Synthesis of novel and biologically potent heteropolycyclics containing bridge head nitrogen

Article abstract of DOI:10.1002/jhet.465

(Chemical Equation Presented) A facile one pot synthesis of 2,3,4,5-tetrahydropyrido [1,2-a] [1,3] diazepine-2,5-dione 2 and 3,4-dihydro-2H-pyrido [1,2-a] pyrimidine-2,4-dione 3 has been achieved. Condensation of 3 with o-aminobenzaldehydes produced the l

Full text of DOI:10.1002/jhet.465

1188
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
Vol 47
Poonam Gupta, Shallu Gupta, Anand Sachar, and R. L. Sharma*
Department of Chemistry, University of Jammu, Jammu 180006, India
*E-mail: rlsharma_hod@rediffmail.com
Received July 3, 2009
DOI 10.1002/jhet.465
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A facile one pot synthesis of 2,3,4,5-tetrahydropyrido [1,2-a] [1,3] diazepine-2,5-dione 2 and 3,4-
dihydro-2H-pyrido [1,2-a] pyrimidine-2,4-dione 3 has been achieved. Condensation of 3 with o-amino-
benzaldehydes produced the linear product 4 and not the angular one 5. Cyclocondensation of 3 with
1,5-diketones afforded a tricyclic linear system 6, a bis assembly system 7 and two novel heterotetracy-
clic nitrogen bridged linear systems 8 and 10. Condensation of o-aminobenzaldehydes with 2 produced
a novel linear system 12 and a new doubly fused hexacyclic system 11. Cyclodehydration of 2 with
1,2-dicarbaldehydes produced 1, 13, and a new heterotetracyclic nitrogen bridged system 14. Condensa-
tion of 3 with aromatic aldehydes in presence of ethylene glycol as solvent without the use of catalyst
generated the doubly nitrogen bridged linear pentacyclic systems 15–17. The synthesized compounds
have been adequately characterized and screened for bronchodilatory and antimicrobial activities with
promising results.
J. Heterocyclic Chem., 47, 1188 (2010).
INTRODUCTION
anti-HIV properties [6,7], anthelmintic [8], antiparkinso-
nium [9], antitubercular [10], hypoglycemic [11], antivi-
ral [12], anticoagulant [13], antifibrillatory [14], cardiac
stimulant [15], CNS depressant [16], neuroleptic [17],
and hypnotic [18]. Vasicine and vasicinone, the two
known alkaloids and a synthetic compound 7,8,9,10-tet-
rahydroazepino [2,1-b] quinazolin-12(6H)-one (RLX) all
bearing quinazoline moiety have been evaluated as
potent bronchodilatory and oxytocic agents [19–22]. The
latter compound has been found to be six times more
potent than aminophylline [23].
Diazepines and benzodiazepines are known to exhibit
a wide variety of biological activities such as anticon-
vulsant, antianxiety, analgesic, sedative, antidepressive,
and hypnotic activity [1–3]. Some of the benzodiazepine
derivatives particularly 7-(p-methoxyphenyl)-8-phenoxy-
1, 5-benzo-3-azanonem (1,5-BDZ-OMe) and 7-phenyl-8-
phenoxy-1,5-benzo-3-azanonem (1,5-BDZ-H) possess
hypnotic activity [4]. Pyrrolo [2,1-c] [1,4] benzodiaze-
pines such as anthramycin and DC-81 are well-known
antitumor antibiotics (PBDS) derived from streptomyces
species [5].
Quinoline and its derivatives are known for their anti-
malarial and therapeutic properties. A number of quino-
line derivatives are known to possess antitumour, anti-
bacterial, antifungal, hypotensive, anti-HIV, analgesic,
Compounds possessing quinazoline and quinazolinone
nuclei show potent biological activities including bron-
chodilatory, anticancer, anticonvulsant, antibacterial,
C
V
2010 HeteroCorporation

September 2010
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
1189
Scheme 1
anti-Leishmanial, and anti-inflammatory activities [24].
In addition, the synthesis of pyrido [1,2-a] pyrimidin-4-
ones provided a wide spectrum of biological activities
[25–31] such as tranquilizer, antiallergic, antiulcerative,
antiasthmetic and bronchodilatory activity, analgesic ac-
tivity, and human platelet aggregation inhibitory proper-
ties. Biologically active evaluations of these constituent
moieties in the recent years encouraged us to generate
the novel condensed heteropolycyclic systems contain-
ing bridge head nitrogen atom, most of them hitherto
unknown in literature and comprising of one or more
than one of these moieties. Such novel systems might
expectedly prove to be the potent therapeutic agents in
near future.
this study. Presence of peculiar bands between 1590 to
1600 cmꢀ1 and 1675 to 1710 cmꢀ1 in IR spectra of
compounds 1 and 2 favored the presence of C¼¼N and
CON< (tertiary amide) functionalities. Presence of sig-
nal of aromatic protons only for compound 1, a down-
field multiplet due to two methylene groups around d
2.35 to 2.43 ppm for compound 2, and the absence of
any D2O exchangable proton in H NMR spectra of ei-
ther of these two compounds confirmed the heterocycli-
sation and their structures unambigously.
1
The active methylene compound 3 was put to Knoe-
venagel condensation with some o-aminobenzaldehydes
followed by subsequent heterocyclodehydration afford-
ing a single product (4a–c) and in one case affording
the main product 4d associated with another very minor
product (TLC). The compounds 4a–d have been charac-
terized as 12H-pyrido [10,20:1,2] pyrimido [4,5-b] quino-
lin-12-ones belonging to a linear ‘‘ortho fused’’ system.
The minor product which could not be separated from
4d might be the angular product, 6H-pyrido [10, 20:1, 2]
pyrimido [4,5-b] quinolin-6-one 5d (Scheme 2). The lit-
erature report [35] regarding compound 4a confirmed its
structure by comparing m.p, analytical, and spectral data
of 4a of this study with that known in literature. The
appearance of peaks of methylenedioxy protons at d
6.10 ppm in 4c, two methoxyl group protons at d 3.70
and 3.75 ppm in compound 4b, and two methoxyl group
protons at d 3.72 and d 3.78 ppm for compound 4d in
1H NMR spectra confirmed their structures unequivo-
RESULTS AND DISCUSSION
In this work, 6H,11H-pyrido[1,2-b][2,4]benzodiaze-
pine-6,11-dione 1 and 2,3,4,5-tetrahydropyrido[1,2-a]
[1,3]diazepine-2,5-dione 2 were designed and generated
by the condensation of 2-aminopyridine with phthalic
acid and succinic acid, respectively, both in presence of
PCl5 in ethanol. An active methylene heterocycle, 3,4-
dihydro-2H-pyrido [1,2-a] pyrimidine-2,4-dione 3 was
produced by the condensation of 2-aminopyridine either
with malonic acid in presence of anhydrous P2O5 in
DMF or with diethyl malonate in the presence of PCl5/
POCl3 in DMF (Scheme 1). Compound 3 has been
known in literature, having been prepared through other
approaches [32–34]. Literature m.p, analytical data, and
spectral data confirmed the structure assigned to it in
1
cally. Other signals in H NMR spectra of 4b–d were
almost identical with those for compound 4a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1190
P. Gupta, S. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Scheme 2
Working on the similar route of synthesis, cyclocon-
annuleno [1,2-d] pyrido [1,2-a] pyrimidine-7,14-dione
10 were also generated from compound 3, the latter
through the intermediacy of 9 (Scheme 3).
Under slightly different conditions, a highly hybrid
quinoline-based doubly fused hexacyclic system,
tetrasubstituted pyrido[10,20:1,2]quino [300,200:6,7][1,3]
diazepino[4,5-b] quinoline 11 and a novel linear disub-
stituted system, pyrido[10,20:1,2] [1:3] diazepino[4,5-
densation of 3 with 1,5-dicarbonyl compounds like glu-
taraldehyde and heptane-2,6-dione in the mole ratio of
1:1 and 1:2 in presence of anhydrous K2CO3 was carried
producing two entirely different product systems, a quin-
azoline based linearly fused tricyclic system, 4-acyl-2,3-
dihydro-11H-pyrido[2,1-b]quinazolin-11-one 6a–b, and
a bis heterocyclic ring assembly system, 1,5-bis (2,4-
dioxo-3,4-dihyro-2H-pyrido [1,2-a] pyrimidin-3-ylidine)
pentane 7a–b, respectively, in each case. The compound
6a obtained from 1:1 condensation showed a character-
istic downfield singlet at d 9.96 ppm due to proton of
CHO at C-4, a downfield triplet at d 5.70 ppm due to
ethylenic proton at position 1, and a multiplet at d 1.7
to 1.85 ppm due to four methylenic protons besides four
b]quinolin-12(13H)-one 12 were generated from
2
whose characterization was done as usual (details in ex-
perimental part). Again, cyclodehydration of 2 with mal-
ealdehyde and succinaldehyde produced 1 and its dihy-
dro analogue 13, respectively, and the condensation
between 2 and phthalaldehyde produced a new heterote-
tracyclic system 6H,13H-pyrido[1,2-a]naphtho[2,3-e]
[1,3] diazepine-6,13-dione 14 (Scheme 4).
1
aromatic protons as multiplet in its H NMR spectrum.
The compound 6b had two prominent singlets of three
protons each at d 2.43 and 2.15 ppm due to COCH3 and
CH3 protons, respectively. The appearance of a multiplet
due to six protons of three methylene groups and a tri-
plet due to two ethylenic protons in the acyclic portion
confirmed unequivocally the structure of 7a. Similarly,
6-aceto-12H-11-methylbenzo [g] pyrido[2,1-b]quinazo-
lin-12-one 8 and 12H,14H-13-methylbenzo [5,6] [8]
In extension of our earlier work [36,37], it was
thought worthwhile to study the condensation of active
methylene compound 3 with aromatic aldehydes in eth-
ylene glycol as solvent without the use of catalyst.
Knoevenagel condensation, Michael addition, and cyclo-
dehydration took place simulataneously resulting in
the formation of a novel linear and heteropentacyclic
system 16 containing
a central pyran ring. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
1191
Scheme 3
intermediates could not be isolated but the second inter-
mediate after the two transformations seemed to be more
interesting for exploitation in the ring closure heterocycl-
ising reaction. Hence, compound 3 was treated with dif-
ferent aromatic aldehydes in ethylene glycol producing
compound 16 and refluxed in DMF in presence of am-
monium acetate, P2O5 and P2S5 giving similar results in
each case producing three novel linear heteropentacyclic
systems 15, 16, and 17 with pyridine, pyran, and thio-
pyran central ring, respectively (Scheme 5). The charac-
terization has been made for these systems on the basis
of elemental analysis and spectral studies. The present
exposition has twofold importance, firstly the study of
the versatility and reactions of compound 3 and 2 with
different aldehydes under different conditions resulting
in generation of various novel-fused heterocyclic sys-
tems most of which are hitherto unknown in literature
and secondly the study of physiological nature of these
systems.
Pharmacology. On preliminary pharmacological
investigations, the compounds 4a–d, 6a–b, 8, 11a–b,
and 12a–b have been found to be promising bronchodi-
latory and oxytocic agents having activities comparable
to those of alkaloid vasicine and its natural and syn-
thetic analogues. The detailed study of the evaluation of
these biological activities is under active exploration
from our research laboratory. The drugs employed in
this study are 7,8,9,10-tetrahydroazepino [2,1-b] quina-
zolin-12(6H)-one; Aminophyllin injection I.P (Bur-
roughs Welcome
&
Co.); Histamine diphosphate
(Sigma); Adrenaline tartarate (IP); Propanolol HCl
(ICI); 5-hydroxytryptamine; and Egg albumin (BDH).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1192
P. Gupta, S. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Scheme 4
The comparative SAR of various compounds [38] and
the results of other details regarding these activities are
being currently determined. The compounds 4a–d, 6a–
b, 8, 11a–b, and 12a have been found to be weakly to
moderately active antimicrobial agents. Compounds 4a–
d, 6a–b, 11a–b, and 12a have been found to be highly
promising, as regards ‘‘Tracheal smooth muscle activ-
ity’’ and ‘‘Antitussive activity.’’
Broncodilatory activity
Tracheal smooth muscle activity. Preparation of tissue
was similar to that described by Castillow and de Beer
[39] except that the tracheal ring was opened by severing
the cartilage. Guineapigs (350–500 g) of either sex were
sacrificed by a blow to the head and the tracheae rapidly
excised. The tracheal chain was prepared and suspended
in a 20 mL tissue bath containing Krebs-henselet solution
(KHS) continuously aerated with 95% O2 and 5% CO2
and maintained at 37ꢁ. The composition (mM) of (KHS)
was NaCl 118, KCl 4.7, MgSO4ꢂ7H2O 1.2, CaCl2 2.2,
KH2PO4 1.2, NaHCO3 24.9, and (þ)-glucose 11.1. The
responses were recorded isotonically on a kymograph.
The tissue was adjusted to an initial tension of 1.5 g and
allowed to equilibrate (60–90) min. Relaxation effect of
the drug was studied on tracheal chain precontracted with
histamine diphosphate (1 ꢃ 10ꢀ6 g/mL) or acetylcholine
chloride (1 ꢃ 10ꢀ6 g/mL). The test drugs were added 8
min after the tonic contraction reached plateau. The
responses were calculated as percent to relaxing of
Antimicrobial activity. The compounds 3, 7a–b,
15a–d, and 4a–d have been screened for their antifungal
activity against Aspergillus, Penicillium, and Cladospo-
rium species. For antibacterial activity, these compounds
have been screened against E.coli, Bacillus subtilis, and
Bacillus cereus. Both the activities were evaluated at the
same concentration of 1000 lg and through well diffu-
sion technique. The standard antifungal agent flucona-
zole and the antibacterial agent norfloxacin were also
screened under similar conditions for a comparative
study. The inhibition zones formed were measured in
mm and are listed in (Table 1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
1193
Scheme 5
Antitussive activity. Kobayshi’s [40] method was used
in this study. Guineapigs (300–400 g) were aneasthe-
tised by I/P urethane (6.5 mL/kg; 25%) and fixed in
precontracted muscle back to base line tension (10%
relaxation). If there was relaxation to muscle slightly
below the base line, it was also taken as 100% relaxation.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1194
P. Gupta, S. Gupta, A. Sachar, and R. L. Sharma
Vol 47
Table 1
Antimicrobial activity of compounds 3, 7a–b, 15a–d, and 4a–d.
Antibacterial activity
Antifungal activity
Compd. No
E. coli
B. subtilis
B. cereus
A. niger
P. species
C. species
3
7a
7b
15a
15b
15c
15d
4a
4b
4c
4d
NR
Flu
14
15
17
20
19
20
20
19
18
20
21
28
–
12
13
11
22
23
19
18
17
16
19
19
26
–
17
16
18
19
23
23
21
14
16
18
17
28
–
17
14
18
19
21
23
20
17
19
20
17
–
13
12
16
18
22
24
19
18
18
17
21
–
16
17
17
20
23
24
20
19
19
17
20
–
32
25
23
Note: 10 mm, inactive; 11–15 mm, weakly active; 16–22 mm, moderately active; 22–25 mm, highly active.
NR, norfloxacin; Flu, fluconazole.
EXPERIMENTAL
dorsal position. The trachea was exposed and a small
incision made at a distance of 1.5 cm from the clavi-
cle. A fine and very thin polythene tube was inserted
into the incision as deep as 3 cm to give the stimulus.
The stimulus was applied two times before and 15, 30,
45, 60, 90 and 120 min after the drug administration
by oral route. If no coughing occurred in two or more
out of five trails after drug administration, the drug
was estimated as effective percent inhibition was
recorded. Results are shown in (Table 2) as follows:
General. Melting points were measured in open capillaries
on perfit melting point apparatus and are uncorrected. IR spec-
tra on KBr were recorded on Brucker—4800 infrared spec-
trometer. NMR and EIMS/HRMS spectra were recorded on
Brucker AC-400 (400 MHz and 100 MHz) and JEOL D-300
mass spectrometer, respectively. Elemental analysis was car-
ried out on simple CHNS analyzer (CHNS-932, LECO Corpo-
ration, USA). H and 13C chemical shifts are reported in parts
per million (ppm) from tetramethylsilane (TMS) as internal
standard. All experiments were performed in oven dried glass
1
Table 2
Bronchodilatory and antitussive activitiesa of compounds 4a–d, 6a–b, 8, 11a–b, and 12a–b.
In vitro guinea pig trachea % relaxation
Antitussive activity (guinea pig)
Compd.
Histamine
Acetylcholine
Concn (l/mL)
% cough inhibition
Dose (mg/kg)
4a
4b
4c
60
80
–
70
–
30
9
–
80b
10
10
10
60–80
70–90
90
40–50
70–80
80–90
–
80–85
60
80–15
40–50
50–60
40–50
60b
20
40
40
9
80b
80b
4d
6a
6b
8
11a
1b
12a
80
80
100b
100c
80c
10
10
10
10
10
10
10
2
–
80
70
30
30
40
30
60c
40–50
50–60
40–50
100d
100d
100e
40–80e
100e
Bromhexine hydrochloride
4
a Minimium of four experiments for each group.
b Onset of action after 45 min and duration of 3 h.
c Onset of action after 45 min and duration >3 h.
d Onset of action after 30 min and duration >3 h .
e Onset of action after 15 min and duration >3 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
1195
apparatus. SISCO silica was used as adsorbent for TLC
(0.5 mm thick plates) and TLC plates were eluted with 1:9
ratios of ethyl acetate and n-hexane. The column chromatogra-
phy was performed over silica gel (60–120 mesh) with graded
solvent systems of ethyl acetate-pet ether (60–80).
67%; IR (KBr) m/cmꢀ1: 1320–1330 (CAN), 1590 (C¼¼N),
1692 (C¼¼O); MS: m/z ¼ 307 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 3.70 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
7.10–7.90 (m, 7H, ArHs); 13C NMR (50 MHz, CDCl3): d
(ppm) ¼ 56.0, 56.3, 110.1, 120.3, 121.4, 122.7, 123.6, 128.9,
130.1, 140.2, 145.7, 158.2, 159.4, 164.3, 165.6, 169.8, 189.0.
Anal. Calcd. for C17H13N3O3: C, 66.44; H, 4.2; N, 13.6.
Found: C, 66.41; H, 4.0; N, 13.8.
12H-[1,3]Dioxolo[4,5-g]pyrido[10,20:1,2]pyrimido[4,5-b]qui-
nolin-12-one (4c). It was obtained from 6-aminopiperonal
(1.65 g, 0.01 mole) and 3 (1.62 g, 0.01 mole); m.p. 190–
192ꢁC; yield 64%; IR (KBr) m/cmꢀ1: 1305–1320 (CAN), 1620
(C¼¼N), 1690 (C¼¼O); MS: m/z ¼ 291 (Mþ); 1H NMR (200
MHz, CDCl3): d(ppm) ¼ 6.10 (s, 2H, CH2O2), 7.20–7.92 (m,
7H, ArHs); 13C NMR (50 MHz, CDCl3) : d (ppm) ¼ 90.5,
108.0, 108.3, 110.1, 114.6, 120.2, 124.1, 124.8, 136.6, 137.1,
140.2, 151.2, 155.3, 162.3, 163.5, 165.4. Anal. Calcd. for
C16H9N3O3: C, 65.97; H, 3.0; N, 14.4. Found: C, 64.12; H,
2.9; N, 14.7.
12H-3,4-Dimethoxypyrido[10,20:1,2]pyrimido[4,5-b]quinolin-
12-one (4d). It was obtained from 2-aminoveratraldehyde
(1.81 g, 0.01 mole) and 3 (1.62 g, 0.01 mole); m.p. 242–
244ꢁC; yield 68%; IR (KBr) m/cmꢀ1: 1320–1330 (CAN), 1590
(C¼¼N), 1692 (C¼¼O); MS: m/z ¼ 307 (Mþ); 1H NMR (200
MHz, CDCl3): d(ppm) ¼ 3.71(s, 3H, OCH3), 3.75 (S, 3H,
OCH3), 6.92–7.90 (m, 7H, ArHs); 13C NMR (50 MHz,
CDCl3): d (ppm) ¼ 54.2, 54.3, 105.8, 110.5, 118.8, 120.2,
121.3, 122.5, 125.7, 130.8, 132.3, 135.6, 137.8, 140.5, 145.3,
162.5, 165.2. Anal. Calcd. for C17H13N3O3 : C, 66.44; H, 4.2;
N, 13.6. Found: C, 66.38; H, 4.16; N, 13.42.
General procedure for the synthesis of 6–9. Dissolved
(0.01/0.02 mole) of appropriate aldehyde or ketone in 40 mL
of hot rectified spirit, added a solution of 3,4-dihydro-2H-pyr-
ido [1,2-a] pyrimidine-2,4-dione (0.01 mole) 3 in 25 mL of
rectified spirit and added (0.02/0.04 mole) of anhydrous potas-
sium carbonate. Swirled to mix and set aside for 5–6 h. The
reaction mixture was finally refluxed for 3 h. Distilled off the
ethanol and added 100 mL of H2O. Filtered, washed the crys-
talline product first with water, and finally with a little cold
ethanol and recrystallized from about 100 mL of hot rectified
spirit to obtain the product 6–9.
3,11-Dihydro-2H-11-oxopyrido[2,1-b]quinazoline-4-carbal-
dehyde (6a). It was obtained from glutaraldehyde (1.00 g,
0.01 mole) and 3 (1.62 g, 0.01 mole); m.p. 80–82ꢁC; yield
62%; IR (KBr) m/cmꢀ1: 1305–1320 (CAN), 1610 (C¼¼N),
1695 (C¼¼O); MS: m/z ¼ 226 (Mþ); 1H NMR (200 MHz,
CDCl3): d(ppm) ¼ 1.7–1.85 (brs, 4H, 2ꢃCH2), 5.7 (s, 1H,
CH-1), 6.87–7.90 (m, 4H, ArHs), 9.96 (s, 1H, CHO); 13C
NMR (50 MHz, CDCl3): d (ppm) ¼ 22.3, 25.5, 110.8, 114.7,
120.3, 135.0, 135.2, 136.8, 138.9, 156.9, 160.2, 163.4, 189.3.
Anal. Calcd. for C13H10N2O2: C, 69.04; H, 4.42; N, 12.38.
Found: C, 68.05; H, 4.37; N, 12.42.
4-Aceto-3,11-dihydro-2H-1-methyl pyrido [2,1-b]quinazo-
lin-11-one (6b). It was obtained from heptane-2,6-dione (1.28
g, 0.01 mole) and 3 (1.62 g, 0.01 mole); m.p. 88–90ꢁC; yield
66%; IR (KBr) m/cmꢀ1: 1305–1320 (CAN), 1615 (C¼¼N),
1690 (C¼¼O); MS: m/z ¼ 254 (Mþ); 1H NMR (200 MHz,
CDCl3): d(ppm) ¼ 1.78–2.02 (brs, 4H, 2ꢃCH2), 2.15 (s, 3H,
CH3), 2.43 (s, 3H, COCH3), 6.92–7.23 (m, 4H, ArHs); 13C
NMR (50 MHz, CDCl3): d (ppm) ¼ 15.6, 20.7, 21.8, 31.7,
112.1, 115.6, 126.3, 128.2, 134.3, 136.1, 144.5, 147.1, 160.2,
General procedure for the synthesis of 1–3. A mixture of
2-aminopyridine (0.01 mole) and appropriate dibasic acid/ester
(0.01 mole) was initially grinded for about 20 min and then
fused or refluxed as such for about 1 h without any solvent in
a round bottom flask and finally refluxed on water bath in
presence of 15 mL of ethanol and PCl5 or at 150–160ꢁC in
presence of anhydrous POCl3/PCl5 in 20 mL of DMF or P2O5
in 20 mL of DMF. After the reaction time (TLC), the solvent
was evaporated under reduced pressure and 100 mL of H2O
was added. The precipitates obtained were filtered, dried, and
then crystallized from hot ethanol to generate pure 1–3.
6H,11H-Pyrido [1,2-b] [2,4]benzodiazepine-6,11-dione
(1). It was obtained from phthalic acid (8.30 g, 0.01 mole) and
2-aminopyridine (4.70 g, 0.01 mole) as colorless solid;
m.p.150–152ꢁC ; yield 78%; IR (KBr) m/cmꢀ1: 1320–1325
(CAN), 1600 (C¼¼N), 1610–1620 (C¼¼C), 1675 (C¼¼O); MS:
m/z ¼ 224 (Mþ); 1H NMR (200 MHz, CDCl3): d (ppm) ¼
7.01–7.81 (m, 8H, ArHs); 13C NMR (50 MHz, CDCl3): d
(ppm) ¼ 110.2, 114.0, 125.4, 126.8, 128.7, 130.4, 132.4,
133.7, 135.1, 136.1, 154.1, 158.9, 162.8. Anal. Calcd. for
C13H8N2O2: C, 69.6; H, 3.5; N, 12.5. Found: C, 68.9; H, 3.3;
N, 12.1.
2,3,4,5-Tetrahydrohyropyrido [1,2-a] [1,3] diazepine-2,5-
dione (2). It was obtained from succinic acid (5.90 g, 0.01
mole) and 2-aminopyridine (4.70 g, 0.01 mole); m.p. 102–
104ꢁC; yield 72%; IR (KBr) v/cmꢀ1: 1305–1320 (CAN), 1594
(C¼¼N), 1685–1710 (C¼¼O); MS: m/z ¼ 176 (Mþ); 1H NMR
(200 MHz, CDCl3): d(ppm) ¼ 2.35–2.43 (m, 4H, 2ꢃCH2),
7.2–7.6 (m, 4H, ArHs); 13C NMR (50 MHz, CDCl3): dppm) ¼
25.7, 31.2, 110.4, 115.5, 120.3, 124.5, 162.9, 165. 8, 180.7.
Anal. Calcd for C9H8N2O2: C, 61.3; H, 4.5; N, 15.9. Found:
C, 58.2; H, 4.4; N, 15.4.
3,4-Dihydro-2H-pyrido [1,2-a] pyrimidine-2,4-dione
(3). Crystallized from DMF, m.p. 301–303ꢁC, (literature m.p.
296–298ꢁC [32]; 295–298ꢁC [33]; 305–308ꢁC [34]).The
observed analytical and spectral data were found in complete
conformity with the literature values.
General procedure for the synthesis of 4. Dissolved (0.01
mole) of substituted o-aminobenzaldehyde in 40 mL of hot
rectified spirit and added to it a solution of 3,4-dihydro-2H-
pyrido[1,2-a]pyrimidine-2,4-dione (0.01 mole) 3 in 25 mL of
rectified spirit and 0.02 mole of fused anhydrous sodium ace-
tate. Swirled to mix and set aside for 5–6 h and finally
refluxed the mixture for an hour. Distilled off the ethanol and
added 100 mL of H2O. Filtered, washed, the crystalline prod-
uct with water twice and with a little cold ethanol and crystal-
lized from about 100 mL of hot rectified spirit to obtain the
pure and dry product 4.
12H-Pyrido[10,20:1,2]pyrimido[4,5-b]quinolin-12-one (4a). Cry-
stallized from butanone, m.p. 272–273ꢁC. The observed and
literature [35] analytical and spectral data were in complete
agreement with each other, thus conforming the structure of
the synthesized compound.
12H-2,3-Dimethoxypyrido[10,20:1,2]pyrimido[4,5-b]quinolin-12-
one (4b). It was obtained from 6-aminoveratraldehyde (1.81 g,
0.01 mole) and 3 (1.62 g, 0.01 mole); m.p. 246–248ꢁC; yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1196
P. Gupta, S. Gupta, A. Sachar, and R. L. Sharma
Vol 47
162.4, 194.5. Anal Calcd. for C15H14N2O2: C, 70.56; H, 5.51;
N, 11.02. Found: C, 70.42; H, 5.42; N, 11.0.
1,5-Bis(2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-3-
ylidene)pentane (7a). It was obtained from gluteraldehyde
(2.00 g, 0.02 mole) and 3 (1.62 g, 0.01 mole); m.p. 74–76ꢁC;
12,14-Dihydro-7H-13-methylbenzo [5,6] [8] annuleno
[1,2-d] pyrido [1,2-a] pyrimidine-7,14-dione. m.p. 78–80ꢁC;
yield 20%; IR (KBr) m/cmꢀ1
: 1300–1310 (CAN), 1625
(Cdsbond]N), 1700 (C¼¼O); MS: m/z ¼ 302 (Mþ); 1H NMR
(200 MHz, CDCl3): d(ppm) ¼ 2.22 (s, 3H, CH3), 2.6–2.8 (brs,
2H, CH2), 6.90–7.25 (m, 8H, ArHs), 7.95 (d, 1H, CH-1); 13C
NMR (50 MHz, CDCl3): d (ppm) ¼ 15.2, 30.8, 111.5, 119.5,
120.3, 126.7, 126.8, 128.2, 129.2, 132.2, 136.8, 137.4, 138.8,
140.2, 151.6, 156.5, 169.5, 175.5. Anal. Calcd. for
C19H14N2O2 : C, 75.49; H, 4.63; N, 9.27. Found: C, 75.38; H,
4.50; N, 9.25.
yield 72%; IR (KBr) m/cmꢀ1
: 1310–1320 (CAN), 1615
(C¼¼N), 1700 (C¼¼O); MS: m/z ¼ 388 (Mþ); 1H NMR (200
MHz, CDCl3): d (ppm) ¼ 1.52–2.20 (m, 6H, 3ꢃCH2), 5.2 (t,
2H, methine protons), 6.92–7.25 (m, 8H, ArHs); 13C NMR (50
MHz, CDCl3): d (ppm) ¼ 15.2, 15.8, 24.3, 24.5, 26.2, 110.5,
110.0, 114.0, 114.8, 122.3, 122.5, 135.5, 138.8, 155.3, 155.7,
158.2,159.3, 160.2, 162.3, 180.5, 180.8. Anal. Calcd. for
C21H16N4O4: C, 64.94; H, 4.12; N, 14.43. Found: C, 63.10; H,
4.11; N, 14.01.
General procedure for the synthesis of 11–12. Dissolved
appropriate 2-aminobenzaldehyde in 40 mL of hot rectified
spirit, added a solution of 2,3,4,5-tetrahydropyrido [1,2-a] [1,3]
diazepine-2,5-dione (0.01 mole) 2 in 25 mL of rectified spirit,
and added 0.02 mole of fused sodium acetate. Swirled to mix
and set aside for 5–6 h. The reaction mixture was finally
refluxed for 3 h. Distilled off the ethanol and added 100 mL
of H2O. Filtered, washed the crystalline product first with
water thrice and finally with a little cold ethanol, and recrystal-
lized from about 100 mL of hot rectified spirit to obtain the
product 11–12.
1,5-Dimethyl-1,5-bis(2,4-dioxo-3,4-dihydro-2H-pyrido[1,2-
a]pyrimidin-3-ylidene) pentane (7b). It was obtained from
heptane-2,6-dione (2.56 g, 0.02 mole) and 3 (1.62 g, 0.01
mole); m.p. 80–82ꢁC; yield 70%; IR (KBr) m/cmꢀ1: 1300–
1320 (CAN), 1620 (C¼¼N), 1705 (C¼¼O); MS: m/z ¼ 416
(Mþ);1H NMR(200 MHz, CDCl3): d(ppm) ¼ 1.40–2.32 (m,
6H, 3ꢃCH2), 2.32 (s, 6H, 2ꢃCH3), 6.68–7.20 (m, 8H, ArHs);
13C NMR (50 MHz, CDCl3): d (ppm) ¼ 14.2, 14.4, 22.2, 30.4,
30.6, 110.8, 114.8, 115.2, 120.3, 120.8, 131.3, 131.6, 133.2,
133.8, 160.2, 160.4, 164.0,164.5, 165.2, 166.2, 180.5, 180.9.
Anal. Calcd. for C23H20N4O4: C, 66.34; H, 4.80; N, 13.46.
Found: C, 65.84; H, 4.78; N, 13.10.
2,3,14,15-Tetramethoxypyrido [10,20:1,2] quino [300,200:6,7]
[1,3] diazepino [4,5-b] quinoline (11a). It was obtained from
4,5-dimethoxy-2-aminobenzaldehyde (6-amino veratraldehyde)
(3.62 g, 0.02 mole) and 2 (1.76 g, 0.01 mole); m.p. 230–
232ꢁC; yield 52%; IR (KBr) m/cmꢀ1: 1300–1325 (CAN), 1605
(C¼¼N), 1695 (C¼¼O); MS: m/z ¼ 466 (Mþ); 1H NMR (200
MHz, CDCl3): d (ppm) ¼ 3.72–3.82 (overlappedpeaks, 12H,
4ꢃOCH3), 6.92–7.25 (m, 10H, ArHs); 13C NMR (50 MHz,
CDCl3): d (ppm) ¼ 55.2, 55.8, 56.2, 56.3, 103.5, 104.8, 105.5,
106.7, 106.8, 107.5, 110.5, 121.5, 121.8, 123.5, 123.9, 124.0,
130.8, 132.4, 132.7, 136.5, 144.2, 142.3, 145.4, 150.0, 152.2,
160.2, 164.8. Anal. Calcd. for C27H22N4O4 : C, 69.52; H,
4.72; N, 12.01. Found: C, 69.41; H, 4.71; N, 12.0.
6-Aceto-12H-11-methylbenzo [g] pyrido [2,1-b] quinazolin-
12-one (8). It was obtained from o-acetophenylpropan-2-one
(1.76 g, 0.01 mole) and 3 (1.62 g, 0.01 mole); m.p. 85–87ꢁC;
yield 64%; IR (KBr) m/cmꢀ1
: 1300–1315 (CAN), 1620
(C¼¼N), 1705 (C¼¼O); MS: m/z ¼ 302 (Mþ); 1H NMR (200
MHz, CDCl3): d(ppm) ¼ 1.80–2.05 (m, 4H, 2 ꢃ CH2), 2.22
(s, 3H, CH3), 2.50 (s, 3H, COCH3), 5.73 (t, 1H, methine pro-
ton), 5.78 (t, 1H, methine proton), 7.42–7.84 (m, 4H, ArHs);
13C NMR (50 MHz, CDCl3): d (ppm) ¼ 13.1, 22.1, 110.2,
114.4, 120.6, 122.8, 124.6, 124.9, 125.5, 125.8, 126.5, 128.8,
130.3, 136.7, 140.1, 144.7, 160.4, 161.5, 186.5. Anal. Calcd.
for C19H14N2O2: C, 75.49; H, 4.63; N, 9.27. Found: C, 75.31;
H, 4.62; N, 9.19.
2,3;14,15-Bismethylenedioxypyrido[10,20:1,2]quino[300,200:6,
7][1,3]diazepino [4,5-b] quinoline (11b). It was obtained
from
4,5-methylenedioxy-2-aminobenzaldehyde(6-aminopi-
peronal) (3.30 g, 0.02 mole) and 2 (1.76 g, 0.01 mole); m.p.
238–240ꢁC; yield 50%; IR (KBr) m/cmꢀ1: 1305–1315 (CAN),
1625 (Cdsbond]N), 1690 (C¼¼O); MS: m/z ¼ 434 (Mþ); 1H
NMR (200 MHz, CDCl3): d (ppm) ¼ 5.95 (s, 2H, CH2O2),
6.05 (s, 2H, CH2O2), 6.90–7.25 (m, 10H, ArHs); 13C NMR
(50 MHz, CDCl3): d (ppm) ¼ 90.2, 91.3, 102.1, 105.2, 106.9,
107.4, 108.2, 110.2, 122.1, 123.5, 123.8, 124.2, 130.1, 132.5,
135.4, 135.8, 136.5, 142.2, 145.2, 148.2, 152.5, 153.8, 155.2,
165.4, 166.2. Anal. Calcd. for C25H14N4O4 : C, 69.12; H,
3.22; N, 12.90. Found: C, 69.10; H, 3.20; N, 12.88 .
2,3-Dimethoxypyrido [10,20:1,2] [1:3] diazepino [4,5-b] qui-
nolin-12(13H)-one (12a). It was obtained from 4,5-dime-
thoxy-2-aminobenzaldehyde (6-amino veratraldehyde) (1.81 g,
0.01 mole) and 2 (1.76 g, 0.01 mole); m.p. 151–153ꢁC; yield
56%; IR (KBr) m/cmꢀ1: 1300–1325 (CAN), 1600 (C¼¼N),
1690 (C¼¼O); MS: m/z ¼ 309 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 2.65–2.85 (brs, 2H, CH2), 3.73 (s, 3H,
OCH3), 3.76 (s, 3H, OCH3), 6.9–7.28 (m, 7H, ArHs); 13C
NMR (50 MHz, CDCl3): d (ppm) ¼ 34.3, 56.3, 56.5, 106.3,
108.0, 111.1, 116.1, 121.9, 124.3, 134.2, 137.4, 144.1, 150.8,
152.8, 164.4, 167.7, 170.8. Anal. Calcd. for C17H15N3O3: C,
66.01; H, 4.85; N, 13.59. Found: C, 65.09 ; H, 4.83; N,
13.51.
3-(1-o-Acetobenzylethylidene)-3,4-dihydro-2H-pyrido[1,2-a]
pyrimidine-2,4-dione (9). It was obtained from o-acetophenyl-
propan-2-one (1.76 g, 0.01 mole) and 3 (1.62 g, 0.01 mole);
m.p. 84–86ꢁC; yield 78%; IR (KBr) m/cmꢀ1: 1300–1338
(CAN), 1585 (C¼¼N), 1680–1710 (C¼¼O); MS: m/z ¼ 320
(Mþ); 1H NMR (200 MHz, CDCl3): d(ppm) ¼ 1.70 (s, 3H,
CH3), 2.35 (s, 3H, COCH3), 2.8–3.0 (brs, 2H, CH2), 6.94–7.28
(m, 7H, ArHs), 8.1 (d, 1H, H-5); 13C NMR (50 MHz, CDCl3):
(ppm) ¼ 13.5, 111.1, 115.7, 125.6, 125.8, 126.4, 126.5, 126.8,
129.5, 129.8, 130.1, 130.5, 136.8, 142.1, 147.7, 150.1, 184.4,
190.5, 196.5. Anal. Calcd. for C19H16N2O3: C, 71.25; H, 5.0;
N, 8.75. Found: C, 71.18; H, 4.8; N, 8.71.
Procedure for the synthesis of 10. Dissolved 9 (0.01 mole)
in 40 mL of hot rectified spirit, added 20 mL 10% ethanolic
KOH and refluxed for about 3 h and distilled off the ethanol.
The reaction mixture was cooled, acidified with very dilute
HCl to the pH 5–6 and set aside for 5–6 h. Colorless crystal-
line compound was formed, filtered, washed the crystalline
product first with water twice and finally with a little
cold ethanol and recrystallized from about 100 mL of hot rec-
tified spirit to obtain the product 10. It was characterized as
follows:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
1197
m/cmꢀ1: 1320–1330 (CAN), 1590 (C¼¼N), 1670 (C¼¼O), 3280
(NH); MS: m/z ¼ 423 (Mþ); 1H NMR (200 MHz, CDCl3):
d(ppm) ¼ 3.71 (s, 3H, OCH3), 5.18 (s, 1H,6-CH), 6.92–7.23
(m, 12H, ArHs), 9.26 (s, 1H, NH); 13C NMR (50 MHz,
CDCl3): d (ppm) ¼ 24.4, 50.8, 54.3, 56.2, 62.4, 108.4, 110.5,
114.2, 114.3, 115.2, 115.7, 124.2, 124.3, 128.3, 128.5, 130.1,
135.5, 136.5, 152.4, 128.8, 162.5, 165.0, 166.2, 168.5. Anal.
Calcd. for C24H17N5O3: C, 68.08; H, 4.01; N, 16.54. Found:
C, 67.10; H, 4.0; N, 16.10.
6,13,14,15-Tetrahydro-14-(4-methylphenyl)dipyrido[1,2-a:10,
20-a0] pyrido[200,300-d:600,500-d0]dipyrimidine-13,15-dione (15b). It
was obtained from 3 (1.62 g, 10 mmole) and p-tolualdehyde
(0.58 ml, 5 mmol); m.p. 238–240ꢁC; yield 77%; IR (KBr) m/
cmꢀ1: 1305–1315 (CAN), 1662 (C¼¼N), 1670 (C¼¼O), 3240
(NH); MS: m/z ¼ 407 (Mþ); 1H NMR (200 MHz,CDCl3): d
(ppm) ¼ 2.30 (s, 3H, CH3), 5.20 (s, 1H, 6-CH), 6.90–7.20 (m,
12H, ArHs), 9.01 (s, 1H, NH); 13C NMR (50 MHz, CDCl3): d
(ppm) ¼ 20.2, 24.3, 50.2, 64.3, 106.8, 110.2, 111.0, 115.2,
115.8, 124.1, 124.3, 128.2, 128.4, 129.5, 129.7, 135.0, 135.5,
137.2, 137.8, 150.8, 160.2, 160.4, 162.5, 168.8. Anal. Calcd.
for C24H17N5O2: C, 70.76; H, 4.17; N, 17.19. Found: C,
69.58; H, 4.09 ; N, 17.12.
6,13,14,15-Tetrahydro-14-(3,4-dimethoxyphenyl)dipyrido[1,
2-a:10,20-a0] pyrido[200,300-d:600,500-d0]dipyrimidine-13,15-dione
(15c). It was obtained from 3 (1.62 g, 10 mmole) and veratral-
dehyde (0.83 g, 5 mmol); m.p.244–246ꢁC; yield 83%; IR
(KBr) m/cmꢀ1:1320–1330 (CAN), 1590 (C¼¼N), 1670 (C¼¼O),
3410 (NH); MS: m/z ¼ 453 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 3.70 (s, 3H, OCH3), 3.75 (s, 3H, OCH3),
4.90 (s, 1H, 6-CH), 6.9–7.21 (m, 11H, ArHs), 9.56 (s, 1H,
NH); 13C NMR (50 MHz, CDCl3): d (ppm) ¼ 24.3, 50.8,
56.2, 56.5, 64.2, 108.1, 110.1, 111.3, 114.8, 115.3, 116.8,
120.1, 122.3, 122.5, 132.1, 135.6, 142.8, 147.5, 150.2, 155.8,
160.5, 162.4, 164.0, 164.2, 170.2. Anal. Calcd. for
C25H19N5O4: C, 66.22; H, 4.19; N, 15.45. Found: C, 65.90; H,
4.17; N, 15.12.
[1,3]Dioxolo[4,5-g]pyrido [10,20:1,2] [1:3] diazepino [4,5-b]
quinolin-12(13H)-one (12b). It was obtained from 4,5-methyl-
enedioxy-2-aminobenzaldehyde (6-aminopiperonal) (1.65 g,
0.01 mole) and 2 (1.76 g, 1 mole); m.p. 140–142ꢁC; yield
62%; IR (KBr) m/cmꢀ1: 1305–1315 (CAN), 1625 (C¼¼N),
1692 (C¼¼O); MS: m/z ¼ 293 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 2.68–2.83 (brs, 2H, CH2), 5.9 (s, 2H,
CH2O2), 6.80–7.25 (m, 7H, ArHs); 13C NMR (50 MHz,
CDCl3): d (ppm) ¼ 34.5, 91.2, 106.3, 108.2, 110.3, 114.3,
120.8, 123.0, 124.2, 132.3, 134.2, 140.1, 150.2, 152.4, 160.2,
168.8, 170.2. Anal. Calcd. for C16H11N3O3: C, 65.52; H, 3.75;
N, 14.33. Found: C, 65.48; H, 3.70; N, 14.01.
General procedure for the synthesis of 1, 13, and
14. Dissolved (0.01 mole) of 2 in 40 mL of hot rectified spirit,
added to it a solution of malealdehyde or succinaldehyde or o-
phthaldehyde (0.01 mole) in 25 mL of rectified spirit, and
added 0.02 moles of (NH4)2CO3, a few drops of dilute NH3
and two drops of piperidene. Swirled to mix and set aside for
5–6 h. The reaction mixture was finally refluxed for 3 h, dis-
tilled off the ethanol, and added dilute HCl till a pH between
5 and 6 of the reaction was achieved. Filtered, washed the
crystalline product first with water twice and finally with a lit-
tle cold ethanol and recrystallized from about 100 mL of hot
rectified spirit to obtain the product 1, 13, and 14.
6H,11H-Pyrido[1,2-b][2,4]benzodiazepine-6,11-dione (1) M.p.
152–154ꢁC; yield 76% and superimposable IR with that of
authentic sample obtained through (Scheme 1).
6,8,9,11-Tetrahydropyrido[1,2-b][2,4]benzodiazepine-6,11-
dione (13). It was obtained from succinaldehyde (0.86 g, 0.01
mole) and 2 (1.76 g, 0.01 mole); m.p. 140–142ꢁC; yield 75%;
IR (KBr) m/cmꢀ1: 1310–1315 (CAN), 1610–1625 (C¼¼C),
1625 (C¼¼N), 1680–1715 (C¼¼O); MS: m/z ¼ 226 (Mþ); 1H
NMR (200 MHz, CDCl3): d(ppm) ¼ 1.90–2.10 (m, 4H,
2ꢃCH2), 6.85–7.85 (m, 6H, ArHs and two methine protons);
13C NMR (50 MHz, CDCl3): d (ppm) ¼ 25.6, 26.8, 110.8,
114.8, 124.2, 135.2, 135.7, 137.2, 140.8, 146.2, 160.2, 162.4,
180.2. Anal.Calcd. for C13H10N2O2: C, 69.02; H, 4.86; N,
12.38. Found: C, 69.06; H, 4.85; N, 12.33.
6H,13H-Pyrido[1,2-a]naphtho[2,3-e][1,3]diazepine-6,13-dione
(14). It was obtained from o-phthaldehyde (1.34 g, 0.01 mole)
and 2 (1.76 g, 0.01 mole); m.p. 234–236ꢁC; yield 55%; IR
(KBr) m/cmꢀ1: 1305–1315 (CAN), 1605 (C¼¼N), 1685 (C¼¼O);
MS: m/z ¼ 274 (Mþ); 1H NMR (200 MHz, CDCl3): d(ppm)
¼ 7.20–8.40 (m, 10H, ArHs); 13C NMR (50 MHz, CDCl3): d
(ppm) ¼ 110.2, 115.4, 124.3, 128.6, 128.8, 129.0, 129.6,
130.1, 130.2, 132.1, 132.5, 134.0, 134.4, 137.1, 164.2, 164.6,
180.2. Anal. Calcd. for C17H10N2O2 : C, 74.45; H, 3.64; N,
10.21. Found; C, 74.40; H, 3.63; N, 10.18.
General procedure for the synthesis of 15a–15d. A mix-
ture of 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-2,4-dione (3.24
g, 20 mmol) 3 and the aromatic aldehyde (10 mmol ) in ethyl-
ene glycol (30 mL) in presence of ammonium acetate
(20 mmol) was heated at 140ꢁC for about 4–5 h and then
cooled to room temperature. The reaction mixture was poured
into 300 mL water. The solid was filtered and then washed
with water twice to remove excess of ammonium acetate. The
crude solid was crystallized from 80–85% EtOH.
6,13,14,15-Tetrahydro-14-(4-methoxyphenyl)dipyrido[1,2-a:10,
20-a0] pyrido[200,300-d:600,500-d0]dipyrimidine-13,15-dione (15a). It
was obtained from 3 (1.62 g, 10 mmole) and p-anisaldehyde
(0.60 mL, 5 mmol); m.p. 244–246ꢁC; yield 76%; IR (KBr)
6,13,14,15-Tetrahydro-14-[1,3]benzodioxol-5yldipyrido[1,2-
a:10,20-a0] pyrido[200,300-d:600,500-d0] dipyrimidine-13,15-dione
(15d). It was obtained from 3 (1.62 g, 10 mmole) and pipero-
nal (0.75 mL, 5 mmol); m.p. 238–240ꢁC; yield 75%; IR (KBr)
m/cmꢀ1: 1315–1325 (CAN), 1615 (C¼¼N), 1670 (C¼¼O), 3410
1
(NH); MS: m/z ¼ 437 (Mþ); H NMR (200 MHz, CDCl3): d
(ppm) ¼ 4.89 (s, 1H, 6-CH), 6.10 (s, 2H, CH2O2), 6.90–7.25
(m, 11H, ArHs), 9.28 (s, 1H, NH); 13C NMR (50 MHz,
CDCl3): d (ppm) ¼ 24.2, 50.8, 56.4, 64.2, 90.2, 107.2, 110.1,
111.3, 114.7, 115.1, 116.2, 116.8, 120.2, 122.3, 122.5, 132.1,
135.5, 140.2, 147.2, 152.2, 160.2, 160.5, 163.5, 168.8. Anal.
Calcd. for C24H15N5O4: C, 65.90; H, 3.43; N, 16.01. Found:
C, 64.70; H, 3.41; N, 15.85.
General procedure for the synthesis of 16a–16d. A mix-
ture of 3, 4-dihydro-2H-pyrido [1,2-a] pyrimidine-2,4-dione
(3.24 g, 20 mmol) 3 and the aromatic aldehyde (10 mmol) in
ethylene glycol (30 mL) in presence of P2O5 (20 mmol) was
heated at 140ꢁC for about 4–5 h and then cooled to room tem-
perature. The reaction mixture was poured into 300 mL water
cautiously and slowly. The solid formed was filtered and, then
washed with water twice to remove excess of adhered materi-
als. The crude solid was recrystallized from 80–85% EtOH.
14,15-Dihydro-13H-14-(4-methoxyphenyl)dipyrido[1,2-a:10,
20-a0] pyrano[200,300-d:600,500-d0]dipyrimidine-13,15-dione (16a). It
was obtained from 3 (1.62 g, 10 mmole) and anisaldehyde
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1198
P. Gupta, S. Gupta, A. Sachar, and R. L. Sharma
Vol 47
(0.60 mL, 5 mmol); m.p. 270–272ꢁC; yield 69%; IR (KBr) m/
cmꢀ1: 1315–1330 (CAN), 1595 (C¼¼N), 1675 (C¼¼O); MS: m/
z ¼ 424 (Mþ); 1H NMR (200 MHz, CDCl3): d(ppm) ¼ 3.70
(s, 3H, OCH3), 4.63 (s, 1H, 6-CH), 6.92–7.32 (m, 12H, ArHs);
13C NMR (50 MHz, CDCl3): d (ppm) ¼ 23.7, 54.1, 56.7, 77.7,
90.5, 110.5, 111.1, 114.3, 114.7, 115.2, 115.5, 124.1, 124.2,
128.3, 128.5, 134.7, 135.1, 136.1, 136.4, 160.2, 162.1, 163.4,
164.2, 168.3. Anal. Calcd. for C24H16N4O4: C, 67.92; H, 3.77;
N, 13.20. Found: C, 67.96; H, 3.76; N, 13.17.
7.01–7.20 (m, 12H, ArHs); 13C–NMR (50 MHz, CDCl3): d
(ppm) ¼ 24.5, 52.1, 54.3, 56.2, 110.5, 110.8, 114.1, 114.5,
115.5, 115.8, 118.2, 124.1, 124.3, 128.2, 128.5, 130.2, 135.5,
135.7, 154.0, 158.2, 160.0, 160.2, 162.1, 168.5. Anal. Calcd.
for C24H16N4O3S: C, 70.58; H, 3.92; N, 13.72; S, 7.84. Found:
C, 70.55; H, 3.91; N, 13.6; S, 7.67.
14,15-Dihydro-13H-14-(4-methylphenyl)dipyrido[1,2-a:10,
20-a0] thiopyarano[200,300-d:600,500-d0]dipyrimidine-13,15-dione
(17b). It was obtained from 3 (1.62 g, 10 mmol) and p-tolual-
dehyde (0.58 mL, 5 mmol); m.p. 252–254ꢁC; yield 66%; IR
(KBr) m/cmꢀ1: 1185 (CAS), 1305–1315 (CAN), 1630 (C¼¼N),
1678 (C¼¼O); MS: m/z ¼ 424 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 2.32 (s, 3H, CH3), 5.50 (s, 1H, 6-CH),
6.90–7.30 (m, 12H, ArHs); 13C NMR (50 MHZ, CDCl3): d
(ppm) ¼ 20.2, 25.3, 52.0, 54.1, 111.0, 111.2, 114.3, 114.5,
115.1, 115.3, 118.3, 124.3, 124.5, 128.1, 128.3, 130.1, 135.3,
135.5, 154.2, 158.1, 160.1, 160.3, 162.3, 169.3. Anal. Calcd.
for C24H16N4O2S: C, 67.92; H, 3.77; N, 13.20; S, 7.54. Found:
C, 66.81; H, 3.76; N, 12.80; S, 7.16
14,15-Dihydro-13H-14-(3,4-dimethoxyphenyl)dipyrido[1,2-
a:10,20-a0] thiopyarano[200,300-d:600,500-d0]dipyrimidine-13,15-
dione (17c). It was obtained from 3 (1.62 g,10 mmol) and ver-
atraldehyde (0.83 g, 5 mmol); m.p. 260–262ꢁC; yield 76%; IR
(KBr) m/cmꢀ1: 1180 (CAS), 1320–1330 (CAN), 1595 (C¼¼N),
1678 (C¼¼O); MS: m/z ¼ 470 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 3.72 (s, 3H, OCH3), 3.74 (s, 3H, OCH3),
4.74 (s, 1H, 6-CH), 6.70–7.20 (m, 11H, ArHs); 13C NMR (50
MHz, CDCl3): d (ppm) ¼ 24.4, 50.4, 56.1, 56.4, 64.4, 108.0,
110.0, 111.2, 114.5, 115.1, 115.5, 116.7, 120.0, 122.7, 132.0,
134.3, 135.5, 142.7,147.3, 150.2, 155.4, 160.5, 162.4, 164.0,
170.5. Anal. Calcd. for C25H18N4O4S: C, 63.82; H, 3.82; N,
11.90; S, 6.80. Found: C, 62.80; H, 3.81; N, 11.10; S, 5.90.
14,15-Dihydro-13H-14-[1,3]benzodioxol-5yldipyrido[1,2-
a:10,20-a0] thiopyarano[200,300-d:600,500-d0]dipyrimidine-13,15-
dione (17d). It was obtained from 3 (1.62 g, 10 mmol) and
piperonal (0.75 mL, 5 mmol); m.p. 250–252ꢁC; yield 72%; IR
(KBr) m/cmꢀ1: 1178 (CAS), 1310–1330 (CAN), 1625 (C¼¼N),
1678 (C¼¼O); MS: m/z ¼ 454 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 4.74 (s, 1H, 6-CH), 6.05 (s, 2H, CH2O2),
7.10–7.30 (m, 11H, ArHs); 13C NMR (50 MHz, CDCl3): d
(ppm) ¼ 24.3, 50.7, 64.1, 90.1, 107.1, 110.2, 111.2, 115.0,
115.5, 116.1, 116.6, 120.1, 122.2, 122.4, 132.0, 135.4, 140.1,
147.3, 152.3, 160.3, 160.3, 163.4, 164.3, 170.2. Anal. Calcd.
for C24H14N4O4S: C, 63.43; H, 3.08; N, 12.33; S, 7.04. Found:
C, 62.13; H, 2.82; N, 12.12; S, 6.20.
14,15-Dihydro-13H-14-(4-methylphenyl)dipyrido[1,2-a:10,20-
a0]pyrano[200,300-d:600,500-d0]dipyrimidine-13,15-dione (16b). It
was obtained from 3 (1.62 g, 10 mmole) and p-tolualdehyde
(0.58 mL, 5 mmol); m.p. 264–266ꢁC; yield 66%; IR (KBr) m/
cmꢀ1: 1300–1310 (CAN), 1598 (C¼¼N), 1675 (C¼¼O); MS: m/
1
z ¼ 408 (Mþ); H NMR (200 MHz, CDCl3): d (ppm) ¼ 2.30
(s, 3H, CH3), 4.93 (s, 1H, 6-CH), 6.72–7.41 (m, 12H, ArHs);
13C NMR (50 MHz, CDCl3): d (ppm) ¼ 20.2, 23.3, 50.5, 77.2,
90.2, 110.2, 111.0, 114.5, 114.9, 124.2, 124.7, 128.1, 128.5,
129.5, 129.5, 134.8, 135.2, 136.2, 136.5, 160.1, 162.2, 163.5,
164.0, 168.2. Anal. Calcd. for C24H16N4O3: C, 70.58; H, 3.92;
N, 13.72. Found: C, 70.55; H, 3.91; N, 13.78.
14,15-Dihydro-13H-14-(3,4-dimethoxyphenyl)dipyrido[1,2-
a:10,20-a0] pyrano[200,300-d:600,500-d0]dipyrimidine-13,15-dione
(16c). It was obtained from 3 (1.62 g, 10 mmol) and veratral-
dehyde (0.83 g, 5 mmol); m.p. 280–282ꢁC; yield 70%; IR
(KBr) m/cmꢀ1: 1320–1330 (CAN), 1620 (C¼¼N), 1675 (C¼¼O);
1
MS: m/z ¼ 454(Mþ); H NMR (200 MHz, CDCl3): d(ppm) ¼
3.72 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 4.70 (s, 1H, 6-CH),
6.90-7.25 (m, 11H,ArHs); 13C NMR (50 MHz, CDCl3): d
(ppm) ¼ 27.1, 52.0, 52.3, 55.4, 74.6, 94.6, 95.2, 98.9, 110.1,
110.4, 115.8, 115.9, 120.8, 122.3, 122.8, 136.5, 137.1, 154.1,
157.1, 159.1, 160.5, 163.1, 164.0, 164.2, 175.6. Anal. Calcd.
for C25H18N4O5: C, 66.12; H, 4.21; N, 11.00. Found: C,
65.22; H, 4.19; N, 10.6.
14,15-Dihydro-13H-14-dipyrido[1,2-a:10,20-a0]pyrano[200,300-
d:600,500-d0] dipyrimidine-13,15-dione (16d). It was obtained
from 3 (1.62 g, 10 mmol) and piperonal (0.75 mL, 5 mmol);
m.p. 245–247ꢁC; yield 64%; IR (KBr) m/cmꢀ1: 1310–1320
1
(CAN), 1620 (C¼¼N), 1675 (C¼¼0); MS: m/z ¼ 438 (Mþ); H
NMR (200 MHz, CDCl3): d(ppm)¼ 5.52 (s, 1H, 6-CH), 5.98
(s, 2H, CH2O2), 7.01–7.80 (m, 11H, ArHs); 13C NMR (50
MHz, CDCl3): d (ppm) ¼ 22.4, 50.5, 77.2, 90.3, 95.5, 110.1,
110.3, 114.8, 115.1, 115.5, 115.8, 120.8, 124.1, 124.3, 130.2,
135.5, 135.7, 142.5, 144.3, 160.5, 160.8, 164.2, 165.2, 170.0.
Anal. Calcd.for C24H14N4O5: C, 65.75; H, 3.19; N, 12.78.
Found: C, 65.12; H, 3.18; N, 12.52.
Acknowledgments. The authors are thankful to the Department
of Chemistry, University of Jammu, Jammu and IIIM Jammu for
providing research and library facilities.
General procedure for the synthesis of 17a–17d. A mix-
ture of 3,4-dihydro-2H-pyrido[1,2-a]pyrimidine-2,4-dione(3.24 g,
20 mmol) 3 and the aromatic aldehyde (10 mmol ) in ethylene
glycol (30 mL) in presence of P2S5 (20 mmol) was heated at
140ꢁC for about 4–5 h and then cooled to room temperature. The
reaction mixture was poured into 300 mL of water. The solid
was filtered and then washed with water twice to remove excess
of P2S5. The crude solid was crystallized from 80–85% EtOH.
14,15-Dihydro-13H-14-(4-methoxyphenyl)dipyrido[1,2-a:10,
20-a0] thiopyarano[200,300-d:600,500-d0]dipyrimidine-13,15-dione
(17a). It was obtained from 3 (1.62 g, 10 mmol) and p-anisal-
dehyde (0.60 mL, 5 mmol); m.p. 240–242ꢁC; yield 62%; IR
(KBr) m/cmꢀ1: 1168 (CAS), 1320–1330 (CAN), 1590 (C¼¼N),
1678 (C¼¼O); MS: m/z ¼ 408 (Mþ); 1H NMR (200 MHz,
CDCl3): d (ppm) ¼ 3.72 (s, 3H, OCH3), 4.64 (s, 1H, 6-CH),
REFERENCES AND NOTES
[1] Posha, M. A.; Jayashankara, V. P. Indian J Heterocycl
Chem 2006, 15, 397.
[2] Fryer, R. I. In Bicyclic Diazepines in the Chemistry of Het-
erocyclic Compounds; Taylor, E., Ed.; Wiley: New York, 1991; Vol.
50, Chapter II.
[3] Haris, R. C.; Straley, J. M. U.S. Pat. 1,537,757; Chem Abstr
1970, 173, 100054 w.
[4] Guerreo, F. A.; Blanco, C.; Guevara, U.; Martinez, R. J.;
Campo, A. E. Proc West Pharmacol Soc 1992, 35, 153.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010
Synthesis of Novel and Biologically Potent Heteropolycyclics
Containing Bridge Head Nitrogen
1199
[5] Remers, W. A.; Mabilia, M.; Hopfinger, A. J. J Med Chem
1986, 29, 2492.
[6] Pellon, P. F.; Carrasco, R.; Rodes, L. Synth Commun 1996,
26, 3869.
[7] Murugan, V.; Padmavathy, N. P.; Ramasarma, G. V. S.;
[23] Atal, C. K. A Text Book of Chemistry and Pharmacology
of Vasicine; Regional Research Laboratory: Jammu, 1980; pp 1–155.
[24] Holla, B. S.; Poojary, K. N.; Poojary, B.; Subramanaya, K.;
Suchetha, N. Indian J Chem 2005, 44, 2114.
[25] Smith, R. L.; Barret, R. J.; Bush, E. S. J Pharmacol Exp
Ther 1995, 275, 1050.
Sharma, S. V.; Suresh, V. Indian J Chem 2003, 13, 143.
[8] Brown, D. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 3,
p 148.
[26] (a) Awouters, F.; Vermeire, J.; Smeyers, F.; Vermote, P.;
Vanbeek, R.; Niemegeers, C. J. E. Drug Dev Res 1986, 8, 95; (b) Her-
meez, I.; Breining, T.; Debreczy, L. V.;Rodriguer. L. J Med Chem
1983, 26, 1494.
[9] Gupta, D. P.; Ahmad, S. A.; Shankar, K. Indian J Chem
1988, 27B, 106.
[27] Matsutani, S.; Mizushima, Y. Eur. Pat. Appl. 89-102635
(1989).
[10] Parmar, S. S.; Singh, S. P. J Heterocycl Chem 1979, 16,
448.
[28] Yanagihara, Y.; Kassai, H.; Kawashima, T.; Shida, T. Jpn J
Pharmacol 1988, 48, 91.
[11] Ram, V. J.; Srimal, R. C.; Kuschwaha, D. S.; Mishra, L.
J Prakt Chem 1990, 332, 629.
[29] Hermeez, I.; Kokosi, J.; de Vos, C.; Rodriguez, L. J Med
Chem 1987, 30, 1543.
[12] Srivastava, V. K.; Singh, S.; Gulati, A.; Shankar, H. Indian
J Chem 1987, 26B, 652.
[30] Knoll, K.; Meszaros, Z.; Szentmiklosi, P.; Furst, S. Arzneim
Forsch 1971, 21, 717.
[13] Pandey, V. K.; Gupta, M.; Mishra, D. Indian Drugs 1996,
33, 409.
[31] (a) Roma, G.; Cinone, N.; Dibraceio, M.; Grossi, G.; Leon-
cini, G.; Signorello, M. G.; Carotti, A. Bio Org Med Chem 2000, 8,
751; (b) Leoncini, G.; Signorello, M. G.; Roma, G.; Di Braccio, M.
Biochem Pharmacol 1997, 53, 1667.
[14] Umio, S.; Kariyone, K.; Zenno, H.; Kamiya, T. Jpn. Pat.
12,670 (1970); Chem Abstr 1968, 68, 2195.
[15] Shetty, B. V. U.S. Pat. 2,549,634 (1970); Chem Abstr
1971, 75, 5940.
[32] Abass, M.; Mayas, A;, S. Heteroatom Chem 2007, 18, 19.
[33] Lappin, G. R.; Petersen, Q. R.; Wheeler, C. E. J Org Chem
1950, 15, 377.
[16] Otto, H.; Houlohan, W. W. Swiss Pat. 499,544 (1971);
Chem Abstr 1971, 75, 20435.
[17] Saksena, R. K.; Amin Khan, M. Indian J Chem 1989, 28B,
443.
[34] Shur, M.; Israeltam, S. S. J Org Chem 1968, 33, 3015.
[35] Roma, G.; Di Braccio, M.; Babli, A.; Mazzei, M.; Ermili,
A. J Heterocycl Chem 1987, 24, 329.
[18] Mukerji, M. L.; Nautiyal, S. R.; Prasad, C. R.; Dhwan, B.
N. Indian J Med Res 1980, 71, 480.
[36] Sharma, R. L.; Kumar, S.; Kour, D.; Singh, J. J Heterocycl
Chem 2006, 43, 1177.
[19] Malhotra, S.; Koul, S. K.; Sharma, R. L.; Anand, K. K.;
Gupta, O. P.; Dhar, K. L. Indian J Chem 1988, 27, 937.
[20] Gupta, O. P.; Sharma, M. L.; Ray Ghatak, B. J.; Atal, C. K.
Indian J Med Res 1977, 66, 680.
[37] Sachar, A.; Gupta, P.; Gupta, S.; Sharma, R. L. Indian J
Chem 2009, 48B, 1187.
[38] Wooley, R. E.; Blue, J. L. J Med Microbiol 1975, 8, 189.
[39] Castillow, J. C.; Debeer, E. J. J Pharm Exp Ther 1947, 90,
104.
[21] Gupta, O. P.; Sharma, M. L.; Ray Ghatak, B. J.; Atal, C. K.
Indian J Med Res 1977, 66, 865.
[22] Gupta, O. P.; Wakhloo, R. L.; Sharma, M. L.; Atal, C. K. J
Obstet Gynaecol India 1979, 29, 935.
[40] Kobayshi, S.; Hasebawa, K.; Muri, M.; Takagi, H. Arzneim
Forech Drug Res 1970, 20, 43.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet