yield (2.56 g, 61 %), m.p 163-165 °C. IR (KBr) υ max
1
cm-1: 3493, 3338 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); H
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Heterocyclization of ethyl benzoylacetate
NMR (DMSO- d6, 200 MHz): δ = 3.66 (s, 3H, OCH3), 7.22-7.52 (m, 14H, 2C6H5, C6H4),
13
9.86 (s, 1H, D2O exchangeable); C NMR (DMSO- d6, 75 MHz): 52.5 (OCH3), 116.5
(CN), 120.4, 120.4, 121.6, 122.8, 123.5, 123.6, 124.9, 126.3, 126.6, 127.2, 127.9, 128.8
(2C6H5, C6H4), 166.7 (CO). Anal. Calculated for C25H18N4O3: C, 71.08; H, 4.29; N,
13.42. Found: C, 71.26; H, 4.37; N, 13.59. MS: m/e 422 (M+, 36 %).
4.1.10.7. 2-Amino-5-((4-chlorophenyl)diazenyl)-6-oxo-1,4-diphenyl-1,6-
dihydropyridine-3-carbonitrile (16g)
Orange crystals from ethanol, yield (2.05g, 48.3 %), m.p 165-168 °C. IR (KBr) υ max
1
cm-1: 3463, 3327 (NH2), 3055 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 4.83 (s, 2H, D2O exchangeable NH2), 7.20-7.52 (m,
14H, 2C6H5, C6H4); 13C NMR (DMSO- d6, 75 MHz): 116.3 (CN), 120.3, 121.2, 121.6,
122.7, 123.2, 124.1, 124.3, 125.7, 125.4, 126.3, 127.8, 128.3 (2C6H5, C6H4), 166.6 (CO).
Anal. Calculated for C24H16ClN5O: C, 67.69; H, 3.79; N, 16.44. Found: C, 67.90; H,
3.81; N, 16.63. MS: m/e 425 (M+, 38 %).
4.1.10.8. 2-Amino-1-(4-chlorophenyl)-5-((4-chlorophenyl)diazenyl)-6-oxo-4-
phenyl-1,6-dihydropyridine-3-carbonitrile (16h)
Organe crystals from ethanol, yield ( 2.957 g, 70 %), m.p 168-170 °C. IR (KBr) υ max
1
cm-1: 3458, 3342 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 4.88 (s, 2H, D2O exchangeable NH2), 7.22-7.53 (m,
13H, C6H5, 2C6H4); 13C NMR (DMSO- d6, 75 MHz): 116.9 (CN), 120.1, 121.4, 121.9,
122.2, 123.1, 123.8, 124.6, 125.2, 125.6, 126.9, 127.1, 128.6 (C6H5, 2C6H4), 166.8 (CO).
Anal. Calculated for C24H15Cl2N5O: C, 62.62; H, 3.28; N, 15.21. Found: C, 62.49; H,
3.25; N, 15.39. MS: m/e 460 (M+, 36 %).
4.1.10.9.
2-Amino-1-(4-chlorophenyl)-5-((4-methoxyphenyl)diazenyl)-6-oxo-4-
phenyl-1,6-dihydropyridine-3-carbonitrile (16i)
Orange crystals from ethanol, yield (1.60 g, 35 %), m.p 156-158 °C. IR (KBr) υ max
1
cm-1: 3470, 3353 (NH2), 3055 (CH, aromatic), 2220 (CN), 1689 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 3.68 (s, 3H, OCH3), 4.83 (s, 2H, D2O exchangeable
NH2), 7.23-7.56 (m, 13H, C6H5, 2C6H4); 13C NMR (DMSO- d6, 75 MHz): 52.6 (OCH3),
116.8 (CN), 120.3, 120.6, 121.8, 122.1, 123.3, 123.9, 124.9, 125.0, 125.6, 126.2, 127.4,
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Heterocyclization of ethyl benzoylacetate
129.3 (C6H5, 2C6H4), 166.5 (CO). Anal. Calculated for C25H18ClN5O2: C, 65.86; H, 3.98;
N, 15.36. Found: C, 65.69; H, 4.25; N, 15.53. MS: m/e 455 (M+, 26 %).
4.1.10.10.
3.15-((4-Chlorophenyl)diazenyl)-2-hydroxy-6-oxo-1,4-diphenyl-1,6-
dihydropyridine-3-carbonitrile (16k)
Orange crystals from ethanol, yield (4.0 g, 94 %), m.p 143-145 °C., IR (KBr) υ max cm-1:
1
3459, 3341 (NH2), 3053 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C); H NMR
(DMSO- d6, 200 MHz): δ = 7.23-7.49 (m, 14H, 2C6H5, C6H4), 9.89 (s, 1H, D2O
exchangeable); 13C NMR (DMSO- d6, 75 MHz): 116.8 (CN), 120.4, 120.9, 121.9,
122.6, 123.8, 123.3, 124.8, 125.3, 126.4, 126.8, 127.3, 128.2 (2C6H5, C6H4), 166.8 (CO).
Anal. Calculated for C24H15ClN4O2: C, 67.53; H, 3.54; N, 13.13. Found: C, 67.63; H,
3.60; N, 13.38. MS: m/e 426 (M+, 28 %).
4.1.10.11.
1-(4-Chlorophenyl)-5-((4-chlorophenyl)diazenyl)-2-hydroxy-6-oxo-4-
phenyl-1,6-dihydropyridine-3-carbonitrile (16l)
Orange crystals from ethanol, yield (2.46 g, 53 %), m.p 157-160 °C. IR (KBr) υ max
1
cm1: 3542-3338 (OH), 3055 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 7.23-7.49 (m, 13H, C6H5, 2C6H4), 10.12 (s, 1H, D2O
13
exchangeable, OH); C NMR (DMSO- d6, 75 MHz): 116.6 (CN), 120.3, 120.5, 121.3,
121.6, 122.4, 123.9, 124.3, 125.0, 126.7, 126.3, 127.6, 128.7 (C6H5, 2C6H4), 166.4 (CO).
Anal. Calculated for C24H14Cl2N4O2: C, 62.49; H, 3.06; N, 12.15. Found: C, 62.33; H,
3.25; N, 11.94. MS: m/e 460 (M+, 30 %).
4.1.10.12. 1-(4-Chlorophenyl)-2-hydroxy-5-((4-methoxyphenyl)diazenyl)-6-oxo-4-
phenyl-1,6-dihydropyridine-3-carbonitrile (16m)
Orange crystals from ethanol, yield (3.438 g, 75 %), m.p 143-145 °C. IR (KBr) υ max
1
cm-1: 3563-3368 (NH2), 3055 (CH, aromatic), 2220 (CN), 1688 (CO), 1630 (C=C); H
NMR (DMSO- d6, 200 MHz): δ = 3.68 (s, 3H, OCH3), 7.23-7.56 (m, 13H, C6H5, 2C6H4),
13
9.89 (s, 1H, D2O exchangeable); C NMR (DMSO- d6, 75 MHz): 52.3 (OCH3), 116.8
(CN), 120.2, 120.3, 121.8, 122.2, 123.6, 123.6, 124.4, 125.7, 126.2, 127.0, 127.4, 128.1
(C6H5, 2C6H4), 166.3 (CO). Anal. Calculated for C25H17ClN4O3: C, 65.72; H, 3.75; N,
12.26. Found: C, 65.61; H, 3.92; N, 12.42. MS: m/e 456 (M+, 40 %).
5.
Supplementary file: 1H NMR and 13C NMR of some selected compounds
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Heterocyclization of ethyl benzoylacetate
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Heterocyclization of ethyl benzoylacetate
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Heterocyclization of ethyl benzoylacetate
Table 1. In vitro growth inhibitory effects (IC50 M) of the selected compounds against
cancer cell lines
Compound
IC50 ± SEM (M)
A549
H460
HT29
MKN-45
U87MG
SMMC-
7721
No
10.42±2.59 9.40 ± 3.53 12.63 ± 4.26 10.52 ± 2.73 9.80 ± 2.19 8.63 ± 2.42
3a
3b
5a
5b
5c
2.08 ± 0.80 1.31± 0.88 2.30 ± 0.80
8.28 ± 4.18 9.62 ± 2.70 8.39 ± 2.73
6.80 ± 1.42 8.59 ± 1.80 7.49 ± 2.73
0.70± 0.29 0.76 ± 0.38 0.65 ± 0.27
0.23 ± 0.08 0.38 ± 0.27 0.19 ± 0.08
7.59 ± 2.31 8.06 ± 3.19 6.59 ± 1.80
0.32 ± 0.20 0.49 ± 0.21 0.63 ± 0.32
1.40 ± 0.69 1.04 ± 0.73 0.86 ± 0.32
0.60 ± 0.24 0.43 ± 0.26 0.62 ± 0.30
10.28±3.57 8.47 ± 2.49 8.29 ± 2.57
0.38± 0.16 0.42 ± 0.24 0.38 ± 0.08
8.72 ± 2.37 6.93 ± 0.26 4.80 ± 1.53
1.28 ± 0.63 1.32 ± 0.92 2.42 ± 0.79
2.73 ± 0.92 4.52 ± 1.69 1.08 ± 0.93
7.09 ± 2.35 8.93 ± 2.73 5.09 ± 1.63
8.09 ± 2.04 7.42 ± 2.69 8.58 ± 2.68
0.42 ± 0.23 0.59 ± 0.18 0.69 ± 0.28
0.26 ± 0.11 0.39 ± 0.21 0.42 ± 0.27
9.14 ± 2.59 6.28 ± 1.49 7.93 ± 1.31
0.59 ± 0.23 0.62 ± 0.18 0.53 ± 0.27
0.59 ± 0.32 0.86 ± 0.52 0.39 ± 0.18
5d
6a
6b
6c
0.39± 0.15
0.43 ± 0.26 0.73 ± 0.31
6d
8
9.36 ± 2.53 8.29 ± 2.44 10.21 ± 2.52
0.72 ± 0.37 0.66 ± 0.26 0.72 ± 0.17
8.38 ± 2.17 9.49 ± 2.58 8.27 ± 2.69
2.29 ± 0.06 1.81 ± 0.20 1.64± 0.21
8.93 ± 2.73 9.71 ± 2.60 8.63 ± 2.59
10
11a
11b
12a
10.37 ±
3.80
8.51 ± 2.72 8.97 ± 1.60
0.35± 0.24 0.43 ± 0.19 0.65 ± 0.26
6.22 ± 2.48 7.80 ± 2.57 8.41 ± 2.39
5.60 ± 1.31 6.27 ± 1.42 5.33 ± 2.41
0.53 ± 0.19 0.63 ± 0.17 0.52 ± 0.28
8.29 ± 2.72 8.93± 2.58 8.36 ± 2.61
6.38 ± 2.08 5.70 ± 2.49 8.90 ± 2.37
0.63 ± 0.36 0.49 ± 0.23 0.71 ± 0.36
12b
13a
13b
13c
0.41 ± 0.28 0.84 ±
0.32
0.52 ± 0.42
0.38 ± 0.16 0.45 ± 0.18 0.39 ± 0.16
0.50 ± 0.24 0.72 ± 0.30 0.45 ± 0.27
9.03 ± 2.42 7.05 ± 1.62 6.99 ± 2.37
0.68 ± 0.28 0.63 ± 0.25 0.52 ± 0.26
0.30 ± 0.17 0.42 ± 0.16 0.41 ± 0.20
0.25 ± 0.08 0.29 ± 0.13 0.38 ± 0.20
13d
14a
14b
14c
14d
16a
16b
6.93 ± 2.30 7.29 2.52 8.04 ± 2.17
0.38± 0.16 0.42 ± 0.27 0.38 ± 0.17
0.25 ± 0.29 0.39 ± 0.23 0.46 ± 0.27
0.31 ± 0.16 0.42 ± 0.12 0.22 ± 0.13
8.40 ± 2.25 7.84 ± 2.60 9.31 ± 2.53
8.52± 2.39
8.63 ± 2.38 8.16 ± 2.38
2.73 ±
1.06
1.38 ±
0.87
3.51 ± 1.63
4.17 ± 1.27 5.02 ± 1.69 3.26 ± 1.16
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Heterocyclization of ethyl benzoylacetate
5.29 ±
2.17
6.68 ±
2.58
8.32 ± 2.70
4.83 ± 1.95 5.07 ± 1.26 6.95 ± 2.41
0.40 ± 0.15 0.52 ± 0.28 0.63 ± 0.27
16c
1.02 ± 0.82 0.99 ± 0.35 0.62 ± 0.41
3.47 ± 1.02 1.40 ± 0.39 0.72 ± 0.38
1.38± 0.68 1.46 ± 0.67 1.34 ± 0.57
2.38 ± 0.89 1.29 ± 0.76 1.32 ± 0.75
16d
16e
16f
0.98 ± 0.33 0.86± 0.52
0.98 ± 0.61
2.63 ± 1.59 1.93 ± 0.82 2.83 ± 0.96
2.61 ± 1.18 2.83 ± 0.83 1.63 ± 0.87
0.79 ± 0.25 1.05 ± 0.69 0.96 ± 0.34
16g
16h
1.40 ±
0.57
0.80 ± 0.62 1.39 ± 0.74
2.30 ± 1.02 1.96 ± 0.88 2.70 ± 1.16
1.97 ± 0.86 1.38 ± 0.94 4.80 ± 1.18
0.30 ± 0.13 0.52 ± 0.17 0.46 ± 0.21
16i
0.33 ±
0.15
0.62 ± 0.21 0.29 ± 0.18
16k
0.42 ± 0.26 0.41 ± 0.21 0.63 ± 0.30
0.49 ± 0.19 0.32 ± 0.11 0.63 ± 0.21
0.48 ± 0.23 0.37 ± 0.25 0.69 ± 0.32
16l
0.29 ± 0.12 0.35 ± 0.17 0.59 ± 0.25
16m
0.08 ± 0.01 0.18 ± 0.03 0.15 ± 0.023 0.03
±0.0055
0.90 ± 0.13 0.44 ± 0.062
Foretinib
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Heterocyclization of ethyl benzoylacetate
Ph
O
PhHNOC
Ph
CN
NH2
CN
CN
CHO
H2C
EtOH
Et3N
O
CONH
Ph
EtOH
Et3N
CN
CN
CHO
H2C
O
OH
PhHNOC
NH
NH2
Ph
O
This article is protected by copyright. All rights reserved.

Heterocyclization of ethyl benzoylacetate
Uses of ethyl benzoyl acetate for the synthesis of thiophene, pyran and pyridine
derivatives with anti-tumor activities
Bishoy Anis Ibrahim,1* Rafat Milad Mohareb1
1Department of chemistry Faculty of Science Cairo University, Giza, Egypt
e-mail: bishoyibrahim191@yahoo.com
Ph
PhHNOC
CN
NH2
CN
CN
Ph
O
CHO
H2C
EtOH
Et3N
O
CONH
Ph
EtOH
Et3N
CN
CN
CHO
H2C
O
OH
PhHNOC
NH
NH2
Ph
O
This article is protected by copyright. All rights reserved.