Synthesis of some new [1,8]naphthyridine, pyrido[2,3- d ]-pyrimidine, and other annulated pyridine derivatives

Article abstract of DOI:10.1002/jhet.990

2-Aminopyridine-3-carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3, 5, 8, 11, and 14, respectivel

Full text of DOI:10.1002/jhet.990

42
Synthesis of Some New [1,8]Naphthyridine, Pyrido[2,3-d]-
Vol 50
Pyrimidine, and Other Annulated Pyridine Derivatives
Abu-Bakr A. A. M. El-Adasy, Ahmed A. Khames,
*
and Mohamed A. M. Gad-Elkareem
Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt
*
E-mail: m65gad@yahoo.com
Received October 19, 2010
DOI 10.1002/jhet.990
View this article online at wileyonlinelibrary.com.
2-Aminopyridine-3-carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate,
benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]
naphthyridine derivatives 3, 5, 8, 11, and 14, respectively. Further annulations of 3, 5, and 8 gave the
corresponding pyrido[2,3-b][1,8]naphthyridine-3-carbonitrile derivative 17, pyrido[2,3-h][1,6]naphthyridine-
3-carbonitrile derivatives 18 and 19, respectively. The reaction of 1 with formic acid, formamide, acetic
anhydride, urea or thiourea, and 4-isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives
20a,b, 21, 22a,b, and 26, respectively. Treatment of compound 1 with sulfuric acid afforded the amide
derivative 27. Compound 27 reacted with 4-chlorobenzaldehyde and 1H-indene-1,3(2H)-dione to give the
pyridopyrimidine derivative 28 and spiro derivative 30, respectively. In addition, compound 1 reacted with halo
compounds afforded the pyrrolopyridine derivatives 32 and 34. Finally, treatment of 1 with hydrazine hydrate
gave the pyrazolopyridine derivative 35. The structures of the newly synthesized compounds were established
by elemental and spectral data.
J. Heterocyclic Chem., 50, 42 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
Naphthyridine systems are of great importance due to their
chemical [1–3] and biological activities. The naphthyridine
derivatives are used as potent acyl-CoA:cholesterol acyl-
transferase inhibitor [4], anticancer [5], anti-inflammatory
[5], antiplatelet [6], for the treatment of Alzheimer’s disease
[7], HIV-1 integrase inhibitors [8], and antimicrobial [9]
agents. Moreover, pyrido[2,3-d]-pyrimidine derivatives form
a class of fused heterocyclic compounds, which have
received considerable attention over the past years [10–13]
due to their wide range of biological activities such as
analgesic [14], ulcerogenic [14], antianexiety [15], antimi-
crobial [16], antioxidant [16], antitumor [17], antiviral [18],
cytotoxic [18], anti-inflammatory [14], [19], antibacterial
[20], antileishmanial [21] activities and used as cyclin-
dependent kinase 4 (Cdk4) inhibitors [22]. In addition,
pyrrolo[2,3-b]pyridine derivatives are of chemotherapeutic
interest because they have been shown to act as antidiabetic
[23], 5-HT6 receptor agonists or antagonists, useful for the
treatment of central nervous system disorders [24],
antitumor [25], and antimicrobial [26] agents.
The key structure 5-acetyl-2-amino-1-(4-methylphenyl)-
6-oxo-4-phenyl-1,6-dihydropyridine-3-carbonitrile (1) used
in our study was prepared from the reaction of benzylidene-
malononitrile with N-(4-methylphenyl)-3-oxobutan-amide
in ethanolic peperidine solution under reflux according to
literature [27] procedure. The reactivity of the 2-aminopyri-
dine-3-carbonitrile derivative 1 toward active methylene
nitriles was investigated. Thus, treatment of compound 1
with malononitrile in refluxing N,N-dimethylformamide in
presence of a catalytic amount of piperidine gave the [1,8]
naphthyridine-3-carbonitrile derivative 3. The structure of
3 was established based on elemental analyses and spectral
data. Thus, the IR spectrum of compound 3 showed bands
at 3433, 3323 (two NH2), 2207 (CN), 1690, 1640 cmꢀ1(two
C═O). Its 1H-NMR (DMSO-d6) revealed singlet signals at
d = 2.35, 2.49 ppm assigned for 2CH3, singlet at d = 4.98
ppm for NH2, multiplet at d = 7.29-7.46 ppm assigned for
CH aromatic, and hump at d = 8.60 ppm for NH2. In a similar
manner, treatment of compound 1 with ethyl cyanoacetate
under reflux in acetic acid gave a colored crystalline product
identified as [1,8]naphthyridine-3-carbonitrile derivative
5 rather than ethyl [1,8]naphthyridine-3-carboxylate
derivative 4. The structure 4 was ruled out on the basis of
The above findings stimulated the interest for the
synthesis of additional new number of these derivatives
that are required in medicinal chemistry programs.
© 2013 HeteroCorporation

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Synthesis of Some New [1,8]Naphthyridine, Pyrido[2,3-d]Pyrimidine, and Other
43
Annulated Pyridine Derivatives
elemental analysis and spectral data. The IR spectrum of
compound 5 revealed the presence of NH2 and NH
absorption bands at n cmꢀ1 3438, 3412, and 3261 cmꢀ1
and CN group at 2182 cmꢀ1 in addition to (three C═O)
at 1722, 1710, and 1633 cmꢀ1 and its 1H-NMR spectrum
revealed the signal of NH at d = 10.2 ppm and absence of
any signals due to OCH2CH3 protons (see Scheme 1 and
Experimental section).
Treatment of compound 1 with benzylidenemalononitrile
in DMF in the presence of a catalytic amount of piperidine
under reflux afforded the [1,8]naphthyridine-3-carbonitrile
derivative 8 in good yield. The structure of the latter
compound was confirmed based on elemental analyses and
spectral data. Compound 8 was formed via the addition of
the amino group in compound 1 to the double bond in
benzylidenemalononitrile to form the intermediate 6, which
cyclized via a nucleophilic addition of methyne hydrogen of
arylidene to the cyano function of pyridine to form
dihydropyridine intermediate 7, the latter released hydrogen
cyanide to form the final product 8 (Scheme 1 and
Experimental section).
carboxylic acid derivative 11. The IR spectrum of the
reaction product indicated the presence of a broad band at
n = 3398–2382 cmꢀ1 due to acidic OH functional group.
1
In addition, its H-NMR spectrum revealed the signal of
acidic OH proton at d = 14.33 ppm and absence of any
signals may be attributed to -CH2CH3 protons. The
formation of 11 in this reaction is assumed to proceed via
the nonisolable intermediate analide 9, which cyclized to
the nonisolable ethyl carboxylate derivative 10 that
underwent hydrolysis under the applied reaction conditions
to give 6-acetyl-4-amino-8-(4-methylphenyl)-2,7-dioxo-5-
phenyl-1,2,7,8-tetrahydro-1,8-naphthyridine-3-carboxylic
acid (11) (see Scheme 2 and Experimental section).
Moreover, compound 1 reacted with ethyl acetoacetate
under the above reaction conditions to give the [1,8]
naphthyridine-3-carboxylic acid derivative 14 rather than
the diacetyl derivative 16. The structure 14 was established
based on elemental analyses and spectral data studies. The
IR spectrum of 14 indicated the presence of a broad band at
n = 3400–2500 cmꢀ1 due to acidic OH functional group. In
addition its 1H-NMR spectrum revealed the signal of acidic
OH proton at d = 14.32 ppm and absence of any signals
may be attributed to -CH2CH3 protons. The formation of
compound 14 in this reaction is assumed to proceed via
The reactivity of 1 toward ester compounds was studied,
thus treatment of 1 with diethyl malonate under reflux in
DMF/piperidine solution afford [1,8]naphthyridine-3-
Scheme 1
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A.-B. A. A. M. El-Adasy, A. A. Khames, and M. A. M. Gad-Elkareem
Vol 50
Scheme 2
the nonisolable condensation product 12, which cyclized
to the nonisolable ethyl carboxylate derivative 13 that
underwent hydrolysis under the applied reaction condi-
tions to give the 1,8-naphthyridine-3-carboxylic acid 14
(see Scheme 2 and Experimental section).
Further annulations of compounds 3, 5 and 8 were also
investigated. Thus, reaction of each of compounds 3, 5,
and 8 with malononitrile in DMF/pepeidine solution under
reflux yielded the corresponding pyrido[2,3b][1,8]-
naphthyridine-3-carbonitrile derivative 17, pyrido[2,3-h]
[1,6]naphthyridine-3-carbonitrile derivatives 18 and 19,
respectively. The structures of 17, 18, and 19 were
confirmed based on elemental analyses and spectral data
(see Scheme 3 and Experimental section).
The key structure 1 was used to synthesize a new series
of the biologically important pyridopyrimidine derivatives.
Thus, the reaction of 1 with formic acid under reflux
afforded the pyridopyrimidine derivative 20a (Scheme 4).
The IR spectrum of compound 20a showed bands at
3210 (NH), 1711, 1670, 1630 cmꢀ1 (three C═O). The
1H-NMR spectrum showed signals at d = 2.02, 2.36 ppm
assigned for 2CH3, singlet at d = 7.47 ppm assumed for
C(2)-H pyrimidine and the signal of NH at d = 14.08
ppm. Similarly, compound 1 reacted with acetic anhydride
to give the corresponding pyridopyrimidine derivative 20b
(Scheme 4), and also, compound 1 was condensed with
formamide under reflux afforded the aminopyridopyrmidine
derivative 21. The structure of compound 21 was confirmed
based on elemental analysis; IR and 1H-NMR spectra
(see Scheme 4 and Experimental section).
When compound 1 was allowed to react with urea in the
presence of sodium ethoxide in ethanol the pyridopyrimi-
dine derivative 22a or 23a was isolated as a reaction
product. The IR spectrum of the reaction product indicated
the presence of the absorption band of CN function group
at 2211 cmꢀ1 and absence of any bands may be attributed
to the CO function groups. Also the 1H-NMR spectrum did
not revealed any signals for the NH protons. From the
above data, the reaction product was formulated as the
pyrido[2,3-d]pyrimidine-6-carbonitrile derivative 22a, and
the 6-acetylpyrido[2,3-d]pyrimidine derivative 23a was
ruled out (see Scheme 4 and Experimental section).
Analogously, compound 1 reacted with thiourea to yield
the pyrido[2,3-d]pyrimidine-6-carbonitrile derivative 22b,
which established based on elemental analysis and spectral
data (see Scheme 4 and Experimental section).
Treatment of 1 with 4-isothiocyanatobenzenesulfonamide
in refluxing pyridine afforded the pyrido[2,3-d]pyrimidine
structure 26. The formation of compound 26 was assumed
to proceed via addition of the amino group of 1 to the
isothiocyanato group to yield the nonisolable thiourea
derivative 24, which cyclized through the addition to the
cyano function giving the intermediate pyridopyrimidine
derivative 25 that underwent Dimroth rearrangement
[13,20b], to give the final product 26 (Scheme 5).
The novel carboxamide derivative 27 was obtained via
treatment of compound 1 with concentrated sulfuric acid
at room temperature through partially hydrolysis of the
cyano group. The IR spectrum of 27 showed the absence
1
of cyano group absorption. The H-NMR showed signals
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45
Annulated Pyridine Derivatives
Scheme 3
at d 5.77, 10.91 ppm for two NH2 protons. Furthermore,
compound 27 also was used as starting compound for
synthesizing other pyrido[2,3-d]pyrimidine derivative
28 and Spiro compound 30. Thus, treatment of 27 with
4-chlorobenzaldehyde in acetic acid or in ethanol containing
a few drops of concentrated hydrochloric acid [28], under
reflux afforded the tetrahydropyridopyrimidine derivative
28. Also refluxing of 27 with 1H-indene-1,3(2H)-dione
under the same conditions afforded the corresponding spiro
[28], compound 30 rather than the Schiff’s base 29. The
1H-NMR of the product revealed the signals of two NH
protons at d = 10, 10.4 ppm and absence of any signals
may be attributed to the NH2 protons (see Scheme 5 and
Experimental section).
ethanolic sodium ethoxide afforded the corresponding
pyrrolo[2,3-b]pyridine derivatives 32 and 34, respectively,
through the alkylation of the NH2 group in 1 which leading
to the N-alkylated intermediates 31 and 33, respectively.
The intermediates 31 and 33 were cyclized under the
applied reaction condition to give the final reaction
products 32 and 34, respectively. The structural assignment
is based on analytical and spectral data (see Scheme 6 and
Experimental section).
Treatment of 1 with hydrazine hydrate under reflux
resulted the formation of either the pyrazolopyridine
structure 35 or 36. The structure 35 was confirmed for
Scheme 5
The reactivity of the aminonitrile derivative 1 toward the
halogenated compounds was investigated. Thus, treatment
of compound 1 with halogenated compounds such as
chloroacetanilide and phenacylbromide derivatives using
Scheme 4
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A.-B. A. A. M. El-Adasy, A. A. Khames, and M. A. M. Gad-Elkareem
Vol 50
Scheme 6
7.29–7.46 (m, 9H, Ar-H), 8.60 (br, 2H, NH2). Anal., for
C24H19N5O2 (409.45), calcd.: C, 70.40; H, 4.68; N, 17.10. Found:
C, 70.62; H, 4.83; N, 17.30%.
6-Acetyl-4-amino-8-(4-methylphenyl)-2,7-dioxo-5-phenyl-
1,2,7,8-tetrahydro-1,8-naphthyridine-3-carbonitrile (5).
A
solution of 1 (0.01 mol) and ethyl cyanoacetate (0.01 mol) in
acetic acid (20 mL) was heated under reflux for 2 h. The solid
formed during refluxing was collected by filtration, washed well
with methanol, and recrystallized from ethanol to give 5 as
brown crystals (62%), m.p. 132ꢁC, IR(KBr) n cmꢀ1: 3438, 3412
(NH2), 3261 (NH), 2182 (CN), 1722, 1710, 1633 (3C═O).
1H-NMR (DMSO-d6) d ppm: 2.21 (s, 3H, CH3), 2.35 (s, 3H,
CH3), 5.92 (s, 2H, NH2), 7.08–7.44 (m, 9H, Ar-H) and 10.2
(s, 1H, NH). Anal., for C24H18N4O3 (410.42), calcd.: C,
70.23; H, 4.42; N, 13.65. Found: C, 70.34; H, 4.60; N, 13.88%.
6-Acetyl-4-amino-8-(4-methylphenyl)-7-oxo-2,5-diphenyl-7,8-
dihydro-1,8-naphthyridine-3-carbonitrile (8). A mixture of
compound 1 (0.01 mol) and benzylidenemalononitrile (0.01 mol)
in DMF (20 mL) containing piperidine (1.0 mL) was refluxed for
5 h. The reaction was left to cool at room temperature, then
poured onto cold water, the solid product, so formed, was
collected by filtration and recrystallization from dioxan to give 8
as brown crystals (63%), m.p. 192ꢁC, IR(KBr) n cmꢀ1: 3426,
the reaction product based on elemental analysis and spectral
data. The IR spectrum of the reaction product revealed the
absorption band of CN at 2208 cmꢀ1 and absence of any
absorption bands may be attributed to the CO functions.
Moreover, no signals were detected in the 1H-NMR
spectrum that may be attributed to NH proton. Based on
the above data, the structure 36 was ruled out (Scheme 6).
1
3320 (NH2), 2186 (CN), 1712, 1629 (2 C═O). H-NMR (DMSO-
d6) d ppm: 1.90 (s, 3H, CH3), 2.35(s, 3H, CH3), 5.85 (s, 2H, NH2),
7.09–7.50 (m, 14H, Ar-H). Anal., for C30H22N4O2 (470.52), calcd.:
C, 76.58; H, 4.71; N, 11.91. Found: C, 76.70; H, 4.96; N, 11.75%.
Synthesis of [1,8]naphthyridine-3-carboxylic acid derivatives
11 and 14. A mixture of compound 1 (0.01 mol) and each of
diethyl malonate and ethyl acetoacetate (0.01 mol) in DMF (20
mL) containing piperidine (1.0 mL) was heated under reflux for 5
h. The reaction was left to cool at room temperature, then poured
onto cold water and acidified with dilute HCl, the solid product,
so formed, was collected by filtration and recrystallization from
EXPERIMENTAL
Melting points were measured with a Gallenkamp apparatus and are
uncorrected. IR spectra in KBr discs were recorded on BRUKER
Vector 22 FTIR spectrophotometer. 1H-NMR spectra were determined
in DMSO-d6 at 300 MHz on Varian Mercury VX spectrometer using
TMS as an internal standard. Chemical shifts are expressed as d ppm
and J as Hz units. Elemental analyses were carried out at the Micro-
analytical Center of Cairo University.
ethanol to give 11 and 14, respectively.
6-Acetyl-4-amino-8-(4-methylphenyl)-2,7-dioxo-5-phenyl-1,2,7,8-
tetra-hydro-1,8-naphthyridine-3-carboxylic acid (11). Yellow
crystals from ethanol (58%), m.p. 140ꢁC, IR(KBr) n cmꢀ1: 3441,
3284 (NH2), 3210 (NH), 3398–2382 (br. OH), 1710, 1699, 1661,
and 1633 (4 C═O). 1H-NMR (DMSO-d6) d ppm: 2.15 (s, 3H,
CH3), 2.33 (s, 3H, CH3), 5.92 (s, 2H, NH2), 6.75–7.37 (m, 9H,
Ar-H), 10.43 (s, 1H, NH) and 14.33 (s, 1H, OH). Anal., for
C24H19N3O5 (429.42) calcd.: C, 67.13; H, 4.46; N, 9.79.
5-Acetyl-2-amino-1-(4-methylphenyl)-6-oxo-4-phenyl-1,6-
dihydropyridine-3-carbonitrile (1). To a solution of N-(4-
methylphenyl)-3-oxobutanamide (0.01 mol) in ethanol (40
mL) containing a catalytic amount of peperidine (0.5 mL),
benzylidenemalononitrile (0.01 mol) was added. The reaction
mixture was heated under reflux for 6 h. The solid product so
formed on cooling was collected by filtration to give
compound 1 as yellow crystals from ethanol (80%), m.p.
202ꢁC, IR(KBr) n cmꢀ1: 3230, 3210 (NH2), 2190 (CN), 1696,
1648 (2 C═O). 1H-NMR (DMSO-d6) d ppm: 2.20 (s, 3H,
CH3), 2.39 (s, 3H, CH3), 5.98 (s, 2H, NH2), 7.29–7.46 (m,
9H, Ar-H). Anal., for C21H17N3O2 (343.39), Calcd.: C, 73.45;
H, 4.99; N, 12.24. Found: C, 73.25; H, 4.73; N, 12.00%.
6-Acetyl-2,4-diamino-8-(4-methylphenyl)-7-oxo-5-phenyl-7,8-
dihydro-1,8-naphthyridine-3-carbonitrile (3). A mixture of
compound 1 (0.01 mol) and malononitrile (0.01 mol) in DMF (20
mL) containing piperidine (1.0 mL) was refluxed for 3 h. The
reaction was left to cool at room temperature, and then poured
onto ice-cold water. The solid product, so formed, was collected
by filtration and recrystallization from ethanol to give 3 as yellow
crystals (78%), m.p. 127ꢁC, IR(KBr) n cmꢀ1: 3433, 3223 (Two
Found: C, 67.34; H, 4.70; N, 9.50%.
6-Acetyl-4-amino-2,methyl-8-(4-methylphenyl)-7-oxo-5-phenyl-
7,8-dihydro-1,8-naphthyridine-3-carboxylic acid (14). Yellow
crystals from ethanol (53%), m.p.160ꢁC, IR(KBr) n cmꢀ1: 3441,
3284 (NH2), 3400–2500 (br. OH), 1705, 1698, and 1632 (3
C═O). 1H-NMR (DMSO-d6) d ppm: 2.27 (s, 3H, CH3), 2.35
(s, 3H, CH3), 5.91 (s, 2H, NH2), 6.80-7.55 (m, 9H, Ar-H) and
14.42 (s, 1H, OH). Anal., for C25H21N3O4 (427.45) calcd.: C,
70.25; H, 4.95; N, 9.83. Found: C, 70.53; H, 4.70; N, 9.66%.
Synthesis of pyridonaphthyridine derivatives 17, 18, and 19. A
mixture of each of compounds 3, 5, or 8 (0.01 mol) and malononitrile
(0.01 mol) in DMF (20 mL) containing piperidine (1.0 mL) was
refluxed for 5 h. The reaction was left to cool at room temperature,
then poured onto cold water, the solid product, so formed, was
collected by filtration and recrystallization from benzene to
give 17, 18, and 19, respectively.
7-Acetyl-2,4,5-triamino-9-(4-methylphenyl)-8-oxo-6-phenyl-
8,9-dihydropyrido[2,3-b][1,8]naphthyridine-3-carbonitrile (17).
1
NH2), 2207 (CN), 1690, 1640 (2 C═O). H-NMR (DMSO-d6) d
Yellow crystals from benzene (50%), m.p.110ꢁC, IR(KBr) n cmꢀ1
:
ppm: 2.35 (s, 3H, CH3), 2.49 (s, 3H, CH3), 4.98 (s, 2H, NH2),
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Annulated Pyridine Derivatives
3441, 3406, 3330 (3NH2), 2208 (CN), 1698, and 1654 (2 C═O).
1H-NMR (DMSO-d6) d ppm: 2.22 (s, 3H, CH3), 2.38 (s, 3H,
CH3), 4.11 (s, 2H, NH2), 4.25 (s, 2H, NH2), 6.70 (s, 2H, NH2)
and 7.03–7.62 (m, 9H, Ar-H). Anal., for C27H21N7O2 (475.50)
calcd.: C, 68.20; H, 4.45; N, 20.62. Found: C, 68.30; H, 4.70; N,
20.35%.
9-Acetyl-2,4-diamino-7-(4-methylphenyl)-5,8-dioxo-10-phenyl-
5,6,7,8-tetrahydropyrido[2,3-h][1,6]naphthyridine-3-carbonitrile
(18). Yellow crystals from benzene (55%), m.p.121ꢁC, IR(KBr)
n cmꢀ1: 3441, 3352, 3289 (2NH2), 3205 (NH), 2209 (CN), 1694,
1658 (2 C═O), and 1632 (C═O with H-bonded). 1H-NMR
(DMSO-d6) d ppm: 2.27 (s, 3H, CH3), 2.33 (s, 3H, CH3), 4.25
(s, 2H, NH2), 4.65 (s, 2H, NH2), 6.90–7.57 (m, 9H, Ar-H) and
10.43 (s, 1H, NH). Anal., for C27H20N6O3 (476.48) calcd.: C,
68.06; H, 4.23; N, 17.64. Found: C, 68.30; H, 4.60; N,17.40%.
7-Amino-4-methyl-8-(4-methylphenyl)-2-oxo-5-phenyl-2,8-
dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (22a). Brown
crystals from ethanol (65%), m.p. 142ꢁC, IR(KBr) n cmꢀ1
:
3390, 3270 (NH2), 2211 (CN), 1680 (C═O). 1H-NMR
(DMSO-d6) d ppm: 2.38 (s, 3H, CH3), 2.49 (s, 3H, CH3),
7.07–7.39 (m, 9H, Ar-H), 10.0 (s, 2H, NH2). Anal., for
C22H17N5O (367.40) calcd.: C, 71.92; H, 4.66; N, 19.06.
Found: C, 71.70; H, 4.80; N, 19.30%.
7-Amino-4-methyl-8-(4-methylphenyl)-5-phenyl-2-thioxo-2,8-
dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (22b). Broꢀw1n
crystals from ethanol (60%), m.p. 170ꢁC, IR(KBr) n cm
:
3326, 3229 (NH2), 2209 (CN). 1H-NMR (DMSO-d6) d ppm:
2.19 (s, 3H, CH3), 2.23 (s, 3H, CH3), 6.98 (s, 2H, NH2), 7.16–
7.57 (m, 9H, Ar-H). Anal., for C22H17N5S (383.64) calcd.: C,
68.61; H, 4.47; N, 18.26; S, 8.36. Found: C, 68.70; H, 4.63;
N, 18.49; S, 8.61%.
9-Acetyl-2,4-diamino-7-(4-methylphenyl)-5-phenyl-8-oxo-10-
phenyl-7,8-dihydropyrido[2,3-h][1,6]naphthyridine-3-carbonitrile
(19). Yellow crystals from benzene (59%), m.p. 100ꢁC, IR(KBr)
n cmꢀ1: 3450, 3381, 3343 (2NH2), 2205 (CN) and 1685, 1661
4-[(6-Acetyl-8-(4-methylphenyl)-7-oxo-5-phenyl-2-thioxo-1,
2,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)amino]benzene-
sulfonamide (26). A mixture of compound 1 (0.01 mol) and
isothiocyanatosulfonamide (0.01 mol) in pyridine (15 mL) was
refluxed for 8 h. The reaction mixture was cooled, poured onto
water, and neutralized with diluted HCl. The resulting solid was
recrystallized from ethanol to give 26 as yellow crystals (60%),
m.p. 134ꢁC, IR(KBr) n cmꢀ1: 3410, 3314 (NH2), 3210, 3130
1
(2 C═O). H-NMR (DMSO-d6) d ppm: 2.23 (s, 3H, CH3), 2.37
(s, 3H, CH3), 4.26 (s, 2H, NH2), 4.43 (s, 2H, NH2) and 6.75-
7.69 (m, 14H, Ar-H). Anal., for C33H24N6O2 (536.58) calcd.:
C, 73.87; H, 4.51; N, 15.66. Found: C, 73.60; H, 4.80; N, 15.40%.
Reaction of 1 with formic acid or acetic anhydride. A
mixture of compound 1 (0.01 mol) and each of formic acid or
acetic anhydride (20 mL) was heated under reflux for 6 h and
then cooled. The solid products thus formed were collected and
recrystallized from ethanol to give 20a,b, respectively.
1
(2NH), 1721, 1696 (2C═O). H-NMR (DMSO-d6) d ppm: 2.06
(s, 3H, CH3), 2.34 (s, 3H, CH3), 4.09 (s, 2H, NH2), 7.01–7.46
(m, 13H, Ar-H), 12.47 (s, 1H, NH), 14.42 (s, 1H, NH). Anal.,
for C28H23N5O4S2 (557.64) calcd.: C, 60.31; H, 4.16; N,
12.56; S, 11.50. Found: C, 60.50; H, 4.40; N, 12.80; S, 11.25%.
6-Acetyl-8-(4-methylphenyl)-5-phenylpyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione (20a). Yellow crystals from ethanol (66%),
m.p. 200–202ꢁC, IR(KBr) n cmꢀ1: 3210 (NH), 1711, 1670, 1630
5-Acetyl-2-amino-1-(4-methylphenyl)-6-oxo-4-phenyl-1,6-
dihydropyridine-3-carboxamide (27). Compound 1 (0.01 mol)
in concentrated H2SO4 (15 mL) was stirred at room
temperature for 1 h and then diluted by water (100 mL). The
solid product thus formed was collected and recrystallized
from ethanol to give 27 as white crystals (58%), m.p. 220–
222ꢁC, IR(KBr) n cmꢀ1: 3382, 3222 (broad, 2NH2), 1752,
1
(3 C═O). H-NMR (DMSO-d6) d ppm: 2.02 (s, 3H, CH3), 2.36
(s, 3H, CH3), 7.11–7.43 (m, 9H, Ar-H), 7.47 (s, 1H, CH-
pyrimidine) and 14.08 (s, 1H, NH). Anal., for C22H17N3O3
(371.38) calcd.: C, 71.15; H, 4.61; N, 11.31. Found: C, 71.40; H,
1
4.80; N, 11.50%.
1716, 1654 (3C═O). H-NMR (DMSO-d6) d ppm: 2.33 (s, 3H,
6-Acetyl-2-methyl-8-(4-methylphenyl)-5-phenylpyrido[2,3d]-
CH3), 2.49 (s, 3H, CH3), 5.77 (s, 2H, NH2), 6.91–7.54 (m, 9H,
Ar-H), 10.91 (s, 2H, NH2). Anal., for C21H19N3O3 (369.31)
calcd.: C, 69.79; H, 5.30; N, 11.63 Found: C, 69.58; H, 5.51; N,
11.90%.
Reactions of compound 27 with carbonyl compounds. A
mixture of compound 27 (0.01 mol) and each of 4-
chlorobenzaldehyde or 1H-indene-1,3(2H)-dione (0.01 mol) in
glacial acetic acid (20 mL) or in ethanol (20 mL) containing a
few drops of concentrated hydrochloric acid was heated at
reflux for 3 h. The products were collected and recrystallized
pyrimidine-4,7(3H,8H)-dione (20b). White crystals from
ethanol (55%), m.p. 230–232ꢁC, IR(KBr) n cmꢀ1: 3360 (NH),
1
1740, 1680, 1635 (3 C═O). H-NMR (DMSO-d6) d ppm: 2.18
(s, 3H, CH3), 2.22 (s, 3H, CH3), 2.31 (s, 3H, CH3), 6.99–7.36
(m, 9H, Ar-H), 12.47 (s, 1H, NH). Anal., for C23H19N3O3
(385.43) calcd.: C, 71.68; H, 4.97; N, 10.90. Found: C, 71.90;
H, 4.75; N, 10.70%.
6-Acetyl-4-amino-8-(4-methylphenyl)-5-phenylpyrido[2,3-d]-
pyrimidin-7(8H)-one (21). Compound
1 (0.01 mol) in
formamide (10 mL) was heated under reflux for 6 h and left to
cool. The crystalline product thus formed was filtered, washed
with ether, and recrystallized from dioxane to give 21 as white
crystals (59%), m.p. 122ꢁC, IR(KBr) n cmꢀ1: 3300, 3185
(NH2), 1700, 1625 (2 C═O). 1H-NMR (DMSO-d6) d ppm:
1.28 (s, 3H, CH3), 2.24 (s, 3H, CH3), 5.00 (s, 2H, NH2), 7.09–
7.44 (m, 9H, Ar-H) and 8.39 (s, 1H, CH-pyrimidine). Anal., for
C22H18N4O2 (370.40) calcd.: C, 71.34; H, 4.90; N, 15.13.
Found: C, 71.60; H, 4.68; N, 15.30%.
from ethanol to give 28 and 30, respectively.
6-Acetyl-2-(4-chlorophenyl)-8-(4-methylphenyl)-5-phenyl-2,3-
dihydropyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione (28). Yellow
crystals from ethanol (64%), m.p. 131ꢁC, IR(KBr) n cmꢀ1: 3390,
1
3200 (2NH), 1703, 1680, 1650 (3C═O). H-NMR (DMSO-d6)
d ppm: 2.10 (s, 3H, CH3), 2.34 (s, 3H, CH3), 6.80 (s, 1H, CH-
pyrimidine), 7.02–7.46 (m, 13H, Ar-H) 10.0 (s, 1H, NH),
10.40 (s, 1H, NH). Anal., for C28H22N3O3Cl (483.94) calcd.:
C, 69.49; H, 4.58; N, 8.68; Cl, 7.33. Found: C, 69.70; H, 4.41;
Reaction of 1 with urea and thiourea. To a solution of
sodium ethoxide (prepared from 0.5 gm of sodium and 50 mL
of absolute ethanol), compound 1 (0.01 mol) and urea or
thiourea (0.01 mol) were added. The reaction mixture was
refluxed for 6 h and then cooled and neutralizing with HCl, a
solid formed, which was collected by filtration, washed with
water, and recrystallized from ethanol to give 22a,b, respectively.
N, 8.97; Cl, 7.56%.
6-Acetyl-8-(4-methylphenyl)-5-phenyl-2,3-dihydrospiro[indan-
10-one-4,30-pyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione] (30).
Yellow crystals from ethanol (67%), m.p. 167ꢁC, IR(KBr) n
cmꢀ1: 3230, 3120 (2NH), 1710, 1685 (4C═O). 1H-NMR
(DMSO-d6) d ppm: 2.33 (s, 3H, CH3), 2.49 (s, 3H, CH3), 4.20
(s, 2H, CH2), 6.91 (s, 1H, NH), 7.08–7.40 (m, 13H, Ar-H)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

48
A.-B. A. A. M. El-Adasy, A. A. Khames, and M. A. M. Gad-Elkareem
Vol 50
[5] (a) Kumar, V.; Jaggi, M.; Singh, A. T.; Madaan, A.; Sanna, V.;
Singh, P.; Sharma, P. K.; Irchhaiya, R.; Burman, A. C. Eur J Med Chem
2009, 44, 3356; (b) Srivastava, S. K.; Jaggi, M.; Singh, A. T.; Madan, A.;
Rani, N.; Vishnoi, M.; Agarwal, S. K.; Mukherjee, R.; Burman, A. C.
Bioorg Med Chem Lett 2007, 17, 6660.
[6] Ferrarini, P. L.; Badawneh, M.; Franconi, F.; Manera, C.;
Miceli, M.; Mori, C.; Saccomanni, G. IL Farmaco 2001, 56, 311.
[7] Soriano, E.; Samadi, A.; Chioua, M.; de los Ríos, C.; Marco-
Contelles, J. Bioorg Med Chem Lett 2010, 20, 2950.
[8] Ravichandran, V.; Shalini, S.; Sundram, K.; Sokkalingam, A.
D. Eur J Med Chem 2010, 45, 2791.
7.93 (s, 1H, NH). Anal., for C30H23N3O4 (489.54); calcd.: C,
73.61; H, 4.74; N, 8.58. Found: C, 73.95; H, 4.52; N, 8.78%.
Synthesis of the pyrrolo[2,3-b]pyridine derivatives 32 and
34. A mixture of compound 1 (0.01 mol), and each of 2-chloro-
N-(4-chlorophenyl)acetamide or 2-bromo-1-phenylethanone
(0.01 mol), and sodium ethoxide (0.01 mL) in absolute ethanol
(30 mL) was heated under reflux for 6 h and then allowed to
cool, poured into cold water, and neutralized with diluted HCl.
The resulting solid products were collected and recrystallized
from ethanol to give 32 and 34, respectively.
5-Acetyl-3-amino-N-(4-chlorophenyl)-7-(4-methylphenyl)-6-oxo-
[9] Ramesh, D.; Chary, M. T.; Laxminarayana, E.; Sreenivasulu,
B. Indian J Chem B 2010, 49, 1271.
4-phenyl-6,7-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide
(32). Brown crystals from ethanol (66%), m.p. 195ꢁC, IR(KBr)
n cmꢀ1: 3354, 3320, 3217 (NH2, 2NH), 1692, 1646 (2C═O).
1H-NMR (DMSO-d6) d ppm: 2.24 (s, 3H, CH3), 2.49 (s, 3H,
CH3), 3.90 (s, 2H, NH2), 7.07–7.39 (m, 13H, Ar-H), 8.60 (s,
1H, NH), 9.98 (s, 1H, NH). Anal., for C29H23N4O3Cl (510.97);
calcd.: C, 68.17; H, 4.54; N, 10.96; Cl, 6.94. Found: C, 68.40;
[10] Tinha, D. V.; Stadlbauer, W. J Heterocycl Chem 2008, 45,
1359.
[11] Goswami, S.; Hazra, A.; Jana, S. Bull Chem Soc Jpn 2009, 82,
1175.
[12] Goswami, S.; Jana, S.; Dey, S.; Adak, A. K. Aust J Chem
2007, 60, 120.
[13] Elneairy, M. A. A.; Gad-Elkareem, M. A. M.; Taha, A. M. J
Sulfur Chem 2005, 26, 381.
[14] (a) Hafez, H. N.; Abbas, H. S.; El-Gazzar, A. B. A. Acta
Pharm 2008, 58, 359; (b) El-Gazzar, A. B. A.; Hafez, H. N. Bioorg
Med Chem Lett 2009, 19, 3392.
[15] Said, S. A. World J Chem 2009, 4, 92.
[16] Suresh, M.; Lavanya, P.; Vasu, K.; Sudhakar, D.; Venkata
Rao, C. J Chem Pharm Res 2010, 2, 82.
[17] Calandrella, N.; Risuleo, G.; Scareslla, G.; Mustazza, C.;
Castelli, M.; Galati, F.; Giuliani, A.; Galati, G. J Exp Clin Cancer Res
2007, 26, 405.
[18] (a) Nasr, M. M. N.; Gineinah, M. M. Arch Pharm 2002, 335,
289; (b) Nair, V.; Chi, G.; Shu, Q.; Julander, J.; Smee, D. F. Bioorg
Med Chem Lett 2009, 19, 1425.
H, 4.80; N, 10.70; Cl, 6.73%.
5-Acetyl-3-amino-2-benzoyl-7-(4-methylphenyl)-4-phenyl-1,7-
di-hydro-6H-pyrrolo[2,3-b]pyridin-6-one (34). Brown crystals
from ethanol (66%), m.p. 145ꢁC, IR(KBr) n cmꢀ1: 3373, 3323,
3215 (NH2 and NH), 1710, 1701, 1635 (3C═O). 1H-NMR
(DMSO-d6) d ppm: 1.90 (s, 3H, CH3), 2.25 (s, 3H, CH3), 5.85
(s, 2H, NH2), 7.01–7.69 (m, 14H, Ar-H), 9.58 (s, 1H, NH).
Anal., for C29H23N3O3 (461.51) calcd.: C, 75.47; H, 5.02; N,
9.10. Found: C, 75.65; H, 5.28; N, 9.32%.
6-Amino-3-methyl-7-(4-methylphenyl)-4-phenyl-7H-pyrazolo-
[3,4-b]-pyridine-5-carbonitrile (35). A solution of 1 (0.01 mol) in
hydrazine hydrate (20 mL) was heated under reflux for 7 h. The
reaction mixture was evaporated under vacuum. The solid product
thus formed was collected and recrystallized from ethanol to gꢀiv1e
[19] Mohamed, M. S.; Awad, S. M.; Sayed, A. I. Molecules 2010,
15, 1882.
[20] (a) Narayana, B. L.; Rao, A. R. R.; Rao, P. S. Eur J Med Chem
2009, 44, 1369; (b) Kanth, S. R.; Reddy, G. V.; Kishore, K. H.; Rao, P. S.;
Narsaiah, B.; Murthy, U. S. N. Eur J Med Chem 2006, 41, 1011.
[21] Agarwal, A.; Ramesh, A.; Goyal, N.; Chauhan, P. M. S.;
Gupta, S. Bioorg Med Chem 2005, 13, 6678.
35 as yellow crystals (58%), m.p. 200–202ꢁC, IR(KBr) n cm
:
3340, 3235 (NH2), 2208 (CN). 1H-NMR (DMSO-d6) d ppm: 2.02
(s, 3H, CH3), 2.20 (s, 3H, CH3), 6.90 (s, 2H, NH2), 7.01–7.48 (m,
9H, Ar-H). Anal., for C21H17N5 (339.39) calcd.: C, 74.32; H,
5.05; N, 20.63 Found: C, 74.55; H, 5.26; N, 20.40%.
[22] Koehler, L.; Graf, F.; Bergmann, R.; Steinbach, J.; Pietzsch, J.;
Wuest, F. Eur J Med Chem 2010, 45, 727.
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Patel, D. N.; Gupta, A. A.; Sharma, A.; Tom, R.; Bandyopadhya, D.;
Modi, H.; Patel, P. R. Bioorg Med Chem 2007, 15, 6782.
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2010, 45, 3911.
[25] Hilmy, K. M. H. Arch Pharm 2004, 337, 15.
[26] Abdel-Mohsen, S. A.; Geies, A. A. Monatsh Chem 2008, 139,
1233.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet