Convenient synthesis and antibacterial activity of tricyclic azine derivatives

Article abstract of DOI:10.3184/174751913X13640546938841

1,4-Phenylenediamine reacted readily with 2 mol of ethyl acetoacetate to give diethyl (2Z,2′Z)-3,3′-[(1,4-phenylene)- bisimino]dibut-2- enoate, which reacted with dimethylformamide dimethylacetal, activated methylene nitriles, ylidenemalononitriles and phenyl and benzoyl isothiocyanate to give, respectively, a 4,7-phenanthroline-2,9-dicarboxylate- 1,10-diol, and tricyclic bispyridine and bispyrimidine derivatives. Two compounds showed strong antibacterial activity against several microorganisms, while six others showed high to moderate activity.

Full text of DOI:10.3184/174751913X13640546938841

248 RESEARCH PAPER
APRIL, 248–252
JOURNAL OF CHEMICAL RESEARCH 2013
Convenient synthesis and antibacterial activity of tricyclic azine
derivatives
Abdel-Zaher A. Elassar*a,b, Abdulhakeem Alsughayerc and Fakhreia Al Sagheera
aChemistry Department, Faculty of Science, Kuwait University, PO Box 5969-Safat-13060, Kuwait
bChemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
cPharmaceutical Science Department, College of Health Science, The Public Authority for Applied Education andTraining, Kuwait
1,4-Phenylenediamine reacted readily with 2 mol of ethyl acetoacetate to give diethyl (2Z,2’Z)-3,3’-[(1,4-phenylene)-
bisimino]dibut-2-enoate, which reacted with dimethylformamide dimethylacetal, activated methylene nitriles,
ylidenemalononitriles and phenyl and benzoyl isothiocyanate to give, respectively, a 4,7-phenanthroline-2,9-dicarb-
oxylate-1,10-diol, and tricyclic bispyridine and bispyrimidine derivatives. Two compounds showed strong antibacte-
rial activity against several microorganisms, while six others showed high to moderate activity.
Keywords: bispyridine, bispyrimidine, 1,4-phenylenediamine, 4,7-phenanthroline
Introduction
showed as a broad signal at 10.47 ppm. The 13C NMR
spectrum showed 170.1 (C=O), 162.3, 136.8, 124.8 (aromatic
carbons), 85.9 (CH=), and 58.6, 19.7, 18.6 (sp3 carbons). The
structure of compound 3 was finally established based on an
X-raystructuredetermination(depositnumberCCDC911401).
Notably, as the ORTEP diagram (Fig. 1) of compound 3
reveals, it is the bis Z-isomer, as depicted in Scheme 1.
All the new compounds that were synthesised were charac-
terised by their spectral data and their elemental analysis. Only
some of the spectral data, as appropriate, are discussed in this
section, but full details appear in the Experimental.
The notable biological and medicinal activities of compounds
containing pyridine1–4 and pyrimidine5–7 rings are responsible
for the extensive work that has been carried out on their syn-
thesis. For example, (aminoaryl)pyridine derivatives are
CDK9 inhibitors,8 and pyridine carboxamides are CXCR4
receptor antagonists9 and are key intermediates in the synthesis
of the anti-AIDS drug, nevirapine10 and of certain anti-HIV
drugs.11–15 Moreover, 1,4-phenylenediamine is known to be
a schistosomicidal agent, as is its condensation product with
acetoacetic ester.16
Compound 3 reacted with dimethylformamide dimethyl
acetal (DMFDMA) to give 4 and 5 (Scheme 2). The amount
of the N,N-dimethyl product 4, which could be detected by
GC-MS, was insignificant. 5 was the major product and its MS
showed m/z 442.26 in agreement with its molecular formula
C24H34N4O4. The 1H NMR and 13C NMR spectra showed imine
protons and carbons at 6.57 ppm and 155.8 ppm, respectively.
Compound 5 reacted with hydrazine hydrate to give the
bispyrazole 7 (Scheme 2). MS showed m/z 324.13 (M+) and its
1H NMR spectrum revealed the absence of ethyl protons and
the presence of four exchangeable NH protons.
Compound 5 also cyclised upon heating in the presence of a
Lewis acid catalyst to give diethyl 3,8-dimethyl-4,7-phenanth-
roline-2,9-dicarboxylate 6 (Scheme 2). Moreover, a product
containing the same ring system, phenanthroline-1,10-diol 8
could also be obtained when heating compound 3 under simi-
lar conditions. The synthesis of 8 by treating compound 3 with
a mixture of acetic anhydride and sulfuric acid was described
earlier.19–21 These products 6 and 8 are consistent with results
reported recently by our group.18
In earlier papers,17,18 we have described the synthesis of
tricyclic azines using 1,4-phenylenediamine as a scaffold. In
this article, we extend that work and describe the synthesis
in one pot reactions of polysubstituted bispyridines, bispyrimi-
dines and phenanthrolines starting from the condensation
product of 1,4-phenylenediamine and ethyl acetoacetate.
Results and discussion
1,4-Phenylenediamine 1 reacted with ethyl acetoacetate 2 in a
molar ratio of 1:2 to give the condensation product diethyl
(2Z,2′Z)-3,3′-[(1,4-phenylene)bisimino]dibut-2-enoate 3,
a
known compound.19–21 The most recent report of its synthesis
was 1954, prior to the routine use of MS and NMR. We have
therefore confirmed its structure by 1H and 13C NMR, MS and
IR. MS showed m/z (M+) 332.17, which agreed with the molec-
ular formula C18H24N2O4. The IR spectrum showed 3252 (NH)
1
and 1659 cm−1 (C=O) and the H NMR spectrum showed a
methyl group at 1.23 ppm (t, J = 7.20 Hz) coupled with a
methylene group at 4.12 ppm (q, J = 7.20 Hz) confirming the
presence of an ethyl group of an ester. Another methyl proton
appeared at 2.08 ppm weakly coupled to an olefinic proton at
4.72 ppm, as expected for MeC(N)=CHCO2Et, the aromatic
protons appeared as a singlet at 7.24 ppm and the NH protons
Compound 3 reacted with malononitrile under basic condi-
tions to give the bis(2-amino-6-methyl-4-oxo-1,4-dihydropyri-
dine) compound 9 (Scheme 3), the IR spectrum of which
revealed the presence of broad bands for a NH2 group at 3334
Fig. 1 ORTEP diagram of compound 3.
* Correspondent. E-mail: aelassar@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2013 249
Scheme 1
Scheme 2
and 3230 cm−1 and sharp signals at 2204 cm−1 for a cyano
group and at 1718 cm−1 for a carbonyl group.
reaction product with benzoyl isothiocyanate. Its IR spectrum
reveals the presence of two carbonyl groups at 1728 and
1670 cm−1, while 1H NMR showed aliphatic protons at
1.76 ppm. Moreover, its mass spectrum showed m/z 566.11
(M+).
4-Aminopyridine reacted with compound 3 to give 15 which
cyclised when reacted with formaldehyde to give 1,1′-
(1,4-phenylene)bis[3-(pyridin-4-yl)dihydropyrimidinone], 16
(Scheme 6). Compounds 15 and 16 showed in their mass spec-
tra m/z 428.20 and 452.20 in agreement with the molecular
formulae C24H24N6O2 and C26H24N6O2, respectively.
Compound 3 reacted with ylidenemalononitriles 10a–c in
basic medium to give the bispyridine derivatives 12a–c through
isolated intermediates 11a–c (Scheme 4). Compound 11 was
formed through Michael addition of the NH groups in com-
pound 3 to the ylidene double bonds of 2 mol of compounds
10. Compounds 11 were cyclised upon heating in pyridine to
give compounds 12 via double enamine addition to the cyano
1
group. The structures of 12 were characterized by their H
NMR spectra which inter alia revealed the presence of two
exchangeable NH protons.
Phenyl isothiocyanate reacted with compound 3 to give the
1,1′-(1,4-phenylene)bis(N-phenyly-thioxo-dihydropyrimidinone)
derivative, 13 (Scheme 5). Similarly, compound 3 reacted with
benzoylisothiocyanate to give the 1,1′-(1,4-phenylene)bis(N-
benzoyl-thioxodihydropyrimidinone) derivative, 14. The IR
spectrum of 13 revealed the presence of carbonyl and thionyl
groups at 1658 and 1200 cm−1, respectively, and its mass
spectrum showed m/z 510.12 (M+). Moreover, elemental anal-
ysis showed sulfur analysis of 12.67% close to the required
value of 12.56%. Similarly, compound 14 was confirmed as a
Bioactivity of synthesised compounds:
The well known diverse biological activities of compounds
containing pyridines and pyrimidines as components of fused
azines8–16,21,22–28 prompted us to test and study the antibacterial
activities of some of the newly synthesised products. Table 1
shows that most of the tested compounds had moderate to high
activity against all four microorganisms. The tetracyclic 2-
thiodihydropyrimidines 13 and 14 were the most active against
all the microorganisms tested, while compounds 3, 12a, 12b

250 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 3
Scheme 4
Scheme 5
Scheme 6
and 16 showed high activity against Escherichia coli. With
Staphylococcus aureus, compounds 12c, 13 and 14 showed the
highest activity. Both 13 and 14 showed severe effects with
Bacillus Subtilis, while 3, 12a, and 12c showed a high effect.
With Pseudomonas Aeruginosa compounds 3, 13 and 14
showed a high effect.
Conclusions
Table 1 Antibacterial activity of a selection of the prepared
Using N,N′-dialkylated 1,4-phenylenediamine as a scaffold
for the synthesis of substituted bisazines was found to be very
efficient, yielding bispyridines and bispyrimidines in one pot
reactions. The antibacterial activity of some of the obtained
bisazines was investigated, thioxopyrimidinones showing the
greatest activity.
compounds
Compound
E. Coli S. Aureus B. Subtilis P. Aeruginosa
3
+++
++
+++
+++
++
++++
++++
+++
++
+++
++
+++
++
+++
++
+++
++++
++++
++
+++
++
9
12a
12b
12c
13
14
16
++
++
+
++
+++
+++
++
Experimental
++++
++++
++++
+++
All melting points are uncorrected. IR spectra were recorded in KBr
with a Shimadzu 408 IR spectrophotometer. NMR spectra were
recorded on a Bruker DPX 400 spectrometer (1H NMR at 400 MHz
and 13C NMR at 100 MHz) in CDCl3 using TMS as an internal refer-
ence with the chemical shifts expressed as δ ppm. Mass spectra were
++++ Severe effect (>30 mm), +++ high effect (25–29 mm),
++ moderate effect (20–24 mm), + weak effect (< 20 mm).

JOURNAL OF CHEMICAL RESEARCH 2013 251
measured on a Shimadzu GCMS-QP 1000 Ex mass spectrometer.
Micro analytical data were obtained from the ANALAB Unit at the
Chemistry Department, Kuwait University.
The reaction mixture was refluxed for 3h and then the solid product
that formed was collected by filtration, washed thoroughly with water
and then dried. Recrystallisation (DMF/EtOH) yielded brown crystals
(55%) of 9, m.p. > 250 °C; IR: 3334, 3230 (NH2), 2204 (CN), 1718
1
cm−1 (CO); H NMR: δ (ppm) 7.95 (br, 4H, 2NH2, D2O-exchange),
X-ray crystallography
A colourless block crystal of C18H24N2O4 having approximate dimen-
sions of 0.200 x 0.200 x 0.200 mm was mounted on a glass fibre. All
measurements were made on a Rigaku R-AXIS RAPID diffractome-
ter using filtered Mo-Kα radiation. The crystal-to-detector distance
was 127.40 mm.
7.21 (s, 4H, aromatic-H), 6.54 (s, 2H, dihydropyridine-H), 2.54 (s,
6H, 2Me); 13C NMR: δ 205.0 (CO), 162.7, 129.3, 121.3, 120.0, 115.0,
114.6, 114.2, 79.4, 20.9 (aromatic, dihydropyridine, and sp3 carbons);
MS: m/z 372.3 (M+); Anal. Calcd for C20H16N6O2 (372.38): C, 64.51;
H, 4.33; N, 22.57. Found: C, 64.33; H, 4.61; N, 22.64%.
Diethyl (2Z,2′Z)-3,3′-[(1,4-phenylene)bisimino]dibut-2-enoate (3):
To a solution of 1,4-phenylenediamine (0.01 mol) in ethanol (30 mL),
ethyl acetoacetate (0.02 mol) was added. The reaction mixture was
refluxed for 3h and the solid product formed then was collected
by filtration, washed thoroughly with water and then dried. Recrystal-
lisation (EtOH) yielded beige crystals (80%) of 3, m.p. 134 °C [lit.
Synthesis of 3,3′-(1,4-phenylene)bis[(2,2-dicyano-1-arylethyl)azaned
iyl)]bis[(2E)-but-2-enoic acid) (11a–c): general procedure
Ylidenemalononitrile (0.02 mol) and triethyl amine (10 drops) were
added To a solution of 3 (0.01mol) in DMF (30 mL),. The reaction
mixture was refluxed for 3h and then the solid product that formed
was collected by filtration, washed thoroughly with water and then
dried.
1
135 °C19,21, 131 °C20,]; IR: 3252 (NH), 1659 cm−1 (CO); H NMR: δ
(ppm) 10.47 (br, 2H, 2NH, D2O-exchange), 7.24 (s, 4H, aromatic-H),
4.72 (s, 2H, 2CH), 4.12 (q, 4H, 2CH2, J = 7.2 Hz), 2.08 (s, 6H, 2Me),
1.23 (t, 6H, 2Me, J = 7.2 Hz ); 13C NMR: δ 170.1 (CO), 162.3, 136.8,
124.8 (aromatic carbons), 85.9 (CH=), 58.6, 19.7, 18.6 (sp3 carbons)
ppm; MS: m/z 332.17 (M+); Anal. Calcd for C18H24N2O4 (332.39): C,
65.04; H, 7.28; N, 8.43. Found: C, 65.13; H, 6.99; N, 8.28%.
3,3′-(1,4-Phenylene)bis[(2,2-dicyano-1-phenylethyl)azanediyl)]bis
[(2E)-but-2-enoic acid) (11a): Recrystallisation (EtOH) yielded dark
green crystals (63%) of 11a, m.p. 73 °C; IR: 2210, 2167 (CN), 1733
1
cm−1 (CO); H NMR: δ (ppm) 7.47–7.25 (m, 10H, 2 C6H5), 7.18 (s,
4H, aromatic-H), 6.56 (s, 2H, ethylenic-H), 4.70 (d, 2H, 2CH), 4.12
(q, 4H, 2CH2, J = 7.2 Hz), 3.91 (d, 2H, 2CH), 1.83 (s, 6H, 2Me), 1.13
(t, 6H, 2Me, J = 7.2 Hz); 13C NMR: δ 169.5, 158.8, 146.8, 135.6,
128.7, 127.9, 126.3, 114.2, 114.1, 85.7, 59.4, 57.2, 19.9, 18.1, 14.5
ppm; MS: m/z 640.26 (M+); Anal. Calcd for C38H36N6O4 (640.73): C,
71.23; H, 5.66; N, 13.12. Found: C, 71.33; H, 5.76; N, 12.99%.
3,3′-(1,4-Phenylene)bis[(2,2-dicyano-1-p-chlorophenylethyl)azane
diyl)]bis[(2E)-but-2-enoic acid) (11b): Recrystallisation (EtOH)
yielded pale brown crystals (80%) of 11b, m.p. 75 °C; IR: 2190, 2170
(CN), 1733 cm−1 (CO); 1H NMR: δ (ppm) 7.57–7.24 (m, 8H, 2 C6H4),
7.18 (s, 4H, aromatic-H), 6.86 (s, 2H, ethylenic-H), 4.56 (d, 2H, 2CH),
4.34 (q, 4H, 2CH2, J = 7.2 Hz), 3.91 (d, 2H, 2CH), 1.82 (s, 6H, 2Me),
1.19 (t, 6H, 2Me, J = 7.2 Hz); 13C NMR: δ 169.5, 159.6, 146.7, 130.7,
128.9, 127.1, 126.2, 124.1, 114.2, 83.1, 59.5, 57.8, 19.8, 18.6, 14.5
ppm; MS: m/z 708.20 (M+); Anal. Calcd for C38H34Cl2N6O4 (709.62):
C, 64.32; H, 4.83; N, 11.84. Found: C, 64.35; H, 4.78; N, 11.94%.
3,3′-(1,4-Phenylene)bis[(2,2-dicyano-1-p-nitrophenylethyl)azaned
iyl)]bis[(2E)-but-2-enoic acid) (11c): Recrystallisation (DMF/EtOH)
yielded pale brown crystals (80%) of 11c, m.p. 91 °C; IR: 2210 (CN),
1733 cm−1 (CO); 1H NMR: δ (ppm) 8.50, 7.82 (dd, 8H, 2 C6H4), 7.17
(s, 4H, aromatic-H), 6.55 (s, 2H, ethylenic-H), 4.68 (d, 2H, 2CH),
4.14 (q, 4H, 2CH2¸ J = 7.2 Hz), 3.94 (d, 2H, 2CH), 1.82 (s, 6H, 2Me),
1.16 (t, 6H, 2Me, J = 7.2 Hz); 13C NMR: δ (ppm) 169.4, 159.4, 146.8,
136.8, 130.6, 128.7, 127.4, 126.7, 124.9, 114.6, 97.9, 58.6, 19.7, 18.6,
14.9 ppm; MS: m/z 730.25 (M+);Anal. Calcd for C38H34N8O8 (730.73):
C, 62.46; H, 4.69; N, 15.33. Found: C, 62.25; H, 4.56; N, 15.16%.
Diethyl (2Z,2′Z,3E,3′E)-3,3′-[(1,4-phenylene)bisazanylidene]bis[2-
(dimethylaminomethanyl-idene)but-2-enoate] (5): DMFDMA (0.02 mol)
was added to a solution of 3 (0.01mol) in DMF (30 mL). The reaction
mixture was refluxed for 3h and then the solid product that formed
was collected by filtration, washed thoroughly with water and then
dried. Recrystallisation (EtOH) yielded brown crystals (70%) of 5,
1
m.p. 75–77 °C; IR: 1724 cm−1 (CO); H NMR: δ (ppm) 7.26 (s, 4H,
aromatic-H), 6.57 (s,2H, 2CH=), 4.35 (q, 4H, 2CH2, J = 7.2 Hz), 2.46
(s, 12H, 4Me), 2.08 (s, 6H, 2Me), 1.32 (t, 6H, 2Me, J = 7.2 Hz); 13
C
NMR: δ 176.1, 166.5, 155.8, 147.2, 123.7, 106.5, 61.0, 40.1, 19.5,
14.1 ppm; MS: m/z 442.26 (M+);Anal. Calcd for C24H34N4O4 (442.55):
C, 65.14; H, 7.74; N, 12.66. Found: C, 65.40; H, 7.60; N, 12.64%.
5,5′-{1,4-Phenylenebis[(E)-azanylylideneethan-1-yl-1-ylidene]}-
bis(1,2-dihydro-3H-pyrazol-3-one) (7): Hydrazine hydrate (0.02 mol)
was added to the reaction mixture of 3 and DMFDMA,. Then the mix-
ture was refluxed for 1h. The solid product that formed was collected
by filtration, washed thoroughly with water and then dried. Recrystal-
lisation (EtOH) yielded brown crystals (65%) of 7, m.p. > 250 °C;
1
IR: 3327 (NH), 1658 cm−1 (CO); H NMR: δ 8.03 (br, 4H, 4NH,
D2O-exchange), 7.21 (s, 4H, aromatic-H), 6.50 (s, 2H, pyrazole-H),
1.23 (s, 6H, 2Me); 13C NMR: δ 175.3, 163.8, 147.4, 132.7, 122.7,
101.0, 20.2 ppm; MS: m/z 324.13 (M+); Anal. Calcd for C16H16N6O2
(324.13): C, 59.25; H, 4.97; N, 25.91. Found: C, 59.11; H, 5.01; N,
26.01.
Synthesis of 3,8-dimethyl-4,7-phenanthroline derivatives (6) and (8):
general procedure
Synthesis of diethyl 1,1′-(1,4-diphenylene)bis(5-cyano-4-imino-2-
methyl-6-aryl-1,4-dihydro-pyridine-3-carboxylate) (12a–c)
A solution of 11a–c in pyridine (30 mL) was refluxed for 5h and the
solid product that formed after adding ice cold water was collected by
filtration, washed thoroughly with water and then dried.
Diethyl 1,1′-(1,4-diphenylene)bis(5-cyano-4-imino-2-methyl-6-
phenyl-1,4-dihydro-pyridine-3-carboxylate) (12a): Recrystallisation
(DMF/EtOH) yielded brown crystals (60%) of 12a, m.p. 110 °C; IR:
3330 (NH), 2210 (CN), 1724 cm−1 (CO); 1H NMR: δ (ppm) 8.56 (br,
2H, 2NH, D2O-exchange), 7.45–7.32 (m, 10H, 2C6H5), 7.17 (s, 4H,
aromatic-H), 4.14 (q, 4H, 2CH2, J = 7.2 Hz), 1.87 (s, 6H, 2Me), 1.32
(t, 6H, 2Me, J = 7.2 Hz); MS: m/z 636.70 (M+); Anal. Calcd for
C38H32N6O4 (636.70): C, 71.68; H, 5.07; N, 13.20. Found: C, 71.54; H,
4.98; N, 13.41%.
Diethyl 1,1′-(1,4-diphenylene)bis(5-cyano-4-imino-2-methyl-6-(p-
chlorophenyl)-1,4-dihydro-pyridine-3-carboxylate) (12b): Recrystal-
lisation (DMF/EtOH) yielded brown crystals (60%) of 12b, m.p.
115 °C; IR: 3330 (NH), 2210 (CN), 1724 cm−1 (CO); 1H NMR:
δ (ppm) 8.56 (br, 2H, 2NH, D2O-exchange), 7.45–7.32 (m, 8H,
2C6H4), 7.17 (s, 4H, aromatic-H), 4.14 (q, 4H, 2CH2, J = 7.2 Hz), 1.87
(s, 6H, 2Me), 1.32 (t, 6H, 2Me, J = 7.2 Hz); MS: m/z 704.17 (M+);
Anal. Calcd for C38H30Cl2N6O4 (705.59): C, 64.68; H, 4.29; N, 11.91.
Found: C, 64.64; H, 4.11; N, 11.81%.
In a dry round-bottomed flask 3 or 5 (0.01 mole) was added to alumi-
num chloride anhydrous (3 g). The two solids were mixed together
and then heated in a fume hood for 3 h. The condenser was fitted with
an anhydrous calcium chloride tube after mixing and removed after
all the HCl had evolved. The reaction product was treated with HCl
solution and the solid product was collected by filtration, washed
thoroughly with water and then dried.
Diethyl 3,8-dimethyl-4,7-phenanthroline-2,9-dicarboxylate (6):
Recrystallisation (DMF/EtOH) yielded deep green crystals (60%)
1
of 6, m.p. > 250 °C; IR: 1734 cm−1 (CO); H NMR: δ 8.63 (s, 2H,
phenanthroline-H), 7.90 (s, 2H, aromatic-H), 4.16 ppm (q, 4H, 2CH2,
J = 7.2 Hz), 2.50 (s, 6H, 2Me), 1.31 (t, 6H, 2Me, J = 7.2 Hz); 13C
NMR: δ 167.6, 158.3, 138.2, 135.8, 130.3, 125.0, (aromatic carbons),
61.3, 18.6, 16.0 ppm (sp3 carbons); MS: m/z 352.14 (M+); Anal. Calcd
for C20H20N2O4 (352.38): C, 68.17; H, 5.72; N, 7.95. Found: C, 68.17;
H, 5.96; N, 7.64.
3,8-Dimethyl-4,7-phenanthroline-1,10-diol (8): Recrystallisation
(EtOH) yielded pale brown crystals (70%) of 8, m.p. > 250 °C; IR:
3422 cm−1 (OH); 1H NMR: δ (ppm) 9.73 (br, 2H, 2OH, D2O-exchange),
8.03 (d, 2H, ArH), 6.92 (s, 2H, aromatic-H), 2.09 (s, 6H, 2Me);13C
NMR: δ 165.3, 158.3, 135.9, 114.6, 110.0, 24.9 ppm; MS: m/z 240.09
(M+); Anal. Calcd for C14H12N2O2 (240.26): C, 69.99; H, 5.03; N,
11.66. Found: C, 69.83; H, 4.96; N, 11.64%.
1,1′-(1,4-Phenylene)bis(2-amino-6-methyl-4-oxo-1,2-dihydropyri-
dine-3-carbonitrile) (9): Malononitrile (0.02 mol) and triethyl amine
(10 drops) were added to a solution of 3 (0.01mol) in DMF (30 mL).
Diethyl 1,1′-(1,4-diphenylene)bis(5-cyano-4-imino-2-methyl-6-(p-
nitrophenyl)-1,4-dihydro-pyridine-3-carboxylate) (12c): Recrystalli-
sation (DMF/EtOH) yielded brown crystals (60%) of 12c, m.p.

252 JOURNAL OF CHEMICAL RESEARCH 2013
1
109 °C; IR: 3330 (NH), 2210 (CN), 1724 cm−1 (CO); H NMR: δ
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(ppm) 8.56 (br, 2H, 2NH, D2O-exchange), 7.45–7.32 (m, 8H, 2C6H4),
7.17 (s, 4H, aromatic-H), 4.14 (q, 4H, 2CH2, J = 7.2 Hz), 1.87 (s, 6H,
2Me), 1.32 (t, 6H, 2Me, J = 7.2 Hz); MS: m/z 726.22 (M+); Anal.
Calcd for C38H30N8O8 (726.69): C, 62.81; H, 4.16; N, 15.42. Found: C,
63.01; H, 4.02; N, 15.43%.
The authors are grateful to the Chemistry Department, and
the Faculty of Science Kuwait University, and for the SAF
facilities project GS01/05, GS03/01 and GS 03/08.
1,1′-(1,4-Phenylene)bis(6-methyl-3-phenyl-2-thioxo-2,3-dihydro-
pyrimidin-4(1H)-one) (13): Phenyl isothiocyanate (0.02 mol) was
added to a solution of 3 (0.01mol) in DMF (30 mL). The reaction
mixture was refluxed for 3h and then the solid product that formed
was collected by filtration, washed thoroughly with water and then
dried. Recrystallisation (DMF/EtOH) yielded yellow crystals (70%)
Received 28 November 2012; accepted 17 February 2013
Paper 1201646 doi: 10.3184/174751913X13640546938841
Published online: 19 April 2013
of 13, m.p. 114–117 °C; IR: 1658 (CO), 1200 cm−1 (CS); H NMR:
1
References
δ (ppm) 8.00–7.56 (m, 10H, 2C6H5),, 7.16 (s, 4H, aromatic-H), 4.68
(s, 2H, pyrimidine-H), 2.00 (s, 6H, 2Me); 13C NMR: δ (ppm) 169.3,
167.9, 155.8, 135.0, 134.9, 129.8, 127.9, 124.6, 122.6, 85.9, 19.8
ppm; MS: m/z 510.12 (M+); Anal. Calcd for C28H22N4O2S2 (510.63):
C, 65.86; H, 4.34; N, 10.97, S, 12.56. Found: C, 65.83; H, 4.34; N,
10.74; S, 12.67%.
1,1′-(1,4-Phenylene)bis(3-benzoyl-6-methyl-2-thioxo-2,3-dihydro-
pyrimidin-4(1H)-one) (14): 3 (0.01 mol) was added to a pre-prepared
solution of benzoylisothiocyanate (0.02 mol) in acetone (30 mL). The
reaction mixture was refluxed for 3h and then treated with ice-cold
water. The solid product so formed was collected by filtration, washed
thoroughly with water and then dried. Recrystallisation (EtOH)
yielded yellow crystals (70%) of 14, m.p. 223 °C; IR: 1728, 1670
(CO), 1200 cm−1 (CS); 1H NMR: δ (ppm) 8.01–7.65 (m, 10H, 2C6H5),
7.35 (s, 4H, aromatic-H), 4.33 ppm (s, 2H, pyrimidine-H), 1.76 (s, 6H,
2Me); 13C NMR: δ (ppm) 169.3, 167.9, 155.8, 135.0, 134.9, 129.8,
127.9, 124.6, 122.6, 85.9, 19.8 ppm; MS: m/z 566.11 (M+); Anal.
Calcd for C30H22N4O4S2 (566.65): C, 63.59; H, 3.91; N, 9.89; S, 11.32.
Found: C, 63.65; H, 4.04; N, 10.01; S, 11.47%.
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3,3′-(1,4-Phenylene)bis(azanediyl)bis[(2E)-N-(pyridin-4-yl)but-2-
enamide] (15): 4-Aminopyridine (0.02 mol) was added to a solution
of 3 (0.01mol) in DMF (30 mL),. The reaction mixture was refluxed
for 3h and then the solid product that formed was collected by filtra-
tion, washed thoroughly with water and then dried. Recrystallisation
(DMF/EtOH) yielded brown crystals (80%) of 15, m.p. 115–118 °C;
IR: 3434, 3251 (NH), 1658 cm−1 (CO); 1H NMR: δ (ppm) 8.51, 6.05
(br, 4H, 4NH, D2O-exchange), 7.97, 6.47 (dd, 8H, pyridine-H), 7.17
(s, 4H, aromatic-H), 4.68 (s, 2H, 2CH), 1.87 (s, 6H, 2Me); 13C NMR:
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67.27; H, 5.65; N, 19.61. Found: C, 67.22; H, 5.45; N, 19.64%.
1,1′-(1,4-Phenylene)bis[6-methyl-3-(pyridin-4-yl)-3,4-dihydropy-
rimidin-4(1H)-one) (16): Formaldehyde (0.02 mol) was added to a
solution of 15 (0.01mol) in DMF (30 mL),. The reaction mixture was
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by filtration, washed thoroughly with water and then dried. Recrystal-
lisation (EtOH) yielded brown crystals (80%) of 16, m.p. > 250 °C;
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H), 7.12 (s, 4H, aromatic-H), 4.69 (s, 4H, pyrimidine-H), 4.75 (s, 2H,
pyrimidine-H), 1.88 (s, 6H, 2Me); 13C NMR: δ (ppm) 166.5, 158.0,
155.2, 149.6, 135.2, 117.3, 109.1, 102.2, 69.7, 18.7 ppm; MS: m/z
452.20 (M+); Anal. Calcd for C26H24N6O2 (452.51): C, 69.01; H, 5.35;
N, 18.57. Found: C, 69.18; H, 5.46; N, 18.63.
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Biological activity: minimum inhibitory concentration (MIC)
The selected compounds were screened for their antibacterial activity
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evaluated by the turbidity method. A loopful of bacteria was inocu-
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24 h. The growth of the bacteria was determined by measuring the
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concentration of drug in the series that prevents the development
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CCDC 668767 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
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