Facile and one pot synthetic routes for various novel, differently fused and promising heteropolycycles

Article abstract of DOI:10.1002/jhet.342

(Chemical Equation Presented) Four-component one pot cyclocondensation of aromatic aldehydes 1, ethyl cyanoacetate 2, barbituric acid 3 and ammonium acetate in methanol gave substituted and functionalised pyrido[2,3-d]pyrimidine derivatives 4 and 4′ after

Full text of DOI:10.1002/jhet.342

334
Facile and One Pot Synthetic Routes for Various Novel,
Differently Fused and Promising Heteropolycycles
Vol 47
Shallu Gupta, Poonam Gupta, Anand Sachar, and R. L. Sharma*
Department of Chemistry, University of Jammu, Jammu 180006, India
*E-mail: rlsharma_hod@rediffmail.com
Received August 6, 2009
DOI 10.1002/jhet.342
Published online 2 March 2010 in Wiley InterScience (www.interscience.wiley.com).
Four-component one pot cyclocondensation of aromatic aldehydes 1, ethyl cyanoacetate 2, barbituric
acid 3 and ammonium acetate in methanol gave substituted and functionalised pyrido[2,3-d]pyrimidine
derivatives 4 and 40 after initial Knoevenagel, subsequent Micheal and final heterocyclization reactions.
Compounds 4 on reaction with different active methylene compounds resulted in the formation of again
functionalized and diversly substituted pyrimidonaphthyridines 5-7, 9 and benzo[b] pyrimidonaphthyri-
dines 8. The various compounds of systems 7 and 8 on further condensation with the reactive and
mostly the bifunctional moieties like urea/thiourea, and 2-aminopyridine generated the novel and differ-
ently fused dipyrimidonaphthyridines 10/11 and pyrimidonaphthyridinoquinazolines 13/14, and pyrido-
pyrimido- pyrimido[1,8]naphthyridines 15 and pyrimidonaphthyridino- pyridoquinazolines 16,
respectively, hitherto unknown in literature. Compounds 7 on condensation with o-phenylenediamine
produced novel pyrimidonaphthyridinobenzodiazepines 12. Other novel systems like pyrido[2,3-d;6,5-
d0]dipyrimidines 17, dipyrimido[4,5-b:50,40-g][1,8]naphthyridines 18, 1,3,4,6,7,8,9,11-octazabenzo[de]-
naphthacenes 19, dipyrimido[4,5-b:50,40-g][1,8]naphthyridines 20, pyrimido[50,40:6,7][1,8]naphthyri-
dino[4,3-b][1,5]benzodiazepines 21, dipyrimido[4,5-b:40,50-f][1,8]naphthyridines 22 and dipyrimido [4,5-
b:50,40-g][1,8] naphthyridines 23 have also been generated in this study.
J. Heterocyclic Chem., 47, 334 (2010).
INTRODUCTION
genic bacteria and have potential activity such as antipy-
retic, diuretic, bacteriostatic, sedative, and coronary
dilating agents [8]. The chemical transformations of the
pyridopyrimidine ring system by the introduction and
assemblage of different substituents and heterocyclic
rings in fused form have allowed expansion of the
research to the structure activity relationship to afford
new insight into the molecular interactions at the recep-
tor level. Many heterocyclic compounds having pyrido-
pyrimidine nucleus are also known to have a wide range
of biological activities [9]. Condensed system having
1,8-naphthyridine and a pyrimidine nucleus constitutes a
The benzodiazepines are a class of drugs with hyp-
notic [1], anxiolytic, anticonvulsant, amnestic, and mus-
cle relaxant properties. They serve as cholecystokinin A
and B antagonists [2], opioid receptor ligands [3], plate-
let-activating factor antagonists [4], HIV inhibitors [5],
and farnesyltransferase inhibitors [6]. Benzodiazepines
[7] can be used in anxiety disorders, insomnia, involun-
tary movement disorders, and in detoxification from
alcohol and other substances. The pyridopyrimidines are
very popularly and widely known compounds as a
consequence of their activity against a variety of patho-
C
V
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March 2010
Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
335
Scheme 1
group of important compounds because of their vital
pharmacological properties. Members of this family
have wide applications in medicinal chemistry, being
used to have antibacterial [10], antithrombic [11], and
anticonvulsant behavior [12]. The quinazoline ring sys-
tem is a commonly encountered structural core in a
number of natural and synthetic molecules with a wide
range of biological activities [13]. Many of the quinazo-
line derivatives are known to exhibit anti-inflammatory
[14], anthelmentic [15], analgesic [16], CNS-depressant
[17], and anticonvulsive activities [18]. Metolazone and
quinethazone are two quinazoline-based drugs that are
used currently as diuretics in medicines [19]. Vasicine
and related naturally occurring quinazoline alkaloids,
and other quinazoline bearing natural metabolites
including a number of tryptoquivalines are the famous
broncodilators [20], oxytocics, and antifungals being
used since time immemorial. The bacterial and bacterio-
lytic activities have not been extensively studied in py-
rimidine, quinazoline, naphthyridine, and benzo[b]diaze-
pine systems in both isolation and in fused assemblages.
Literature survey reveals that a fair amount of work has
been published in the condensation reactions of barbituric
acid, dimedone, and other active methylene carbocyclic
and heterocyclic compounds. Because of long standing in-
terest in our laboratory in the condensation reactions of
active methylene compounds [21–23] and generation of
new fused (‘‘ortho’’ and ‘‘ortho and peri’’), bridged [23],
spiro [24], ring assembly and cyclophane [25] heterocy-
clic compounds, we have extended our synthetic activity
along these lines to include the synthesis of some pyrido-
pyrimidine, pyrimidonaphthyridine, benzo[b]pyrimido-
naphthyridine, dipyrimidonaphthyridine, pyrimidonaph-
thyridinoquinazoline, pyrimidonaphthyridinobenzodiaze-
pine, pyridopyrimido- pyrimido- naphthyridine, pyrimi-
donaphthyridino-pyridoquinazoline, and 1,3,4,6,7,8,9,11-
octazabenzo[de]naphthacene systems.
heterocyclic systems containing various vital nitrogen
heterocyclic moieties, expectedly enriched with potential
antimicrobial, antifungal, and other important biological
activities. To prepare these novel classes of compounds,
we synthesized and used ethyl 7-amino-2,4-diketo-5-
aryl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-6-car-
boxylate 4 as the key intermediate synthon.
RESULTS AND DISCUSSION
The key intermediates 4a–4d used as starting materi-
als [26] have been prepared in better yields by refluxing
the aromatic aldehydes 1, ethyl cyanoacetate 2, barbitu-
ric acid, 3 and excess of ammonium acetate in methanol
though some traces of compound 40 in each case were
formed. The main product 4 was separated by fractional
crystallization and from the mother liquor a pale yellow
colored side product 40 was isolated in each case that
was characterized as 6-cyano-5-aryl-1,2,3,4,5,6,7,8-octa-
hydropyrido[2,3-d]pyrimidine-2,4,7-trione. The forma-
tion of these key intermediates 4 and mechanism of
their formation have been exhibited (Scheme 1 and 2
respectively).
The reaction sequence in the formation of 4 may be
proceeding via initial formation of ethyl arylidenecya-
noacetate 10 by reaction of aromatic aldehyde 1 and
ethyl cyanoacetate 2 through typical Knoevenagel con-
densation. Subsequently, the intermediate 10 reacts with
6-amino uracil 30 obtained through the aminodehydra-
tion of barbituric acid 3 to produce another intermediate
300 which on cyclocondensation results in the formation
of 4 and 40 (Scheme 2).
The structure of 4a was established on the basis of
1
elemental analysis, IR and H NMR spectral data. The
IR spectrum of compound 4a showed strong absorption
bands at t 3333 and 3423 cmꢀ1 for amino group and at
t 1675, 1682, 1690 cmꢀ1 for (C¼¼O) group. Its 1H
NMR spectrum showed as usual a quartet and a triplet
It was interesting to study these di- and tri- and
unknown and unreported tetra-, penta-, and hexa- cyclic
Journal of Heterocyclic Chemistry
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S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Scheme 2
due to CH2 and CH3 protons respectively of the ethyl
ester functionality besides other protons including a
multiplet of aromatic proton, a singlet of chiral proton,
a singlet at d 3.75 due to OCH3 group and D2O
exchangeable protons. Treatment of compounds 4a–4d
with malononitrile under refluxing in DMF in the pres-
ence of catalytic amount of piperidine gave products
identified as 8-amino-7-cyano-5-aryl-1,2,3,4,5,6,9,10-
octahydropyrimido[4,5-b][1,8]naphthyridine-2,4,6-triones
5a–5d (Scheme 3). The structures of these products
were established on the basis of their analytical and
spectral data.
Condensation of compounds 4a–4d with ethyl cyanoa-
cetate under similar conditions gave major products identi-
fied as 8-amino-7-ethoxycarbonyl-5-aryl-1,2,3,4,5,6, 7,10-
octahydro-pyrimido[4,5-b][1,8]naphthyridine-2,4,6-triones
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Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
337
Scheme 3
6a–6d and minor products identified as 7-cyano-5-aryl-
1,2,3,4,5,6,7,8,9,10-decahydropyrimido[4,5-b][1,8]naphthyr-
idine-2,4,6,8-tetraones 60a–60d. Their structures were
established as usual on the basis of elemental and spectral
data. Similar condensation of compounds 4a–4d with ace-
tylacetone [27] under refluxing in DMSO in the presence
of catalytic amount of P2O5 gave the enamine ketones in
good yields. The enamine ketones were then cyclized in
presence of K2CO3 and copper powder in refluxing dry ac-
etone giving substituted pyrimidonaphthyridine derivatives
7a–7d. Condensation of compounds 4a–4d with other
active methylene compounds like dimedone and ethyl ace-
toacetate resulted in the formation of substituted benzo[b]
pyrimidonaphthyridine 8a–8d and substituted pyrimido-
naphthyridine compounds 9a–9d and 90a–90d, respectively.
The structures of all these compounds were established as
usual by elemental analysis and spectral studies, details of
which are given in the experimental section. Cycloconden-
sation of compounds 7a–7d with urea/thiourea separately
resulted in the formation of substituted dipyrimidonaph-
thyridines 10a–10d and 11a–11d and similar treatment of
8a–8d resulting in the formation of pyrimidonaphthyridi-
noquinazoline derivatives 13a–13d and 14a–14d. On con-
densation with o-phenylenediamine, compounds 7a–7d
resulted in the formation of substituted pyrimidonaphthyri-
1
dinobenzodiazepine compounds 12a–12d. The H NMR
data of compound 12b showed two singlets at d 3.73 and
3.78 indicating the presence of two methoxyl groups, a sin-
glet at d 4.74 indicating the presence of chiral CH proton,
peaks at d 8.79, 8.95 and 9.74 due to three D2O
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S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
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1
exchangeable (NH) protons. The three aromatic protons of
3,4-dimethoxyphenyl group appeared at d 6.64–6.95 as a
multiplet and another multiplet was located at d 7.13–7.32
due to four aromatic protons of the benzodiazepine moiety.
A singlet at d 2.47 due to methyl group attached to diaze-
pine ring and another very highly downfield singlet at d
2.83 revealed the presence of methyl group attached to pyr-
idine ring. These assignments richly characterized the com-
pound 12b as 7,8-dimethyl-15-(3,4-dimethoxy phenyl)-
2,3,4,5,7a,15-hexahydro-1H-pyrimido[50,40:6,7][1,8]naph-
thyridino[4,3-b][1,5]benzo- diazepine-1,3-dione. Further,
compounds 7a–7d and 8a–8d on similar cyclocondensa-
tions with 2-aminopyridine were attributed to generate
substituted pyrido[20,10:2,3]pyrimido[4,5-f] pyrimido[4,5-
b][1,8]naphthyridine-11,13-diones 15a–15d and substi-
tuted pyrimido [50,40:6,7] [1,8]naphthyridino[4,3,2-de]
pyrido[2,1-b]quinazolines 16a–16d, respectively, on the
grounds that the 1H NMR data of compound 15c revealed
the presence of two D2O exchangeable (NH) protons at d
8.96 and 9.74, a singlet at d 2.22 due to methyl group of
p-methylphenyl ring, a singlet at d 4.74 indicating the
presence of chiral CH proton, a double doublet at d 6.80–
6.95 and 6.65–6.67 with ortho coupling indicating the
presence of p-methylphenyl ring, a multiplet at d 6.39–
6.62 showing the presence of another set of four aromatic
protons and two sharp singlets at d 2.29 and 2.72 due to
data. In the H NMR spectra, the singlet at d 2.26 ppm
due to the proton on the fused tertiary carbon atom (C-
4a) of the structure 22 (experimental data given for 22b)
does not appear as downfield as the singlet at d 3.92
ppm due to the proton on the fused tertiary carbon atom
(C-6a) of the structure 23 (experimental details given
for 23a), latter is flanked on either side by C¼¼O groups.
There is a marked D2O exchangeable singlet at d 3.85
1
ppm for 22b due to NH2 group in the H NMR spec-
1
trum. Such chemical shift value is absent in H NMR
spectrum of 23a. Analytical data of 22a and 23a (with
same aryl substituents) have revealed their molecular
formulae to be C19H15N7O4S and C19H14N6O5S, respec-
tively, which are same as calculated for their proposed
structures. So, structure 22 is a H15N7O4 compound
without aryl groups, whereas structure 23 is a H14N6O5
compound without aryl groups. The observed % of
Nitrogen in former is 22.54 and in latter 19.19. Same is
true for the other pairs, i.e., 22b and 23b, 22c and 23c,
and 22d and 23d. The m/z for the parent peak (Mþ)
could also speak for different molecular masses of the
two structures 22 and 23.
In compound 23a, the pure ketonic group on Carbon-
6 shows C¼¼O stretching frequency 1715 cmꢀ1, higher
than the other carbonyl stretching frequencies (1660–
1680cmꢀ1) of lactam and thiolactam rings present in
structures 22 and 23. This higher valued carbonyl
stretching frequency is absent in the IR spectrum of
structure 22b. The free amino group on the unsaturated
carbon atom shows marked NAH stretching frequency
(3200–3500cmꢀ1) in structures 22 and this is lacking in
IR spectrum of structure 23a.
1
other two methyl groups in the compound; and H NMR
data of compound 16d showing peaks due to two D2O
exchangeable (NH) protons at d 8.97 and 9.79, two singlet
at d 1.88 and 2.12 due to two methylene groups, a singlet
at d 1.11 due to six protons of two gem dimethyl groups,
a singlet at d 4.74 due to chiral CH proton, a multiplet at
d 6.49–6.62 showing the presence of four protons of
Nitrogen bridged pyrimidine ring, a sharp singlet at d
5.87 due to two methylenedioxy protons and a multiplet
at d 6.47–6.89 due to three aromatic protons of the meth-
ylenedioxyphenyl group.
The preliminary tests of the keto compound like for-
mation of 2,4-dinitrophenyl hydrazone, phenylhydra-
zone, semicarbazone, and oxime could be confirmed
only for structure 23 (keto group at C-6). Structure 22
could not respond to these tests as it contains carbonyl
groups only in the form of lactam and thiolactam func-
tionalities. Similarly, Structures 22 give all the prelimi-
nary tests of free amino group.
Compounds 4, 5 and 6 on condensation with formam-
ide could close the recurring generation of the COOR/
CN group at adjacent position to NH2 group in the same
ring resulting in the production of pyrido[2,3-d;6,5-
d0]dipyrimidines 17, dipyrimido[4,5-b:50,40-g][1,8]naph-
thyridines 18 which subsequently generated 1,3,4,6,7,
8,9,11-octaza benzo[de]naphthacenes 19 with more of
formamide and dipyrimido[4,5-b:50,40-g][1,8]naphthyri-
dines 20, respectively. In addition, compound 6 on treat-
ment with o-phenylenediamine produced a novel penta-
cyclic heterocyclic system, pyrimido [50,40:6,7]
[1,8]naphthyridino[4,3-b][1,5]benzodiazepines 21, and
on heating with thiourea, it produced dipyrimido[4,5-
b:40,50-f][1,8]naphthyridine 22 and dipyrimido[4,5-
b:50,40-g][1,8]naphthyridine 23 the two differently fused
systems (Scheme 4). The compounds 22 and 23 have
been distinguished on the basis of analytical and spectral
All the other products were similarly characterized by
1H NMR and 13C NMR data, and their elemental analy-
sis data was also in complete agreement with the
assigned structures. The structural formulae, m.ps, yield,
molecular formulae, and elemental analysis for these
compounds are shown in tabular form (Table 1).
The novel fused heterocyclic systems belonging to
compounds 8a–8d, 10a–10d, 12a–12d, 13a–13d, 15a–
15d, 16a–16d, 18a–18d, and 19a–19d are highly fasci-
nating and interesting and are being reported for the first
time in literature especially as regards their generation.
The heterocyclic compounds 8 and 18 with linear,
‘‘ortho’’ fused structures; 10, 12, and 15 with angular
‘‘ortho’’ fused structures; and compounds 13, 16, and 19
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Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
339
Scheme 4
with ‘‘ortho’’ and ‘‘ortho and peri’’ fused structures con-
tain various component heterocyclic moieties like py-
rimidine, pyridine, quinazoline, quinoline, [1,8]naphthyr-
idine, and benzodiazepine present in different modes of
combinations and all known for their remarkable, varied,
and highly useful physiological activities.
strate, it can be summarily concluded that a reaction of
an active methylene compound like malononitrile, ethyl
cyanoacetate, and ethyl acetoacetate with a cyclic sys-
tem having NH2 and groups like CN/COOH/COOR in
adjacent position to each other can serve as a recurring
contributor for the transformation of a linear system into
another linear system having one more ring till the reac-
tion gets stopped due to very high cyclicity
(7,8,9. . .membered) and molecular weight or availability
of very small amount of substrates to proceed further
From the study of the key reactions discussed in the
present exposition for transformation of an active meth-
ylene cyclic compound into a polycyclic ring system
containing one six-membered ring more than the sub-
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340
S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Table 1
Differently substituted compounds with mp’s, yields, and molecular formulae.
Calcd. formula%
Obsd. formula%
Compound
Ar
Mp’s (ꢁC)
294
Yield (%)
83
Mol. formulae (Mþ)
C17H18N4O5
C
H
N
S
–
4a
4-CH3O.C6H4
56.97
56.92
55.66
55.58
59.64
59.60
54.83
54.88
57.69
57.75
56.14
56.10
60.80
60.76
55.22
55.17
57.14
57.12
55.88
55.85
59.66
59.60
55.10
55.07
56.46
56.43
55.38
55.32
58.67
58.62
54.67
54.63
56.99
56.93
55.74
55.73
59.50
59.46
54.96
54.93
60.91
60.84
59.43
59.40
63.48
63.56
58.82
58.85
63.58
63.63
62.06
62.08
66.01
66.08
61.60
61.58
59.43
59.39
5.06
5.02
5.19
5.17
5.29
5.32
4.33
4.35
3.87
3.89
4.12
4.09
4.08
4.09
3.08
3.12
3.73
3.72
3.94
3.97
3.89
3.86
3.08
3.09
4.50
4.52
4.64
4.62
4.67
4.69
3.90
3.92
3.45
3.42
3.69
3.61
3.60
3.64
2.81
2.79
4.60
4.65
4.75
4.78
4.79
4.77
3.94
3.92
5.10
5.08
5.20
5.23
5.29
5.25
4.49
4.51
4.75
4.76
15.63
15.75
14.42
14.50
16.36
16.42
15.04
15.12
17.94
17.87
16.36
16.48
18.91
18.98
17.17
17.25
22.21
22.28
20.57
20.65
23.19
23.25
21.42
21.47
16.46
16.54
15.37
15.43
17.10
17.16
15.93
15.97
18.46
18.55
17.10
17.13
19.27
19.32
17.80
17.85
14.20
14.25
13.20
13.24
14.80
14.82
13.72
13.70
12.89
12.92
12.06
12.14
13.38
13.41
12.49
12.48
13.20
13.28
4b
4c
3,4-(CH3O)2.C6H3
4-CH3.C6H4
275
210
298
205
202
218
220
145
149
135
141
187
188
189
182
201
206
209
205
188
172
174
179
215
211
203
245
218
86
84
85
70
69
72
74
70
72
69
71
70
68
65
63
68
69
71
73
68
70
71
73
62
64
61
62
59
C18H20N4O6
C17H18N4O4
C17H16N4O6
C15H12N4O4
C16H14N4O5
C15H12N4O3
C15H10N4O5
C18H14N6O4
C19H16N6O5
C18H14N6O3
C18H12N6O5
C20H19N5O6
C21H21N5O7
C20H19N5O5
C20H17N5O7
C18H13N5O5
C19H15N5O6
C18H13N5O4
C18H11N5O6
C20H18N4O5
C21H20N4O6
C20H18N4O4
C20H16N4O6
C23H22N4O5
C24H24N4O6
C23H22N4O4
C23H20N4O6
C21H20N4O6
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4d
40a
40b
40c
40d
5a
3,4-OCH2O.C6H3
4-CH3O.C6H4
3,4-(CH3O)2.C6H3
4-CH3.C6H4
3,4-OCH2O.C6H3
4-CH3O.C6H4
5b
5c
3,4-(CH3O)2.C6H3
4-CH3.C6H4
5d
6a
3,4-OCH2O.C6H3
4-CH3O.C6H4
6b
6c
3,4-(CH3O)2.C6H3
4-CH3.C6H4
6d
60a
60b
60c
60d
7a
3,4-OCH2O.C6H3
4-CH3O.C6H4
3,4-(CH3O)2.C6H3
4-CH3.C6H4
3,4-OCH2O.C6H3
4-CH3O.C6H4
7b
7c
3,4-(CH3O)2.C6H3
4-CH3.C6H4
7d
70a
70b
70c
70d
9a
3,4-OCH2O.C6H3
4-CH3O.C6H4
3,4-(CH3O)2.C6H3
4-CH3.C6H4
3,4-OCH2O.C6H3
4-CH3O.C6H4
(Continued)
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Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
341
Table 1
(Continued)
Calcd. formula%
Obsd. formula%
Compound
Ar
Mp’s (ꢁC)
202
Yield (%)
57
Mol. formulae (Mþ)
C22H22N4O7
C
H
N
S
–
9b
3,4-(CH3O)2.C6H3
58.14
58.17
61.75
61.83
57.53
57.65
57.57
57.58
56.33
56.42
59.99
59.95
55.61
55.65
58.05
58.09
56.88
56.83
60.27
60.23
56.24
56.21
60.28
60.23
58.92
58.98
62.68
62.73
58.33
58.36
66.94
66.98
65.31
65.36
69.32
69.34
64.99
64.93
60.74
60.70
59.51
59.62
62.86
62.87
59.00
59.04
62.87
62.85
61.46
61.43
65.14
65.19
61.01
61.05
66.36
66.32
64.72
64.74
4.88
4.89
4.93
4.94
4.13
4.11
4.06
4.08
4.25
4.22
4.24
4.22
3.43
3.41
4.17
4.14
4.34
4.30
4.33
4.30
3.59
3.62
4.33
4.30
4.49
4.55
4.50
4.46
3.73
3.76
4.75
4.77
4.87
4.86
4.92
4.96
4.19
4.23
4.67
4.65
4.79
4.76
4.83
4.81
4.12
4.14
4.83
4.85
4.95
4.97
5.01
5.05
4.26
4.29
4.45
4.49
4.59
4.52
12.32
12.38
13.71
13.68
12.78
12.77
14.13
14.25
13.14
13.15
14.73
14.78
13.65
13.74
19.34
19.28
18.09
18.15
20.08
20.16
18.74
18.79
20.08
20.15
18.74
18.70
20.88
20.92
19.43
19.38
18.01
18.10
16.92
16.96
18.65
18.69
17.49
17.56
17.71
17.76
16.65
16.63
18.32
18.34
17.20
17.26
18.33
18.42
17.20
17.29
18.99
18.97
17.78
17.87
18.57
18.63
17.41
17.53
9c
4-CH3.C6H4
206
228
58
56
53
52
56
51
55
52
54
55
54
51
49
47
48
46
46
48
45
47
47
48
43
45
44
45
44
42
C21H20N4O5
C21H18N4O7
C19H16N4O6
C20H18N4O7
C19H16N4O5
C19H14N4O7
C21H18N6O3S
C22H20N6O4S
C21H18N6O2S
C21H16N6O4S
C21H18N6O4
C22H20N6O5
C21H18N6O3
C21H16N6O5
C26H22N6O3
C27H24N6O4
C26H22N6O2
C26H20N6O4
C24H22N6O3S
C25H24N6O4S
C24H22N6O2S
C24H20N6O4S
C24H22N6O4
C25H24N6O5
C24H22N6O3
C24H20N6O5
C25H20N6O3
C26H22N6O4
–
–
–
–
–
–
9d
3,4-OCH2O.C6H3
4-CH3O.C6H4
90a
249
90b
3,4-(CH3O)2.C6H3
4-CH3.C6H4
245
90c
221
90d
3,4-OCH2O.C6H3
4-CH3O.C6H4
233
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13a
13b
13c
13d
14a
14b
14c
14d
15a
15b
295
7.38
7.44
6.90
6.94
7.66
7.69
7.15
7.18
–
3,4-(CH3O)2.C6H3
4-CH3.C6H4
>300
>300
>300
284
3,4-OCH2O.C6H3
4-CH3O.C6H4
3,4-(CH3O)2.C6H3
4-CH3.C6H4
296
–
–
–
–
–
–
–
299
3,4-OCH2O.C6H3
4-CH3O.C6H4
>300
>300
310
3,4-(CH3O)2.C6H3
4-CH3.C6H4
306
3,4-OCH2O.C6H3
4-CH3O.C6H4
298
290
6.75
6.79
6.35
6.37
6.99
6.97
6.56
6.58
–
3,4-(CH3O)2.C6H3
4-CH3.C6H4
285
288
3,4-OCH2O.C6H3
4-CH3O.C6H4
296
276
3,4-(CH3O)2.C6H3
4-CH3.C6H4
279
–
–
–
–
–
288
3,4-OCH2O.C6H3
4-CH3O.C6H4
>300
>300
>300
3,4-(CH3O)2.C6H3
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

342
S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Table 1
(Continued)
Calcd. formula%
Obsd. formula%
Compound
Ar
Mp’s (ꢁC)
Yield (%)
44
Mol. formulae (Mþ)
C25H20N6O2
C
H
N
S
–
15c
15d
16a
16b
16c
16d
17a
17b
17c
17d
18a
18b
18c
18d
19a
19b
19c
19d
20a
20b
20c
20d
21a
21b
21c
21d
22a
22b
22c
4-CH3.C6H4
>300
68.79
68.76
64.37
64.31
68.28
68.20
66.65
66.63
70.57
70.61
66.39
66.36
56.63
56.58
55.28
55.20
59.44
59.40
54.39
54.25
56.29
56.23
55.17
55.15
58.60
58.57
54.41
54.37
57.97
57.92
56.75
56.78
60.29
60.32
56.07
56.03
56.16
56.11
55.04
55.00
58.46
58.41
54.29
54.24
61.40
61.48
60.11
60.15
63.57
63.62
59.62
59.65
52.16
52.07
51.38
51.41
54.15
54.19
4.61
4.64
3.89
3.83
4.91
4.87
5.01
5.03
5.07
5.09
4.37
4.35
3.86
3.89
4.09
4.07
4.05
4.08
3.13
3.14
3.73
3.74
3.93
3.90
3.88
3.85
3.12
3.10
3.40
3.38
3.62
3.60
3.54
3.51
2.82
2.80
3.47
3.44
3.69
3.68
3.61
3.58
2.87
2.84
4.07
4.10
4.23
4.19
4.22
4.20
3.54
3.55
3.45
3.48
3.66
3.60
3.58
3.60
19.25
19.32
18.01
18.09
17.06
17.09
16.08
16.14
17.63
17.67
16.59
16.61
20.64
20.70
18.96
18.99
21.66
21.68
19.82
19.87
24.18
24.15
22.51
22.48
25.18
25.26
23.38
23.45
27.04
27.09
25.21
25.28
28.12
28.17
26.15
26.23
20.68
20.72
19.25
19.32
21.52
21.57
19.99
20.23
20.88
20.94
19.63
19.69
21.62
21.65
20.28
20.33
22.41
22.54
20.97
20.98
23.26
23.29
3,4-OCH2O.C6H3
4-CH3O.C6H4
>300
>300
>300
>300
>300
198
46
38
39
43
45
55
58
52
54
51
53
50
52
48
47
44
46
44
42
45
42
46
41
43
45
41
42
42
C25H18N6O4
C28H24N6O3
C29H26N6O4
C28H24N6O2
C28H22N6O4
C16H13N5O4
C17H15N5O5
C16H13N5O3
C16H11N5O5
C19H15N7O4
C20H17N7O5
C19H15N7O3
C19H13N7O5
C20H14N8O3
C21H16N8O4
C20H14N8O2
C20H12N8O4
C19H14N6O5
C20H16N6O6
C19H14N6O4
C19H12N6O6
C24H19N7O4
C25H21N7O5
C24H19N7O3
C24H17N7O5
C19H15N7O4S
C20H17N7O5S
C19H15N7O3S
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
3,4-(CH3O)2.C6H3
4-CH3.C6H4
3,4-OCH2O.C6H3
4-CH3O.C6H4
3,4-(CH3O)2.C6H3
4-CH3.C6H4
206
215
3,4-OCH2O.C6H3
4-CH3O.C6H4
195
267
3,4-(CH3O)2.C6H3
4-CH3.C6H4
251
276
3,4-OCH2O.C6H3
4-CH3O.C6H4
289
284
3,4-(CH3O)2.C6H3
4-CH3.C6H4
298
>300
>300
290
3,4-OCH2O.C6H3
4-CH3O.C6H4
3,4-(CH3O)2.C6H3
4-CH3.C6H4
>300
287
3,4-OCH2O.C6H3
4-CH3O.C6H4
>300
298
3,4-(CH3O)2.C6H3
4-CH3.C6H4
292
>300
>300
274
3,4-OCH2O.C6H3
4-CH3O.C6H4
7.33
7.30
6.86
6.92
7.60
7.64
3,4-(CH3O)2.C6H3
4-CH3.C6H4
289
>300
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
343
Table 1
(Continued)
Calcd. formula%
Obsd. formula%
Compound
Ar
Mp’s (ꢁC)
Yield (%)
44
Mol. formulae (Mþ)
C19H13N7O5S
C
H
N
S
22d
3,4-OCH2O.C6H3
>300
50.55
50.60
52.05
52.09
51.28
51.32
54.02
54.08
50.44
50.47
2.90
2.94
3.21
3.28
3.44
3.46
3.34
3.36
2.67
2.68
21.71
21.70
19.16
19.19
17.94
17.95
19.89
19.86
18.57
18.59
7.10
7.14
7.31
7.35
6.84
6.87
7.59
7.66
7.08
7.04
23a
23b
23c
23d
4-CH3O.C6H4
>300
>300
>300
>300
40
41
44
42
C19H14N6O5S
C20H16N6O6S
C19H14N6O4S
C19H12N6O6S
3,4-(CH3O)2.C6H3
4-CH3.C6H4
3,4-OCH2O.C6H3
due to large number of steps having occurred till then or
the reaction is terminated intentionally according to
desirability of the required cyclicity by closing the reac-
tion by condensation of the product with formamide and
finally generating another terminal pyrimidine ring
(Scheme 4).
initial OD minus the final OD gives the bacteriolytic ac-
tivity. The ANHA group and the AOA group on the
given moieties may bind with the negatively charged
phosphate group on phospholipids present on the wall of
bacteria. This causes inhibition of the activities of lysoso-
mal phospholipases because of the neutralization of the
negative charges of phospholipid bilayer, leading to
potential antibacterial activity.
All the compounds under various heterocyclic systems
discussed herein were obtained either as a racemic mix-
ture of a pair of enantiomers or as a mixture of two
racemates or as only enantiomer or a diastereomer of
unknown stereochemistry. The resolution of the racemic
mixtures into the chiral enantiomers could not be carried
in this study, and the compounds were used and charac-
terized as obtained.
Observations. The active compounds exhibited a
range between mild to strong bactericidal activity
against gram-negative bacteria Escherichia coli (Table
2). The compounds were also subjected to bacteriolytic
activity against E. coli. The compounds 4d, 5d, 6d, 8d,
11d, 18d, 20d, 21d, and 22d showed mild bacteriolytic
activity; compounds 9d, 10d, 13d, 14d, 15d, 17d, 19d,
and 23d exhibited moderate bacteriolytic activity; and
compounds 7d, 12d, and 16d showed strong bacterio-
lytic activity against E. coli (Table 3). Ciprofloxacin
was used as standard antibiotic in this study.
Pharmacology. One compound each from the sys-
tems synthesized in this study was subjected to bacteri-
cidal and bacteriolytic activity against Escherichia coli.
The clinical syndromes associated with human beings
are urinary track infections, neonatal meningitis, and
gastroenteritis.
The bactericidal and bacteriolytic activity. The
compounds under study (20mg) were dissolved in 500
IL of DMSO. Five microlitres (0.2 mg approx) of the
stock solution was taken and 95 IL bacterial suspension
in Tris buffer saline (0.8 OD at 580 nm) was added to
it. The mixture was incubated at 14ꢁC for 14 h. After
incubation, it was subjected to plating in TCBS agar
(Thiosulphate, Citric, Bile salt, Sucrose agar). After
12 h, the culture plate was observed for bacterial
growth.
EXPERIMENTAL
General. The melting points were determined in open capil-
lary tubes in Perfit melting point apparatus and are uncor-
rected. The purity of the products was checked on TLC plates
coated with silica gel-G and detected by iodine vapors. The IR
spectra were recorded on Perkin Elmer Infrared model S99-B
and on Shimdzu IR-435 spectrophotometer (tmax in cmꢀ1). H
1
NMR and 13C NMR spectra were recorded on a varian unity
200 MHz NMR spectrophotometer using ppm on d scale). Ele-
mental analysis was performed on a simple CHNS analyzer
(model: CHNS-932, LECO Corporation, USA; IR Technology
Services).
For bacteriolytic activity, bacterial suspension in TBS
was prepared with an optical density of 0.8 OD at 580
nm (double beam UV spectrometer). TBS (Tris buffer sa-
line) served as the blank. The test compound (10mg) was
dissolved in 150 L of DMSO and 2850 IL of bacterial
suspension in TBS was added to it. The initial OD of the
sample was recorded. The mixture was incubated for 90
min at 23ꢁC. Final OD of the mixture was recorded. The
General procedure for the synthesis of ethyl 7-amino-2,4-
diketo-5-aryl-1,2,3,4,5,8-hexahydropyrido[2,3-d]pyrimidine-
6-carboxylates 4a–4d and 6-cyano-5-aryl-1,2,3,4,5, 6,7, 8-
octahydropyrido[2,3-d]pyrimidine-2,4,7-trione
mixture of equimolar amounts (0.01 moles) of aromatic alde-
40a–40d. A
hydes 1, ethyl cyanoacetate 2, and barbituric acid 3 along with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

344
S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Table 2
(d, 2H, ArH’s), 6.64–6.69 (d, 2H, ArH’s), 8.75–9.85 (br.s, 3H,
NH, D2O exchangeable).
In vitro screening of bactericidal activity of compounds
against E. coli.
6-Cyano-5-(3,4-dimethoxyphenyl)-1,2,3,4,5,6,7,8-octahydro-
pyrido[2,3-d]pyrimidine-2,4,7-trione (40b). It was obtained
using veratraldehyde as a minor product along with 4b as
major product. IR(KBr,t,cmꢀ1): 1605 (C¼¼C) 1670, 1682,
Entry
Compounds
B.A. against E.coli
1
1690 (C¼¼O), 2194 (C¼¼N), 3333–3405 (3NH) cmꢀ1; H NMR
1
2
3
4d
5d
6d
7d
8d
9d
10d
11d
12d
13d
14d
15d
16d
17d
18d
19d
20d
21d
22d
þ
þ
(CDCl3) : d 3.73 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.25 (s,
1H, CH), 4.52 (s, 1H, 5-CH), 6.46–6.54 (m, 3H, ArH’s), 8.71–
9.83 (br.s, 3H, NH).
þ
4
5
þ
þþ
þ
General procedure for the synthesis of 8-amino-7-cyano-
5-aryl-1,2,3,4,5,6,9,10-octahydropyrimido[4,5-b][1,8]naphthyri-
dine-2,4,6-triones 5a–5d. A mixture of 4 (10 mmoles) and
malononitrile (10 mmoles) in DMF (20 mL) containing piperi-
dine (0.1 mL) was refluxed for 5–6 h. The reaction was left to
cool at room temperature and then poured into ice-cold water
with stirring. The solid product 5 so formed was collected by
filtration and crystallized from acetic acid as brown crystals.
8-Amino-7-cyano-5-(3,4-dimethoxyphenyl)-1,2,3,4,5,6,9,10-
octahydropyrimido[4,5-b][1,8] naphthyridine-2,4,6-trione (5b). It
was obtained from 4b. IR(KBr,t,cmꢀ1): 1605 (C¼¼C), 1610,
1635, 1674 (C¼¼O), 2223 (C¼¼N), 3430 (NH2), 3445–3538
6
7
þþ
þþ
þþþ
þþ
þþ
þþþ
þþþ
þ
8
9
10
11
12
13
14
15
16
17
18
19
20
21
þ
þþþ
þþ
þþþ
þþ
þþ
þþþ
1
(4NH),cmꢀ1; H NMR(CDCl3): d 3.73 (s, 3H, OCH3), 3.78 (s,
23d
Ciprofloxacin
3H, OCH3), 4.74 (s, 1H, 5-CH), 6.78–6.95 (m, 3H, ArH’s),
7.98 (s, 2H, NH2), 8.82–9.89 (br.s, 4H, NH).
8-Amino-7-cyano-5-(3,4-methylenedioxyphenyl)-1,2,3,4,5,6,
9,10-octahydropyrimido[4,5-b][1,8]naphthyridine-2,4,6-trione
(5d). It was obtained from 4d. IR(KBr,t,cmꢀ1): 1605 (C¼¼C),
1612, 1625, 1674 (C¼¼O), 2198 (C¼¼N), 3423 (NH2), 3425–
Bacterial activity: B.A.
Concentration is 2 mg/mL.
(þ): mild bacterial activity was observed.
(þþ): moderate bacterial activity was observed.
(þþþ): strong bacterial activity was observed.
3536 (4NH) cmꢀ1 1H NMR (CDCl3): d 4.74 (s, 1H, 5-CH),
;
5.86 (s, 2H, O2CH2), 6.54–6.68 (m, 3H, ArH’s), 7.95 (s, 2H,
NH2), 8.83–9.87 (br.s, 4H, NH).
excess of ammonium acetate in methanol was refluxed on
water bath for 8–10 h. After the reaction is over as monitored
on TLC, the reaction mixture was concentrated and cooled at
room temperature. The solid products 4 was separated by frac-
tional crystallization as a major product and from the mother
liquor a pale yellow colored solid product 40 was isolated on
prolonged cooling as a minor product. The spectral data along
with IUPAC names of the products and names of the starting
materials for some of the compounds is mentioned below:
Ethyl 7-amino-2,4-diketo-5-(3,4-dimethoxyphenyl)-1,2,3,4,5,
8-hexahydropyrido[2,3-d] pyrimidine-6-carboxylate (4b). It
was obtained using veratraldehyde. IR(KBr,t,cmꢀ1): 1605
(C¼¼C), 1675, 1682, 1695 (C¼¼O), 3254 (NH2), 3334–3410
General procedure for the synthesis of substituted pyri-
mido[4,5-b][1,8]naphthyridines 6a–6d, 60a–60d, 9a–9d, and
90a–90d. A mixture of 4 (10 mmoles) and ethyl cyanoacetate/
ethyl acetoacetate (10 mmoles) in DMF (20 mL) containing pi-
peridine (0.1 mL) was refluxed for 6–8 h yielding 6, 60 and 9,
90, respectively. The reaction was left to cool at room tempera-
ture and then poured on to ice-cold water. The solid product
so formed was collected by filtration and crystallized from ace-
tic acid. Using ethyl cyanoacetate, the main product 6 sepa-
rated out first and from the mother liquor another minor prod-
uct 60 separated on keeping in refrigerator. Similarly, 9 and 90
were separated as major and minor products, respectively,
while using ethyl acetoacetate.
1
(3NH) cmꢀ1; H NMR (CDCl3): d 1.37 (t, 3H, CH3), 2.94 (q,
8-Amino-7-ethoxycarbonyl-5-(4-methoxyphenyl)-1,2,3,4,5,6,
7,10-octahydropyrimido[4,5-b][1,8]naphthyridine-2,4,6-trione
2H, OCH2), 3.73 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.72 (s,
1H, 5-CH), 5.58 (s, 2H, NH2), 6.74–6.96 (m, 3H, ArH’s),
8.76–9.86 (br.s, 3H, NH).
(6a). It was obtained from 4a as
a
major product.
IR(KBr,t,cmꢀ1): 1076 (CAOAC), 1528 (C. . ...C of aromatic
ring), 1645, 1658, 1672, 1695 (C¼¼O), 2926 (CAH, aliphatic),
Ethyl 7-amino-2,4-diketo-5-(3,4-methylenedioxyphenyl)-1,2,
3,4,5,8-hexahydropyrido [2,3-d]pyrimidine-6-carboxylate (4d). It
was obtained using piperonal. IR(KBr,t,cmꢀ1): 1605 (C¼¼C),
1675, 1680, 1695 (C¼¼O), 3256 (NH2), 3334–3412 (3NH)
3047 (CAH, aromatic ), 3336–3486 (3NH), 3428 (NH2) cmꢀ1
;
1H NMR(CDCl3): d 1.37 (t, 3H, CH3), 2.92 (q, 2H, OCH2),
3.73 (s, 3H, OCH3), 4.21 (s, 1H, CH), 4.42 (s, 1H, 5-CH),
6.65–6.67 (d, 2H, ArH’s), 6.70–6.93 (d, 2H, ArH’s), 7.89 (s,
2H, NH2), 8.80–9.86 (br.s, 3H, NH).
cmꢀ1 1H NMR (CDCl3): d 1.37 (t, 3H, CH3), 2.94 (q, 2H,
;
OCH2), 4.72 (s, 1H, 5-CH), 5.58 (s, 2H, NH2), 5.79 (s, 2H,
O2CH2), 6.57–6.67 (m, 3H, ArH’s), 8.78–9.89 (br.s, 3H, NH).
6-Cyano-5-(4-methoxyphenyl)-1,2,3,4,5,6,7,8-octahydropyrido
[2,3-d]pyrimidine-2,4,7-trione (40a). It was obtained using ani-
saldehyde as a minor product along with 4a as major product.
IR(KBr,t,cmꢀ1): 1605 (C¼¼C), 1670, 1680, 1692 (C¼¼O), 2195
8-Amino-7-ethoxycarbonyl-5-(3,4-dimethoxyphenyl)-1,2,3,4,5,
6,7,10-octahydropyrimido [4,5-b][1,8]naphthyridine-2,4,6-trione
(6b). It was obtained from 4b as
a
major product.
IR(KBr,t,cmꢀ1): 1078 (CAOAC), 1527 (C. . ...C of aromatic
ring), 1647, 1662, 1680, 1690 (C¼¼O), 2928 (CAH, aliphatic),
3048 (CAH, aromatic ), 3425 (NH2), 3436–3538 (3NH)cmꢀ1
;
1
(C¼¼N), 3333–3405 (NH) cmꢀ1; H NMR (CDCl3) : d 3.74 (s,
3H, OCH3), 4.25 (s, 1H, CH), 4.42 (s, 1H, 5-CH), 6.83–6.95
1H NMR (CDCl3): d 1.35 (t, 3H, CH3), 2.92 (q, 2H, OCH2),
Journal of Heterocyclic Chemistry
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Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
345
Table 3
In vitro screening of bacteriolytic activity of compounds against E. coli.
Bacteriolytic test
Bacterial suspension in
optical density (OD)
Entry
Compounds
Initial (OD)
Final (OD)
Activity (OD)
B.A.
1
2
4d
5d
6d
7d
8d
9d
10d
11d
12d
13d
14d
15d
16d
17d
18d
19d
20d
21d
22d
23d
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.833
0.787
0.788
0.786
0.770
0.788
0.778
0.780
0.788
0.773
0.775
0.776
0.777
0.770
0.775
0.788
0.774
0.788
0.786
0.788
0.778
0.046
0.045
0.047
0.063
0.045
0.055
0.053
0.045
0.060
0.058
0.057
0.056
0.063
0.058
0.045
0.059
0.045
0.047
0.045
0.055
þ
þ
3
4
þ
þþþ
þ
5
6
7
þþ
þþ
þ
8
9
þþ
þþ
þþ
þþ
þþþ
þþ
þ
10
11
12
13
14
15
16
17
18
19
20
þþ
þ
þ
þ
þþ
Bacterial activity: B.A.
Concentration is 2 mg/mL.
(þ): mild bacterial activity was observed.
(þþ): moderate bacterial activity was observed.
(þþþ): strong bacterial activity was observed.
3.74 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 4.18 (s, 1H, CH),
4.74 (s, 1H, 5-CH), 6.67–6.90 (m, 3H, ArH’s), 8.12 (s, 2H,
NH2), 8.87–9.87 (br.s, 3H, NH).
4.72 (s, 1H, 5-CH), 6.70–6.74 (m, 3H, ArH’s), 8.88–9.85 (br.s,
3H, NH).
7-Ethoxycarbonyl-8-methyl-5-(4-methylphenyl)-1,2,3,4,5,6,
7,10-octahydropyrimido[4,5-b][1,8]naphthyridine-2,4,6-trione
7-Cyano-5-(4-methoxyphenyl)-1,2,3,4,5,6,7,8,9,10-decahydro-
pyrimido[4,5-b][1,8] naphthyridine-2,4,6,8–tetraone (60a). It
was obtained from 4a as a minor product along with 6a.
IR(KBr,t,cmꢀ1): 1527 (C. . ...C of aromatic ring), 1627, 1640,
1675, 1694 (C¼¼O), 2198 (C¼¼N), 2926 (CAH, aliphatic),
(9c). It was obtained from 4c as
a
major product.
IR(KBr,t,cmꢀ1): 1079 (CAOAC), 1525 (C. . ...C of aromatic
ring), 1605, 1625, 1635, 1674 (C¼¼O), 2935 (CAH, aliphatic),
3045 (CAH, aromatic ), 3424 (NH2), 3435–3537 (3NH) cmꢀ1
;
1H NMR (CDCl3): d 1.23 (s, 3H, CH3), 1.38 (t, 3H, CH3),
2.74 (q, 2H, OCH2), 4.52 (s, 1H, CH), 4.74 (s, 1H, 5-CH),
6.64–6.68 (d, 2H, ArH’s), 6.72–6.74 (d, 2H, ArH’s), 8.89–9.75
(br.s, 3H, NH).
3045 (C¼¼H, aromatic ), 3448–3535 (4NH) cmꢀ1
;
1H NMR
(CDCl3): d 3.73 (s, 3H, OCH3), 4.25 (s, 1H, CH), 4.74 (s, 1H,
5-CH), 6.65–6.69 (d, 2H, ArH’s), 6.70–6.72 (d, 2H, ArH’s),
8.73–11.93 (br.s, 4H, NH).
7-Aceto-5-(4-methoxyphenyl)-1,2,3,4,5,6,7,8,9,10-decahydro-
pyrimido[4,5-b][1,8] naphthyridine-2,4,6,8–tetraone (90a). It
was obtained from 4a as a minor product along with 9a.
7-Cyano-5-(3,4-methylenedioxyphenyl)-1,2,3,4,5,6,7,8,9,10-
decahydropyrimido[4,5-b][1,8] naphthyridine-2,4,6,8–tetraone
(60d). It was obtained from 4d as a minor product along with
6d. IR(KBr,t,cmꢀ1): 1598 (C¼¼C), 1605, 1635, 1672, 1695
(C¼¼O), 2198 (C¼¼N), 2829 (CAH, aliphatic), 3048 (CAH, ar-
IR(KBr,t,cmꢀ1): 1527 (C. . ...
C
of aromatic ring), 1647,
1659, 1678, 1694 (C¼¼O), 2926 (CAH, aliphatic), 3045
(CAH, aromatic ), 3425 (NH2), 3448–3535 (4NH) cmꢀ1
;
omatic ), 3448–3535 (4NH) cmꢀ1 1H NMR (CDCl3): d 4.25
;
1H NMR (CDCl3): d 2.24 (s, 3H, CH3), 3.74 (s, 3H,
OCH3), 4.22 (s, 1H, CH), 4.72 (s, 1H, 5-CH), 6.65–6.67
(d, 2H, ArH’s), 6.70–6.73 (d, 2H, ArH’s), 8.89–11.95 (br.s,
4H, NH).
(s, 1H, CH), 4.68 (s, 1H, 5-CH), 5.89 (s, 2H, O2CH2), 6.49–
6.57 (m, 3H, ArH’s), 9.89–11.98 (br.s, 4H, NH).
7-Ethoxycarbonyl-8-methyl-5-(3,4-dimethoxyphenyl)-1,2,3,
4,5,6,7,10-octahydropyrimido [4,5-b][1,8]naphthyridine-2,4,6-
trione (9b). It was obtained from 4b as a major product.
IR(KBr,t,cmꢀ1): 1078 (CAOAC), 1525 (C. . ...C of aromatic
ring), 1627, 1657, 1672, 1694 (C¼¼O), 2928 (CAH, aliphatic),
7-Aceto-5-(3,4-methylenedioxyphenyl)-1,2,3,4,5,6,7,8,9,10-
decahydropyrimido[4,5-b] [1,8]naphthyridine-2,4,6,8–tetraone
(90d). It was obtained from 4d as a minor product along with
9d. IR(KBr,t,cmꢀ1): 1528 (C. . ...C of aromatic ring), 1647,
1662, 1678, 1694 (C¼¼O), 2928 (CAH, aliphatic), 3048 (CAH,
3048 (CAH, aromatic ), 3428 (NH2), 3435–3536 (3NH)cmꢀ1
;
1H NMR (CDCl3): d1.36 (t, 3H, CH3), 2.95 (q, 2H, OCH2),
3.73 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.58 (s, 1H, CH),
1
aromatic ), 3458–3538 (4NH) cmꢀ1; H NMR (CDCl3): d 2.27
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S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
Vol 47
(s, 3H, CH3), 4.24 (s, 1H, CH), 4.74 (s, 1H, 5-CH), 5.78 (s, 2H,
O2CH2), 6.70–6.76 (m, 3H, ArH’s), 8.86–11.95 (br.s, 4H, NH).
General procedure for the synthesis of substituted pyri-
mido[4,5-b][1,8]naphthyridine-2,4,6-triones 7a–7d and sub-
stituted benzo[b]pyrimido[5,4-g][1,8]naphthyridine-2,4,6,7-
tetraones 8a–8d. A suspension of 4 (0.02 mole), the appropri-
ate active methylene compounds, i.e., acetylacetone/dimedone
(0.02 mole) and P2O5 (0.10 g) in dry toluene 20 mL was
refluxed for 4 h, and the water was collected in a Dean Stark
trap. After cooling, the reaction mixture was filtered. The fil-
trate was evaporated to dryness. The resulting residue (enam-
ine ketone) was crystallized from ethyl acetate. To (0.03 mole)
of the residue was added K2CO3 (2.0 mmole) and copper pow-
der (0.03 mole) in dry acetone (10 mL) and refluxed for 5–6
h. After completion of reaction, the warm reaction solution
was filtered. The filtrate was evaporated to dryness and crystal-
lized from hot ethanol to get 7 and 8, respectively.
4,5-Dimethyl-12-(4-methoxyphenyl)-2-thioxo-2,4a,7,8,9,10,
11,12-octahydrodipyrimido [4,5-b;40,50-f] [1,8]naphthyridine-
9,11-dione (10a). It was obtained from 7a using thiourea.
IR(KBr,t,cmꢀ1): 1605 (C. . ...C of aromatic ring), 1640, 1670
(C¼¼O), 2925 (CAH, aliphatic), 3052 (CAH, aromatic ),
3334–3485 (3NH) cmꢀ1 1H NMR (CDCl3): d 2.20 (s, 3H,
;
CH3), 2.24 (s, 1H, CH), 2.52 (s, 3H, CH3), 3.74 (s, 3H,
OCH3), 4.74 (s, 1H, 12-CH), 6.64–6.67 (d, 2H, ArH’s), 6.74–
6.96 (d, 2H, ArH’s), 8.78–9.84 (br.s, 3H, NH).
4,5-Dimethyl-12-(3,4-methylenedioxyphenyl)-2-thioxo-2,4a,7,
8,9,10,11,12-octahydrodi pyrimido[4,5-b;40,50-f] [1,8]naphthyri-
dine-9,11-dione (10d). It was obtained from 7d using thiourea.
IR(KBr,t,cmꢀ1): 1645, 1670 (C¼¼O), 1605 (C. . ...C of aromatic
ring), 2850 (CAH, aliphatic), 3048 (CAH, aromatic ), 3333–
3484 (3NH) cmꢀ1; 1H NMR (CDCl3): d 2.21 (s, 3H, CH3), 2.26
(s, 1H, CH), 2.53 (s, 3H, CH3), 4.74 (s, 1H, 12CH), 5.79 (s, 2H,
O2CH2), 6.65–6.69 (m, 3H, ArH’s), 8.78–9.76 (br.s, 3H, NH).
4,5-Dimethyl-12-(3,4-dimethoxyphenyl)-2,4a,7,8,9,10,11,12-
octahydrodipyrimido[4,5-b; 40,50-f][1,8]naphthyridine-2,9,11-
trione (11b). It was obtained from 7b using urea.
IR(KBr,t,cmꢀ1): 1595, 1605, 1648 (C¼¼O), 1605 (C. . ...C of ar-
omatic ring), 2850 (CAH, aliphatic), 3042 (CAH, aromatic ),
7-Aceto-8-methyl-5-(4-methoxyphenyl)-1,2,3,4,5,6,7,10-octa-
hydropyrimido[4,5-b][1,8] naphthyridine-2,4,6-trione (7a). It
was obtained from 4a. IR(KBr,t,cmꢀ1): 1625 (C. . ...C of aro-
matic ring), 1638, 1675, 1680, 1695 (C¼¼O), 2932 (CAH, ali-
phatic), 3048 (CAH, aromatic ), 3335–3485 (3NH) cmꢀ1 1H
;
3330–3488 (3NH) cmꢀ1 1H NMR (CDCl3): d 2.21 (s, 3H,
;
NMR (CDCl3): d 1.68 (s, 3H, CH3), 2.95 (s, 3H, CH3), 3.72
(s, 3H, OCH3), 3.76 (s, 1H, CH), 4.71 (s, 1H, 5-CH), 6.62–
6.65 (d, 2H, ArH’s), 6.73–6.94 (d, 2H, ArH’s), 8.80–9.83
(br.s, 3H, NH).
CH3), 2.26 (s, 1H, CH), 2.54 (s, 3H, CH3), 3.71 (s, 3H,
OCH3), 3.78 (s, 3H, OCH3), 4.75 (s, 1H, 12-CH), 6.67–6.72
(m, 3H, ArH’s), 8.78–9.76 (br.s, 3H, NH). 13C NMR
(CDCl3):16.1, 24.7, 30.1, 56.3, 79.7, 94.8, 115.0, 115.8, 122.6,
130.0, 140.5, 144.6, 145.2, 147.5, 151.6, 161.0, 162.2, 164.1,
164.6, 165.1, 194.5.
7-Aceto-8-methyl-5-(3,4-methylenedioxyphenyl)-1,2,3,4,5,6,7,
10-octahydropyrimido [4,5-b][1,8] naphthyridine-2,4,6-trione
(7d). It was obtained from 4d. IR(KBr,t,cmꢀ1): 1595 (C. . ...
C
of aromatic ring), 1657, 1675, 1685, 1694 (C¼¼O), 2898
;
cmꢀ1 1H NMR (CDCl3): d 2.32 (s, 3H, CH3), 2.98 (s, 3H,
CH3), 3.76 (s, 1H, CH), 4.74 (s, 1H, 5-CH), 5.75 (s, 2H,
O2CH2), 6.64–6.67 (m, 3H, ArH’s), 8.92–9.85 (br.s, 3H,
NH).
4,5-Dimethyl-12-(4-methylphenyl)-2,4a,7,8,9,10,11,12-octa-
hydrodipyrimido[4,5-b;40,50-f] [1,8]naphthyridine-2,9,11-trione
(11c). It was obtained from 7c using urea. IR(KBr,t,cmꢀ1):
1605 (C. . ...C of aromatic ring), 1594, 1645, 1670 (C¼¼O),
2926 (CAH, aliphatic), 3054 (CAH, aromatic ), 3334–3487
(CAH, aliphatic), 3045 (CAH, aromatic ), 3338–3483 (3NH)
(3NH)cmꢀ1 1H NMR (CDCl3): d 2.20 (s, 3H, CH3), 2.24 (s,
;
9,9-Dimethyl-5-(4-methoxyphenyl)-1,2,3,4,5,6,6a,7,8,9,10,12-
1H, CH), 2.36 (s, 3H, CH3), 2.52 (s, 3H, CH3), 4.73 (s, 1H,
12-CH), 6.62–6.67 (d, 2H, ArH’s), 6.74–6.98 (d, 2H, ArH’s),
8.76–9.86 (br.s, 3H, NH).
dodecahydrobenzo[b]
2,4,6,7-tetraone (8a). It
pyrimido[5,4-g][1,8]naphthyridine-
was obtained from 4a.
IR(KBr,t,cmꢀ1): 1625 (C.. ...C of aromatic ring), 1657, 1663,
1675, 1690 (C¼¼O), 2928 (CAH, aliphatic), 3025 (CAH, aro-
General procedure for the synthesis of substituted
pyrimido[50,40:6,7] [1,8]naphthyridino[4,3-b][1,5]benzodia-
zepine-1,3-diones 12a–12d. A mixture of 7 (10 mmoles) and
o-phenylenediamine (10 mmoles) in DMF (20 mL) was
refluxed for 8–10 h. The reaction was left to cool at room tem-
perature and then poured into ice-cold water with stirring. The
solid product 12 so formed was collected by filtration and
crystallized from ethanol.
matic ), 3330–3484 (3NH) cmꢀ1; H NMR (CDCl3): d 1.11 (s,
1
6H, 2CH3), 2.54 (d, 2H, CH2), 2.98 (d, 2H, CH2), 3.74 (s, 3H,
OCH3), 3.83 (s, 1H, CH), 4.74 (s, 1H, 5-CH), 6.64–6.67 (d, 2H,
ArH’s), 6.73–6.98 (d, 2H, ArH’s), 8.83–9.53 (br.s, 3H, NH).
9,9-Dimethyl-5-(4-methylphenyl)-1,2,3,4,5,6,6a,7,8,9,10,12-
dodecahydrobenzo[b]
2,4,6,7-tetraone (8c). It
pyrimido[5,4-g][1,8]naphthyridine-
was obtained from 4c.
7,8-Dimethyl-15-(4-methoxyphenyl)-2,3,4,5,7a,15-hexahy-
dro-1H-pyrimido[50,40:6,7][1,8] naphthyridino[4,3-b][1,5]ben-
zodiazepine-1,3-dione (12a). It was obtained from 7a.
IR(KBr,t,cmꢀ1): 1595 (C. . ...C of aromatic ring), 1675, 1690
(C¼¼O), 2923 (CAH, aliphatic), 3059 (CAH, aromatic ),
IR(KBr,t,cmꢀ1): 1625 (C. . ...C of aromatic ring), 1645, 1669,
1680, 1695 (C¼¼O), 2925 (CAH, aliphatic), 3048 (CAH, aro-
matic), 3338–3480 (3NH) cmꢀ1; H NMR (CDCl3): d 1.12 (s,
1
6H, 2CH3), 2.52 (s, 3H, CH3), 2.56 (d, 2H, CH2), 2.96 (d, 2H,
CH2), 3.85 (s, 1H, CH), 4.72 (s, 1H, 5-CH), 6.62–6.67 (d, 2H,
ArH’s), 6.72–6.95 (d, 2H, ArH’s), 8.87–9.58 (br.s, 3H, NH).
General procedure for the synthesis of substituted dipyr-
imido[4,5-b;40,50-f] [1,8]naphthyridines 10a–10d and 11a–
11d. A mixture of 7 (10 mmoles) and thiourea/urea (10
mmoles) in DMF (20 mL) was melted and refluxed for 5–6 h.
The reaction was left to cool at room temperature and then
poured into ice-cold water with stirring. The solid products so
formed, 10 and 11, respectively, were collected by filtration
and crystallized from ethanol as light brown crystals.
3328–3484 (3NH)cmꢀ1 1H NMR (CDCl3): d 1.57 (s, 1H,
;
CH), 2.47 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.74 (s, 3H,
OCH3), 4.71 (s, 1H, 15-CH), 6.64–6.67 (d, 2H, ArH’s), 6.74–
6.95 (d, 2H, ArH’s), 7.13–7.35 (m, 4H, ArH’s), 8.88–9.76
(br.s, 3H, NH). 13C NMR (CDCl3): 16.1, 16.5, 24.7, 26.2,
28.3, 56.0, 79.7, 95.0, 114.0, 123.3, 128.3, 129.6, 130.3, 142.5,
143.0, 145.2, 151.5, 159.1, 164.1, 164.6.
7,8-Dimethyl-15-(3,4-methylenedioxyphenyl)-2,3,4,5,7a,15-
hexahydro-1H-pyrimido[50,40: 6,7] [1,8]naphthyridino[4,3-
b][1,5]benzodiazepine-1,3-dione (12d). It was obtained from
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Facile and One Pot Synthetic Routes for Various Novel, Differently Fused
and Promising Heteropolycycles
347
7d. IR(KBr,t,cmꢀ1): 1640, 1695 (C¼¼O), 1605 (C. . ...C of aro-
matic ring), 2850 (CAH, aliphatic), 3048 (CAH, aromatic ),
products so formed, 15 were collected by filtration and crystal-
lized from ethanol.
3333–3485 (3NH) cmꢀ1
;
1H NMR (CDCl3): d 1.52 (s, 1H,
6,7-Dimethyl-14-(4-methoxyphenyl)-11,12,13,14-tetrahydro-
10H-pyrido[20,10:2,3] pyrimido[4,5-f]pyrimido[4,5-b][1,8]naph-
thyridine-11,13-dione (15a). It was obtained from 7a.
IR(KBr,t,cmꢀ1): 1595 (C. . ...C of aromatic ring), 1675, 1695
(C¼¼O), 2923 (CAH, aliphatic), 3059 (CAH, aromatic ),
CH), 2.47 (s, 3H, CH3), 2.84 (s, 3H, CH3), 4.74 (s, 1H, 15-
CH), 5.76 (s, 2H, O2CH2), 6.68–6.72 (m, 3H, ArH’s), 7.13–
7.32 (m, 4H, ArH’s), 8.86–9.78 (br.s, 3H, NH).
General procedure for the synthesis of substituted
pyrimido[50,40:6,7] [1,8]naphthyridino[4,3,2-de]quinazolines
13a–13d and 14a–14d. A mixture of 8 (10 mmoles) and thio-
urea/urea (10 mmoles) in DMF (20 mL) was refluxed for 5–6
h. The reaction was left to cool at room temperature and then
poured into ice-cold water with stirring. The solid products 13
and 14, respectively, so formed were collected by filtration
and crystallized from ethanol as light brown crystal.
3329–3481 (2NH) cmꢀ1 1H NMR (CDCl3): d 2.32 (s, 3H,
;
CH3), 2.71 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.45 (s, 1H, 14-
CH), 6.47–6.62 (m, 4H, ArH’s), 6.64–6.67 (d, 2H, ArH’s),
6.74–6.95 (d, 2H, ArH’s), 8.88–9.78 (br.s, 2H, NH). 13C NMR
(CDCl3): 26.9, 27.7, 48.1, 48.8, 56.6, 81.7, 115.0, 115.8,
116.7, 120.6, 122.4, 130.1, 144.6, 147.5, 151.3, 155.6, 157.0,
157.2, 159.1, 161.6, 164.4, 168.9.
5,5-Dimethyl-13-(4-methoxyphenyl)-2-thioxo-4,5,6,8,9,10,
11,12,13,13c-decahydro-2H-pyrimido[50,40:6,7][1,8]naphthyridino
[4,3,2-de]quinazoline-10,12-dione (13a). It was obtained from
8a using thiourea. IR(KBr,t,cmꢀ1): 1605 (C. . ...C of aromatic
ring), 1672, 1685 (C¼¼O), 2925 (CAH, aliphatic), 3052 (CAH,
6,7-Dimethyl-14-(4-methylphenyl)-11,12,13,14-tetrahydro-
10H-pyrido[20,10:2,3]pyrimido [4,5-f]pyrimido[4,5-b][1,8]naph-
thyridine-11,13-dione (15c). It was obtained from 7c.
IR(KBr,t,cmꢀ1): 1590 (C. . ...C of aromatic ring), 1670, 1695
(C¼¼O), 2926 (CAH, aliphatic), 3054 (CAH, aromatic ),
1
aromatic ), 3334–3485 (3NH)cmꢀ1; H NMR (CDCl3): d 1.11
3333–3480 (2NH)cmꢀ1 1H NMR (CDCl3): d 2.22 (s, 3H,
;
(s, 6H, 2CH3), 2.48 (s, 2H, CH2), 2.81 (s, 2H, CH2), 2.86 (s,
1H, CH), 3.74 (s, 3H, OCH3), 4.74 (s, 1H, 13-CH), 6.64–6.67
(d, 2H, ArH’s), 6.74–6.96 (d, 2H, ArH’s), 8.75–9.87 (br.s, 3H,
NH).
CH3), 2.29 (s, 3H, CH3), 2.72 (s, 3H, CH3), 4.74 (s, 1H, 14-
CH), 6.39–6.62 (m, 4H, ArH’s), 6.65–6.67 (d, 2H, ArH’s),
6.80–6.95 (d, 2H, ArH’s), 8.96–9.74 (br.s, 2H, NH). 13C NMR
(CDCl3): 16.2, 18.2, 20.9, 96.5, 100.4, 106.9, 116.8, 121.6,
126.7, 128.5, 129.0, 129.4, 134.7, 137.5, 140.3, 141.6, 149.5,
151.5, 159.1, 164.0, 164.6.
General procedure for the synthesis of substituted
pyrimido[50,40:6,7] [1,8]naphthyridino[4,3,2-de]pyrido[2,1-
b]quinazoline-10,12-diones 16a–16d. A mixture of 8 (10
mmoles) and 2-aminopyridine (10 mmoles) in DMF (20 mL)
was refluxed for 8–10 h. The reaction was left to cool at room
temperature and then poured into ice-cold water with stirring.
The solid products 16 so formed were collected by filtration
and crystallized from ethanol.
5,5-Dimethyl-13-(4-methylphenyl)-2-thioxo-4,5,6,8,9,10,11,12,
13,13c-decahydro-2H-pyrimido[50,40:6,7][1,8]naphthyridino[4,3,2-
de]quinazoline-10,12-dione (13c). It was obtained from 8c using
thiourea. IR(KBr,t,cmꢀ1): 1598 (C. . ...C of aromatic ring),
1645–1680 (C¼¼O), 2928 (CAH, aliphatic), 3047 (CAH, aro-
1
matic ), 3336–3483 (3NH) cmꢀ1; H NMR (CDCl3): d 1.11 (s,
6H, 2CH3), 2.34 (s, 3H, CH3), 2.48 (s, 2H, CH2), 2.81 (s, 2H,
CH2), 2.86 (s, 1H, CH), 4.74 (s, 1H, 13-CH), 6.67–6.68 (d,
2H, ArH’s), 6.74–6.98 (d, 2H, ArH’s), 8.79–9.88 (br.s, 3H,
NH). 13C NMR (CDCl3): 19.6, 20.9, 27.1, 27.9, 45.1, 45.9,
79.7, 94.8, 128.6, 129.4, 134.7, 141.8, 145.2, 151.6, 164.4,
164.9, 235.8.
7,7-Dimethyl-15-(4-methoxyphenyl)-6,7,8,11,12,13,14,15-octahy-
dropyrimido[50,40:6,7][1,8]naphthyridino[4,3,2-de]pyrido[[2,1-
b]quinazoline-12,14-dione (16a). It was obtained from 8a.
IR(KBr,t,cmꢀ1): 1595 (C. . ...C of aromatic ring), 1665, 1685
(C¼¼O), 2927 (CAH, aliphatic), 3058 (CAH, aromatic ),
5,5-Dimethyl-13-(3,4-dimethoxyphenyl)-4,5,6,8,9,10,11,12,
13,13c-decahydro-2H-pyrimido[50,40:6,7] [1,8]naphthyridino[4,3,2-
de]quinazoline-2,10,12-trione (14b). It was obtained from 8b
using urea. IR(KBr,t,cmꢀ1): 1595, 1638, 1658 (C¼¼O), 1605
(C. . ...C of aromatic ring), 2850 (CAH, aliphatic), 3044 (CAH,
3336–3487 (2NH) cmꢀ1 1H NMR (CDCl3): d 1.11 (s, 6H,
;
2CH3), 2.48 (s, 2H, CH2), 2.81 (s, 2H, CH2), 3.42 (s, 3H,
OCH3), 4.74 (s, 1H, 15-CH), 6.47–6.62 (m, 4H, ArH’s), 6.64–
6.67 (d, 2H, ArH’s), 6.74–6.96 (d, 2H, ArH’s), 8.75–9.87
(br.s, 2H, NH).
1
aromatic ), 3330–3486 (3NH)cmꢀ1; H NMR (CDCl3): d 1.11
(s, 6H, 2CH3), 2.27 (s, 2H, CH2), 2.43 (s, 2H, CH2), 2.88 (s,
1H, CH), 3.74 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.75 (s,
1H, 13-CH), 6.87–6.96 (m, 3H, ArH’s), 8.78–9.76 (br.s, 3H,
NH).
7,7-Dimethyl-15-(3,4-methylenedioxyphenyl)-6,7,8,11,12,13,14,
15-octahydropyrimido [50,40:6,7][1,8]naphthyridino[4,3,2-de]pyr-
ido[[2,1-b]quinazoline-12,14-dione (16d). It was obtained from
8d. IR(KBr,t,cmꢀ1): 1595 (C. . ...C of aromatic ring), 1638,
1680 (C¼¼O), 2890 (CAH, aliphatic), 3049 (CAH, aromatic ),
5,5-Dimethyl-13-(3,4-methylenedioxyphenyl)-4,5,6,8,9,10,11,12,
13,13c-decahydro-2H-pyrimido[50,40:6,7][1,8]naphthyridino[4,3,2-
de]quinazoline-2,10,12-trione (14d). It was obtained from 8d
using urea. IR(KBr,t,cmꢀ1): 1595, 1635, 1648 (C¼¼O), 1605
(C. . ...C of aromatic ring), 2850 (CAH, aliphatic), 3333–3484
3333–3485 (2NH)cmꢀ1 1H NMR (CDCl3): d 1.11 (s, 6H,
;
2CH3), 1.88 (s, 2H, CH2), 2.12 (s, 2H, CH2), 4.74 (s, 1H, 15-
CH), 5.87 (s, 2H, O2CH2), 6.17–6.59 (m, 3H, ArH’s), 6.49–
6.62 (m, 4H, ArH’s), 8.97–9.79 (br.s, 2H, NH). 13C NMR
(CDCl3): 21.1, 27.1, 45.6, 47.8, 91.3, 100.4, 106.9, 115.0,
115.8, 116.9, 120.1, 122.7, 126.6, 131.4, 138.5, 140.2, 143.1,
144.6, 147.5, 149.6, 151.5, 161.2, 163.6, 164.0, 164.8.
General procedure for the synthesis of substituted pyr-
ido[2,3-d;6,5-d0]dipyrimidine-2,4,6-triones 17a–17d. A mix-
ture of equimolar quantity of 4 (0.01 moles) and formamide
(0.01 moles) was refluxed on a water bath for 6 h. After the
completion of the reaction, the reaction mixture was poured into
1
(3NH) cmꢀ1; H NMR (CDCl3): d 1.11 (s, 6H, 2CH3), 2.23 (s,
2H, CH2), 2.53 (s, 2H, CH2), 2.86 (s, 1H, CH), 4.74 (s, 1H,
13-CH), 5.74 (s, 2H, O2CH2), 6.68–6.82 (m, 3H, ArH’s),
8.81–9.82 (br.s, 3H, NH).
General procedure for the synthesis of substituted pyri-
do[20,10:2,3]pyrimido[4,5-f] pyrimido[4,5-b][1,8]naphthyri-
dine-11,13-diones 15a–15d. A mixture of 7 (10 mmoles) and
2-aminopyridine (10 mmoles) in DMF (20 mL) was refluxed
for 8–10 h. The reaction was left to cool at room temperature
and then poured into ice-cold water with stirring. The solid
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

348
S. Gupta, P. Gupta, A. Sachar, and R. L. Sharma
Vol 47
ice-cold water with stirring. The solid product was collected by
filtration and crystallized from hot methanol to afford 17.
5-(4-methoxyphenyl)-1,2,3,4,5,6,7,10-octahydropyrido[2,3-
d;6,5-d0]dipyrimidine-2,4,6-trione (17a). It was obtained
from 4a. 1H NMR (CDCl3): d 3.73 (s, 3H, OCH3), 4.74 (s,
1H, 5-CH), 6.63–6.65 (d, 2H, ArH’s), 6.85–6.95 (d, 2H,
ArH’s), 7.48 (s, 1H, CH), 8.50–11.95 (br.s, 4H, NH). 13C
NMR (CDCl3): 39.1, 55.9, 79.7, 100.9, 114.2, 114.9, 129.1,
130.1, 134.5, 150.1, 150.5, 151.2, 157.0, 157.7, 162.5, 163.8.
General procedure for the synthesis of substituted dipyr-
imido[4,5-b:50,40-g] [1,8]naphthyridine-2,4,6-trione 18a–
18d. A mixture of equimolar quantity of 5 (0.01 moles) and
formamide (0.01 moles) was refluxed on a water bath for 6 h.
After the completion of the reaction, the reaction mixture was
poured into ice-cold water. The solid product was collected by
filtration and crystallized from hot methanol to produce 18. On
the other hand, a mixture of 5 and formamide (1:2 ratios) was
refluxed on a water bath for 6–8 h. After the completion of the
reaction, the reaction mixture was poured into the ice-cold
water. The solid product was collected by filtration and crys-
tallized from hot methanol to produce 19 as the main product.
From the mother liquor a minor product was also separated on
cooling which was exactly identical with 18.
7-Amino-15-(4-methoxyphenyl)-2,3,4,5,7a,8,9,15-octahydro-
1H-pyrimido[50,40:6,7][1,8] naphthyridino[4,3-b[1,5]benzodia-
zepine-1,3,8-trione (21a). It was obtained from 6a. 1H
NMR(CDCl3): d 1.59 (s, 1H, 7a-CH), 3.74 (s, 3H, OCH3), 3.89 (s,
2H, NH2), 4.72 (s, 1H, 15-CH), 6.64–6.67 (d, 2H, ArH’s), 6.74–
6.95 (d, 2H, ArH’s), 7.23–7.58 (m, 4H, ArH’s), 8.85–11.90 (br.s,
4H, NH). 13C NMR (CDCl3) : 37.5, 39.2, 55.9, 79.5, 93.0, 114.8,
114.1, 122.5, 122.9, 125.6, 127.4, 130.1, 130.6, 132.5, 134.7, 142.6,
150.4, 151.2, 151.6, 157.7, 163.8, 164.0, 164.8, 168.2.
General procedure for the synthesis of substituted dipyr-
imido[4,5-b;40,50-f] [1,8]naphthyridines 22a–22d and substi-
tuted dipyrimido[4,5-b;50,40-g] [1,8]naphthyridines 23a–
23d. A mixture of 6 (10 mmoles) and thiourea (10 mmoles) in
DMF (20 mL) was refluxed for 5–6 h. The reaction was left to
cool at room temperature and then poured into ice-cold water
with stirring. The solid product so formed, a mixture of 22 and
23 was collected by filtration and separated by column chro-
matography (eluant:Pet ether:Methanol::90:10; Pet ether:
Methanol::85:15).
5-Amino-12-(3,4-dimethoxyphenyl)-2-thioxo-2,3,4,4a,7,8,9,10,
11,12-decahydro dipyrimido[4,5-b; 40,50-f][1,8]naphthyridine-
4,9,11-trione (22b). It was obtained from 6a using thiourea.
IR(KBr,t,cmꢀ1): 1625 (C. . ...C of aromatic ring), 1660, 1670,
1675 (C¼¼O), 2890 (CAH, aliphatic), 3049 (CAH, aromatic ),
7-Amino-5-(3,4-dimethoxyphenyl)-1,2,3,4,5,6,11,12-octahy-
drodipyrimido[4,5-b;50,40-g] [1,8]naphthyridine-2,4,6-trione
1
3235 (NH2), 3330–3400 (4NH)cmꢀ1; H NMR(CDCl3): d 2.26
1
(18b). It was obtained from 5b. H NMR (CDCl3): d 3.72 (s,
(s, 1H, 4a-CH), 3.71 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.85
(s, 2H, NH2), 4.74 (s, 1H, 12-CH), 6.67–6.72 (m, 3H, ArH’s),
8.85–11.92 (br.s, 4H, NH). 13C NMR (CDCl3): 36.5, 38.9,
55.6, 79.6, 93.2, 114.2, 114.8, 130.1, 130.6, 134.5, 150.6,
151.0, 151.8, 157.6, 159.8, 163.8, 164.0, 164.8, 170.7. MS: m/
z, 467 (Mþ).
3H, OCH3), 3.78 (s, 3H, OCH3), 4.74 (s, 1H, 5-CH), 5.92 (s,
2H, NH2), 6.52–6.58 (m, 3H, ArH’s), 7.85 (s, 1H, CH), 8.85–
11.92 (br.s, 4H, NH). 13C NMR (CDCl3): 36.5, 56.2, 56.8,
79.5, 85.6, 99.3, 114.5, 115.2, 122.6, 135.5, 146.7, 150.2,
150.9, 151.5, 154.5, 155.9, 163.8, 172.6, 183.5.
13-(3,4-Methylenedioxyphenyl)-8,9,10,11,12,13-hexahydro-
3H-1,3,4,6,7,8,9,11-octaza- benzo[de]naphthacene-10,12-dio-
nes (19d). It was obtained from 5d. H NMR (CDCl3): d 4.72
(s, 1H, 13-CH), 5.82 (s, 2H, O2CH2), 6.48–6.59 (m, 3H,
ArH’s), 7.50 (s, 1H, 5-CH), 8.37 (s, 1H, 2-CH), 8.71–11.92
(br.s, 4H, NH). 13C NMR (CDCl3): 32.8, 81.7, 100.2, 101.4,
111.4, 114.1, 115.2, 122.4, 128.4, 145.8, 146.3, 148.7, 150.5,
155.2, 155.9, 156.0, 156.9, 158.0, 158.7, 163.8.
5-(4-Methoxyphenyl)-9-thioxo-1,2,3,4,5,6,6a,7,8,9,10,12-
dodecahydrodipyrimido[4,5-b; 50,40-g][1,8]naphthyridine-
2,4,6,7-tetraone (23a). It was obtained from 6a using thiou-
rea. IR(KBr,t,cmꢀ1): 1605 (C. . ...C of aromatic ring), 1657,
1665, 1678, 1715 (C¼¼O), 2895 (CAH, aliphatic), 3042 (CAH,
1
aromatic ), 3330–3470 (5NH)cmꢀ1 1H NMR(CDCl3): d 3.92
;
(s, 1H, 6a-CH), 4.43 (s, 1H, 5-CH), 6.63–6.67 (d, 2H, ArH’s),
6.85–6.95 (d, 2H, ArH’s), 8.69–11.92 (br.s, 5H, NH). 13C
NMR (CDCl3): 36.5, 55.8, 56.9, 79.5, 107.5, 114.2, 114.8,
130.0, 131.6, 134.5, 150.5, 151.2, 152.9, 155.8, 157.6, 163.8,
164.2, 170.7, 196.5. MS: m/z, 438 (Mþ).
General procedure for the synthesis of substituted dipyr-
imido[4,5-b:50,40-g] [1,8]naphthyridines 20a–20d. A mixture
of equimolar quantity of 6 (0.01 moles) and formamide (0.01
moles) was refluxed on a water bath for 6 h. After the comple-
tion of the reaction, the reaction mixture was poured into ice-
cold water with stirring. The solid product was collected by fil-
tration and crystallized from hot methanol to produce 20.
5-(4-Methoxyphenyl)-1,2,3,4,5,6,6a,7,8,12-decahydrodipyri-
mido[4,5-b;50,40-g][1,8]naphthyridine-2,4,6,7-tetraone (20b). It
was obtained from 6b. 1H NMR (CDCl3): d 3.78 (s, 3H,
OCH3), 3.98 (s, 1H, 6a-CH), 4.48 (s, 1H, 5-CH), 6.63–6.65 (d,
2H, ArH’s), 6.85–6.95 (d, 2H, ArH’s), 7.89 (s, 1H, 9-CH),
8.59–11.72 (br.s, 4H, NH). 13C NMR (CDCl3): 36.5, 55.1,
55.9, 79.5, 107.5, 114.2, 114.8, 130.0, 130.6, 134.5, 150.2,
150.5, 150.9, 155.9, 157.8, 163.8, 164.2, 170.5, 196.5.
General procedure for the synthesis of substituted
pyrimido[50,40:6,7] [1,8]naphthyridino[4,3-b][1,5]benzodia-
zepine-1,3,8-triones 21a–21d. A mixture of 6 (10 mmoles)
and o-phenylenediamine (10 mmoles) in DMF (20mL) was
refluxed for 8–10 h. The reaction was left to cool at room tem-
perature and then poured into ice-cold water with stirring. The
solid product 21 so formed was collected by filtration and
crystallized from ethanol.
Acknowledgment. The authors are thankful to the Department
of Chemistry, University of Jammu, Jammu, and IIIM, Jammu,
for providing research, instrumentation, and library facilities.
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