Uses of ethyl benzoylacetate for the synthesis of thiophene, thiazole, pyridine, and pyran derivatives with antitumor activities

Article abstract of DOI:10.1002/jhet.3865

The reaction of ethyl benzoylacetate with malononitrile in an oil bath at 120°C gave the condensation product 3. The latter compound underwent a series of heterocyclization to give thiophene, thiazole, pyridine, and pyran derivatives. The structures of the synthesized products were established on the basis of analytical and spectral data. The antitumor evaluation of the newly synthesized products against the six cancer cell lines namely human gastric cancer (NUGC and HR), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), human breast cancer (MCF), nasopharyngeal carcinoma (HONE1), and normal fibroblast cells (WI38) indicated that many compounds expressed high inhibition against the six cancer cell lines. Compounds 3, 8a, 8c, 14b, 16b, 16c, 16d, 19a, 19b, 20a, 22a, 27b, and 28a were the most cytotoxic compounds among the tested compounds.

Full text of DOI:10.1002/jhet.3865

Received: 7 November 2019
DOI: 10.1002/jhet.3865
Revised: 28 November 2019
Accepted: 6 December 2019
A R T I C L E
Uses of ethyl benzoylacetate for the synthesis of thiophene,
thiazole, pyridine, and pyran derivatives with antitumor
activities
Rafat M. Mohareb
| Bahaa M. Mostafa
Department of Chemistry, Faculty of
Science, Cairo University, Giza, Egypt
Abstract
The reaction of ethyl benzoylacetate with malononitrile in an oil bath at 120ꢀC
Correspondence
gave the condensation product 3. The latter compound underwent a series of
heterocyclization to give thiophene, thiazole, pyridine, and pyran derivatives.
The structures of the synthesized products were established on the basis of
analytical and spectral data. The antitumor evaluation of the newly synthe-
sized products against the six cancer cell lines namely human gastric cancer
(NUGC and HR), human colon cancer (DLD1), human liver cancer (HA22T
and HEPG2), human breast cancer (MCF), nasopharyngeal carcinoma
(HONE1), and normal fibroblast cells (WI38) indicated that many compounds
expressed high inhibition against the six cancer cell lines. Compounds 3, 8a,
8c, 14b, 16b, 16c, 16d, 19a, 19b, 20a, 22a, 27b, and 28a were the most cytotoxic
compounds among the tested compounds.
Rafat M. Mohareb, Department of
Chemistry, Faculty of Science, Cairo
University, Giza, Egypt.
Email: raafat_mohareb@yahoo.com
1 | INTRODUCTION
2 | RESULTS AND DISCUSSION
The synthesis of heterocyclic compounds attracted the
attention of many researchers all over the world due to
their high potentialities of biological and pharmaceutical
activities. In the market, there are many drugs such as thia-
zole, thiophene, and pyridine derivatives. For such exces-
sive benefits, these compounds were used in many efficient
synthetic transformations and are used as intermediates in
many chemical reactions.[1–10] It has been reported that
many thiazole, thiophene, and pyrazole derivatives showed
potent analgesic,[11,12] anticonvulsant, anti-inflammatory
and antibacterial,[13,14] antipyretics,[15] antitumor,[16,17]
antiparasitic,[18] antimicrobial,[19] antihistaminic,[20] anti-
anexiety test in mice,[21] antiarrhythmic,[22] and serotonin
antagonist.[23] In the present work, we studied the reaction
of ethyl benzoylacetate with some cyanomethylene
reagents followed by reaction with elemental sulfur. More-
over, studying of different heterocyclization for the reaction
products together with their anti-tumor activities of
towards cancer cell lines was recorded.
Our research group was involved in recent years
through a program, which involves synthesis of new
heterocyclic compounds that were evaluated as antican-
cer agents.[24–26] As continuation of this program, we
were concentrated in this work through the synthesis of
novel compounds followed by their cytotoxic evalua-
tions toward different cancer cell lines. To achieve this
goal, our strategy was to synthesize a series of thiazole,
thiophene, pyridine, and pyridazine derivatives using
ethyl benzoylacetate that reacted with active methylene
reagents followed by heterocyclization of the product.
Thus, the reaction of ethyl benzoylacetate (1) with
malononitrile (2) in the presence of ammonium acetate
in an oil bath at 120ꢀC gave the Knoevenagel condensa-
tion product 3. The structure of compound 3 was eluci-
dated on the basis of its analytical and spectral data.
The reaction of compound 3 with elemental sulfur
yielded the polyfunctionally substituted thiophene
derivative 4.
J Heterocycl Chem. 2020;1–16.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals, Inc.
1

2
MOHAREB AND MOSTAFA
Recently, our research group was involved through a
(Scheme 1). Structures of compounds 8a-c were con-
firmed on the basis of their respective analytical and
spectral data. Thus, the H NMR spectrum of compound
series of reactions involving the reaction of active methy-
lene reagents with phenylisothiocyanate in basic
dimethylformamide to produce the corresponding inter-
mediate potassium salts. Heterocyclization of the inter-
mediate potassium salts took place through their
individual reaction with any of the α-halocarbonyl deriv-
atives. The reaction leading to the formation of either
thiophene or thiazole derivatives depended on the nature
of the active methylene compound that is being
used.[27–29] The active methylene moiety present in com-
pound 3 showed interesting reactivity toward the forma-
tion of potassium sulfide salts. Thus, compound 3 was
reacted with phenylisothiocyanate (5) in DMF/KOH
solution to give the intermediate potassium salt 6. The
latter intermediate was reacted with any of the
α-halocarbonyl compounds namely 2-bromo-1-(p-tolyl)
ethanone (7a), ethyl chloroacetate (7b), or chloroacetone
(7c) to give the thiazole derivatives 8a-c, respectively
1
8a showed besides the expected signals, a singlet at δ
2.69 ppm equivalent to the CH3 group, a singlet at δ
6.03 ppm due to thiazole H-5, and a multiplet at δ
7.23-7.42 ppm corresponding to the two C6H5 and one
C6H4 groups. In addition, the 13C NMR spectrum showed
the presence of two signals at 116.3 and 117.5 equivalent
to the two CN groups, signals at 120.3, 122.5, 123.1,
123.9, 124.2, 124.8, 125.0, 126.3, 127.5, 128.0, 128.5, 129.0,
139.2, 140.1 equivalent to the two C6H5, one C6H4 group,
and thiazoles C-3, C-4, and a singlet at 164.8 due to the
CO group.
On the other hand, the reaction of compound 3 with
benzenediazonium chloride (9) in ethanolic solution con-
taining ammonium acetate gave the pyridazine derivative
10. The structure of the latter product was based on its
analytical and spectral data (see experimental section)
SCHE ME 1 Synthesis of
compounds 3, 4 and 8a-c

MOHAREB AND MOSTAFA
3
besides its synthesis using another reaction route.
Thus, the reaction of the ethyl 3-oxo-3-phenyl-
2-(2-phenylhydrazono)propanoate (11) with malononitrile
(2) in sodium ethoxide solution gave the same reaction
product 10 (m.p., mixed m.p, and fingerprint IR spectrum).
Moreover, compound 10, which resulted by the two reac-
tion pathways, underwent C=NH moiety hydrolysis upon
its heating in ethanol containing sodium hydroxide pellets
to give the 3-oxopyridazine derivative 12 through ammo-
nia elimination.
The anilide derivatives 14a,b were formed through the
reaction of ethyl benzoyl acetate (1) with either
4-methylaniline (13a) or 4-chloroaniline (13b) according to
the reported work.[30] The reaction of either compound 14a
or 14b with either of malononitrile (2) or ethyl cyanoacetate
(15) gave the pyridine derivatives 16a-d, respectively. The
reaction took place through the first condensation of the
active methylene with either 14a or 14b followed by cycliza-
tion. The reaction of either compound 16a or 16c with ben-
zenediazonium (9) gave the polyfunctionally substituted
SCHEME 2 Synthesis of
compounds 10, 12, 14a,b; 16a-d
and 17a,b

4
MOHAREB AND MOSTAFA
pyridine derivatives 17a and 17b, respectively (Scheme 2).
The analytical and spectral data of compounds 17a and 17b
were in agreement with their respective structures.
On the other hand, the reaction of either compound
16a or 16c with thioglycolic acid (18) gave the thiazole
derivatives 19a and 19b respectively. The analytical and
spectral data of the latter products were consistent with
their respective structures.
The 2-imino group present in each of the com-
pounds 16a and 16c showed interesting reactivity
toward alkylation and addition reactions. Thus, the
reaction of either compound 16a or 16c with ethyl
chloroacetate (7b) gave the pyridin-2(1H)-ylidene)
amino)acetate derivatives 20a and 20b, respectively.
Structures of the latter products were based on their
respective analytical and spectral data (see experimen-
tal section). The existence of the =NCH2-COOEt moi-
ety in compounds 20a and 20b can be confirmed based
on their further cyclization in sodium ethoxide solution
to give the pyrrolo[2,3-b]pyridine derivatives 21a and
21b, respectively. On the other hand, the reaction of
either compound 16a or 16c with phenylisothiocyanate
(5) in 1,4-dioxane solution gave pyridin-2(1H)-ylidene)-
3-phenylthiourea derivatives 22a and 22b, respectively
(Scheme 3).
SCHEME 3 Synthesis of compounds 19a,b; 20a,b; 21a,b and 22a,b

MOHAREB AND MOSTAFA
5
Compound 16 reacted with either malononitrile (2) or
ethyl cyanoacetate (15) to give the 7,8-dihydro-2H-pyrano
[2,3-b]pyridine-6-carbonitrile derivatives 23a and 23b,
respectively. The 2-imino moiety present in compound 16c
reacted with ethyl cyanoacetate (15) in dimethylformamide
to give 1,8-naphthyridine-3-carbonitrile derivative 25
(Scheme 4). The reaction took place through the intermedi-
ate formation of 24 followed by cyclization.
synthetic time and effort[31]; as a result, no separation of
reaction intermediates occurs.[32]. In addition, these reac-
tions were characterized by high atom economy and high
selectivity products.[33] Due to such great benefits of
MCRs, the synthesis of many heterocyclic compounds
was carried out applying such MCRs.[34] On the other
hand, many pharmaceutical drugs contained 4-H pyran
moieties[35–37]; this encouraged us to synthesize 4-H
pyran derivatives through the MCRs of compound 14a.
Therefore, the reaction of compound 14a with either of
the aromatic aldehydes 26a, 26b, or 26c and
malononitrile (2) in 1,4-dioxane containing triethylamine
gave the pyran derivatives 27a-c, respectively. Moreover,
Recently,
a
major concern about the multi-
component reactions (MCRs) has been considered as
through such types of reactions, three or more compo-
nents are combined together in one reaction vessel to
produce final products with the privilege of a short
SCHEME 4 Synthesis of
compounds 23a,b and 25

6
MOHAREB AND MOSTAFA
the reaction of compound 14a with either of the aromatic
aldehydes 26a, 26b, or 26c and malononitrile (2) in
1,4-dioxane containing ammonium acetate gave the pyri-
dine derivatives 28a-c, respectively (Scheme 5).
L-glutamine were purchased from Gibco Invitrogen
Co. (Scotland, UK). RPMI-1640 medium was purchased
from Cambrex (New Jersey). Dimethyl sulfoxide
(DMSO), doxorubicin, penicillin, streptomycin, and sul-
forhodamine B (SRB) were purchased from Sigma
Chemical Co. (Saint Louis).
3 | BIOLOGICAL ASSAY
3.1 | In vitro cytotoxic assay
3.1.1 | Chemicals
3.1.2 | Cell cultures
The cancer cell lines NUGC, DLDI, HA22T, HEPG2,
HONE1, and MCF were provided from the National Can-
cer Institute (NCI, Cairo, Egypt).
The newly synthesized compounds throughout this
work were evaluated according to standard methods for
Through this work, all chemicals that were used
through screening process were purchased from interna-
tional companies. Fetal bovine serum (FBS) and
SCHEME 5 Synthesis of
compounds 27a-c and 18a-c

MOHAREB AND MOSTAFA
7
their in vitro cytotoxicity against the six human cancer
cell lines, which are derived from human gastric cancer
(NUGC), human colon cancer (DLD1), human liver can-
cer (HA22T and HEPG2), human breast cancer (MCF),
nasopharyngeal carcinoma (HONE1), and normal fibro-
blast cells (WI38). All of the IC50 values were listed in
Table 1. Some heterocyclic compounds were observed
with significant cytotoxicity against most of the cancer
cell lines tested (IC50 = 10-1000 nM). The normal cell
line fibroblast cells (WI38) were affected to a much lesser
extent (IC50 > 10 000 nM). The reference compound
used during measurements is CHS-828, which is a pyridyl
cyanoguanidine anti-tumor agent.
3.1.3 | Structure-activity relationship
It is clear from Table 1 that compounds 3, 8a, 8c, 14b,
16b, 16c, 16d, 19a, 19b, 20a, 22a, 27b, and 28a were most
cytotoxic among the tested compounds. Compound
3 showed high cytotoxicity against DLDI, HA22T,
HEPG2, HONE1, and MCF cell lines. Its activity is attrib-
uted to the presence of the two CN groups together with
the COOEt group. Considering the thiophene derivative
4, it showed low cytotoxicities toward NUGC, HA22T,
and HEPG2 cell lines, whereas it showed moderate activi-
ties toward DLDI, HONE1, and MCF cell lines. For the
thiazole derivatives 8a-c, it is obvious that compounds 8a
TABLE 1 Cytotoxicity of the selected synthesized compounds against a variety of cancer cell lines [IC50b (nM)]
Compound
Cytotoxic assay
NUGC
1327
2160
130
DLDI
328
HA22T
529
HEPG2
1160
2761
168
HONE1
128
MCF
427
WI38
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
399
865
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
3
4
1142
315
3277
402
1265
624
1290
143
8a
8b
2138
452
1760
82
1410
116
1272
320
1265
160
265
8c
172
10
2401
3277
327
1468
2159
423
2153
1273
431
2041
3217
128
2183
2180
219
2159
2913
1265
2258
1273
1022
529
14a
14b
16a
16b
16c
16d
17a
17b
19a
19b
20a
20b
22a
22b
25
1756
284
1088
3809
48
1761
2341
213
2111
1209
76
2870
2196
683
1463
38
1036
146
272
120
417
1760
2160
132
1630
1272
810
1833
2129
266
1872
2250
1830
1196
168
1336
1266
320
2208
241
742
639
130
283
1620
1046
1562
339
1020
2255
382
158
542
320
2269
213
1194
94
1672
62
1438
1402
1148
1643
1180
388
1086
2120
1820
89
2779
2840
1368
96
1429
1621
1225
253
622
1241
2251
2373
220
2837
329
27a
27b
27c
28a
28b
28c
CHS828
238
2657
265
1878
563
2282
1530
1172
2793
2067
1362
2677
1893
2260
1245
1829
1523
1539
1209
15
2422
672
1038
1485
25
2318
2236
2315
1730
2446
18
Abbreviations: DLDI, colon cancer; HA22T, liver cancer; HEPG2, liver cancer; HONEI, nasopharyngeal carcinoma; HR, gastric cancer; MCF, breast cancer;
NUGC, gastric cancer; WI38, normal fibroblast cells.

8
MOHAREB AND MOSTAFA
(R' = 4-CH3-C6H4) and 8c (R' = CH3) were more cyto-
toxic than 8b (R' = OH). The pyridazine derivative 10
showed low cytotoxicity toward the five cancer cell lines
NUGC, HA22T, HEPG2, HONE1, and MCF while it
showed moderate activity toward DLDI cell line with
IC50 1468 nM. For the anilide derivatives 14a,b, it is clear
that compound 14b (X = Cl) revealed high cytotoxicities
with IC50's 327, 423, 431, 128, and 219 nM toward NUGC,
DLDI, HA22T, HEPG2, and HONE1 cell lines and these
are higher than those of compound 13a (X = CH3)
although the latter exhibited moderate inhibition toward
HA22T cell line with IC50 1273 nM. On the other hand,
for compounds 16a-d, it is clear that compounds 16b
(X = CH3, Y = O), 16c (X = Cl, Y = NH), and 16d
(X = Cl, Y = O) showed high cytotoxicities. For the pyri-
dine derivatives 17a,b, compound 17a exhibited moderate
inhibitions toward the six cancer cell lines while com-
pound 17b showed low inhibitions. Considering the
1,2-dihydropyridin-3-yl)thiazol derivatives 19a,b where
compound 19a (X = CH3) high inhibitions toward the
five cancer cell lines NUGC, DLDI, HA22T, HEPG2 and
MCF cell lines with IC50's 132, 241, 810, 266 and 320 nM
while it showed moderate inhibition toward HONE1 cell
line. On the other hand, compound 19b (X = Cl) showed
high cytotoxicities toward NUGC, DLDI, HA22T, and
HEPG2. Considering pyridine derivatives 20a,b and
22a,b, it is clear from Table 1 that compounds 20a
(X = CH3) and 22a (X = CH3) were more cytotoxic than
compounds 20b (X = Cl) and 22b (X = Cl). Compound 25
showed low inhibitions toward the six cancer cell line.
For the pyran derivatives 27a-c, it is obvious that com-
pound 27b (X = OCH3) is the most cytotoxic compound
among the three compounds. Although, compound 27a
(X = H) showed high inhibition toward HEPG2 cell line
with IC50 329 nM. However, for the pyridine derivatives
28a-c, it is obvious that compound 28a (X = H) exhibited
high inhibitions toward the three cancer cell lines NUGC,
DLDI, MCF with IC50's 265, 563, and 672 nM while com-
pound 28b (X = Cl) showed moderate inhibitions and
compound 28c (X = OCH3) exhibited low inhibitions.
groups enhances the cytotoxicity of the tested
compound.
5 | EXPERIMENTAL
5.1 | General
The obtained compounds showed their melting points
using electrothermal digital melting point apparatus and
are uncorrected. IR spectra (KBr disks) were measured
on an FTIR plus 460 or Pye Unicam SP-1000 spectropho-
1
tometer (Pye Unicam, Cambridge, UK). H NMR spectra
were obtained using Varian Gemini-300 (300 MHz, Var-
ian, 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) instrument. Analytical data were obtained from
Vario EL III Elemental CHNS analyzer. Compounds 12a
and 12b were synthesized according to the reported
literature.[27]
5.2 | Ethyl 4,4-dicyano-3-phenylbut-
3-enoate (3)
To a dry solid of compound 1 (1.92 g, 0.01 mol), each of
malononitrile (0.66 g) and ammonium acetate (0.50 g)
were added. The reaction mixture was heated in an oil
bath at 120ꢀC for 15 minutes and then was left to cool.
The formed solid was triturated with diethyl ether, and
the crystallized product was collected by filtration.
Orange crystals from 1,4-dioxane yield (1.68 g, 70%),
mp 120-122ꢀC, IR (KBr) νmax 2984 (CH2), 2225, 2220
1
(2CN), 1689 (C=O), 1625 (C=C); H NMR (DMSO-d6,
200 MHz): δ = 1.28 (t, 3H, J = 7.28 Hz, CH3), 4.22 (q, 2H,
J = 7.28 Hz, CH2), 7.29-7.37 (m, 5H, C6H5); 13C NMR
(DMSO-d6, 75 MHz): δ 16.3 (OCH2CH3), 38.2 (CH2), 50.6
(OCH2CH3), 86.7, 103.5 (C=C), 116.3, 117.0 (2CN), 120.2,
122.6, 124.8, 128.0 (C6H5), 163.8 (CO). EIMS: m/z
240 [M]+ (38%). Analysis calculated for C14H12N2O2
(240.26): C, 69.99; H, 5.03; N, 11.66%. Found: C, 70.21; H,
4.83; N, 11.80%.
4 | CONCLUSIONS
Through this work, we have synthesized new series of
pyridine, pyran, and thiophene derivatives. The
obtained compounds were screened against NUGC,
DLDI, HA22T, HEPG2, HONE1, and MCF and the nor-
mal cell line WI38. The results showed that compounds
3, 8a, 8c, 14b, 16b, 16c, 16d, 19a, b, 20a, 22a, 27b, and 28
were the most active compounds toward the six cancer
cell lines and no activity toward the normal cell line. In
most cases, the presence of electronegative Cl or OCH3
5.3 | Ethyl 5-amino-4-cyano-
3-phenylthiophene-2-carboxylate (4)
Elemental sulfur (0.32 g, 0.01 mol) was added to a solu-
tion of compound 3 (2.40 g, 0.01 mol) in 1,4-dioxane
(30 mL) containing triethylamine (0.50 mL). The reaction
mixture was heated under reflux for 1 hour and then

MOHAREB AND MOSTAFA
9
poured onto ice/water containing few drops of
hydrochloric acid, and the formed solid product was col-
lected by filtration.
5.6 | Ethyl 4,4-dicyano-2-(4-hydroxy-
3-phenylthiazol-2(3H)-ylidene)-
3-phenylbut-3-enoate (8b)
Yellow crystals from acetic acid yield (1.57 g, 58%),
mp 160-162ꢀC, IR (KBr) νmax 3452, 3339 (NH2), 2980
Pale yellow crystals from ethanol yield (3.23 g, 78%), mp
109-111ꢀC, IR (KBr) νmax 3525-3323 (NH), 2989, 2876
(CH3, CH2), 2222, 2220 (2CN), 1688 (C=O), 1623 (C=C);
1H NMR (DMSO-d6, 200 MHz): δ = 1.16 (t, 3H,
J = 6.30 Hz, CH3), 4.23 (q, 2H, J = 6.30 Hz, CH2), 6.06 (s,
1H, thiazole H-5), 7.25-7.46 (m, 10H, 2C6H5), 10.28 (s,
1H, D2O exchangeable, OH); 13C NMR (DMSO-d6,
75 MHz): δ 16.8 (OCH2CH3), 50.3 (OCH2CH3), 90.1,
105.3, 108.6, 109.4 (2 C=C), 116.8, 117.2 (2CN), 120.1,
122.3, 122.9, 123.8, 124.2, 124.8, 126.2, 127.3, 138.5, 140.3
(2C6H5, thiazole C-3, C-4), 164.4 (CO). EIMS: m/z
415 [M]+ (38%). Analysis calculated for C23H17N3O3S
(415.46): C, 66.49; H, 4.12; N, 10.11; S, 7.72%. Found: C,
66.53; H, 4.29; N, 9.84; S, 7.58%.
1
(CH2), 2221 (CN), 1687 (C=O), 1623 (C=C); H NMR
(DMSO-d6, 200 MHz): δ = 1.25 (t, 3H, J = 6.59 Hz, CH3),
4.24 (q, 2H, J = 6.59 Hz, CH2), 4.79 (s, 2H, D2O
exchangeable, NH2), 7.28-7.39 (m, 5H, C6H5); 13C NMR
(DMSO-d6, 75 MHz):
δ
16.3 (OCH2CH3), 50.3
(OCH2CH3), 116.8 (CN), 120.8, 123.2, 126.9, 129.0 (C6H5),
164.5 (CO). EIMS: m/z 272 [M]+ (42%). Analysis calcu-
lated for C14H12N2O2S (272.32): C, 61.75; H, 4.44; N,
10.29; S, 11.77%. Found: C, 61.83; H, 4.53; N,
11.03; S, 11.53%.
5.4 | General procedure for the synthesis
of the thiazole derivatives 8a-c
Phenylisothiocyanate (1.30 g, 0.01 mol) was added to a
5.7 | Ethyl 4,4-dicyano-2-(4-methyl-
3-phenylthiazol-2(3H)-ylidene)-
3-phenylbut-3-enoate (8c)
solution of compound
1
(1.92 g, 0.01 mol) in
dimethylformamide (40 mL) containing potassium
hydroxide (0.40 mL, 0.01 mol). The reaction mixture was
kept at room temperature with continuous stirring for
24 hours. On the next day, either of the α-halocarbonyl
compounds 7a (215 g, 0.01 mol), 7b (1.22 g, 0.01 mol), or
7c (0.92 g, 0.01 mol) was added. The whole reaction mix-
ture was kept at room temperature for another 24 hours
with continuous stirring. The solid product, formed in
each case upon pouring onto ice/water mixture con-
taining few drops of hydrochloric acid, was collected by
filtration.
Yellow crystals from dioxane yield (2.97 g, 72%), mp
130-132ꢀC, IR (KBr) νmax 2986, 2872 (CH3, CH2), 2224,
1
2220 (2CN), 1689 (C=O), 1623 (C=C); H NMR (DMSO-
d6, 200 MHz): δ = 1.14 (t, 3H, J = 7.42 Hz, CH3), 2.67 (s,
3H, CH3), 4.21 (q, 2H, J = 7.42 Hz, CH2), 6.06 (s, 1H, thi-
azole H-5), 7.25-7.46 (m, 10H, 2C6H5); 13C NMR (DMSO-
d6, 75 MHz): δ 16.2 (OCH2CH3), 50.6 (OCH2CH3), 90.6,
105.2, 108.3, 110.6 (2 C=C), 116.1, 117.8 (2CN), 120.1,
122.6, 123.8, 124.0, 124.6, 125.8, 125.9, 126.2, 126.9, 127.1,
128.2, 130.3, 138.6, 140.6 (2C6H5, C6H4, thiazole C-3, C-
4), 164.5 (CO). EIMS: m/z 413 [M]+ (28%). Analysis cal-
culated for C24H19N3O2S (413.49): C, 69.71; H, 4.63; N,
10.16; S, 7.75%. Found: C, 69.92; H, 4.72; N,
10.36; S, 7.83%.
5.5 | Ethyl 4,4-dicyano-3-phenyl-
2-(3-phenyl-4-(p-tolyl)thiazol-2(3H)-
ylidene)but-3-enoate (8a)
Yellow crystals from 1,4-dioxane yield (3.22 g, 66%), mp
140-142ꢀC, IR (KBr) νmax 2988, 2875 (CH3, CH2), 2223,
2220 (2CN), 1689 (C=O), 1626 (C=C); H NMR (DMSO-
5.8 | 3-Imino-2,5-diphenyl-
2,3-dihydropyridazine-4-carbonitrile (10)
1
d6, 200 MHz): δ = 1.14 (t, 3H, J = 7.17 Hz, CH3), 2.69
(s, 3H, CH3), 4.21 (q, 2H, J = 7.17 Hz, CH2), 6.03 (s, 1H,
thiazole H-5), 7.23-7.42 (m, 14H, 2C6H5, C6H4); 13C NMR
(DMSO-d6, 75 MHz): δ 16.4 (OCH2CH3), 24.3 (CH3), 50.2
(OCH2CH3), 90.3, 105.6, 108.1, 110.1 (2 C=C), 116.3,
117.5 (2CN), 120.3, 122.5, 123.1, 123.9, 124.2, 124.8, 125.0,
126.3, 127.5, 128.0, 128.5, 129.0, 139.2, 140.1 (2C6H5,
C6H4, thiazole C-3, C-4), 164.8 (CO). EIMS: m/z 489 [M]+
(32%). Analysis calculated for C30H23N3O2S (489.59): C,
73.60; H, 4.74; N, 8.58; S, 6.55%. Found: C, 73.52; H,
4.81; N, 8.72; S, 6.73%.
Method (A). Benzenediazonium chloride (0.01 mol) (pre-
pared by the addition of sodium nitrite (0.70 g, 0.01 mol)
dissolved in water (5 mL) to a cold solution of aniline
(0.93 g, 0.01 mol) dissolved in concentrated hydrochloric
acid [18 mol, 8 mL] was added with continuous stirring
to a solution of compound 1 (1.92 g, 0.01 mol) in ethanol
(50 mL) containing ammonium acetate (4.00 g). The
reaction mixture was stirred at room temperature for
2 hours and the formed solid product formed was col-
lected by filtration.

10
MOHAREB AND MOSTAFA
Method (B). To a suspension of compound 11 (2.96 g,
triethylamine (0.50 mL). The reaction mixture was
heated under reflux for 3 hours and then poured onto
ice/water mixture containing a few drops of hydrochloric
acid and the formed solid product, in each case, was col-
lected by filtration.
0.01 mol) in sodium ethoxide (prepared by the addition
of metallic sodium (0.36 g, 0.02 mol) to absolute ethanol
(40 mL) till all sodium is being dissolved), malononitrile
(0.66 g, 0.01 mol) was added. The reaction mixture, in
each case, was heated in a boiling water bath for 3 hours
and then poured onto ice/water mixture containing a few
drops of hydrochloric acid and the formed solid product
was collected by filtration.
5.11 | 6-Hydroxy-2-imino-4-phenyl-1-(p-
tolyl)-1,2-dihydropyridine-
3-carbonitrile (16a)
Orange crystals from 1,4-dioxane yield (1.90 g, 70%),
mp 100-102ꢀC, IR (KBr) νmax 3455-3328 (NH), 2986
1
(CH2), 2221 (CN), 1687 (C=O), 1623 (C=C); H NMR
Orange crystals from 1,4-dioxane yield (2.40 g, 80%), mp
133-135ꢀC, IR (KBr) νmax: 3582-3348 (OH, NH), 3055
(CH aromatic), 2220 (CN), 1657 (exocyclic C=N), 1623
(DMSO-d6, 200 MHz): δ = 1.13 (t, 3H, J = 6.84 Hz, CH3),
4.23 (q, 2H, J = 6.84 Hz, CH2), 7.26-7.39 (m, 10H,
2C6H5), 8.25 (s, 1H, D2O exchangeable, NH); 13C NMR
(DMSO-d6, 75 MHz): δ 16.9 (ester CH3), 52.1 (ester CH2),
116.8 (CN), 120.2, 122.6, 124.8, 125.8, 126.9, 127.1, 128.2,
130.3, 132.6, 134.8 (2C6H5, pyridazine C-4, C-5), 168.5,
170.2 (2C=N). EIMS: m/z 344 [M]+ (39%). Analysis calcu-
lated for C20H16N4O2 (344.37): C, 69.76; H, 4.68; N,
16.27%. Found: C, 70.19; H, 4.63; N, 16.45%.
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 2.68 (s, 3H,
CH3), 6.29 (s, 1H, pyridine H-4), 7.27-7.41 (m, 9H, C6H5,
C6H4), 8.28 (s, 1H, D2O exchangeable, NH), 10.19 (s, 1H,
D2O exchangeable, OH); 13C NMR (DMSO-d6, 75 MHz):
δ 116.5 (CN), 120.8, 123.2, 124.8, 125.8, 126.9, 128.0,
129.6, 130.1, 132.6, 133.5, 138.7, 142.6 (C6H5, C6H4, pyri-
dine C-2, C-3, C-4, C-5), 170.8 (C=N). EIMS: m/z
301 [M]+ (28%). Analysis calculated for C19H15N3O
(301.34): C, 75.73; H, 5.02; N, 13.94%. Found: C, 75.92; H,
4.88; N, 14.28%.
5.9 | Ethyl 5-cyano-6-oxo-1,4-diphenyl-
1,6-dihydropyridazine-3-carboxylate (12)
To a solution of compound 11 (3.29 g, 0.01 mol) in etha-
nol (50 mL), sodium hydroxide pellets (0.80 g, 0.02 mol)
were added. The reaction mixture was heated under
reflux for 4 hours and then poured onto ice/water con-
taining hydrochloric acid (18 mol, 3 mL) till pH 6 and
the formed solid product was collected by filtration.
Orange crystals from 1,4-dioxane yield (1.90 g, 70%),
mp 100-102ꢀC, IR (KBr) νmax 3482-3346 (NH), 2985
5.12 | 6-Hydroxy-2-oxo-4-phenyl-
1-(p-tolyl)-1,2-dihydropyridine-
3-carbonitrile (16b)
Orange crystals from 1,4-dioxane yield (2.32 g, 77%), mp
116-118ꢀC, IR (KBr) νmax: 3542-3323 (OH), 3056
(CH aromatic), 2220 (CN), 1693 (CO), 1623 (C=C); H
1
NMR (DMSO-d6, 200 MHz): δ = 2.65 (s, 3H, CH3), 6.27
(s, 1H, pyridine H-4), 7.29-7.46 (m, 9H, C6H5, C6H4),
10.25 (s, 1H, D2O exchangeable, OH); 13C NMR (DMSO-
d6, 75 MHz): δ 24.6 (CH3), 116.3 (CN), 121.2, 122.7, 123.4,
125.5, 126.3, 127.2, 128.9, 130.4, 132.8, 134.2, 136.9, 142.2
(C6H5, C6H4, pyridine C-2, C-3, C-4, C-5), 165.2 (C=O).
EIMS: m/z 302 [M]+ (42%). Analysis calculated for
C19H14N2O2 (302.33): C, 75.48; H, 4.67; N, 9.27%.
Found: C, 75.19; H, 4.72; N, 9.03%.
1
(CH2), 2223 (CN), 1689, 1687 (2C=O), 1626 (C=C); H
NMR (DMSO-d6, 200 MHz): δ = 1.12 (t, 3H, J = 7.22 Hz,
CH3), 4.23 (q, 2H, J = 7.22 Hz, CH2), 7.28-7.42 (m, 10H,
2C6H5); 13C NMR (DMSO-d6, 75 MHz): δ 16.4 (ester
CH3), 52.3 (ester CH2), 116.9 (CN), 120.4, 121.3, 123.5,
124.6, 125.2, 126.7, 127.6, 130.1, 132.8, 136.3 (2C6H5,
pyridazine C-4, C-5), 168.2, 170.6 (2C=N). EIMS: m/z
345 [M]+ (48%). Analysis calculated for C20H15N3O3
(345.35): C, 69.56; H, 4.38; N, 12.17%. Found: C, 69.38; H,
4.52; N, 12.40%.
5.13 | 1-(4-Chlorophenyl)-6-hydroxy-
2-imino-4-phenyl-1,2-dihydropyridine-
3-carbonitrile (16c)
5.10 | General procedure for the
synthesis of the pyridine derivatives 16a-d
Orange crystals from 1,4-dioxane yield (2.11 g, 66%), mp
170-172ꢀC, IR (KBr) νmax: 3568-3315 (OH, NH), 3056
(CH aromatic), 2220 (CN), 1659 (exocyclic C=N), 1621
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 6.26 (s, 1H,
pyridine H-4), 7.22-7.46 (m, 9H, C6H5, C6H4), 8.26 (s, 1H,
Either of malononitrile (0.66 g, 0.01 mol) or ethyl
cyanoacetate (1.13 g, 0.01 mol) was added to a solution
of either compound 14a (2.53 g, 0.01 mol) or 14b
(2.73 g, 0.01 mol) in 1,4-dioxane (40 mL) containing
1

MOHAREB AND MOSTAFA
11
D2O exchangeable, NH), 10.22 (s, 1H, D2O exchangeable,
OH); 13C NMR (DMSO-d6, 75 MHz): δ 116.8 (CN), 120.6,
122.8, 123.6, 124.1, 125.3, 126.8, 128.3, 130.6, 131.2, 134.8,
139.9, 142.9 (C6H5, C6H4, pyridine C-2, C-3, C-4, C-5),
170.2 (C=N). EIMS: m/z 321 [M]+ (42%). Analysis calcu-
lated for C18H12ClN3O (321.76): C, 67.19; H, 3.76; N,
13.06%. Found: C, 67.42; H, 3.80; N, 12.92%.
(CN), 120.8, 123.2, 124.8, 125.8, 126.9, 127.2, 127.8, 128.0,
129.6, 129.8, 130.1, 131.2, 132.6, 133.5, 138.7, 142.6
(2C6H5, C6H4, pyridine C-2, C-3, C-4, C-5), 170.3 (C=N).
EIMS: m/z 405 [M]+ (33%). Analysis calculated for
C25H19N5O (405.45): C, 74.06; H, 4.75; N, 17.27%.
Found: C, 75.29; H, 4.82; N, 17.19%.
5.17 | 1-(4-Chlorophenyl)-6-hydroxy-
2-imino-4-phenyl-5-(phenyldiazenyl)-
1,2-dihydropyridine-3-carbonitrile (17b)
5.14 | 1-(4-Chlorophenyl)-6-hydroxy-
2-oxo-4-phenyl-1,2-dihydropyridine-
3-carbonitrile (16d)
Orange crystals from 1,4-dioxane yield (2.81 g, 66%), mp
180-182ꢀC, IR (KBr) νmax: 3480-3319 (NH), 3056
(CH aromatic), 2221 (CN), 1652 (exocyclic C=N), 1628
Orange crystals from 1,4-dioxane yield (2.42 g, 77%), mp
160-162ꢀC, IR (KBr) νmax: 3562-3342 (OH), 3054
1
1
(CH aromatic), 2221 (CN), 1690 (CO), 1626 (C=C); H
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 2.68 (s, 3H,
NMR (DMSO-d6, 200 MHz): δ = 6.28 (s, 1H, pyridine H-
4), 7.22-7.48 (m, 9H, C6H5, C6H4), 10.25 (s, 1H, D2O
exchangeable, OH); 13C NMR (DMSO-d6, 75 MHz): δ
116.8 (CN), 120.8, 123.1, 123.6, 124.3, 125.9, 128.1, 128.8,
130.6, 132.9, 136.5, 138.8, 142.9 (C6H5, C6H4, pyridine C-
2, C-3, C-4, C-5), 164.8 (C=O). EIMS: m/z 322 [M]+
(32%). Analysis calculated for C18H11ClN2O2 (322.75): C,
66.99; H, 3.44; N, 8.68%. Found: C, 67.26; H,
3.69; N, 8.92%.
CH3), 7.22-7.46 (m, 14H, 2C6H5, C6H4), 8.27 (s, 1H, D2O
exchangeable, NH), 10.23 (s, 1H, D2O exchangeable,
OH); 13C NMR (DMSO-d6, 75 MHz): δ 116.9 (CN), 120.3,
121.8, 123.6, 124.1, 125.2, 126.0, 126.5, 127.5, 128.4, 129.2,
130.6, 130.8, 132.8, 134.9, 136.3, 142.1 (2C6H5, C6H4, pyri-
dine C-2, C-3, C-4, C-5), 170.6 (C=N). EIMS: m/z
425 [M]+ (26%). Analysis calculated for C24H16ClN5O
(425.87): C, 67.69; H, 3.79; N, 16.44%. Found: C, 67.48; H,
3.60; N, 16.58%.
5.15 | General procedure for the
synthesis of the phenylazo derivatives 17a,b
5.18 | General procedure for the
synthesis of the 1,2-dihydropyridin-3-yl)
thiazole derivatives 19a,b
Benzenediazonium chloride (0.01 mol) (prepared by the
addition of sodium nitrite [0.70 g, 0.01 mol] dissolved in
water [5 mL] to a cold solution of aniline [0.93 g,
0.01 mol] dissolved in concentrated hydrochloric acid
[18 mol, 8 mL]) was added with continuous stirring to a
solution of either compound 16a (3.01 g, 0.01 mol) or 16c
(3.21 g, 0.01 mol) in ethanol (50 mL) containing ammo-
nium acetate (4.00 g). The reaction mixture was stirred at
room temperature for 2 hours and the formed solid prod-
uct formed was collected by filtration.
Thioglycolic acid (0.92 g, 0.01 mol) was added to a solu-
tion of either compound 16a (3.01 g, 0.01 mol) or 16c
(3.21 g, 0.01 mol) in acetic acid (40 mL). The reaction
mixture was heated under reflux for 2 hours and then
evaporated in vacuum. The remaining product was tritu-
rated with ethanol and the formed solid product was col-
lected by filtration.
5.19 | 2-(6-Hydroxy-2-imino-4-phenyl-
1-(p-tolyl)-1,2-dihydropyridin-3-yl)thiazol-4
(5H)-one (19a)
5.16 | 6-Hydroxy-2-imino-4-phenyl-
5-(phenyldiazenyl)-1-(p-tolyl)-
1,2-dihydropyridine-3-carbonitrile (17a)
Orange crystals from 1,4-dioxane yield (2.17 g, 58%), mp
103-105ꢀC, IR (KBr) νmax: 3580-3319 (OH, NH), 3052
(CH aromatic), 2222 (CN), 1680 (CO), 1658 (exocyclic
C=N), 1626 (C=C); 1H NMR (DMSO-d6, 200 MHz):
δ = 2.68 (s, 3H, CH3), 5.26 (s, 2H, thiazole CH2),
7.22-7.37 (m, 10H, C6H5, C6H4, pyridine H-5), 8.27 (s, 1H,
D2O exchangeable, NH), 10.26 (s, 1H, D2O exchangeable,
OH); 13C NMR (DMSO-d6, 75 MHz): δ 24.6 (CH3), 60.8
(thiazole CH2), 116.8 (CN), 120.8, 123.2, 124.8, 125.8,
Orange crystals from 1,4-dioxane yield (2.79 g, 79%), mp
137-139ꢀC, IR (KBr) νmax: 3463-3323 (NH), 3055
(CH aromatic), 2220 (CN), 1655 (exocyclic C=N), 1623
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 2.65 (s, 3H,
CH3), 7.25-7.38 (m, 14H, 2C6H5, C6H4), 8.25 (s, 1H, D2O
exchangeable, NH), 10.26 (s, 1H, D2O exchangeable,
OH); 13C NMR (DMSO-d6, 75 MHz): δ 24.6 (CH3), 116.7

12
MOHAREB AND MOSTAFA
126.9, 127.2, 127.8, 128.0, 129.6, 129.8, 130.1, 131.2, 132.6,
133.5, 138.7, 142.6 (2C6H5, C6H4, pyridine C-2, C-3, C-4,
C-5), 165.8 (CO), 169.3, 170.8 (2C=N). EIMS: m/z
375 [M]+ (28%). Analysis calculated for C21H17N3O2S
(375.44): C, 67.18; H, 4.56; N, 11.19; S, 8.54%. Found: C,
67.24; H, 4.63; N, 11.38; S, 8.29%.
(OCH2CH3), 22.6 (CH3), 53.2 (OCH2CH3), 58.4 (CH2),
116.6 (CN), 120.3, 123.2, 124.80, 124.2, 125.2, 125.5, 129.3,
130.6, 132.6, 134.2, 136.7, 141.8 (C6H5, C6H4, pyridine C-
2, C-3, C-4, C-5), 164.6 (CO), 170.4 (C=N). EIMS: m/z
387 [M]+ (52%). Analysis calculated for C23H21N3O3
(387.43): C, 71.30; H, 5.46; N, 10.85%. Found: C, 71.58; H,
5.83; N, 11.06%.
5.20 | 2-(1-(4-Chlorophenyl)-6-hydroxy-
2-imino-4-phenyl-1,2-dihydropyridin-3-yl)
thiazol-4(5H)-one (19b)
5.23 | Ethyl 2-((1-(4-chlorophenyl)-
3-cyano-6-hydroxy-4-phenylpyridin-2(1H)-
ylidene)-amino)acetate (20b)
Orange crystals from 1,4-dioxane yield (2.68 g, 68%), mp
212-214ꢀC, IR (KBr) νmax: 3573-3331 (OH, NH), 3058
(CH aromatic), 2220 (CN), 1685 (CO), 1655 (exocyclic
C=N), 1628 (C=C); 1H NMR (DMSO-d6, 200 MHz):
δ = 2.63 (s, 3H, CH3), 5.24 (s, 2H, thiazole CH2),
7.23-7.45 (m, 10H, C6H5, C6H4, pyridine H-5), 8.29 (s, 1H,
D2O exchangeable, NH), 10.23 (s, 1H, D2O exchangeable,
OH); 13C NMR (DMSO-d6, 75 MHz): δ 60.6 (thiazole
CH2), 116.4 (CN), 120.2, 122.6, 123.7, 124.3, 126.6, 127.0,
128.3, 129.2, 129.3, 132.3, 132.8, 133.8, 134.6, 136.2, 138.8,
142.2 (2C6H5, C6H4, pyridine C-2, C-3, C-4, C-5), 165.8
(CO), 169.1, 170.5 (2C=N). EIMS: m/z 395 [M]+ (52%).
Analysis calculated for C20H14ClN3O2S (395.86): C,
60.68; H, 3.56; N, 10.61; S, 8.10%. Found: C, 60.88; H,
3.72; N, 10.42; S, 8.23%.
Orange crystals from 1,4-dioxane yield (2.40 g, 59%), mp
160-162ꢀC, IR (KBr) νmax: 3549-3322 (OH), 3056
(CH aromatic), 2220 (CN), 1651 (exocyclic C=N), 1626
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 1.14 (t, 3H,
J = 6.23 Hz, CH3), 4.23 (q, 2H, J = 6.23 Hz, CH2), 5.79 (s,
2H, CH2), 7.21-7.46 (m, 10H, C6H5, C6H4, pyridine H-5),
10.24 (s, 1H, D2O exchangeable, OH); 13C NMR (DMSO-
d6, 75 MHz): δ 17.0 (OCH2CH3), 22.8 (CH3), 52.9
(OCH2CH3), 58.7 (CH2), 116.5 (CN), 120.1, 122.8, 123.6,
124.1, 124.6, 127.3, 129.2, 130.9, 131.2, 134.6, 135.2, 142.3
(C6H5, C6H4, pyridine C-2, C-3, C-4, C-5), 164.9 (CO),
170.2 (C=N). EIMS: m/z 407 [M]+ (36%). Analysis calcu-
lated for C22H18ClN3O3 (407.85): C, 64.79; H, 4.45; N,
10.30%. Found: C, 64.88; H, 4.26; N, 10.52%.
5.21 | General procedure for the N-ethyl
acetate pyridine derivatives 20a,b
5.24 | General procedure for the
synthesis of the pyrrolo[2,3-b]pyridin-2-yl
propionate derivatives 21a,b
Ethyl chloroacetate (1.22 g, 0.01 mol) was added to a
solution of either compound 16a (3.01 g, 0.01 mol) or 16c
(3.21 g, 0.01 mol) in 1,4-dioxane (40 mL) containing
potassium carbonate (0.80 g). The reaction mixture was
heated under reflux for 4 hours and then poured onto
ice/water mixture and the formed solid product, in each
case, was collected by filtration.
To a suspension of either compound 20a (3.87 g,
0.01 mol) or 20b in sodium ethoxide solution prepared by
dissolving metallic sodium (0.26 g, 0.02 mol) in absolute
ethanol (50 mL) was heated under reflux in a boiling
water bath for 6 hours. The reaction mixture in each case
was left to cool and poured onto ice/water mixture con-
taining a few drops of hydrochloric acid (till pH 6), and
the precipitated solid product was collected by filtration.
5.22 | Ethyl 2-((3-cyano-6-hydroxy-
4-phenyl-1-(p-tolyl)pyridin-2(1H)-ylidene)
amino)-acetate (20a)
5.25 | 3-Amino-6-hydroxy-4-phenyl-7-(p-
tolyl)-7H-pyrrolo[2,3-b]pyridin-2-yl
propionate (21a)
Orange crystals from 1,4-dioxane yield (3.21 g, 87%), mp
107-108ꢀC, IR (KBr) νmax: 3563-3348 (OH), 3055
(CH aromatic), 2220 (CN), 1655 (exocyclic C=N), 1623
Pale yellow crystals from 1,4-dioxane yield (2.32 g, 60%),
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 1.15 (t, 3H,
mp 240-244ꢀC, IR (KBr) νmax: 3548-3328 (OH), 3055
1
J = 5.93 Hz, CH3), 2.67 (s, 3H, CH3), 4.22 (q, 2H,
J = 5.93 Hz, CH2), 5.78 (s, 2H, CH2), 7.25-7.38 (m, 10H,
C6H5, C6H4, pyridine H-5), 10.28 (s, 1H, D2O exchange-
able, OH); 13C NMR (DMSO-d6, 75 MHz): δ 17.2
(CH aromatic), 1659 (exocyclic C=N), 1628 (C=C); H
NMR (DMSO-d6, 200 MHz): δ = 1.13 (t, 3H, J = 7.21 Hz,
CH3), 2.69 (s, 3H, CH3), 4.21 (q, 2H, J = 7.21 Hz, CH2),
4.52 (s, 2H, D2O exchangeable, NH2), 7.23-7.42 (m, 10H,

MOHAREB AND MOSTAFA
13
C6H5, C6H4, pyridine H-5), 10.30 (s, 1H, D2O exchange-
able, OH); 13C NMR (DMSO-d6, 75 MHz): δ 16.8
(OCH2CH3), 22.8 (CH3), 52.7 (OCH2CH3), 120.2, 122.6,
123.7, 124.1, 124.7, 125.2, 127.8, 128.0, 130.8, 132.6, 134.1,
136.5, 140.3, 141.6, 143.8 (C6H5, C6H4, pyridine C-2, C-3,
C-4, C-5, pyrrole C-3, C-4), 164.9 (CO), 171.6 (C=N).
EIMS: m/z 387 [M]+ (100%). Analysis calculated for
C23H21N3O3 (387.43): C, 71.30; H, 5.46; N, 10.85%.
Found: C, 71.22; H, 5.36; N, 10.63%.
δ = 2.68 (s, 3H, CH3), 7.26-7.46 (m, 15H, 2C6H5, C6H4,
pyridine H-5), 8.29 (s, 1H, D2O exchangeable, NH), 10.25
(s, 1H, D2O exchangeable, OH); 13C NMR (DMSO-d6,
75 MHz): δ 22.9 (CH3), 116.9 (CN), 120.3, 122.1, 122.8,
124.1, 124.8, 125.7, 125.1, 127.2, 127.9, 128.3, 129.3, 130.8,
132.2, 134.2, 138.1, 142.2 (2C6H5, C6H4, pyridine C-2, C-3,
C-4, C-5), 171.9 (C=N), 179.2 (C=S). EIMS: m/z 436 [M]+
(68%). Analysis calculated for C26H20N4OS (436.53): C,
71.54; H, 4.62; N, 12.83; S, 7.35%. Found: C, 71.38; H,
4.79; N, 13.05; S, 7.66%.
5.26 | 3-Amino-7-(4-chlorophenyl)-
6-hydroxy-4-phenyl-7H-pyrrolo[2,3-b]
pyridin-2-yl propionate (21b)
5.29 | 1-(1-(4-Chlorophenyl)-3-cyano-
6-hydroxy-4-phenylpyridin-2(1H)-ylidene)-
3-phenylthiourea (22b)
Pale yellow crystals from 1,4-dioxane yield (2.68 g, 66%),
mp 288-291ꢀC, IR (KBr) νmax: 3551-3348 (OH), 3055
(CH aromatic), 1653 (exocyclic C=N), 1628 (C=C); H
Pale yellow crystals from ethanol yield (2.50 g, 55%), mp
152-154ꢀC, IR (KBr) νmax: 3583-3326 (OH), 3054
(CH aromatic), 2220 (CN), 1652 (exocyclic C=N), 1620
(C=C), 1210 (C=S); 1H NMR (DMSO-d6, 200 MHz):
δ = 7.23-7.49 (m, 15H, 2C6H5, C6H4, pyridine H-5), 8.27
(s, 1H, D2O exchangeable, NH), 10.28 (s, 1H, D2O
exchangeable, OH); 13C NMR (DMSO-d6, 75 MHz): δ
116.5 (CN), 120.1, 121.4, 123.6, 124.1, 125.1, 125.7, 126.7,
127.0, 128.2, 129.8, 130.1, 130.8, 132.9, 135.6, 139.8, 142.8
(2C6H5, C6H4, pyridine C-2, C-3, C-4, C-5), 171.7 (C=N),
179.6 (C=S). EIMS: m/z 456 [M]+ (30%). Analysis calcu-
lated for C25H17ClN4OS (456.95): C, 65.71; H, 3.75; N,
12.26; S, 7.02%. Found: C, 65.80; H, 3.85; N,
12.41; S, 7.25%.
1
NMR (DMSO-d6, 200 MHz): δ = 1.12 (t, 3H, J = 6.29 Hz,
CH3), 4.22 (q, 2H, J = 6.29 Hz, CH2), 4.58 (s, 2H, D2O
exchangeable, NH2), 7.23-7.49 (m, 10H, C6H5, C6H4, pyri-
dine H-5), 10.27 (s, 1H, D2O exchangeable, OH); 13C
NMR (DMSO-d6, 75 MHz): δ 16.8 (OCH2CH3), 22.9
(CH3), 52.9 (OCH2CH3), 120.4, 121.8, 122.9, 124.6, 125.1,
126.7, 127.1, 128.3, 130.6, 132.3, 133.8, 135.9, 140.1, 141.4,
142.9 (C6H5, C6H4, pyridine C-2, C-3, C-4, C-5, pyrrole C-
3, C-4), 164.97 (CO), 170.6 (C=N). EIMS: m/z 407 [M]+
(80%). Analysis calculated for C22H18ClN3O3 (407.85): C,
64.79; H, 4.45; N, 10.30%. Found: C, 64.46; H,
4.69; N, 10.23%.
5.27 | General procedure for the
synthesis of the N-phenylthiourea
derivatives 22a,b
5.30 | General procedure for the
synthesis of the pyrano[2,3-b]pyridin-7
(8H)-imine derivatives 23a,b
Phenylisothiocyanate (1.30 g, 0.01 mol) was added to a
solution of either compound 16a (3.01 g, 0.01 mol) or 16c
(3.21 g, 0.01 mol) in 1,4-dioxane (40 mL). The reaction
mixture was heated under reflux for 2 hours and then
was left to cool. The formed solid product, in each case,
was collected by filtration.
Either of malononitrile (0.66 g, 0.01 mol) or ethyl
cyanoacetate (1.13 g, 0.0 mol) was added to a solution of
compound 16c (3.21 g, 0.01 mol) in 1,4-dioxane (40 mL)
containing triethylamine (0.50 mL). The reaction mix-
ture was heated under reflux for 4 hours and then
poured onto ice/water containing few drops of
hydrochloric acid and the formed solid product was col-
lected by filtration.
5.28 | 1-(3-Cyano-6-hydroxy-4-phenyl-
1-(p-tolyl)pyridin-2(1H)-ylidene)-3-phenyl-
thiourea (22a)
5.31 | 4-Amino-8-(4-chlorophenyl)-
2,7-diimino-5-phenyl-7,8-dihydro-2H-pyrano
[2,3-b]pyridine-6-carbonitrile (23a)
Pale yellow crystals from ethanol yield (3.22 g, 74%), mp
105-107ꢀC, IR (KBr) νmax: 3579-3353 (OH), 3057
(CH aromatic), 2220 (CN), 1653 (exocyclic C=N), 1622
(C=C), 1200 (C=S); 1H NMR (DMSO-d6, 200 MHz):
Pale brown crystals from 1,4-dioxane yield (2.78 g, 72%),
mp 150-152ꢀC, IR (KBr) νmax: 3493-3328 (NH, NH2),

14
MOHAREB AND MOSTAFA
3054 (CH aromatic), 2220 (CN), 1659 (exocyclic C=N),
1623 (C=C); H NMR (DMSO-d6, 200 MHz): δ = 4.80 (s,
(388.81): C, 64.87; H, 3.37; N, 14.41%. Found: C, 64.69; H,
3.42; N, 14.55%.
1
2H, D2O exchangeable, NH2), 7.26-7.41 (m, 10H, C6H5,
C6H4, H-6), 8.23, 8.31 (2 seconds, 2H, D2O exchangeable,
2NH); 13C NMR (DMSO-d6, 75 MHz): δ 108.6, 111.7 (C-5,
C-6), 117.1 (CN), 120.5, 122.8, 124.0, 125.8, 126.5, 127.5,
128.4, 130.8, 131.8, 135.3, 138.7, 140.6 (C6H5, C6H4, pyri-
dine C-2, C-3, C-4, C-5), 168.2, 170.6 (2 C=N). EIMS: m/z
387 [M]+ (55%). Analysis calculated for C21H14ClN5O
(387.82): C, 65.04; H, 3.64; N, 18.06%. Found: C, 64.88; H,
3.47; N, 18.28%.
5.34 | General procedure for the
synthesis of the pyran derivatives 27a-c
Any of the benzaldehyde (1.06 g, 0.01 mol),
4-chlorobenzaldehyde
4-methoxybenzaldehyde
(1.40 g,
(1.83 g,
0.01 mol)
0.01 mol),
or
and
malononitrile (0.66 g, 0.01 mol) was added to a solution of
compound 14a (2.53 g, 0.01 mol), in 1,4-dioxane (40 mL)
containing triethylamine (0.50 mL). The whole reaction
mixture was heated under reflux for 3 hours and then left
to cool and the formed solid product, in each case, was col-
lected by filtration.
5.32 | 4-Amino-8-(4-chlorophenyl)-
7-imino-2-oxo-5-phenyl-7,8-dihydro-2H-
pyrano[2,3-b]pyridine-6-carbonitrile (23b)
Pale brown crystals from 1,4-dioxane yield (3.25 g, 84%),
mp 160-162ꢀC, IR (KBr) νmax: 3474-3341 (NH, NH2),
3055 (CH aromatic), 2220 (CN), 1656 (exocyclic C=N),
5.35 | 6-Amino-5-cyano-2,4-diphenyl-N-
(p-tolyl)-4H-pyran-3-carboxamide (27a)
1
1621 (C=C); H NMR (DMSO-d6, 200 MHz): δ = 4.83 (s,
2H, D2O exchangeable, NH2), 7.23-7.45 (m, 10H, C6H5,
C6H4, H-6), 8.25 (s, 1H, D2O exchangeable, NH); 13C
NMR (DMSO-d6, 75 MHz): δ 108.9, 111.2 (C-5, C-6),
117.3 (CN), 120.2, 123.4, 124.3, 126.0, 126.8, 127.5, 128.2,
130.5, 133.3, 136.9, 138.3, 140.9 (C6H5, C6H4, pyridine C-
2, C-3, C-4, C-5), 164.8 (CO), 170.8 (C=N). EIMS: m/z
388 [M]+ (34%). Analysis calculated for C21H13ClN4O2
(388.81): C, 64.87; H, 3.37; N, 14.41%. Found: C, 64.92; H,
3.29; N, 14.60%.
Pale yellow crystals from ethanol yield (2.73 g, 68%), mp
110-112ꢀC, IR (KBr) νmax: 3479-3353 (NH, NH2), 3054
(CH aromatic), 2220 (CN), 1688 (CO), 1656 (C=C), 1622
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 2.68 (s, 3H,
CH3), 5.02 (s, 2H, D2O exchangeable, NH2), 6.03 (s, 1H,
pyran H-4), 7.26-7.48 (m, 14H, 2C6H5, C6H4), 8.29 (s, 1H,
D2O exchangeable, NH); 13C NMR (DMSO-d6, 75 MHz):
δ 22.7 (CH3), 116.6 (CN), 120.1, 122.6, 123.8, 124.4, 124.8,
125.9, 126.8, 127.2, 127.9, 128.3, 129.3, 130.8, 134.7, 136.5,
138.8, 142.2 (2C6H5, C6H4, pyran C-2, C-3, C-5, C-6),
165.9 (CO). EIMS: m/z 407 [M]+ (27%). Analysis calcu-
lated for C26H21N3O2 (407.46): C, 76.64; H, 5.19; N,
10.31%. Found: C, 76.56; H, 4.84; N, 10.25%.
5.33 | 4-Amino-8-(4-chlorophenyl)-
7-hydroxy-2-oxo-5-phenyl-2,8-dihydro-
1,8-naphthyridine-3-carbonitrile (25)
Ethyl cyanoacetate (1.13 g, 0.01 mol) was added to a solu-
tion of compound 16c (3.21 g, 0.01 mol) in
dimethylformamide (40 mL). The reaction mixture was
heated under reflux for 3 hours and then poured onto
ice/water mixture. The formed solid product was col-
lected by filtration.
Pale brown crystals from 1,4-dioxane yield (2.71 g,
77%), mp 290-292ꢀC, IR (KBr) νmax: 3564-3323 (OH, NH,
NH2), 3055 (CH aromatic), 2220 (CN), 1654 (exocyclic
C=N), 1624 (C=C); 1H NMR (DMSO-d6, 200 MHz):
δ = 4.88 (s, 2H, D2O exchangeable, NH2), 7.26-7.49 (m,
10H, C6H5, C6H4, H-6), 10.32 (s, 1H, D2O exchangeable,
NH); 13C NMR (DMSO-d6, 75 MHz): δ 107.3, 111.8 (C-5,
C-6), 117.1 (CN), 120.8, 122.6, 123.8, 126.4, 127.2, 127.9,
128.0, 130.7, 132.9, 135.2, 137.0, 141.7 (C6H5, C6H4, pyri-
dine C-2, C-3, C-4, C-5), 170.4 (C=N). EIMS: m/z
388 [M]+ (32%). Analysis calculated for C21H13ClN4O2
5.36 | 6-Amino-4-(4-chlorophenyl)-
5-cyano-2-phenyl-N-(p-tolyl)-4H-pyran-
3-carboxamide (27b)
Yellow crystals from ethanol yield (2.98 g, 72%), mp
240-242ꢀC, IR (KBr) νmax: 3442-3322 (NH, NH2), 3056
(CH aromatic), 2222 (CN), 1688 (CO), 1656 (C=C), 1626
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 2.68 (s, 3H,
CH3), 5.16 (s, 2H, D2O exchangeable, NH2), 6.05 (s, 1H,
pyran H-4), 7.21-7.47 (m, 14H, 2C6H5, C6H4), 8.23 (s, 1H,
D2O exchangeable, NH); 13C NMR (DMSO-d6, 75 MHz):
δ 22.8 (CH3), 116.8 (CN), 120.8, 123.1, 123.5, 124.2, 124.8,
125.7, 127.0, 127.8, 128.1, 128.3, 129.3, 130.4, 133.2, 135.5,
138.2, 142.8 (2C6H5, C6H4, pyran C-2, C-3, C-5, C-6),
165.4 (CO). EIMS: m/z 441 [M]+ (34%). Analysis calcu-
lated for C26H20ClN3O2 (441.91): C, 70.67; H, 4.56; N,
9.51%. Found: C, 70.45; H, 4.78; N, 9.76%.

MOHAREB AND MOSTAFA
15
5.37 | 6-Amino-5-cyano-
4-(4-methoxyphenyl)-2-phenyl-N-(p-tolyl)-
4H-pyran-3-carboxamide (27c)
5.40 | 6-Amino-4-(4-chlorophenyl)-
5-cyano-2-phenyl-N-(p-tolyl)-
1,4-dihydropyridine-3-carboxamide (28b)
Pale yellow crystals from ethanol yield (3.34 g, 79%), mp
50-52ꢀC, IR (KBr) νmax: 3458-3320 (NH, NH2), 3056
(CH aromatic), 2220 (CN), 1689 (CO), 1652 (C=C), 1628
Yellow crystals from ethanol yield (2.72 g, 62%), mp
90-92ꢀC, IR (KBr) νmax: 3461-3353 (NH, NH2), 3055
1
(CH aromatic), 2220 (CN), 1688 (CO), 1628 (C=C); H
1
(C=C); H NMR (DMSO-d6, 200 MHz): δ = 2.68 (s, 3H,
NMR (DMSO-d6, 200 MHz): δ = 2.66 (CH3), 5.13 (s, 2H,
D2O exchangeable, NH2), 6.09 (s, 1H, pyridine H-4),
7.25-7.49 (m, 13H, C6H5, 2C6H4), 8.24, 8.29 (2 seconds,
2H, D2O exchangeable, 2NH); 13C NMR (DMSO-d6,
75 MHz): δ 22.6 (CH3), 116.4 (CN), 120.3, 123.6, 124.2,
125.9, 126.1, 126.9, 128.3, 128.9, 129.2, 129.6, 130.3, 131.6,
132.8, 134.9, 137.4, 142.2 (C6H5, 2C6H4, pyridine C-2, C-3,
C-5, C-6), 165.4 (CO). EIMS: m/z 440 [M]+ (62%). Analy-
sis calculated for C26H21ClN4O (440.92): C, 70.82; H,
4.80; N, 12.71%. Found: C, 70.69; H, 4.53; N, 12.93%.
CH3), 3.66 (s, 3H, OCH3), 5.08 (s, 2H, D2O exchangeable,
NH2), 6.02 (s, 1H, pyran H-4), 7.22-7.45 (m, 13H, C6H5,
2C6H4), 8.29 (s, 1H, D2O exchangeable, NH); 13C NMR
(DMSO-d6, 75 MHz): δ 22.8 (CH3), 52.3 (OCH3), 116.68
(CN), 120.9, 123.2, 123.8, 124.1, 125.8, 125.9, 126.4, 127.0,
128.2, 129.0, 129.3, 130.6, 134.9, 136.2, 138.8, 142.6 (C6H5,
2C6H4, pyran C-2, C-3, C-5, C-6), 165.7 (CO). EIMS: m/z
437 [M]+ (18%). Analysis calculated for C27H23N3O3
(437.49): C, 74.12; H, 5.30; N, 9.60%. Found: C, 74.31; H,
5.42; N, 9.88%.
5.41 | 6-Amino-5-cyano-
4-(4-methoxyphenyl)-2-phenyl-N-(p-tolyl)-
1,4-dihydropyridine-3-carboxamide (28c)
5.38 | General procedure for the
synthesis of the pyridine derivatives 28a-c
Any of the benzaldehyde (1.06 g, 0.01 mol),
Pale yellow crystals from ethanol yield (3.319 g, 73%), mp
70-72ꢀC, IR (KBr) νmax: 3470-3355 (NH, NH2), 30 565
(CH aromatic), 2221 (CN), 1688 (CO), 1623 (C=C); 1H NMR
(DMSO-d6, 200 MHz): δ = 2.69 (s, 3H, CH3), 3.68 (s, 3H,
OCH3), 5.12 (s, 2H, D2O exchangeable, NH2), 6.16 (s, 1H,
pyridine H-4), 7.27-7.42 (m, 13H, C6H5, 2C6H4), 8.26, 8.31
(2 seconds, 2H, D2O exchangeable, 2NH); 13C NMR (DMSO-
d6, 75 MHz): δ 22.5 (CH3), 52.1 (OCH3), 116.9 (CN), 120.3,
122.8, 124.1, 124.5, 126.2, 126.9, 127.1, 127.3, 128.6, 129.1,
129.5, 130.3, 134.2, 136.8, 137.2, 141.9 (C6H5, 2C6H4, pyridine
C-2, C-3, C-5, C-6), 165.5 (CO). EIMS: m/z 436 [M]+ (22%).
Analysis calculated for C27H24N4O2 (436.51): C, 74.29; H,
5.54; N, 12.84%. Found: C, 74.42; H, 5.63; N, 12.63%.
4-chlorobenzaldehyde
4-methoxybenzaldehyde
(1.40 g,
(1.83 g,
0.01 mol)
0.01 mol),
or
and
malononitrile (0.66 g, 0.01 mol) was added to a solution
of either compound 14a (2.53 g, 0.01 mol) in 1,4-dioxane
(40 mL) containing ammonium acetate (0.50 mL). The
whole reaction mixture was heated under reflux condi-
tions for 3 hours and then left to cool, and the formed
solid product, in each case, was collected by filtration.
5.39 | 6-Amino-5-cyano-2,4-diphenyl-N-
(p-tolyl)-1,4-dihydropyridine-
3-carboxamide (28a)
ACKNOWLEDGMENTS
Pale yellow crystals from ethanol yield (2.96 g, 73%), mp
This article paper did not get any specific grant from any
funding agencies.
50-52ꢀC, IR (KBr) νmax: 3493-3325 (NH, NH2), 3056
1
(CH aromatic), 2221 (CN), 1689 (CO), 1620 (C=C); H
NMR (DMSO-d6, 200 MHz): δ = 2.69 (s, 3H, CH3), 5.08
(s, 2H, D2O exchangeable, NH2), 6.13 (s, 1H, pyridine
H-4), 7.28-7.43 (m, 14H, 2C6H5, C6H4), 8.25, 8.27 (2 sec-
onds, 2H, D2O exchangeable, 2NH); 13C NMR (DMSO-
d6, 75 MHz): δ 22.9 (CH3), 116.5 (CN), 120.6, 121.3,
122.6, 123.4, 125.6, 125.8, 126.1, 127.7, 128.0, 128.6,
129.8, 131.6, 133.9, 135.2, 137.3, 142.2 (2C6H5, C6H4,
pyridine C-2, C-3, C-5, C-6), 165.7 (CO). EIMS: m/z
406 [M]+ (19%). Analysis calculated for C26H22N4O
(406.48): C, 76.83; H, 5.46; N, 13.78%. Found: C,
76.92; H, 5.29; N, 13.92%.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest.
ORCID
Rafat M. Mohareb https://orcid.org/0000-0003-3922-
803X
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How to cite this article: Mohareb RM,
Mostafa BM. Uses of ethyl benzoylacetate for the
synthesis of thiophene, thiazole, pyridine, and
pyran derivatives with antitumor activities.
J Heterocycl Chem. 2020;1–16. https://doi.org/10.
1002/jhet.3865