Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e][1,3,4]triazolo and Tetrazolo[1,5-c]pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Article abstract of DOI:10.1002/jhet.3058

A novel series of pyrido[2,3-d]pyrimidines 3a–d, 4a–d, 5a–d, 6a–d, and 7a–d; pyrido[3,2-e][1,3,4]triazolo; and tetrazolo[1,5-c]pyrimidines 10a–d and 11a–d was synthesized through different chemical reactions starting from 2-amino-3-cyano-4,6-diarylpyridines. The newly synthesized heterocycles were characterized by elemental analysis, IR, ¹H-NMR, ¹³C-NMR, and mass spectral data. Compounds have been screened for their antibacterial and antifungal activities. The data showed that the presence of electron-donating group such as p-methoxyphenyl increases the antimicrobial activity. Also, the compounds have shown anticancer activity for colon and liver cancer cells.

Full text of DOI:10.1002/jhet.3058

Month 2017
Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e]
[1,3,4]triazolo and Tetrazolo[1,5-c]pyrimidine Derivatives as Potential
Antimicrobial and Anticancer Agents
*
Elsayed Mohmoud AbedelRehim
and Mohamed AbdEllatif
Chemistry Department, Faculty of Science, Damanhour University, Damanhour, Egypt
*
E-mail: elsayedabdelrehim@sci.dmu.edu.eg
Received December 19, 2016
DOI 10.1002/jhet.3058
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
A novel series of pyrido[2,3-d]pyrimidines 3a–d, 4a–d, 5a–d, 6a–d, and 7a–d; pyrido[3,2-e][1,3,4]
triazolo; and tetrazolo[1,5-c]pyrimidines 10a–d and 11a–d was synthesized through different chemical
reactions starting from 2-amino-3-cyano-4,6-diarylpyridines. The newly synthesized heterocycles were
characterized by elemental analysis, IR, 1H-NMR, 13C-NMR, and mass spectral data. Compounds have been
screened for their antibacterial and antifungal activities. The data showed that the presence of electron-
donating group such as p-methoxyphenyl increases the antimicrobial activity. Also, the compounds have
shown anticancer activity for colon and liver cancer cells.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
because of their different and significant biological
activities [12–14]. The synthesis of pyridino[2,3-d]
pyrimidines is mainly by two ways, that is, annulations
of pyrimidine ring over pyridine or vice versa [15]. The
therapeutic importance of this nucleus is enthused us to
develop selective procedures for synthesis in which
substituents could be arranged in a pharmacophoric
pattern to display high-order pharmacological activities.
The known starting materials 2-amino-3-cyano-4-(5-
substituted furan-2-yl)-6-(4-substituted phenyl)pyridines
2a–d according to Equation 1 [16].
Pyrido[2,3-d]pyrimidines derivatives comprise a diverse
and interesting group of drugs [1,2]. Pyrido[2,3-d]
pyrimidines in general are extremely important for their
biological activities. For example, some are antitumour
[3], antibacterial [4], anticonvulsant [5], antipyretic [6],
analgesic [7], and CNS depressant activity [8],
Specifically, pyrido[2,3-d]pyrimidines known to inhibit
Pneumocystis carinii (pc), Toxoplasma gondii (tg) of
tumor cell lines in culture [9], and the activity is
attributed to inhibition of dihydrofolate reductase [10,11].
RESULTS AND DISCUSSION
Chemistry. In our work on pyrido[2,3-d]pyrimidines,
we became interested to incorporate a triazol or tetrazol
group in pyrimidine ring. The reason for this is that
triazolo or tetrazolo derivatives are gaining importance
© 2017 Wiley Periodicals, Inc.

E. M. AbedelRehim and M. AbdEllatif
Vol 000
The synthetic pathways adopted for the preparation of the
desired new compounds are illustrated in Schemes 1 and 2.
The starting materials 2-amino-3-cyano-4,6-diphenyl
pyridines 2a–d were subjected to react with formic acid
(99%), acetic acid in the presence of a few drops of
concentrated sulfuric acid and benzoyl chloride in the
presence of pyridine to give 3a–d, 4a–d, and 5a–d,
respectively, in high yield percent (Scheme 1). The
structures of 3a–d, 4a–d, and 5a–d were confirmed on the
basis of their elemental and spectral data, the absence of
cyano and amino groups of 2a–d, and the appearance of
IR absorption bands at 3184–3256 cmÀ1 for NH groups
and at 1663–1689 cmÀ1 for C=O groups of the products.
Furthermore, 1H-NMR spectrum also showed an
exchangeable singlet signals at 10.13–13.37 ppm
corresponding to NH groups, beside a singlet at δ
1.97–2.23 ppm for CH3 of 4a–d. Moreover, the mass
spectrum showed molecular ion peaks at m/z 289, 303,
and 365 corresponding to 3a, 4a, and 5a, respectively. On
the other hand, compounds 2a–d were reacted with
formamide and acetamide to give 6a–d and 7a–d,
respectively. The IR spectrum of 6a–d and 7a–d revealed
the absence of cyano group and the appearance of
6.95–7.39 ppm for NH2 and at 1.89–2.32 ppm for CH3 of
7a–d. The mass spectrum presented the molecular ion
peaks at m/z 288 and 302 corresponding to 6a and 7a,
respectively.
However, treatment of the pyrido[2,3-d]pyrimidin-4-
ones derivatives 3a–d with phosphorous oxychloride
gave the expected 4-chloropyrido[2,3-d]pyrimidin-4-ones
derivatives 8a–d (Scheme 2). The proposed structures of
8a–d were supported by their elemental and spectral data.
The spectrum of 8a–d showed the absence the NH and
carbonyl group of 3a–d, and the mass spectrum of 8a
presented the molecular ion peaks (m/z): 307 (M+, 90.45),
309 (M+2, 29.65), which agree with chlorine atom
isotopes ratio. The hydrazinolysis of 8a–d using (99%)
hydrazine hydrate yielded the corresponding pyrido[2,3-
d]pyrimidin-4-yl]hydrazine derivatives 9a–d, which were
cyclized with formic acid or sodium nitrite in the
presence of acetic acid resulted in the expected
pyrido[3,2-e][1,3,4]triazolo[1,5-c]pyrimidine 10a–d and
pyrido[3,2-e]tetrazolo[1,5-c]pyrimidine 11a–d derivatives,
respectively (Scheme 2). The 1H-NMR of 9a–d
showed the presence of the amino group signals at
4.14–4.73 ppm and NH signals at 8.41–8.65 ppm.
Additionally, IR spectrum of 9a–d confirmed the obtained
structure by the presence of absorption bands at 3193–
1
absorption bands at 3114–3449 cmÀ1 for NH2, and H-
NMR spectrum showed an exchangeable singlet signal at
Scheme 1. Formation of Pyrido[2,3-d]pyrimidines derivatives from 2-amino-3-cyano-4,6diaryl pyridines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e][1,3,4]triazolo and
Tetrazolo[1,5-c]pyrimidineDerivativesasPotentialAntimicrobialandAnticancerAgents
Scheme 2. Formation of pyrido[3,2-e][1,3,4]triazolo and tetrazolo [1,5-c] pyrimidines from Pyrido[2,3-d]pyrimidines derivatives.
3421 cmÀ1 for (NH and NH2 stretching), while the absence
of the amino and NH groups signals in both IR and H-
NMR spectrum of 10a–d and 11a–d, and their elemental
analysis confirmed their structures.
minimal inhibitory concentration (MIC) (Table 2) by
means of the agar well-diffusion method in DMSO.
Streptomycin (10 μg/disc) was used as a standard
antibacterial, while Ketoconazole (5 μg/disc) was used
as standard antifungal. DMSO was used as a blank,
which exhibited no activity against any of the used
organisms.
1
BIOLOGICAL ACTIVITIES
It is well noticed that compounds 2a, 2c, 3a, 3c, 4a, 4c,
5a, 5c, 6a, 6c, 7a, 7c, 8a, 8c, 9a, 9c, 10a, 10c, 11a, and 11c
showed lower potency against all bacteria and fungi
compared with the reference standard. These compounds
2b,2d, 3d, 4b, 5b, 6b, 6d,7b, 7d, and 10b were
equipotent similar to reference standard. Furthermore,
compounds 3b, 4d, 5d, 8b, 8d, 9b, 9d, 10d, 11b, and
11d were found to be more active than reference
standard. In this work, we have synthesized compounds,
which were screened for their antimicrobial activities.
The tested compounds 3b, 4d, 5d, 8b, 8d, 9b, 9d, 10d,
11b, and 11d demonstrated excellent antimicrobial
activity. The data showed that the presence of
electron-donating group such as p-methoxyphenyl
increase. Hence, this study has widened the scope for
evolving the new and promising antimicrobial drugs.
Antimicrobial activity.
The antimicrobial screenings
for the synthesized compounds were undertaken using
agar well-diffusion assay [17,18]. Table 1 listed the
screening results of the tested compounds against the
Gram-negative bacteria (Escherichia coli ATCC873 and
Pseudomonas sp. ATCC9027), Gram-positive bacteria
(Bacillus subtilis ATCC6051, Streptococcus pneumonia
ATCC6303, and Staphylococcus aureus ATCC6538P),
and three fungal strains (Aspergillusniger ATCC6275,
Penicillium sp. ATCC11709, and Candida albicans
ATCC2091). The obtained data revealed that most of
the compounds showed moderate-to-excellent activities
against the microorganisms used at a dose of 1 μg/mL.
Compounds showing inhibition of at least 15 mm were
considered active and were further evaluated for their
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. AbedelRehim and M. AbdEllatif
Vol 000
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e][1,3,4]triazolo and
Tetrazolo[1,5-c]pyrimidineDerivativesasPotentialAntimicrobialandAnticancerAgents
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. AbedelRehim and M. AbdEllatif
Vol 000
Figure 1. The inhibitory activities against HCT-116 cell lines. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Figure 3. The inhibitory activities against HepG-2 cell lines. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Figure 2. The inhibitory activities against HCT-116 cell lines. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Figure 4. The inhibitory activities against HepG-2 cell lines. [Color
figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Table 4
Evaluation of cytotoxicity of pyrido-pyrimidine derivatives against HepG-2.
Samples concd (μg)
Cell viability (%)
50
25
12.5
6.25
3.125
1.56
0.00
2d
3d
4d
5d
6d
7d
8d
9d
4.19
28.50
29.87
38.99
5.79
6.67
7.00
4.33
7.01
30.73
35.22
50.91
9.21
10.28
9.87
7.09
9.20
44.29
40.11
61.49
12.47
19.58
14.10
14.11
40.09
67.99
24.92
15.19
58.66
62.03
73.20
16.38
29.38
20.08
24.39
69.57
83.67
44.86
20.11
62.55
75.18
83.84
29.18
35.01
24.28
30.37
82.07
90.04
56.30
30.88
77.99
89.12
99.54
41.40
44.15
55.03
36.28
90.87
95.69
73.11
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
100.00
10d
11d
22.54
29.85
13.16
32.98
44.07
16.54
Vinblastine standard
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e][1,3,4]triazolo and
Tetrazolo[1,5-c]pyrimidineDerivativesasPotentialAntimicrobialandAnticancerAgents
Anticancer activity.
In this study, the anticancer
serum and 50 μg/mL gentamycin. The monolayers of
10,000 cells adhered at the bottom of the wells in a
96-well microtiter plate incubated for 24 h at 37°C in a
humidified incubator with 5% CO2. The monolayers were
then washed with sterile phosphate buffered saline
(0.01 M pH 7.2), and simultaneously, the cells were
treated with 100 μL from different dilutions of the test
sample in fresh maintenance medium and incubated at
37°C. A control of untreated cells was made in the
absence of the test sample. Six wells were used for each
concentration of the test sample. Every 24 h, the
observation under the inverted microscope was made.
The number of the surviving cells was determined by
staining the cells with crystal violet [19,20] followed by
cell lysis using 33% glacial acetic acid and read the
absorbance at 490 nm using ELISA reader (SunRise,
TECAN, Inc., Morrisville, NC) after well mixing. The
absorbance values from untreated cells were considered
as 100% proliferation.
The number of viable cells was determined using ELISA
reader as previously mentioned before, and the percentage
of viability was calculated as [1-(ODt/ODc × 100%],
where ODt is the mean optical density of wells treated
with the test sample and ODc is the mean optical density
of untreated cells.
The 50% inhibitory concentration (IC50), which is the
concentration required to cause toxic effect in 50% of
inactivated cells, was estimated from graphic plots.
activity of the 10 synthesized pyrido-pyrimidine
derivatives has been evaluated on human cancer cell
lines, representing colon and liver cancer. The inhibitory
activities against colon carcinoma cells (HCT-116) and
hepatocellular carcinoma cells (HepG-2) was tested using
different concentrations of the samples (50, 25, 12.5,
6.25, 3.125, and 1.56 μg), and the cell viability (%) was
determined by colorimetric method.
The 50% inhibitory concentration (IC50) of the HCT-116
cell line was calculated from Table 3 and Figures 1 and 2.
The 50% inhibitory concentration (IC50) of the HepG-2
cell line was calculated from Table 4 and Figures 3 and 4.
The results of 50% inhibitory concentration (IC50) data
are summarized in Table 5.
In comparison with standard antitumor drug vinblastine,
compounds 2b, 6b, 7b, 8b, and 9b were found to be active
against HCT-116 and HepG-2 cell lines, while another
compounds 3b, 4b, 5b, 10b, and 11b were observed to
be weak active against HCT-116 and HepG-2.
IN VITRO STUDIES
Cell lines. Human colon carcinoma (HCT-116) cells
and human hepatocellular carcinoma (HepG-2) cells were
obtained from the American Type Culture Collection
(ATCC, Rockville, MD, USA). The cells were grown on
RPMI-1640 medium supplemented with 10% inactivated
fetal calf serum and 50 μg/mL gentamycin. The cells
were maintained at 37°C in a humidified atmosphere with
5% CO2 and were subcultured two to three times a week.
CONCLUSIONS
Cytotoxic assay of pyrido-pyrimidine derivatives. The
cells were grown as monolayers in growth RPMI-1640
medium supplemented with 10% inactivated fetal calf
A new series of pyrido-pyrimidine derivatives were
prepared in good yield. The structures of these
1
compounds were confirmed by IR, H-NMR, 13C-NMR,
MS, and elemental analysis. Antitumor activities of
synthesized compounds were evaluated on human colon
and liver cancer cell lines. As a result of the cell culture
studies, all of the compounds have shown anticancer
activity for colon and liver cancer cells. In conclusion,
novel pyrido-pyrimidine derivatives might be potentially
useful in the field of cancer treatment. Finally,
compounds 2b, 6b, 7b, 8b, and 9b can be suggested as
potent candidates for colon and liver cancer drug.
Table 5
IC50 (μg) values of pyrido-pyrimidine derivatives after 24 h continuous
exposure of tumor cell lines.
Tumor type/cell line
Compound no.
HCT-116
HepG-2
2d
3d
4d
5d
3.40
35.12
22.97
51.38
4.12
7.12
42.15
28.45
60.29
6.83
6d
7d
8d
6.81
3.55
5.99
8.29
EXPERIMENTAL
9d
10d
11d
4.82
10.12
62.10
49.82
5.11
43.58
34.01
2.78
Chemistry.
Melting points were determined on
MEL_TEMP II apparatus and are uncorrected. IR
spectra (KBr) were measured on Perkin-Elmer FTIR
spectrophotometer, 1H NMR, and 13C NMR spectra
were recorded on JEOL (500 MHz), in DMSO-d6 as
solvent, using tetramethylsilane (TMS) as internal
Vinblastine standard
IC50 value is the concentration that induces 50% growth inhibition
compared with untreated control cells. HCT-116 means human colon
carcinoma cell lines. HepG-2 means human hepatocellular carcinoma cell
lines.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. AbedelRehim and M. AbdEllatif
Vol 000
reference standard. The chemical shifts values are
expressed in ppm. The NMR spectra were performed at
Faculty of Science, Alexandria University. Elemental
microanalyses were performed at the Micro Analytical
Center, Faculty of Science, Cairo University. All
compounds were within 0.4% of the theoretical values.
Mass spectra were run on DI analysis Shimadzu QP-
2010 plus mass spectrometer at the Micro Analytical
Unit of Cairo University. The progress of the reaction
and the purity of the compounds were monitored by
TLC analytical silica gel plates 60 F254. The chemical
reagents used in synthesis were purchased from Fluka,
Sigma, and Aldrich.
C18H13N3O2 (303): C, 71.29; H, 4.29; N, 13.86. Found:
C, 70.98; H, 4.22; N, 13.51.
5-(5-Methylfuran-2-yl)-7-(4-methoxyphenyl)-3H-pyrido[2,3-
d]pyrimidin-4-one 3d.
White crystals, yield: 65%, mp:
281–283°C. IR (KBr) cmÀ1: 3205 (NH), 3076 (C–H
aromatic), 1683 (C=O amide) and 1632, 1576
(conjugated C=C, C=N). 1H-NMR (DMSO-d6) δ ppm:
2.13 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 7.02–8.39 (m,
8H, Ar–H), 11.08 (1H, s, NH amide, D2O exchangeable).
Anal. Calcd for C19H15N3O3 (333): C, 68.47; H, 4.50; N,
12.61. Found: C, 68.51; H, 4.44; N, 12.67.
General procedure for synthesis of 5-(5-substituted
furan-2-yl)-2-methyl-7-(4-substituted phenyl)-3H-pyrido[2,3-
d]pyrimidin-4-one (4a–d). A mixture of 2a–d (0.01 mol)
in acetic acid (30 mL) and catalytic amount of concd
H2SO4 was heated under reflux for 16 h. The reaction
mixture was cooled and poured into ice cold water, and
the separated solid was filtered, washed with water, dried,
and recrystallized from DMF.
5-(Furan-2-yl)-2-methyl-7-phenyl-3H-pyrido[2,3-d]pyrimidin-
4-one 4a. White crystals, yield: 72%, mp: 312–314°C IR
General method for the preparation of 5-(5-substituted
furan-2-yl)-7-(4-substituted phenyl)-3H-pyrido[2,3-d]pyrimidin-
4-one (3a–d). A mixture of 2a–d (0.01 mol) in formic
acid (99%, 30 mL) and catalytic amount of concd H2SO4
was heated under reflux for 16 h. Then the reaction
mixture was cooled and poured into ice cold water, and
the separated solid was filtered, washed with water, dried,
and recrystallized from the proper solvent, ethanol, or
DMF.
(KBr) cmÀ1: 3143 (NH), 3022 (C–H aromatic), 2976
(C–H aliphatic), 1672 (C=O), 1612, 1574 (C=C, C=N);
1H-NMR (DMSO-d6) δ ppm: 2.23 (s, 3H, CH3), 6.91–8.34
(m, 9H, Ar–H), 12.23 (s, 1H, NH, D2O exchangeable).
(m/z): 303 (M+, 83.72), 275 (M-CO, 65.27), 77 (C6H5,
100). 13C NMR (100 MHz, CDCl3): δ = 19.5, 105.0,
111.5, 118.5, 120.7, 127.1(3 C), 129.0 (2 C), 139.7, 142.0,
147.5, 154.0, 157.7, 163.0, 170.0. Anal. Calcd for
C18H13N3O2 (303): C, 71.29; H, 4.29; N, 13.86. Found: C,
71.11; H, 4.17; N, 13.77.
5-Furan-2-yl-7-phenyl-3H-pyrido[2,3-d]pyrimidin-4-one 3a.
White crystals, yield: 71%, mp: 289–291°C. IR (KBr) cmÀ1
:
3201 (NH), 3077 (C–H aromatic), 1676 (C=O amide) and
1
1623, 1589 (conjugated C=C, C=N). H-NMR (DMSO-d6)
δ ppm: 6.82–8.27 (m, 10H, Ar–H), 10.86 (1H, s, NH amide,
D2O exchangeable). 13C NMR (100 MHz, CDCl3):
δ = 105.0, 111.5, 118.5, 120.7, 127.1(3 C), 129.0 (2 C),
139.7, 142.0, 147.5, 154.0, 157.7, 163.0, 170.0. Mass (m/z):
289 (M+, 91.23), 261 (M-CO, 73.23), 235 (M-
C2NO, 63.11), 77 (C6H5, 100). Anal. Calcd for C17H11N3O2
(289): C, 70.59; H, 3.81; N, 14.53. Found: C, 70.88; H,
3.72; N, 14.41.
5-(Furan-2-yl)-2-methyl-7-(4-methoxyphenyl)-3H-pyrido[2,3-
d]pyrimidin-4-one 4b.
White crystals, yield: 69%, mp:
304–306°C IR (KBr) cmÀ1: 3221 (NH), 3043 (C–H
aromatic), 2985 (C–H aliphatic), 1683 (C=O), 1617, 1579
1
5-Furan-2-yl-7-(4-methoxyphenyl)-3H-pyrido[2,3-d]pyrimidin-
4-one 3b. White crystals, yield: 66%, mp: 276–278°C. IR
(C=C, C=N); H-NMR (DMSO-d6) 2.18 (s, 3H, CH3), δ
ppm: 3.91 (s, 3H, OCH3), 6.87–8.23 (m, 8H, Ar–H), 11.87
(s, 1H, NH, D2O exchangeable). 13C NMR (100 MHz,
CDCl3): δ = 19.5, 56.0, 105.0, 111.5, 114.6 (2 C),
118.5, 120.7, 128.1(2 C), 129.0, 142.0, 147.5, 154.0,
157.7, 160.6, 170.0. Anal. Calcd for C19H15N3O3 (333): C,
68.47; H, 4.50; N, 12.61. Found: C, 68.34; H, 4.53;
(KBr) cmÀ1: 3188 (NH), 3062 (C–H aromatic), 1668
(C=O amide) and 1611, 1578 (conjugated C=C, C=N). 1H-
NMR (DMSO-d6) δ ppm: 3.65 (s, 3H, OCH3), 6.95–8.27
(m, 9H, Ar–H), 10.13 ((1H, s, NH amide, D2O
exchangeable). 13C NMR (100 MHz, CDCl3): δ = 56.0,
105.0, 111.5, 114.6 (2 C), 118.5, 120.7, 128.1(2 C), 129.0,
142.0, 147.5, 154.0, 157.7, 160.6, 170.0. Anal. Calcd for
C18H13N3O3 (319): C, 67.71; H, 4.08; N, 13.17. Found: C,
67.58; H, 3.92; N, 13.31.
N, 12.58.
5-(5-Methylfuran-2-yl)-2-methyl-7-phenyl-3H-pyrido[2,3-d]
pyrimidin-4-one 4c.
White crystals, yield: 69%, mp:
317–319°C IR (KBr) cmÀ1: 3198 (NH), 3009 (C–H
aromatic), 2956 (C–H aliphatic), 1663 (C=O), 1607, 1575
5-(5-Methylfuran-2-yl)-7-phenyl-3H-pyrido[2,3-d]pyrimidin-
4-one 3c. White crystals, yield: 70%, mp: 272–274°C. IR
1
(C=C, C=N); H-NMR (DMSO-d6) δ ppm: 2.09 (s, 3H,
(KBr) cmÀ1: 3223 (NH), 3087 (C–H aromatic), 1686 (C=O
amide) and 1621, 1583 (conjugated C=C, C=N). 1H-NMR
(DMSO-d6) δ ppm: 2.02 (s, 3H, CH3), 7.07–8.31 (m, 9H,
Ar–H), 11.27 ((1H, s, NH amide, D2O exchangeable).
13C NMR (100 MHz, CDCl3): δ = 15.0, 105.0, 111.5,
118.5, 120.7, 127.1(3 C), 129.0 (2 C), 139.7, 142.0,
147.5, 154.0, 157.7, 163.0, 170.0. Anal. Calcd for
CH3), 2.27 (s, 3H, CH3), 6.73–8.29 (m, 8H, Ar–H),
11.39 (s, 1H, NH, D2O exchangeable). 13C NMR
(100 MHz, CDCl3): δ = 15.0, 19.5, 105.0, 111.5, 118.5,
120.7, 127.1(3 C), 129.0 (2 C), 139.7, 142.0, 147.5,
154.0, 157.7, 163.0, 170.0 (Anal. Calcd for C19H15N3O2
(317): C, 71.92; H, 4.73; N, 13.25. Found: C, 71.74; H,
4.63; N, 13.34.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e][1,3,4]triazolo and
Tetrazolo[1,5-c]pyrimidineDerivativesasPotentialAntimicrobialandAnticancerAgents
5-(5-Methylfuran-2-yl)-2-methyl-7-(4-methoxyphenyl)-3H-
5-(5-Methylfuran-2-yl)-7-(4-methoxyphenyl)-2-phenyl-3H-
pyrido[2,3-d]pyrimidin-4-one 4d.
White crystals, yield:
pyrido[2,3-d]pyrimidin-4-one 5d.
Yellow crystals, yield:
64%, mp: 326–328°C IR (KBr) cmÀ1: 3202 (NH), 3014
(C–H aromatic), 2978 (C–H aliphatic), 1676 (C=O),
54%, mp: 309–311°C IR (KBr) cmÀ1: 3210 (NH), 3027
(C–H aromatic), 2953 (C–H aliphatic), 1680 (C=O),
1
1
1613, 1578 (C=C, C=N); H-NMR (DMSO-d6) δ ppm:
1606, 1542 (C=C, C=N); H-NMR (DMSO-d6) δ ppm:
1.97(s, 3H, CH3), 2.23 (s, 3H, CH3), 3.85 (s, 3H, OCH3),
6.54–8.21 (m, 7H, Ar–H), 11.39 (s, 1H, NH, D2O
exchangeable). 13C NMR (100 MHz, CDCl3): δ = 15.0,
19.5, 56.0, 105.0, 111.5, 114.6 (2 C), 118.5, 120.7,
128.1(2 C), 129.0, 142.0, 147.5, 154.0, 157.7, 160.6,
170.0 (Anal. Calcd for C20H17N3O3 (347): C, 69.16; H,
4.90; N, 12.10. Found: C, 69.03; H, 4.82; N, 12.21.
2.09 (s, 3H, CH3), 3.61 (s, 3H, OCH3), 7.06–8.52
(m, 12H, Ar–H), 13.37 (s, 1H, NH, D2O exchangeable).
Anal. Calcd for C25H19N3O3 (409): C, 73.35; H, 4.65; N,
10.27. Found: C, 73.41; H, 4.56; N, 10.38.
General procedure for synthesis of 5-(5-substituted
furan-2-yl)-7-(4-substituted phenyl)-pyrido[2,3-d]pyrimidin-
4-ylamine (6a–d).
A mixture of 2a–d (0.01 mol) and
formamide (20 mL) was refluxed on an oil bath for 16 h.
The reaction mixture was allowed to cool and poured
into ice cold water, and the separated solid was filtered,
washed with water, dried, and recrystallized from ethanol.
5-(Furan-2-yl)-7-phenylpyrido[2,3-d]pyrimidin-4-ylamine 6a.
General method for the preparation of 5-(5-substituted
furan-2-yl)-7-(4-substituted phenyl)-2-phenyl-3H-pyrido[2,3-
d]pyrimidin-4-one (5a–d). A mixture of 2a–d (0.01 mol)
and benzoyl chloride (20 mL) was heated for 3 h.
The reaction mixture was allowed to cool; the formed
solid was washed with ethanol and recrystallized from
White crystals, yield: 77%, mp: 314–316°C IR (KBr) cmÀ1
:
3287, 3412 (NH2 stretching), 3066 (C–H aromatic), 1623,
1586 (C=N, C=C); 1H-NMR (DMSO-d6) δ ppm: 6.95
(s, 2H, NH2, D2O exchangeable), 7.13–8.43 (m, 8H,
Ar–H), 7.68 (s, 1H, Ar–H of pyridine), 8.43 (s, 1H, Ar–H
of pyrimidine). 13C NMR (100 MHz, CDCl3): δ = 105.0,
105.2, 111.5, 118.5, 120.7, 127.1(3 C), 129.0 (2 C), 139.7,
142.0, 147.5, 154.0, 157.1, 157.9, 159.2, 167.7 (m/z): 288
(M+, 93.65), 77 (C6H5, 100). Anal. Calcd for C17H12N4O
(288): C, 70.83; H, 4.17; N, 19.44. Found: C, 70.63; H,
DMF.
5-(Furan-2-yl)-2,7-diphenyl-3H-pyrido[2,3-d]pyrimidin-4-
one 5a. White crystals, yield: 56%, mp: 324–326°C IR
(KBr) cmÀ1: 3209 (NH), 3022 (C–H aromatic), 2955
(C–H aliphatic), 1686 (C=O), 1601, 1535(C=C, C=N);
1H-NMR (DMSO-d6) δ ppm: 6.95–8.34 (m, 14H, Ar–H),
12.89 (s, 1H, NH, D2O exchangeable). 13C NMR
(100 MHz, CDCl3): δ = 105.0, 111.5, 118.5, 120.7, 125.9,
(2C), 127.1(3 C), 128.6 (2C), 129.0 (2 C), 129.9, 132.9,
139.7, 142.0, 147.5, 154.0, 157.7, 164.0, 170.0 (m/z): 365
(M+, 90.34), 337(M-CO, 77.23), 77 (C6H5, 100). Anal.
Calcd for C23H15N3O2 (365): C, 75.62; H, 4.11; N, 11.51.
4.23; N, 19.23.
5-(Furan-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidin-
4-ylamine 6b. White crystals, yield: 68%, mp: 299–301°C
IR (KBr) cmÀ1: 3276, 3433 (NH2 stretching), 3076 (C–H
aromatic), 1613, 1575 (C=N, C=C); 1H-NMR (DMSO-d6)
δ ppm: 3.62 (s, 3H, OCH3),7.05 (s, 2H, NH2, D2O
exchangeable), 7.24–8.37 (m, 7H, Ar–H), 7.51 (s, 1H,
Ar–H of pyridine), 8.56 (s, 1H, Ar–H of pyrimidine). 13C
NMR (100 MHz, CDCl3): δ = 56.0, 105.0, 105.2, 111.5,
114.6 (2 C), 118.5, 120.7, 128.1(2 C), 129.0, 142.0,
147.5, 154.0, 157.1, 157.9, 159.2, 167.7. Anal. Calcd for
C18H14N4O2 (318): C, 67.72; H, 4.40; N, 17.61. Found:
Found: C, 75.43; H, 4.19; N, 11.32.
5-(Furan-2-yl)-7-(4-methoxyphenyl)-2-phenyl-3H-pyrido[2,3-
d]pyrimidin-4-one 5b. Yellowish white crystals, yield: 52%,
mp: 305–307°C IR (KBr) cmÀ1: 3233 (NH), 3035 (C–H
aromatic), 2942 (C–H aliphatic), 1676 (C=O), 1613,
1
1562(C=C, C=N); H-NMR (DMSO-d6) δ ppm: 3.43 (s,
3H, OCH3), 6.78–8.46 (m, 13H, Ar–H), 12.79 (s, 1H, NH,
D2O exchangeable). 13C NMR (100 MHz, CDCl3):
δ = 56.0, 105.0, 111.5, 114.6 (2 C), 118.5, 120.7, 125.9
(2C), 128.1(2 C), 128.6 (2C), 129.0, 129.9, 132.9, 142.0,
147.5, 154.0, 157.7, 160.6, 170.0. Anal. Calcd for
C24H17N3O3 (395): C, 72.91; H, 4.30; N, 10.63. Found: C,
72.87; H, 4.33; N, 10.45.
5-(5-Methylfuran-2-yl)-2,7-diphenyl-3H-pyrido[2,3-d]
C, 67.65; H, 4.34; N, 17.68.
5-(5-Methylfuran-2-yl)-7-phenylpyrido[2,3-d]pyrimidin-4-
ylamine 6c. White crystals, yield: 73%, mp: 308–310°C
IR (KBr) cmÀ1: 3244, 3421 (NH2 stretching), 3053 (C–H
1
aromatic), 1604, 1562 (C=N, C=C); H-NMR (DMSO-
pyrimidin-4-one 5c.
White crystals, yield: 58%, mp:
d6) δ ppm: 2.14 (s, 3H, CH3),7.12 (s, 2H, NH2, D2O
exchangeable), 7.18–8.28 (m, 7H, Ar–H), 7.87 (s, 1H,
Ar–H of pyridine), 8.49 (s, 1H, Ar–H of pyrimidine). 13C
NMR (100 MHz, CDCl3): δ = 15.0, 105.0, 105.2, 111.5,
118.5, 120.7, 127.1(3 C), 129.0 (2 C), 139.7, 142.0,
147.5, 154.0, 157.1, 157.9, 159.2, 167.7. Anal. Calcd for
C18H14N4O (302): C, 71.52; H, 4.64; N, 18.54. Found:
313–315°C IR (KBr) cmÀ1: 3233 (NH), 3035 (C–H
aromatic), 2942 (C–H aliphatic), 1676 (C=O), 1613, 1562
1
(C=C, C=N); H-NMR (DMSO-d6) δ ppm: 2.24 (s, 3H,
CH3), 6.93–8.37(m, 13H, Ar–H), 13.04 (s, 1H, NH,
D2O exchangeable). 13C NMR (100 MHz, CDCl3):
δ = 15.0, 105.0, 111.5, 118.5, 120.7, 125.9(2C), 127.1(3
C), 128.6(2C), 129.0 (2 C), 129.9, 132.9, 139.7, 142.0,
147.5, 154.0, 157.7, 163.0, 170.0. Anal. Calcd for
C24H17N3O2(379): C, 75.99; H, 4.49; N, 11.08.
Found: C, 75.82; H, 4.51; N, 10.97.
C, 71.42; H, 4.60; N, 18.45.
5-(5-Methylfuran-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]
pyrimidin-4-ylamine 6d. White crystals, yield: 64%, mp:
302–304°C IR (KBr) cmÀ1: 3276, 3449 (NH2 stretching),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. AbedelRehim and M. AbdEllatif
Vol 000
1
3032 (C–H aromatic), 1596, 1562 (C=N, C=C); H-NMR
(DMSO-d6) δ ppm: 2.05 (s, 3H, CH3), 3.71 (s, 3H,
OCH3),7.03 (s, 2H, NH2, D2O exchangeable), 7.21–8.13
(m, 6H, Ar–H), 7.52 (s, 1H, Ar–H of pyridine), 8.31
(s, 1H, Ar–H of pyrimidine). Anal. Calcd for C19H16N4O2
(332): C, 68.67; H, 4.82; N, 16.87. Found: C, 68.45; H,
4.73; N, 16.63.
3.29 (s, 3H, OCH3),7.02 (s, 2H, NH2, D2O exchangeable),
6.78–8.56 (m, 7H, Ar–H). 13C NMR (100 MHz, CDCl3):
δ = 15.1, 20.9. 56.0, 105.0, 111.5, 114.6 (2 C), 118.5, 120.7,
125.9 (2C), 128.1(2 C), 128.6 (2C), 129.0, 129.9, 132.9,
142.0, 147.5, 154.0, 157.7, 158.8, 165.9, 167.9 Calcd for
C20H18N4O2 (346): C, 69.36; H, 5.20; N, 16.19. Found: C,
69.41; H, 5.02; N, 16.21.
General method for the preparation of 5-(5-substituted
General method for the preparation of 4-chloro-5-(5-
substituted furan-2-yl)-7-(4-substituted phenyl)pyrido[2,3-d]
furan-2-yl)-2-methyl-7-(4-substituted
pyrimidin-4-ylamine (7a–d).
phenyl)pyrido[2,3-d]
mixture of 2a–d
A
pyrimidine (8a–d).
A mixture of 3a–d (0.01 mol) in
(0.01 mol) and acetamide (0.01 mol) was refluxed in
mixture of glacial acetic acid and hydrochloric acid (3:1)
for 5 h. The reaction mixture was allowed to cool and
poured into ice cold water, and the separated solid was
filtered, washed with water, dried, and recrystallized from
phosphorous oxychloride (20 mL) was refluxed for 8 h.
The reaction mixture was allowed to cool and poured
into ice cold water, stirred well, filtered, washed with
water, dried, and recrystallized from ethanol.
4-Chloro-5-(furan-2-yl)-7-phenylpyrido[2,3-d]pyrimidine 8a.
White crystals yield: 83%, mp: 192–194°C. IR (KBr) cmÀ1
:
DMF.
5-(Furan-2-yl)-2-methyl-7-phenylpyrido[2,3-d]pyrimidin-4-
ylamine 7a. White crystals, yield: 84%, mp: 286–288°C
3089 (C–H aromatic) 1589, 1577 (conjugated C=C, C=N).
1H-NMR (DMSO-d6) δ ppm: 6.67–8.19 (m, 8H, Ar–H),
7.88 (s, 1H, Ar–H of pyridine), 8.43 (s, 1H, Ar–H of
pyrimidine). (m/z): 307 (M+, 90.45), 309 (M + 2, 29.65).77
(C6H5, 100). Anal. Calcd for C17H10N3OCl (307): C,
66.45; H, 3.26; N, 13.68. Found: C, 66.29; H, 3.52; N, 13.52.
4-Chloro-5-(furan-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]
IR (KBr) cmÀ1: 3114, 3323 (NH2 stretching), 3052 (C–H
1
aromatic),1563, 1544(C=N, C=C); H-NMR (DMSO-d6)
δ ppm: 2.46 (s, 3H, CH3),7.23 (s, 2H, NH2, D2O
exchangeable), 6.89–8.34 (m, 9H, Ar–H). 13C NMR
(100 MHz, CDCl3): δ = 20.9, 102.2, 105.2, 111.5, 118.5,
120.7, 127.1(3 C), 129.0 (2 C), 139.7, 142.0, 144.9,
154.0, 157.9, 158.8, 165.9, 167.9 (m/z): 302 (M+, 89.77),
77 (C6H5, 100). Anal. Calcd for C18H14N4O (302): C,
71.52; H, 4.64; N, 18.54. Found: C, 71.67; H, 4.45; N,
pyrimidine 8b.
Yellow crystals, yield: 74%, mp:
183–185°C. IR (KBr) cmÀ1: 3044 (C–H aromatic) 1597,
1566 (conjugated C=C, C=N). 1H-NMR (DMSO-d6) δ
ppm: 3.52 (s, 3H, OCH3), 6.56–8.31 (m, 7H, Ar–H), 7.32
(s, 1H, Ar–H of pyridine), 8.39 (s, 1H, Ar–H of
pyrimidine). Anal. Calcd for C18H12N3O2Cl (337): C,
64.10; H, 3.56; N, 12.46. Found: C, 64.16; H, 3.46; N,
18.39.
5-(Furan-2-yl)-2-methyl-7-(4-methoxyphenyl)-2-methylpyrido
[2,3-d]pyrimidin-4-ylamine 7b. Yellow crystals, yield: 79%,
mp: 277–279°C IR (KBr) cmÀ1: 3176, 3384 (NH2
stretching), 3025 (C–H aromatic),1573, 1565 (C=N, C=C);
1H-NMR (DMSO-d6) δ ppm: 2.19 (s, 3H, CH3), 3.93
(s, 3H, OCH3),7.34 (s, 2H, NH2, D2O exchangeable),
6.84–8.47 (m, 8H, Ar–H).13C NMR (100 MHz, CDCl3):
δ = 20.9, 56.0, 102.2, 105.2, 111.5, 114.6 (2 C), 118.5,
120.7, 128.1(2 C), 129.0, 142.0, 144.9, 154.0, 157.9, 158.8,
165.9, 167.9 Calcd for C19H16N4O2 (332): C, 68.67; H,
12.37.
4-Chloro-5-(5-methylfuran-2-yl)-7-phenylpyrido[2,3-d]
pyrimidine 8c. White crystals, yield: 79%, mp: 188–190°C.
IR (KBr) cmÀ1: 3076 (C–H aromatic) 1572, 1553
(conjugated C=C, C=N). 1H-NMR (DMSO-d6) δ ppm:
2.17 (s, 3H, CH3), 6.54–8.23 (m, 7H, Ar–H), 8.21 (s, 1H,
Ar–H of pyridine), 8.55 (s, 1H, Ar–H of pyrimidine). Anal.
Calcd for C18H12N3OCl (321): C, 67.92; H, 3.74; N,
4.82; N, 16.87. Found: C, 68.48; H, 4.64; N, 16.90.
5-(5-Methylfuran-2-yl)-2-methyl-7-phenylpyrido[2,3-d]
pyrimidin-4-ylamine 7c. White crystals, yield: 76%, mp:
13.08. Found: C, 67.68; H, 3.81; N, 13.01.
4-Chloro-5-(5-methylfuran-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-
d]pyrimidine 8d. White crystals, yield: 75%, mp: 195–197°C.
265–267°C IR (KBr) cmÀ1: 3201, 3425 (NH2 stretching),
IR (KBr) cmÀ1: 3035 (C–H aromatic) 1599, 1583 (conjugated
C=C, C=N). 1H-NMR (DMSO-d6) δ ppm: 1.92 (s, 3H, CH3),
3.40 (s, 3H, OCH3), 6.92–8.46 (m, 6H, Ar–H), 8.02 (s, 1H,
Ar–H of pyridine), 8.37 (s, 1H, Ar–H of pyrimidine). Anal.
Calcd for C19H14N3O2Cl (351): C, 64.96; H, 3.99; N, 11.96.
Found: C, 64.81; H, 3.84; N, 11.83.
1
3078 (C–H aromatic),1602, 1575(C=N, C=C); H-NMR
(DMSO-d6) δ ppm: 2.09 (s, 3H, CH3), 2.24 (s, 3H,
CH3),7.11 (s, 2H, NH2, D2O exchangeable), 6.84–8.47
(m, 8H, Ar–H). 13C NMR (100 MHz, CDCl3): δ = 15.0,
20.9, 102.2, 105.2, 111.5, 118.5, 120.7, 127.1 (3 C),
129.0 (2 C), 139.7, 142.0, 147.5, 154.0, 157.9, 158.8,
165.9, 167.9 Calcd for C19H16N4O (316): C, 72.15; H,
General procedure for synthesis of 5-(5-substituted
furan-2-yl)-7-(4-substituted phenyl)-pyrido[2,3-d]pyrimidin-
4-yl)hydrazine (9a–d). A mixture of 8a–d (0.01 mol)
in 99% hydrazine hydrate (15 mL) and ethanol
(10 mL) was refluxed for 3 h. The reaction mixture
was allowed to cool and poured into ice cold water,
stirred well, filtered, washed with water, dried, and
recrystallized from ethanol.
5.06; N, 17.72. Found: C, 72.18; H, 4.89; N, 17.65.
5-(5-Methylfuran-2-yl)-2-methyl-7-(4-methoxyphenyl)pyrido[2,3-
d]pyrimidin-4-ylamine 7d. White crystals, yield: 81%, mp:
275–277°C IR (KBr) cmÀ1: 3233, 3432 (NH2 stretching),
3061 (C–H aromatic),1607, 1572(C=N, C=C); 1H-NMR
(DMSO-d6) δ ppm: 2.09 (s, 3H, CH3), 2.24 (s, 3H, CH3),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Synthesis of Some Novel Pyrido[2,3-d]pyrimidine and Pyrido[3,2-e][1,3,4]triazolo and
Tetrazolo[1,5-c]pyrimidineDerivativesasPotentialAntimicrobialandAnticancerAgents
5-(Furan-2-yl)-7-phenylpyrido[2,3-d]pyrimidin-4-yl)hydrazine
9a. White crystals, yield: 87%, mp: 265–267°C. IR (KBr)
NMR (100 MHz, CDCl3): δ = 105.0, 111.6, 119.9, 120.9,
127.1 (3C), 129.0(2C), 139.7, 142.0, 144.9, 147.9 (2C),
154.0, 156.9, 157.9, 158.0 (m/z): 313 (M+, 89.23), 77
(C6H5, 100). Anal. Calcd for C18H11N5O (313): C, 69.01;
H, 3.51; N, 22.36. Found: C, 69.23; H, 3.41; N, 22.43.
10-(Furan-2-yl)-8-(4-methoxyphenyl)pyrido[3,2-e][1,3,4]
triazolo[1,5-c]pyrimidine 10b. Yellow crystals, yield: 69%,
cmÀ1: 3207, 3232 and 3409 (NH and NH2 stretching), 3064
(C–H aromatic) 1579, 1557 (conjugated C=C, C=N).
1H-NMR (DMSO-d6) δ ppm: 4.14 (s, 2H, NH2, D2O
exchangeable), 6.83–8.31 (m, 8H, Ar–H), 7.92 (s, 1H,
Ar–H of pyridine), 8.34 (s, 1H, Ar–H of pyrimidine), 8.54
(s, 1H, NH, D2O exchangeable). (m/z): 303 (M+, 82.22),
77 (C6H5, 100). Anal. Calcd for C17H13N5O (303): C,
67.33; H, 4.29; N, 23.10. Found: C, 67.41; H, 4.31;
N, 23.01.
mp: 228–230°C. IR (KBr) cmÀ1: 3052 (C–H aromatic) and
1612, 1562 (conjugated C=C, C=N). 1H-NMR (DMSO-d6)
δ ppm: 3.77 (s, 3H, OCH3), 6.56–8.17 (m, 8H, Ar–H), 8.58
and 8.93 (s, 1H, Ar–H of pyrimidine and s, 1H, Ar–H of
triazol).13C NMR (100 MHz, CDCl3): δ = 56.0, 105.0,
111.6, 119.9, 120.9, 114.6 (2C), 128.1(2C), 132.0, 142.0,
144.9, 147.9(2C), 154.0, 156.9, 157.9, 158.0, 160.6.
Anal. Calcd for C19H13N5O2 (343): C, 66.47; H, 3.79; N,
5-(Furan-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]pyrimidin-
4-yl)hydrazine 9b.
White crystals, yield: 83%, mp:
248–250°C. IR (KBr) cmÀ1: 3193, 3201 and 3386 (NH
and NH2 stretching), 3079 (C–H aromatic) 1603, 1578
(conjugated C=C, C=N). 1H-NMR (DMSO-d6) δ ppm:
3.73 (s, 3H, OCH3), 4.38 (s, 2H, NH2, D2O exchangeable),
6.64–8.22 (m, 8H, Ar–H and H of pyridine), 8.29 (s, 1H,
Ar–H of pyrimidine), 8.41 (s, 1H, NH, D2O exchangeable).
Anal. Calcd for C18H15N5O2 (333): C, 64.86; H, 4.50; N,
20.41. Found: C, 66.27; H, 3.52; N, 20.35.
10-(5-Methylfuran-2-yl)-8-phenylpyrido[3,2-e][1,3,4]triazolo[1,5-
c]pyrimidine 10c.
White crystals, yield: 73%, mp: 231–
232°C. IR (KBr) cmÀ1: 3033 (C–H aromatic) and 1623,
1539 (conjugated C=C, C=N). 1H-NMR (DMSO-d6) δ
ppm: 2.31 (s, 3H, CH3), 6.72–8.09 (m, 8H, Ar–H), 8.74
and 9.21 (s, 1H, Ar–H of pyrimidine and s, 1H, Ar–H of
triazol). 13C NMR (100 MHz, CDCl3): δ = 15.0, 105.0,
111.6, 119.9, 120.9, 127.1 (3C), 129.0(2C), 139.7, 142.0,
144.9, 147.9(2C), 154.0, 156.9, 157.9, 158.0. Anal. Calcd for
C19H13N5O (327): C, 69.72; H, 3.98; N, 21.41. Found: C,
21.02. Found: C, 64.66; H, 4.34; N, 20.87.
5-(5-Methylfuran-2-yl)-7-phenypyrido[2,3-d]pyrimidin-4-yl)
hydrazine 9c. White crystals, yield: 84%, mp: 254–256°C;
IR (KBr) cmÀ1: 3267, 3288 and 3421 (NH and NH2
stretching), 3087 (C–H aromatic) 1609, 1574 (conjugated
1
C=C, C=N); H-NMR (DMSO-d6) δ ppm: 2.02 (s, 3H,
CH3), 4.67 (s, 2H, NH2, D2O exchangeable), 6.49–8.18
(m, 8H, Ar–H and H of pyridine), 8.31 (s, 1H, Ar–H of
pyrimidine), 8.65 (s, 1H, NH, D2O exchangeable). Anal.
Calcd for C18H15N5O (317): C, 68.14; H, 4.73; N, 22.08.
Found: C, 68.01; H, 4.75; N, 21.89.
5-(5-Methylfuran-2-yl)-7-(4-methoxyphenyl)pyrido[2,3-d]
pyrimidin-4-yl)hydrazine 9d. Yellow crystals, yield: 79%,
69.53; H, 3.84; N, 21.47.
10-(5-Methylfuran-2-yl)-8-(4-methoxyphenyl)-[3,2-e][1,3,4]
triazolo[1,5-c]pyrimidine 10d. Yellow crystals, yield: 70%,
mp: 237–239°C. IR (KBr) cmÀ1: 3023 (C–H aromatic) and
1603, 1521 (conjugated C=C, C=N). 1H-NMR (DMSO-d6)
δ ppm: 2.27 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 6.88–8.23
(m, 7H, Ar–H), 8.94 and 9.30 (s, 1H, Ar–H of
pyrimidine and s, 1H, Ar–H of triazol). 13C NMR
(100 MHz, CDCl3): δ = 15.0, 56.0, 105.0, 111.6, 119.9,
120.9, 114.6 (2C), 128.1(2C), 132.0, 142.0, 144.9,
147.9(2C), 154.0, 156.9, 157.9, 158.0, 160.6. Anal. Calcd
for C20H15N5O2 (357): C, 67.23; H, 4.20; N, 19.61.
Found: C, 67.15; H, 4.04; N, 19.57.
mp: 243–245°C. IR (KBr) cmÀ1: 3235, 3263 and 3413
(NH and NH2 stretching), 3065 (C–H aromatic) 1589,
1562(conjugated C=C, C=N).1H-NMR (DMSO-d6) δ
ppm: 2.23 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 4.73 (s, 2H,
NH2, D2O exchangeable), 6.79–8.23 (m, 7H, Ar–H and
H of pyridine), 8.36 (s, 1H, Ar–H of pyrimidine), 8.57
(s, 1H, NH, D2O exchangeable). Anal. Calcd for
C19H17N5O2 (347): C, 65.71; H, 4.99; N, 20.17. Found:
C, 65.48; H, 4.82; N, 20.03.
General procedure for synthesis of 10-(5-substituted
furan-2-yl)-8-(4-substituted phenyl)-pyrido[3,2-e]tetrazolo[1,5-
c]pyrimidine (11a–d).
A total of 5 mL of an aqueous
solution of (20% w/v) sodium nitrite was added slowly to
9a–d (0.01 mol) in acetic acid (40 mL). The reaction
mixture was stirred in ice bath for 2 h, then poured into
water, stirred well, filtered, washed with water, dried, and
recrystallized from ethanol.
General procedure for synthesis of 10-(5-substituted
furan-2-yl)-8-(4-substituted
phenyl)pyrido[3,2-e][1,3,4]
triazolo[1,5-c]pyrimidine (10a–d).
A mixture of 9a–d
(0.01 mol) in formic acid (99%, 30 mL) was refluxed for
6 h. The reaction mixture was allowed to cool and
poured into ice cold water, stirred well, filtered, washed
10-(Furan-2-yl)-8-phenylpyrido[3,2-e]tetrazolo[1,5-c]
pyrimidine 11a.
White crystals, yield: 85%, mp: 248–
with water, dried, and recrystallized from ethanol.
10-(Furan-2-yl)-8-phenylpyrido[3,2-e][1,3,4]triazolo[1,5-c]
pyrimidine 10a. Yellowish white crystals, yield: 74%, mp:
250°C. IR (KBr) cmÀ1: 3067 (C–H aromatic) and 1631,
1575 (conjugated C=C, C=N). 1H-NMR (DMSO-d6) δ
ppm: 6.88–8.31 (m, 9H, Ar–H), 8.89 (s, 1H, Ar–H of
pyrimidine). (m/z): 314 (M+, 87.98), 77 (C6H5, 100).
Anal. Calcd for C17H10N6O (314): C, 64.97; H, 3.18; N,
26.75. Found: C, 65.04; H, 3.11; N, 26.56.
235–237°C. IR (KBr) cmÀ1: 3032 (C–H aromatic) and
1601, 1543 (conjugated C=C, C=N). 1H-NMR (DMSO-d6)
δ ppm: 6.72–8.05 (m, 9H, Ar–H), 8.64 and 9.03 (s, 1H,
Ar–H of pyrimidine and s, 1H, Ar–H of triazol). 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. M. AbedelRehim and M. AbdEllatif
Vol 000
[2] Zhang, F.; Zhao, Y.; Sun, L.; Ding, L.; Gu, Y.; Gong, P. Eur J
Med Chem 2011, 46, 3149.
10-(Furan-2-yl)-8-(4-methoxyphenyl)pyrido[3,2-e]
tetrazolo[1,5-c]pyrimidine 11b.
Yellowish white crystals,
[3] Kurumurthy, C.; Sambasiva, P.; Veeraswamy, B.;
Santhoshkumar, G.; Shanthan, P.; Narsaiah, B.; Velatooru, L. R.; Pamanji,
R.; Venkateswara J Eur J Med Chem 2011, 46, 3462.
[4] (a) Masuda, S. JpnKokai TokkyoKohoJp 2000, 03, 106, 880.
C.A.15: 183361d; (b) Tamura Jpn Kokai TokkyoKohoJp 2000, 61, 249,
983, C.A. 106: 213979.
yield: 81%, mp: 243–245°C. IR (KBr) cmÀ1: 3072 (C–H
aromatic) and 1641, 1583 (conjugated C=C, C=N).
1H-NMR (DMSO-d6) δ ppm: 3.33 (s, 3H, OCH3),
6.89–8.34 (m, 8H, Ar–H), 9.24 (s, 1H, Ar–H of
pyrimidine). Anal. Calcd for C18H12N6O2 (344): C,
62.79; H, 3.49; N, 24.42. Found: C, 62.67; H, 3.33;
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Mohammed, E. A. Heterocycles 1994, 38, 57.
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N, 24.34.
10-(5-Methylfuran-2-yl)-8-phenylpyrido[3,2-e]tetrazolo[1,5-
c]pyrimidine 11c.
White crystals, yield: 80%, mp:
245–247°C. IR (KBr) cmÀ1: 3102 (C–H aromatic) and
1
1634, 1565 (conjugated C=C, C=N). H-NMR (DMSO-
d6) δ ppm: 2.13 (s, 3H, CH3), 6.82–8.27 (m, 8H, Ar–H),
9.49 (s, 1H, Ar–H of pyrimidine). Anal. Calcd for
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Research (S) 1997, 452.
C18H12N6O (328): C, 65.85; H, 3.66; N, 25.61. Found: C,
65.71; H, 3.69; N, 25.53.
10-(5-Methylfuran-2-yl-8-(4-methoxyphenyl))pyrido[3,2-e]
tetrazolo[1,5-c]pyrimidine 11d.
Yellow crystals, yield:
83%, mp: 252–254°C. IR (KBr) cmÀ1: 3083 (C–H
aromatic) and 1622, 1551 (conjugated C=C, C=N).
1H-NMR (DMSO-d6) δ ppm: 2.09 (s, 3H, CH3), 3.67 (s,
3H, OCH3), 6.56–8.01 (m, 7H, Ar–H), 9.57 (s, 1H, Ar–H
of pyrimidine). Anal. Calcd for C19H14N6O2 (358): C,
63.69; H, 3.91; N, 23.46. Found: C, 63.55; H, 3.79; N, 23.37.
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Acknowledgements. The authors are thankful to the
Microbiology Department, Faculty of Pharmacy, Alexandria
University, for helping in evaluating antimicrobial activity.
REFERENCES AND NOTES
SUPPORTING INFORMATION
[1] (a) Furth, P. S.; Reitman, M. S.; Gentles, R.; Cook, A. F.
Tetrahedron Lett 1997, 38, 6643; (b) Furth, P. S.; Reitman, M. S.; Cook,
A. F. Tetrahedron Lett 1997, 38, 5403.
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet