A Facile One-pot Synthesis and Anticancer Evaluation of Interesting Pyrazole and Pyrimidinthione via Heterocyclic Interconversion

Article abstract of DOI:10.1002/jhet.3625

Design and synthesis of new pyrazole, pyrimidinthione, and triazepinthione derivatives via heterocyclic ring opening of azacoumarin were promoted with grinding and ultrasonic reaction conditions. Efficient solventless one-pot synthesis can be well progressed to afford the good yield of new heterocyclic products that were characterized by IR, ¹H-NMR, MS, and microanalytical data. Anticancer evaluation for the synthesized compounds exhibited moderate to good cytotoxicity such as pyrazole derivatives 5, 9, and 14 that displayed best cytotoxic activities with IC₅₀ 8.16 ± 1.1, 7.02 ± 0.6, and 5.12 ± 0.41 μg/mL and 9.28 ± 0.7, 6.45 ± 0.9, and 5.85 ± 0.26 μg/mL for MCF-7 and WI cells, respectively. Pyrimidine derivatives 6, 11, and 15 exhibited strong cytotoxicity with IC₅₀ 8.9 ± 0.62, 7.16 ± 0.5, and 7.72 ± 0.41 μg/mL against MCF-7.

Full text of DOI:10.1002/jhet.3625

Month 2019
A Facile One-pot Synthesis and Anticancer Evaluation of Interesting
Pyrazole and Pyrimidinthione via Heterocyclic Interconversion
Sameh A. Rizk*
and Safa Shaban
Chemistry Department, Faculty of Science, Ain Shams University, Cairo 11566, Egypt
*
E-mail: samehrizk2006@gmail.com; samehrizk@sci.asu.edu.eg
Received November 9, 2018
DOI 10.1002/jhet.3625
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Design and synthesis of new pyrazole, pyrimidinthione, and triazepinthione derivatives via heterocyclic
ring opening of azacoumarin were promoted with grinding and ultrasonic reaction conditions. Efficient sol-
ventless one-pot synthesis can be well progressed to afford the good yield of new heterocyclic products that
1
were characterized by IR, H-NMR, MS, and microanalytical data. Anticancer evaluation for the synthesized
compounds exhibited moderate to good cytotoxicity such as pyrazole derivatives 5, 9, and 14 that displayed
best cytotoxic activities with IC50 8.16 ± 1.1, 7.02 ± 0.6, and 5.12 ± 0.41 μg/mL and 9.28 ± 0.7, 6.45 ± 0.9,
and 5.85 ± 0.26 μg/mL for MCF-7 and WI cells, respectively. Pyrimidine derivatives 6, 11, and 15 exhibited
strong cytotoxicity with IC50 8.9 ± 0.62, 7.16 ± 0.5, and 7.72 ± 0.41 μg/mL against MCF-7.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
RESULTS AND DISCUSSION
Many heterocyclic compounds encircling pyridine,
pyrazole, and pyrimidine rings are correlated with diverse
Chemistry. It was previously reported that the thermal
and microwave reflux of chalcone 1 with diversity of active
methylene, for instance, ethyl cyanoacetate, ethyl
acetoacetate, and diethyl malonate with ammonium
acetate, produced the pyridine esters 2a–c and 2-pyridone
derivatives 3a–c in good yield that were outlined in
Scheme 1 [16–21].
pharmacological
belongings.
These
classes
of
heterocyclic compounds have synchronized the
cardiovascular system and antimicrobial [1–3], anticancer
[4], anticonvulsant [5], antiviral [6–8], anti-human
immunodeficiency virus [9], antifungal [10], and anti-
leishmanial [11] activities. Pyrano[2,3-b]-pyridine (8-
azacoumarin) structure is considered a key starting
material for many heterocyclic compounds and screening
a broad spectrum of biological activity [12]. Also, 8-
azacoumarin system is significant because of numerous
biological activities associated with this scaffold. Some
analogues have been associated with scaffold antitumor
via stopping the dihydrofolate reductases or tyrosine
kinases [13,14], while others are known antiviral agents
Moreover, the authors reported the reaction of chalcone
1 and ethyl cyanoacetate in the presence of ammonium
acetate in
a multicomponent reaction (MCR) by
mechano-grindstone all together or by sonication using
tetrahydrofuran for 25–30 min to afford crude yellow
solid products (4a–c) (Scheme 2) [22–24].
The IR spectrum of compound 4a reveals stretching
ꢀ
1
absorption bands at 3434 and 3329 cm attributed to
ꢀ
1
asymmetric and symmetric NH , respectively, 2223 cm
2
ꢀ
1
[15]. This prompted us a specific simple synthesis aiming
for CN group, and 1732 cm for C¼O group of the
to construct some new pyridine flattened with pyrazole or
pyrimidine thione derivatives in a single molecular
framework as a unique key precursor designing new,
potent, selective agent appear to be promising for
anticancer evaluation.
coumarin ring that assigned structure to this compound.
1
The H-NMR spectrum of compound 4a shows δ
6.80 ppm corresponding to H3 in pyridine nucleus and
broad singlet at δ 5.43 ppm corresponding to the NH
protons with the absence of any band at 9.8
2
©
2019 Wiley Periodicals, Inc.

S. A. Rizk and S. Shaban
Vol 000
Scheme 1. Conventional thermal and microwave promoted the pyridine derivatives 2 and 3. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. Reaction under ultrasonic condition. [Color figure can be viewed at wileyonlinelibrary.com]
corresponding to NH of pyridine 3 are good evidence in
formation of compound 4a. So the ultrasonic irradiation
caused the isomerization of the 2-pyridone 3 to the
reactive lactim intermediate, which reacts with another
ethyl cyanoacetate affording the pyrano[2,3-b]pyridine
derivatives 4a–c as sole products (Scheme 3).
Reaction of azacoumarin 4a with various nitrogen
precursors such as hydrazine hydrate, thiourea,
ethylglycinate, and thiosemicarbazide yielded interesting
incorporating heterocyclic compounds that have classy
anticancer activity. Reaction of cyano azacoumarin 4a
with hydrazine hydrate, thiourea, ethylglycinate, and
thiosemicarbazide afforded pyrazole 5, pyrimidinthione 6,
of carbonyl of the amide groups in pyridone, pyrazolone,
pyrimidone, and triazepinone rings, respectively. The H-
NMR spectra of compounds 5, 6, 7, and 8 display H3 of
1
pyridone protons at δ 6.80–6.77 ppm, and NH protons
2
are detected at δ 4.22–4.16 ppm for two types of protons
of two different amino groups and at δ 9.80 ppm as a
singlet corresponding to NH proton.
The authors would think that the heterocyclic
interconverted compounds 5, 6, and 8 become more
stable when they dehydrated to afford the 1,8-
naphthyridine derivatives via intramolecular reaction of
the amino group with carbonyl in the pyridone moiety
(Scheme 4). The optimization of the heterocyclic
compounds is designed as minimized energetic
geometrical structures of the synthesized compounds 5, 6,
and 8 (Fig. 1). The electronic structures of compounds 5,
6, and 8 revealed entirely spread over all molecular
structure and confirmed these energetic structures of
synthesized compounds. Frontier molecular orbitals have
the highest occupied molecular orbital and the lowest
unoccupied molecular orbital [25–31].
diazepinone 7, and triazepinthione
8
derivatives,
respectively (Scheme 4). IR spectra will be considered
good spectroscopic characterization to investigate the
heterocyclic products. The reaction was processed via
ring opening followed by ring closure and formation of
heterocyclic
compounds
involving
geometrical
isomerization due to formation of intramolecular
hydrogen bond in the heterocyclic products. The IR
spectra of compounds 5, 6, 7, and 8 reveal absorption
Similarly, reaction of acetylazacoumarin 4b with
hydrazine hydrate, aniline, thiourea, ethylglycinate, and
thiosemicarbazide afforded pyrazole 9, arylidene 10,
pyrimidinthione 11, ester 12, and triazepinthione 13
ꢀ
1
broad bands at 3347–3179 cm
attributed to NH2
asymmetric and symmetric stretching frequency and at
ꢀ
1
1
670–1652 cm corresponding to stretching frequency
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Facile One-pot Synthesis and Anticancer Evaluation of Interesting Pyrazole and
Pyrimidinthione via Heterocyclic Interconversion
Scheme 3. The proposal mechanistic equations of the chalcone with ethyl cyanoacetate in the presence of ammonium acetate under ultrasonic reaction
conditions. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 4. Reaction of azacoumarin 4a with different nitrogen nucleophiles under conventional thermal condition. [Color figure can be viewed at
wileyonlinelibrary.com]
derivatives, respectively (Scheme 5). IR spectra will be
considered good spectroscopic characterization to
investigate the heterocyclic products. The reaction was
processed via ring opening followed by ring closure and
formation of heterocyclic compounds involving lactam–
lactim dynamic equilibrium due to formation of
intramolecular hydrogen bond in the heterocyclic
products 9, 11, and 13. The appearance of broad bands at
3347–3179 attributed to NH asymmetric and symmetric
2
peaks and 1668–1652 for carbonyl of amide groups in
pyrazole, pyrimidine, and triazepine moieties and devoid
any band at 2223 for cyano group in the IR spectra of 9,
10, 11, 12, and 13 are respectable confirmation for the
1
assigned structures of these compounds. H-NMR
spectrum of compound 9 exhibits signal at δ 6.80 ppm
for pyridine proton and 7.22 ppm for broad singlet for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk and S. Shaban
Vol 000
Figure 1. Outline of the optimized structures of compounds 5, 6, and 8. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 5. Reaction of azacoumarin 4b with different nitrogen nucleophiles under conventional thermal condition. [Color figure can be viewed at
wileyonlinelibrary.com]
acidic OH proton and signal at δ 9.80 ppm for singlet NH
proton.
hydrogen bond in the heterocyclic products 14, 15, and
17. The appearance of broad bands at 3347–3179
Moreover, the behavior of azacoumarin ester 4c with
hydrazine hydrate, thiourea, ethylglycinate, and
thiosemicarbazide afforded pyrazole 14, pyrimidinthione
attributed to NH asymmetric and symmetric stretching
frequency in the IR spectra of 14, 15, and 17 confirmed
2
the
assigned
structure
of
these
compounds.
1
5, 1,4-oxazepindione ester 16, and triazepinthione 17
Disappearance of two stretching frequencies of carbonyl
ꢀ
1
derivatives, respectively (Scheme 6). IR spectra will be
considered good spectroscopic characterization to
investigate the heterocyclic products. The reaction was
processed via ring opening followed by ring closure and
formation of heterocyclic compounds involving
tautomerization due to formation of intramolecular
of ester and pyrone at 1745 and 1735 cm band is due
to the absence of the 2CO of ester and lactone groups,
ꢀ
1
and appearance carbonyl of amide group at 1652 cm in
pyrazole, pyrimidine, and triazepine rings, respectively.
1
H-NMR spectrum of compound 15 shows definite
singlet bands at δ 6.84, 5.32, 8.12, and 9.82 for pyridine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Facile One-pot Synthesis and Anticancer Evaluation of Interesting Pyrazole and
Pyrimidinthione via Heterocyclic Interconversion
Scheme 6. Reaction of azacoumarin 4c with different nitrogen nucleophiles under conventional thermal condition. [Color figure can be viewed at
wileyonlinelibrary.com]
proton, the 2OH protons, and NH acidic proton,
respectively.
cells have better IC50 at 8.9 ± 0.62, 7.16 ± 0.5, and
7.72 ± 0.41 μg/mL and 7.8 ± 0.23, 8.48 ± 1.2, and
5
.6 ± 0.22 μg/mL, respectively.
Biological activity. Antitumor assay in vitro Ehrlich
ascites.
The authors evaluated the cytotoxicity result
The newly prepared compounds conserved MCF-7 and
(
IC ) at 50 μg/mL [29,31,32] of synthesized compounds
WI-38 cells and their cytotoxic needful dose controls
more than 50% of the cell death. So they showed a
variation in inhibition of cell growth with changed their
concentration. Compounds 5, 6, 9, 11, 14, and 15
exhibited promising activity than compounds 10, 13, and
16 toward MCF-7. 8-Azacoumarins 4a, 4b, and 4c
displayed moderate IC50 against MCF-7 cancer cell line
related to DOX.
50
listed in Table 1 against mammary gland breast MCF-7
and human lung fibroblast WI-38 tumors. Antitumor
activity was detected by all synthesized compounds that
ranged from very strong to non-cytotoxic. Enhanced the
tumor activity MCF-7 and WI cells for pyrazole
derivatives 5, 9, and 14 at IC50 8.16 ± 1.1, 7.02 ± 0.6,
and 5.12 ± 0.41 μg/mL and 9.28 ± 0.7, 6.45 ± 0.9, and
5
2
.85 ± 0.26 μg/mL, respectively. In addition, pyrimidin-
-thione derivatives 6, 11, and 15 for MCF-7 and WI
Structure–activity relationship. Nitrogen bases of DNA
(chemical building blocks, adenine, guanine, cytosine, and
thymine) were structured from pyrimidine nucleus. The
cytotoxicity of pyrimidine toward different cell lines
depends on intermolecular hydrogen bond with
nucleotides and positive charge on prepared drug
compacted with negative charge on the cell wall.
Experimental cytotoxicity of the prepared compounds
was matching with their structures. Compounds such as
Table 1
Cytotoxic activity of some compounds against cancer cell line.
a
In vitro cytotoxicity IC50 (μM)
No.
Compound
MCF-7
WI-38
1
2
3
4
5
6
7
8
9
5-Flourouracil
6.23 ± 0.2
36.28 ± 1.7
23.79 ± 1.9
22.37 ± 3.0
20.83 ± 1.3
8.16 ± 1.1
8.9 ± 0.62
38.91 ± 2.8
31.85 ± 2.5
7.02 ± 0.6
18.97 ± 0.9
7.16 ± 0.5
17.72 ± 4.6
19.83 ± 3.2
5.12 ± 0.41
7.72 ± 0.41
19.83 ± 3.2
22.12 ± 2.1
7.65 ± 0.5
55.11 ± 1.9
40.36 ± 4.0
38.01 ± 3.2
36.46 ± 2.5
9.28 ± 0.7
7.8 ± 0.23
32.79 ± 2.3
59.37 ± 3.9
6.45 ± 0.9
27.23 ± 1.6
8.48 ± 1.2
20.42 ± 1.8
25.12 ± 2.7
5.85 ± 0.26
5.60 ± 0.22
25.12 ± 2.7
38.85 ± 3.6
5
, 6, 9, 11, 14, and 15 exhibited potent activity because
of incorporation of the pyrazole, pyrimidin-2-thione, and
,2,4-triazepinthione to 2-pyridone. OH and NH groups,
1
4a
4b
4c
5
6
7
8
9
10
11
12
13
14
15
16
17
1
which may be formed through hydrogen bonding with
one of the nucleotides of the DNA and enable the
elimination of an oxygen from the phosphate group
producing damage to the DNA (Scheme 7) via lack of
hydroxyl, prohibited repair and control of the tumor cells.
Moreover, the pyrazole derivatives 5, 9, and 14 have
controlled growth of pieces of tumors through their
combination with triphosphate, and extension during
replication leads to lesions and disruptions on DNA
strands (Scheme 7) [20–32]. The same mechanism
occurred in the 2-pyrimidinthione derivatives 6, 11, and
15, same with compounds 5, 6, 9, 11, 15, and 16.
10
11
12
13
14
15
16
17
18
a
IC50 (μM): 1–10 (very strong), 11–20 (strong), 21–50 (moderate activ-
ity), 51–100 (weak), and above 100 (non-cytotoxic).
2
Combination of 1,2,4-triazepinthione with sp carbon-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk and S. Shaban
Vol 000
Scheme 7. Mechanism of the antitumor action of compound 14. [Color figure can be viewed at wileyonlinelibrary.com]
+
+
bearing hydrophobic 2-pyridone moiety in compounds 8,
3, and 17 would demonstrate cytotoxic activities toward
the two surveyed tumor cells.
abundance): 327 [M] (100%), 329 [M + 2] (3.3%).
1
Anal. for C H NO (327). Cal: C, 84.37; H, 6.46; N,
4.28. Found: C, 84.23; H, 6.24; N, 4.12.
23 21
General procedure for synthesis of azacoumarin
(
pyrano[2,3-b]pyridine derivatives 4a–c). Method (i).
EXPERIMENTAL
Sonicate a mixture of chalcone 1 (1 mmol), ethyl
cyanoacetate, ethyl acetoacetate or diethyl malonate
Melting points are uncorrected and measured in open-
glass capillaries. FT-IR Shimadzu 8400S
Spectrophotometer (New York, NY, USA) in KBr pellets
(1 mmol), and ammonium acetate (0.04 mol) together in
a mortar and then transfer into 10 mL of ethanol in
round-bottom flask located in an ultrasonic cleaning bath
with Emax measured at 30°C. Reaction progress sustained
until the reactants disappeared by TLC. Irradiation at 20–
ꢀ
1
1
was used to chart IR spectra (υmax, cm ). H-NMR and
1
3
C-NMR
spectrophotometer (Rheinstetten, Germany), 300 and
25 MHz, respectively, in DMSO-d solvents and TMS
spectra
were
registered
on
300
2
5 min afforded yellow solid product, decanted with
1
6
crushed ice, dried, and recrystallized.
as internal standard. Shimadzu GCMS-QP-1000 EX mass
spectrometer (Shimadzu Corp., Kyoto, Japan) was used
to measure the mass spectra via EI technique (70 eV).
CHN automatic analyzer was used in elemental analyses
and measured at Central Security Forces, Cairo, Egypt.
Sonication (Toshcon model SW 4 cleaner, 37 kHz,
Method (ii). Grind a mixture of chalcone (1 mmol),
ethyl cyanoacetate, ethyl acetoacetate or diethylmalonate
(1 mmol), and ammonium acetate (0.04 mol) together in
an agate mortar and pestle checked by TLC for 25–
30 min until the color of reaction mixture turned into
yellow, left overnight, and was recrystallized from ethanol.
1
50 W) achieved the synthesized compounds. Check the
7
-([1,1-Biphenyl]-4-yl)-4-amino-5-(4-(dimethylamino)
phenyl)-2-oxo-2H-pyrano[2,3-b]pyridine-3-carbonitrile
4a). Yield 82%, mp 112–114°C. IR (KBr) υmax (cm ):
purity of synthesized compounds with thin-layer chroma-
tography (TLC). All chemical reagents and solvents were
achieved from Alibaba Fine Chemical Company (New
Delhi, India) without further purification.
ꢀ
1
(
3438, 3329 (asymmetric and symmetric amino group),
2208 (CN group), 1704 (carbonyl group). H-NMR
1
1
-([1,1-Biphenyl]-4-yl)-3-(4-(dimethylamino)phenyl)prop-
(DMSO-d ) δ (ppm): 3.20 (s, 6H, –N(CH ) ), 4.34 (s,
6
3 2
2
(
(
-en-1-one (1).
Grind a mixture of 4-acetylbiphenyl
2H, NH ), 6.98–8.32 (m, 14H, Ar–H; biphenyl and
2
13
0.01 mol, 1.96 g), 4-dimethylamino benzaldehyde
0.01 mol, 1.49 g), and 2 g of KOH and mix with a few
phenyl groups and pyridine H5). C-NMR (DMSO):
1.7, 77.6, 104.1, 112.5, 116.1, 127.3, 127.7, 128.2,
4
drops of water for 20 min until the colorless reaction
mixture turned light yellow. Then 50 mL of water added
to the reaction mixture, the solid that separated was
filtered, dried, and crystallized from ethanol as light
129.1, 130.2, 137.6, 139.2, 140.9, 145.7, 146.9, 155.5,
+
156.3, 164.6, 180.9. MS m/z (% abundance): 459 [M]
+
(
1.2%), 460 [M + H] (5.4%). Anal. for C H N O
29
22
4
2
(459). Cal: C, 75.97; H, 4.84; N, 12.22. Exp: C, 75.68;
H, 4.62; N, 12.14.
yellow crystals. Yield 98%, mp 88–90°C. IR (KBr) υ
max
ꢀ
1
1
(cm ): 1679 (C¼O), 1600 (C¼C). H-NMR (DMSO-d )
6
4-Methyl-7-([1,1′-biphenyl]-4-yl)-3-acetyl-5-(4-
δ (ppm): 2.99 (s, 6H, –N(CH ) ), 6.8–8.02 (m, 13H, Ar–
(dimethylamino)phenyl)-2H-pyrano[2,3-b]pyridin-2-one
3
2
ꢀ
1
H; biphenyl and phenyl groups), 7.82 (dd, 1H, H–C¼,
(4b). Yield 84%, mp 80–82°C. IR (KBr) υ
(cm ):
max
13
1
J = 16.2 Hz), 8.02 (dd, 1H, H–C¼, J = 16.2 Hz). C-
3325, 1723, 1678, 1600. H-NMR (DMSO-d ) δ (ppm):
6
NMR (DMSO): 41.9, 111.3, 121.5, 128.1, 129.4, 130.1,
2.22 (s, 3H, CH CO), 2.38 (s, 3H, CH , pyrone C-4),
3
3
13
136.6, 140.9, 145.3, 146.4, 150.5, 188.9. MS m/z (%
3.04 (s, 6H, N(CH ) ), 6.98–8.5 (m, 14H, Ar–H). C-
3 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Facile One-pot Synthesis and Anticancer Evaluation of Interesting Pyrazole and
Pyrimidinthione via Heterocyclic Interconversion
NMR (DMSO): 20.9, 29.7, 41.1, 104.4, 112.4, 122.6,
Anal. for C H N O S (535). Cal: C, 67.40; H, 4.90; N,
30 26 6 2
1
1
27.1, 127.7, 128.3, 129.7, 129.9, 137.6, 139.6, 145.8,
15.72; S, 6.00. Exp: C, 67.52; H, 4.78; N, 15.59; S, 5.88.
46.3, 155.7, 159.2, 159.6, 164.6, 198.5. MS m/z (%
9-([1,1′-Biphenyl]-4-yl)-5-amino-11-(4-(dimethylamino)
phenyl)-1,3-dihydro-pyrido[3′,2′:5,6]pyrano[4,3-e][1,4]
diazepine-2,6-dione (7). Compound 4a (0.01 mol, 4.59 g)
+
+
abundance): 475 [M] (11%), 476 [M + H] (2.5%).
Anal. for C H N O (475). Cal: C, 78.46; H, 5.52; N,
31 26 2 3
was allowed to react with ethyl glycinate hydrochloride
5.90. Exp: C, 78.29; H, 5.35; N, 5.72.
(
3
0.01 mol, 1.39 g) in refluxing pyridine/ethanol (1:10) for
h, and the separated solid was filtered off, fractionally
Ethyl-4-hydroxy-7-([1,1′-biphenyl]-4-yl)-5-(4-
dimethylamino)phenyl)-2-oxo-2H-pyrano[2,3-b]pyridine-3-
(
carboxylate (4c). Yield 81%, mp 108–110°C. IR (KBr)
crystallized from benzene, and gave yellow crystals.
ꢀ
1
1
ꢀ1
υmax (cm ): 3430, 1726, 1699, 1679, 1591. H-NMR
DMSO-d ) δ (ppm): 1.2 (t, 3H, J = 8.42, CH CH ,
Yield 57%, mp 160–162°C. IR (KBr) υ
(cm ): 3441,
max
1
(
1640, 1598. H-NMR (DMSO-d ) δ (ppm): 3.2 (s, 6H, –
6
3
2
6
ester), 2.99 (s, 6H, –N(CH ) ), 4.12 (q, 2H, J = 8.42,
N(CH ) ), 5.58 (s, 2H, CH CO, diazepine nucleus), 6.46
3
2
3 2
2
CH CH , ester), 7.02–8.13 (m, 14H, Ar–H), 13.02 (s,
(s, 2H, NH , diazepin-2-one C-4), 6.98–8.6 (m, 14H, Ar–
H), 8.86 (s, 1H, NH, diazepine). C-NMR (DMSO):
3
2
2
13
13
1
1
1
H, OH). C-NMR (DMSO): 14.7, 41.9, 61.9, 100.1,
04.6, 112.9, 127.4, 128.3, 129.3, 130.1, 137.4, 139.8,
40.7, 145.4, 146.3, 155.6, 159.5, 164.8, 165.1, 172.8.
41.8, 57.3, 93.9, 104.6, 112.4, 123.1, 126.9, 127.3,
127.7, 128.1, 129.1, 130.2, 137.6, 145.9, 146.5, 151.3,
+
+
+
MS m/z (% abundance): 507 [M] (14%), 508 [M + H]
159.2, 164.7, 168.4. MS m/z (% abundance): 516 [M]
+
(
1.9%). Anal. for C H N O (507). Cal: C, 73.50; H,
(2%), 517 [M + H] (2.8%). Anal. for C H N O (516).
3
1
26
2
5
31 25 5 3
5
.17; N, 5.53. Exp: C, 73.62; H, 5.02; N, 5.34.
Cal: C, 72.22; H, 4.89; N, 13.58. Exp: C, 72.38; H, 4.76;
N, 13.42.
6
-([1,1′-Biphenyl]-4-yl)-3-(amino(3-amino-5-oxo-1,5-
dihydro-4H-pyrazol-4-ylidene)methyl)-4-(4-(dimethylamino)
phenyl)pyridin-2(1H)-one (5). A mixture of compound 4a
6
-(2-((l2-Azanyl)carbonyl)-1-amino-3-(4-(dimethylamino)
phenyl)allylidene)-5-amino-3-thioxo-1,2,3,6-tetrahydro-7H-
1,2,4-triazepin-7-one (8). A mixture of 4a (1 mmol,
(1 mmol, 4.59 g) and hydrazine hydrate (2 mmol) in
boiling EtOH (50 mL) was refluxed for 3 h. After
cooling, the separated solid was collected and
recrystallized from ethanol to afford white crystals. Yield
4.59 g) and thiosemicarbazide (1 mmol, 0.91 g) was
refluxed in AcOH/MeOH (1:10) for 2 h. The separated
solid after cooling was filtered off, dried, and
ꢀ
1
8
8%, mp 254–255°C. IR (KBr) υmax (cm ): 3442, 1655.
recrystallized from ethanol to afford yellow crystals.
1
ꢀ1
H-NMR (DMSO-d ) δ (ppm): 3.2 (s, 6H, –N(CH ) ),
Yield 86%, mp 150–152°C. IR (KBr) υ
(cm ): 3441,
6
3 2
max
1
4
.52 (s, 2H, NH ), 6.02 (s, 1H, pyridone C-5), 6.43 (s,
1609. H-NMR (DMSO-d ) δ (ppm): 3.1 (s, 6H, –
2
6
2
H, NH , pyrazole, C ), 6.8–7.8 (m, 13H, Ar–H), 12.02
N(CH ) ), 6.12 (s, 2H, NH ), 6.53 (s, 1H, CHCO, py),
2
3
3 2
2
1
3
(s, 2H, 2NH, 2 lactam rings). C-NMR (DMSO): 41.9,
6.89 (s, 2H, NH , diazepin-2-one C-7), 6.88–8.11 (m,
2
1
1
02.7, 104.9, 111.3, 126.8, 127.3, 129.5, 130.2, 139.9,
14H, Ar–H), 8. 86 (s, 1H, NHCO, diazepine), 10. 86 (s,
13
40.6, 150.1, 152.1, 160.4, 161.9, 164.8, 174.3. MS m/z
1H, NHCS, diazepine). C-NMR (DMSO): 41.9, 49.3,
101.3, 105.3, 111.9, 1277, 128.1, 128.7, 129.5, 140.9,
142.4, 150.2, 160.1, 164, 167.4. MS m/z (% abundance):
+
+
(% abundance): 491 [M] (14%), 492 [M + H] (6%).
Anal. for C H N O (491). Cal: C, 71.00; H, 5.34; N,
1
29 26 6 2
+
+
7.13. Exp: C, 71.08; H, 5.22; N, 17.24.
373 [M] (100%), 374 [M + H] (2.6%). Anal. for
C H N O S (573). Cal: C, 67.01; H, 4.71; N, 17.10; S,
4
-(4-(Dimethylamino)phenyl)-5-((6-([1,1′-biphenyl]-4-yl)-2-
32 27 7 2
oxo-1,2-dihydropyridin-3-yl)(amino)methylene)-6-amino-2-
5.58. Exp: C, 66.78; H, 4.54; N, 16.81; S, 5.60.
thioxo-2,5-dihydropyrimidin-4(3H)-one (6). A mixture of
6
-([1,1′-Biphenyl]-4-yl)-4-(4-(dimethylamino)phenyl)-3-(1-
(3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene)ethyl)
pyridin-2(1H)-one (9).
4
a (0.01 mol, 4.59 g), thiourea (0.01 mol, 0.76 g), and
sodium ethoxide (0.68 g, 0.01 mol) in boiling ethanol
20 mL) was refluxed for 6 h. The reaction mixture was
A solution of compound 4b
(
(0.01 mol, 4.75 g) in EtOH (40 mL) and hydrazine
hydrate (0.02 mol, 99%) was refluxed for 2 h. After
cooling, the separated solid was collected and
recrystallized from ethanol as white crystals. Yield 76%,
mp 265–266°C. IR (KBr) υ
cooled and then poured onto ice (25 g) and neutralized
with dil HCl. The solid that separated was filtered and
recrystallized from ethanol. Yield 89%, mp 167–169°C.
ꢀ
1
1
ꢀ1
IR (KBr) υmax (cm ): 3345, 3256, 1659. H-NMR
DMSO-d ) δ (ppm): 3.2 (s, 6H, –N(CH ) ), 4.52 (s, 2H,
(cm ): 3440, 3329,
max
1
(
3197, 1745, 1605. H-NMR (DMSO-d ) δ (ppm): 2.3 (s,
6
3 2
6
NH , enamine moiety), 6.52 (s, 2H, NH , thiopyrimidine
3H, CH , pyrazolone C-3), 2.6 (s, 3H, CH ), 3.2 (s, 6H,
2
2
3
3
C-4), 6.6–7.8 (m, 14H, Ar–H), 11.2 (s, 1H, NH, pyridone
moiety), 12.94 (s, 1H, NH, thiopyrimidine moiety). C-
NMR (DMSO): 41.9, 88.1, 104.9, 111.5, 126.7, 127.6,
–N(CH ) ), 6.2 (s, 1H, pyridone C-5), 6.78–7.98 (m,
3 2
13
13
13H, Ar–H), 12.54 (s, 2H, 2NH, 2 lactam rings). C-
NMR (DMSO): 13.7, 23.4, 41.9, 104.6, 105.9, 111.3,
127.6, 129.9, 130.2, 134.5, 139.8, 140.6, 143.9, 150.1,
159.8, 160.1, 161.7, 164.9. MS m/z (% abundance): 489
1
1
29.1, 129.5, 130.2, 134.5, 140.1, 140.9, 150.5, 158.7,
60.3, 161.8, 166.6, 167.8, 185.9. MS +m/z (%
+
+
+
abundance): 535 [M] (2.8%), 536 [M + H] (4.2%).
[M] (10.5%), 490 [M + H] (2.5%). Anal. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk and S. Shaban
Vol 000
C H N O (489). Cal: C, 76.21; H, 5.78; N, 11.47. Anal. for C H N O (595). Cal: C, 74.73; H, 5.09; N,
3
1
28
4
2
37 30 4 4
Found: C, 76.38; H, 5.62; N, 11.26.
9.42. Found: C, 74.82; H, 5.00; N, 9.34.
7
-([1,1′-Biphenyl]-4-yl)-5-(4-(dimethylamino)phenyl)-4-
5-(1-(6-([1,1′-Biphenyl]-4-yl)-4-(4-(dimethylamino)phenyl)-
methyl-3-(1-(phenylimino)ethyl)-2H-pyrano[2,3-b]pyridin-2-
one (10a). A solution of compound 4b (0.01 mol, 4.75 g)
2-oxo-1,2-dihydropyridin-3-yl)ethylidene)-6-methyl-2-thioxo-
2,5-dihydropyrimidin-4(3H)-one (11).
A mixture of 4b
in EtOH (50 mL) and aniline (0.01 mol, 0.93 g) was
refluxed for 2 h. After cooling, the separated solid was
collected and recrystallized from ethanol, as yellow
(1 mmol, 4.75 g), thiourea (1 mmol, 0.76 g), and sodium
ethoxide (0.7 g, 1 mmol) in ethanol (20 mL) was refluxed
for 6 h. The reaction mixture was cooled upon ice (25 g)
and neutralized with dil HCl. The separated solid was
filtered off and recrystallized from EtOH to afford
pyrimidine as orange crystals. Yield 88%, mp 140–
crystals. Yield 89%, mp 114–116°C. IR (KBr) υ
max
ꢀ
1
1
(
cm ): 3444, 1729, 1679. H-NMR (DMSO-d ) δ
6
(
ppm): 2.11 (s, 3H, CH , CH –C¼N), 2.52 (s, 3H, CH ,
3
3
3
ꢀ
1
1
pyrone C-4), 3.2 (s, 6H, N(CH ) ), 6.96–7.5 (m, 9H, Ar–
142°C. IR (KBr) υmax (cm ): 3451, 1630. H-NMR
(DMSO-d ) δ (ppm): 2.02 (s, 3H, CH , thiopyrimidine C-
3
2
H, biphenyl moiety), 7.52–8.8 (m, 10H, Ar–H, 2 aryl and
6
3
1
3
pyridine C-5 precursors). C-NMR (DMSO): 20.2, 21.8,
4), 2.5 (s, 3H, CH , CH –C¼C–), 3.2 (s, 6H, –N(CH ) ),
3
3
3 2
4
1
1
1.9, 104.3, 112.1, 119.4, 127.5, 128.3, 129.2, 130.3,
36.1, 137.6, 139.7, 140.1, 146.1, 146.9, 152.3, 155.3,
6.22 (s, 1H, pyridine H-5), 6.7–7.8 (m, 13H, Ar–H),
11.32 (s, 1H, NH, pyridone), 13.08 (s, 1H, NH,
+
13
59.1, 164.6, 175.8. MS m/z (% abundance): 550 [M]
thiopyrimidine). C-NMR (DMSO): 13.7, 20.9, 41.9,
+
(
(
1.2%), 551 [M + H] (2.1%). Anal. for C H N O
550). Cal: C, 80.85; H, 5.68; N, 7.64. Found: C, 80.98;
126.3, 127.6, 129.1, 130.2, 130.5, 134.6, 139.9, 140.1,
3
7
31
3
2
140.7, 143.4, 150.1, 160.2, 161.3, 164.8, 232.9. MS m/z
+
+
H, 5.72; N, 7.50.
(% abundance): 533 [M] (1.1%), 534 [M + H] (4.2%).
Anal. for C H N O S (533). Cal: C, 72.16; H, 5.30; N,
7
-([1,1′-Biphenyl]-4-yl)-5-(4-(dimethylamino)phenyl)-4-
32 28 4 2
methyl-3-(1-(p-tolyl-imino)ethyl)-2H-pyrano[2,3-b]pyridin-2-
one (10b). A solution of compound 4b (0.01 mol, 4.75 g)
in EtOH (50 mL) and p-toluidine (0.01 mol, 1.07 g) was
refluxed for 2 h. After cooling, the separated solid was
collected and recrystallized from ethanol as yellow
10.52; S, 6.02. Found: C, 72.29; H, 5.18; N, 10.36; S, 6.00.
Ethyl((1-(7-([1,1′-biphenyl]-4-yl)-5-(4-(dimethylamino)
phenyl)-4-methyl-2-oxo-2H-pyrano[2,3-b]pyridin-3-yl)
ethylidene)amino)acetate (12). A mixture of 4b (1 mmol,
4.75 g), NH CH COOEt (1.39 g, 1 mmol), and
2
2
crystals. Yield 92%, mp 108–110°C. IR (KBr) υ
Py : EtOH (1:10) was refluxed for 3 h. The separated
solid was filtered off and crystallized from ethanol as
yellow crystals. Yield 62%, mp 214–215°C. IR (KBr)
max
ꢀ
1
1
(
cm ): 3444, 1729, 1679. H-NMR (DMSO-d ) δ
6
(
ppm): 1.98 (s, 3H, CH , CH –C¼N), 2.2 (s, 3H, CH ),
3
3
3
ꢀ
1
1
2
6
1
.5 (s, 3H, CH , pyrone C-4), 3.2 (s, 6H, N(CH ) ),
υmax (cm ): 3451, 1610. H-NMR (DMSO-d ) δ (ppm):
3
3 2
6
.92–7.3 (m, 8H, Ar–H, 2 phenyl moiety), 7.5–8.8 (m,
1.1 (t, 3H, CH , ester), 2.33 (s, 3H, CH , coumarin), 2.74
3
3
1
3
0H, Ar–H, biphenyl and pyridine C-5).
C-NMR
(s, 3H, CH imine), 3.2 (s, 6H, –N(CH ) ), 3.82 (q, 2H,
3 3 2
(
1
1
DMSO): 20.2, 21.5, 21.8, 41.9, 104.3, 112.1, 119.4,
27.5, 128.3, 129.2, 130.3, 136.1, 137.6, 139.7, 140.1,
CH , ester), 5.12 (s, 2H, CH , imine), 6.78–7.60 (m,
2 2
13
14H, Ar–H). C-NMR (DMSO): 14.7, 17.4, 21.9, 41.9,
52.6, 61.7, 112.9, 127.1, 127.8, 128.1, 129.4, 137.7,
139.1, 140.5, 145.1, 146.2, 152.3, 155.6, 159.1, 164.6,
46.1, 146.9, 152.3, 155.3, 159.1, 164.6, 175.8. MS m/z
+
+
(
% abundance): 564 [M] (2.1%), 565 [M + H] (2.7%).
+
Anal. for C H N O (564). Cal: C, 80.97; H, 5.90; N,
7
170.7, 177.4. MS m/z (% abundance): 559 [M] (36%),
38 33 3 2
+
.45. Found: C, 81.00; H, 5.8; N, 7.33.
560 [M + H] (6.6%). Anal. for C H N O (559). Cal:
3
5 33 3 4
7
-([1,1′-Biphenyl]-4-yl)-5-(4-(dimethylamino)phenyl)-4-
methyl-3-(1-((4-nitrophenyl)imino)ethyl)-2H-pyrano[2,3-b]
pyridin-2-one (10c).
(
(
C, 75.13; H, 5.90; N, 7.51. Found: C, 74.85; H, 5.71; N,
7.32.
A solution of compound 4b
0.01 mol, 4.75 g) in EtOH (50 mL) and p-nitroaniline
0.01 mol, 1.38 g) was refluxed for 4 h. After cooling,
6
-(1-(6-([1,1′-Biphenyl]-4-yl)-4-(4-(dimethylamino)phenyl)-
-oxo-1,2-dihydropyridin-3-yl)ethylidene)-5-methyl-3-thioxo-
1,2,3,6-tetrahydro-7H-1,2,4-triazepin-7-one (13).
2
A
the separated solid was collected and recrystallized from
mixture of 4b (1 mmol, 4.75 g), NH CSNHNH2
2
ethanol as yellow crystals. Yield 96%, mp 130–132°C.
IR (KBr) υmax (cm ): 3444, 1729, 1679. H-NMR
(1 mmol, 0.91 g), and AcOH/MeOH (1:10) was refluxed
for 2 h and then cooled, and the solid formed was filtered
off, dried, and recrystallized from EtOH as reddish brown
ꢀ
1
1
(
(
DMSO-d ) δ (ppm): 2.2 (s, 3H, CH , CH –C¼N), 2.6
6
3
3
s, 3H, CH , pyrone C-4), 3.22 (s, 6H, –N(CH ) ), 6.7–
crystals. Yield 89%, mp 210–212°C. IR (KBr) υ
3
3 2
max
ꢀ
1
1
7
.9 (m, 8H, Ar–H, 2 phenyl moiety), 7.52–8.7 (m, 10H,
(cm ): 3440, 1605. H-NMR (DMSO-d ) δ (ppm): 2.1
6
1
3
Ar–H, biphenyl and pyridine C-5). C-NMR (DMSO):
(s, 3H, CH ), 2.54 (s, 3H, CH ), 3.2 (s, 6H, –N(CH ) ),
3
3
3 2
2
1
1
0.2, 21.8, 41.9, 104.3, 112.1, 119.4, 125.1, 127.5,
28.3, 129.2, 130.3, 136.1, 137.6, 139.7, 140.1, 146.1,
46.2, 146.9, 152.3, 155.3, 159.1, 164.6, 175.8. MS m/z
6.3 (s, 1H, pyridine H-5), 6.78–7.60 (m, 13H, Ar–H), 8.9
(s, 1H, NH, lactam of triazepine nucleus), 11.08 (s, 1H,
NH, thiolactam of triazepine nucleus), 12.02 (s, 1H, NH,
+
+
13
(% abundance): 595 [M] (1.8%), 596 [M + H] (11.2%).
pyridone). C-NMR (DMSO): 13.8, 21.7, 41.9, 104.7,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
A Facile One-pot Synthesis and Anticancer Evaluation of Interesting Pyrazole and
Pyrimidinthione via Heterocyclic Interconversion
1
1
10.9, 111.4, 127.6, 129.1, 134.4, 134.87, 139.89, 140.6,
43.98, 150.1, 155.1, 160.2, 160.94, 164.6, 188.7. MS
CH , ester), 6.03 (s, 1H, pyridone H-5), 6.7–7.68 (m, 13H,
2
Ar–H), 7.98 (s, 1H, NH, oxazepine), 11.02 (s, 1H, NH,
+
+
13
m/z (% abundance): 548 [M] (37%), 550 [M + 2]
pyridone). C-NMR (DMSO): 13.9, 41.9, 45.8, 60.8,
(
5
1
2.6%). Anal. for C H N O S (548). Cal: C, 70.18; H,
.34; N, 12.79; S, 5.85 Found: C, 70.32; H, 5.26; N,
2.65; S, 5.78.
102.2, 104.5, 111.9, 126.9, 128.1, 128.9, 129.6, 130.4,
134.5, 139.8, 140.6, 149.8, 159.8, 161.9, 166.9, 168.3,
3
2 29 5 2
+
172.4. MS m/z (% abundance): 564 [M] (1.8%), 565
+
[
M + H] (2.5%). Anal. for C H N O (564). Cal: C,
6
-([1,1′-Biphenyl]-4-yl)-4-(4-(dimethylamino)phenyl)-3-
hydroxy(3-hydroxy-5-oxo-1,5-dihydro-4H-pyrazol-4-
ylidene)methyl)pyridin-2(1H)-one (14).
33 29 3 6
(
70.33; H, 5.19; N, 7.46. Found: C, 70.46; H, 5.02; N, 7.35.
A solution of
6
-((6-([1,1′-Biphenyl]-4-yl)-4-(4-(dimethylamino)phenyl)-2-
compound 4c (0.01 mol, 5.07 g) in EtOH (50 mL) and
hydrazine hydrate (0.02 mol, 99%) was refluxed for 3 h.
After cooling, the separated solid was collected and
recrystallized from ethanol as white crystals. Yield 88%,
oxo-1,2-dihydropyridin-3-yl)(hydroxy)methylene)-7-hydroxy-
3-thioxo-2,3,4,6-tetrahydro-5H-1,2,4-triazepin-5-one (17).
A mixture of 5c (1 mmol, 5.07 g), NH NHCSNH2
2
(1 mmol, 0.91 g), and AcOH : MeOH (1:10) was grinded
for 20 min and then refluxed for 2 h. The separated solid
was filtered off, dried, and recrystallized from EtOH to
afford brown crystals. Yield 78%, mp 198–200°C. IR
ꢀ
1
mp 290–292°C. IR (KBr) υ
(cm ): 3443, 3328,
max
1
1
6
1
720, 1670, 1607. H-NMR (DMSO-d ) δ (ppm): 3.2 (s,
6
H, –N(CH ) ), 6.22 (s, 1H, pyridine H-5), 6.9–7.88 (m,
3
2
ꢀ
1
1
3H, Ar–H), 10.02 (s, 1H, OH), 11.82 (s, 2H, 2NH of 2
(KBr) υmax (cm ): 3441, 1721, 1635, 1604. H-NMR
(DMSO-d ) δ (ppm): 3.2 (s, 6H, N(CH ) ), 6.2 (s, 1H,
1
3
lactam rings), 12.67 (s, 1H, OH, pyrazol C-3). C-NMR
DMSO): 41.9, 104, 111.8, 126.1, 127.3, 127.9, 128.9,
6
3 2
(
pyridine H-5), 6.6–7.62 (m, 13H, ArH), 10.32 (s, 2H,
1
1
29.9, 130.3, 134.4, 150.1, 150.8, 159.9, 161.2, 174.5,
2OH, 2 hydroxyl groups), 11.2 (s, 1H, NH, pyridone),
12.8 (s, 2H, 2NH, triazepine). C-NMR (DMSO): 41.9,
+
13
96.8. MS m/z (% abundance): 493 [M] (1.8%), 494
+
[M + H] (2.0%). Anal. for C H N O (493). Cal: C,
95.1, 105.2, 111.4, 126.2, 127.8, 128.1, 129.4, 129.8,
134.1, 139.8, 140.7, 150.1, 154.8, 161.7, 168.8., 195.9.
2
9 24 4 4
7
1
0.72; H, 4.91; N, 11.38. Found: C, 70.84; H, 4.80; N,
1.22.
+
+
MS m/z (% abundance): 551 [M] (1.5%), 552 [M + H]
(4.5%). Anal. for C30 S (551). Cal: C, 65.32; H,
5
-((6-([1,1′-Biphenyl]-4-yl)-4-(4-(dimethylamino)phenyl)-2-
oxo-1,2-dihydropyridin-3-yl)(hydroxy)methylene)-6-hydroxy-
-thioxo-2,5-dihydropyrimidin-4(3H)-one (15). A mixture
H N O
25 5 4
4.57; N, 12.70; S, 5.81. Found: C, 65.45; H, 4.60; N,
12.62; S, 5.9.
2
of 4c (1 mmol, 5.07 g), thiourea (1 mmol, 0.76 g), and
sodium ethoxide (1 mmol, 0.7 g) in EtOH (4 mL) was
grinded for 25–30 min. The reaction mixture was
refluxed for 2 h, cooled, and neutralized with dil HCl.
The solid was filtered and recrystallized from EtOH as
yellow crystals. Yield 83%, mp 158–160°C. IR (KBr)
REFERENCES AND NOTES
[
1] Patel, N. B.; Agravat, S. N.; Shaikh, F. M. Med Chem Res
2011, 20, 1033.
[
2] Patel, N. B.; Agravat, S. N. Chem Heterocycl Compd 2009,
4
4
5, 1343.
ꢀ
1
1
υmax (cm ): 3442, 1632, 1601. H-NMR (DMSO-d ) δ
6
[3] Tarik, E. S. A. Eur J Med Chem 2009, 44, 4385.
[4] Srivastava, A.; Pandeya, S. N. Int J Cur Pharm Rev Res 2011,
(
ppm): 3.2 (s, 6H, –N(CH ) ), 6.22 (s, 1H, pyridine H-5),
3 2
, 5.
6.9–7.88 (m, 13H, Ar–H), 10.02 (s, 1H, OH, enol
[
5] Paronikyan, E. G.; Noravyan, A. S.; Dzhagatspany, I. A.;
moiety), 11.2 (s, 1H, NH, pyridone), 12.82 (s, 1H, OH,
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Nazaryan, I. M.; Paronikyan, R. G. Pharm Chem J 2002, 36, 465.
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Nascimento, M.; Ferreira, D.; Rebello, M. A. Med Chem Res 2007, 16,
1
3
C-NMR (DMSO): 41.9, 85.2, 104.5, 110.9, 126.7,
27.4, 128.1, 129.6, 130.3, 134.9, 139.9, 140.5, 150.1,
59.8, 160.1, 160.5, 161.1, 166.7, 185.9. MS m/z (%
1
1
3
52.
[
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9] Tucker, T. J.; Sisko, J. T.; Tynebor, R. M.; Williams, T. M.;
+
+
abundance): 537 [M] (2.1%), 538 [M + H] (5.1%).
[
Anal. for C H N O S (537). Cal: C, 67.15; H, 4.51; N,
30 24 4 4
Felock, P. J.; Flynn, J. A.; Lai, M.; Liang, Y.; McGaughey, G.; Liu, M.
J Med Chem 2008, 51, 6503.
10.44; S, 5.97. Found: C, 67.34; H, 4.42; N, 10.31; S, 6.02.
Ethyl
7-(6-([1,1′-biphenyl]-4-yl)-4-(4-(dimethylamino)
[10] Mamolo, M. G.; Zampieri, D.; Falagiani, V.; Vio, L.;
Fermeglia, M.; Ferrone, M.; Pricl, S.; Banfi, E.; Scialino, G. ARKIVOC
phenyl)-2-oxo-1,2-dihydropyridin-3-yl)-2,5-dioxo-2,3,4,5-
tetrahydro-1,4-oxazepine-6-carboxylate (16). A mixture of
c (1 mmol, 5.07 g), ethyl glycinate (1 mmol, 1.39 g), and
Py : EtOH (1:10) was refluxed for 3 h, and the separated
solid was filtered off and crystallized from EtOH as yellow
2004, 5, 231.
[11] Mellol, H.; Echevarria, A.; Bernardino, A. M. R.; Canto-
4
Cavalheiro, M.; Leon, L. L. J Med Chem 2004, 47, 5427.
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Chem 1999, 42, 2447.
[13] Geffken, D.; Soliman, R.; Soliman, F. S. G.; Abdel-Khalek, M.
crystals. Yield 83%, mp 240–242°C. IR (KBr) υ
max
M. J Med Chem Res 2011, 20, 408.
ꢀ
1
1
(
cm ): 3324, 3265, 1765, 1745, 1690. H-NMR (DMSO-
[14] Nasr, M. N.; Gineinah, M. M. Arch Pharm 2002, 335, 289.
[15] Katritzky, A. R.; Serdyuk, L.; Chassaing, C.; Toader, D.;
Wang, X. J.; Forood, B.; Flatt, B.; Sun, C. C. K J Comb Chem 2000, 2,
d ) δ (ppm): 1.2 (t, 3H, CH , ester), 3.2 (s, 6H, –N(CH ) ),
.94 (s, 2H, CH CO, oxazepine nucleus), 4.23 (q, 2H,
6
3
3 2
3
2
182.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. A. Rizk and S. Shaban
Vol 000
[
16] Zhuravel, I. O.; Kovalenko, S. M.; Ivachtchenko, A. V.;
Balakin, K. V.; Kazmirchuk, V. V. Bioorg Med Chem Lett 2005, 15,
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Nogueras, M.; Cobo, J. Lett Org Chem 2011, 8, 652.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet