Design, synthesis and in vitro evaluation of antitubercular and antimicrobial activity of some novel pyranopyrimidines

Article abstract of DOI:10.1016/j.ejmech.2010.08.014

The clinical significance of pyran and pyrimidine condensed systems and the raise in problem of multidrug resistant bacterial pathogens has directed us to synthesize pyranopyrimidine derivatives via the reactions of the versatile, 2-amino-4-(4-methoxyphenyl)-4H-substitutedchromene-3-carbonitrile with the appropriate reagents. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, Mass spectra and Elemental analysis. The compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Rv [ATCC-27294] and antibacterial activity against Staphylococcus aureus [ATCC-25923] and Streptococcus pyogenes [MTCC-443] as Gram-positive, Escherichia coli [ATCC-25922] and Pseudomonas aeruginosa [MTCC-441] as Gram-negative bacterial strains and antifungal activity against Aspergillus niger [MTCC-282]. Several derivatives exhibited pronounced antitubercular and antimicrobial activities.

Full text of DOI:10.1016/j.ejmech.2010.08.014

European Journal of Medicinal Chemistry 45 (2010) 5056e5063
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and in vitro evaluation of antitubercular and antimicrobial
activity of some novel pyranopyrimidines
*
Nimesh R. Kamdar, Dhaval D. Haveliwala, Prashant T. Mistry, Saurabh K. Patel
Department of Chemistry, Veer Narmad South Gujarat University, Surat-395007, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The clinical significance of pyran and pyrimidine condensed systems and the raise in problem of
multidrug resistant bacterial pathogens has directed us to synthesize pyranopyrimidine derivatives via
the reactions of the versatile, 2-amino-4-(4-methoxyphenyl)-4H-substitutedchromene-3-carbonitrile
Received 22 January 2010
Received in revised form
2 August 2010
Accepted 8 August 2010
Available online 12 August 2010
with the appropriate reagents. The newly synthesized compounds were characterized by IR, 1H NMR, 13
C
NMR, Mass spectra and Elemental analysis. The compounds were evaluated for their in vitro antituber-
cular activity against Mycobacterium tuberculosis H37Rv [ATCC-27294] and antibacterial activity against
Staphylococcus aureus [ATCC-25923] and Streptococcus pyogenes [MTCC-443] as Gram-positive, Escher-
ichia coli [ATCC-25922] and Pseudomonas aeruginosa [MTCC-441] as Gram-negative bacterial strains and
antifungal activity against Aspergillus niger [MTCC-282]. Several derivatives exhibited pronounced anti-
tubercular and antimicrobial activities.
Keywords:
Pyranopyrimidine
Pyrimidone
Pyrimidine thiones
Antitubercular activity
Antimicrobial activity
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
antioxidant [6], antigenotoxic [7], ATP sensitive potassium channel
openers [8] and antiangiogenic activity [9]. On the other hand
Infectious diseases are influencing the world with their
morbidity and mortality out of which tuberculosis is major infec-
tious’ diseases caused by Mycobacterium tuberculosis [1]. TB
(Tuberculosis) is still the single largest infection having a high
mortality rate and 0.1e0.3 percent of the population become
infected each year in the developed countries. The World Health
Organization estimates that 8 million people get TB every year and
3 million people die yearly from TB [2]. The current chemotherapy
is based on age-old drugs like Pyrazinamide, Isoniazid and Rifam-
picin for tuberculosis [3]. The available treatment establishes
a multidrug regime lasting a minimum of six months; although
there is no guarantee that the complete sterilization of the infection
will be obtained. Furthermore, the increase in TB cases caused by
MDR and XDR strains, and coinfection with HIV have pointed out
the urgent need to develop new antitubercular drugs which will
effectively kill MDR strains, less toxic, shortened duration of
therapy, rapid mycobactericidal mechanism of action in the intra-
cellular environment.
pyrimidine scaffold was the base of many bioactive molecules such
as antitubercular [10], antibacterial [11], antitumor [12], antiin-
flammatory [13], antifungal [14] and antileishmanial agent [15].
Consequently, synthetic methodologies for synthesis of novel
pyrimidines or pyrimidine fused compounds are of particular
interests to organic and medicinal chemists. For example, synthetic
methods have been reported for the efficient syntheses of benzo-
pyrano[4,3-d]pyrimidine [16] dihydropyrido[2,3-d]pyrimidine [17]
pyrimido[1,2-a]pyrimidine [18] fluorinated 2-amino-pyrimidine-
N-oxide [19].
As our research is devoted to the synthesis of diverse hetero-
cycles as anti-infective agents, we identified the pyrimidine and
pyran (separately) as good antitubercular [20e22] and anti-
microbiol agents [23,24]. Keeping this in view we designed new
prototypes by combining both pyrimidine and pyran, and synthe-
sized hybrid molecules consisting of pyrimidines along with pyran
moiety and investigated for their in vitro antitubercular and anti-
microbial activities.
The benzopyrans have displayed an impressive assay of phar-
macological properties like anti HBV, cytotoxic [4], antibacterial [5],
2. Results and discussion
2.1. Chemistry
* Corresponding author. Tel.: þ91 9825121977; fax: þ91 2612227312.
E-mail addresses: nimesh_r_kamdar@yahoo.co.in (N.R. Kamdar), haveliwala_
dhaval@yahoo.co.in (D.D. Haveliwala), prashant_mistry15@yahoo.com (P.T.
Mistry), saurabh@vnsgu.ac.in (S.K. Patel).
Since the isolation of pyrimidine derivatives, considerable
attention has been devoted to their chemistry and biological
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.014

N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
5057
activity. In recent years, there has been increasing interest in the
synthesis of pyrimidine derivatives and there are some methods
used to synthesize the pyrimidine ring, allowing access to a large
number of multifunctionalized pyrimidine derivatives [25e27].
The 2-amino-4-(4-methoxyphenyl)-4H-substitutedchromene-3-
carbonitrile 4(aee) are easily obtained via one pot reaction of malo-
nonitrile, 4-methoxybenzaldehyde and various substituted phenols
in presence of cetyltrimethylammoniumchloride [28]. Compounds 4
(aee) were used as precursors for the synthesis of new pyrano[4,5-d]
pyrimidine derivatives. The structure assigned for compound 4(aee)
was based on the analytical and spectroscopic data. Reaction of
2-amino-4-(4-methoxyphenyl)-4H-substitutedchromene-3-carboni-
trile 4(aee) with carbon disulphide in refluxing pyridine affords the
corresponding 5-(4-methoxyphenyl)-1,5-dihydro-2H-substituted-
chromeno[2,3-d]pyrimidine-2,4(3H)-dithione (5aee). Treatment of
different 2-amino-4-(4-methoxyphenyl)-4H-substitutedchromene-
3-carbonitrile (4aee) with formic acid affords the corresponding
5-(4-methoxyphenyl)-3,5-dihydro-4H-substitutedchromeno[2,3-
d]pyrimidine-4-one (6aee). Treatment of different 2-amino-4-(4-
methoxyphenyl)-4H-substitutedchromene-3-carbonitrile (4aee)
with urea in ethanol and sodium ethoxide affords the corre-
sponding 4-amino-5-(4-methoxyphenyl)-1,5-dihydro-2H-substitu-
tedchromeno[2,3-d]pyrimidine-2-one 7(aee). An alternative
method for the synthesis of compound 4-amino-5-phenyl-1,5-dihy-
dro-2H-substitutedchromeno[2,3-d]pyrimidine-2-thione(8aee)was
completed by refluxing 2-amino-4-(4-methoxyphenyl)-4H-sub-
stitutedchromene-3-carbonitrile 4(aee) with thiourea in ethanol
containing sodium ethoxide (Scheme 1).
2.2. Antitubercular activity
All of the synthesized compounds were tested for their anti-
tubercular activity (MIC) in vitro by Agar micro dilution
method against M. tuberculosis H37Rv (ATCC-27294). The results
are summarized in Table 1, a standard drug Rifampicin used
for comparison. Among the newly synthesized compounds,
7-(4-methoxyphenyl)-7,9-dihydro-8H-pyrimido [50,40:5,6] pyrano
[3,2-h]quinoline-8-one (6e) and 8-amino-7-(4-methoxyphenyl)-
7,11-dihydro-10H-pyrimido[50,40:5,6]pyrano[3,2-h]quinoline-10-
thione (8e) had the highest potency and exhibited inhibition at
R1
H
R2
R3
O
N
S
CS2 / Pyridine
NH
H
R4
S
O
5(a-e)
CH3
R1
R2
O
N
Excess of HCOOH
NH
R3
H
R4
O
R1
R2
R3
O
O
NH2
CN
O
CH3
6(a-e)
R1
H
R4
H
R2
O
N
O
C2H5ONa / C2H5OH
NH2CONH2
N
R3
CH3
H
R4
NH2
4(a-e)
O
CH3
R1 7(a-e)
H
N
R2
O
S
C2H5ONa / C2H5OH
NH2CSNH2
N
NH2
R3
H
R4
1,4,5,6,7,8
R1
- H
- H
R2
- H
R3
R4
- H
- H
- H
- H
- H
- H
a
b
c
- OH
O
CH3
- CH=CHCH=CH-
- H - H
- CH=CHCH=N-
8(a-e)
- CH=CHCH=CH-
- H - H
d
e
Scheme 1.

5058
N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
Table 1
4. Experimental
The in vitro antitubercular activity of the synthesized compounds against
M. tuberculosis H37Rv.
4.1. Chemistry
Compd. MIC (
m
g/ml) Compd. MIC (
m
g/ml) Compd.
MIC (mg/ml)
4a
4b
4c
4d
4e
5a
5b
5c
5d
500
250
1000
1000
250
250
125
500
500
5e
6a
6b
6c
6d
6e
7a
7b
7c
125
500
250
125
125
62.5
500
125
7d
7e
8a
8b
8c
8d
8e
1000
250
500
250
500
500
Melting points were taken in open capillaries and are uncor-
rected. IR spectra were recorded on a Hitachi 270-50 double beam
spectrophotometer in KBr. 1H NMR spectra were recorded on a Var-
ian 300 MHz spectrometer using DMSO-d6 or CDCl3 as the solvent
depending upon the solubility of the synthesized compounds and
TMS as the internal standard. Electron impact MS spectra were
obtained on a JEOL JMS-HX 100 at 70 eV. Elemental analyses were
performed by Perkin Elmer-2400 and were all within ꢀ0.03% of the
theoretical values for C, H, and N. The progress of the reaction was
monitored by silica gel 60 F254 (Merck, 0.25 mm thick) coated TLC
plates and column chromatography was performed on silica gel
(Merck No. 9385) using suitable mixture of solvents as eluent. The
reagent grade chemicals were purchased from the commercial
sources and purified by either distillation or recrystallization.
All the synthesized compounds have been checked for their
melting points, physical nature, IR, 1H NMR, 13C NMR, Mass spec-
troscopy and Elemental analysis for individual compounds and the
data are summarized as under.
62.5
40
Rifampicin
1000
MIC 62.5 mg/ml which was more potent than the corresponding
lead molecule 4(aee) followed by 5b, 5e, 6c, 6d and 7e which
showed moderate inhibitory activity with MIC 125 g/ml
m
respectively. The hydroxyl group substituted derivative 6b, dis-
played relatively higher inhibitory activity in general. However,
replacement of phenyl substitution at chromene with a quinoline
improves antitubercular activity. These results clearly showed
that 5,8(aee) demonstrated more significant antitubercular
activity than the corresponding lead molecules. Presence of
a hydroxyl and quinoline substituent on chromene caused
a remarkable improvement in antitubercular activity.
4.2. General preparation of 2-amino-4-(4-methoxyphenyl)-4H-
substitutedchromene-3-carbonitrile 4(aee)
A mixture of phenol 1(aee) (2.0 mmol), malononitrile (2)
(132.0 mg, 2.0 mmol), 4-methoxybenzaldehyde (3) (272.0 mg,
2.0 mmol) and catalytic amount of cetyltrimethylammonium-
chloride in water (50 ml) was refluxed with continuous stirring for
6 h to give 4(aee).
2.3. Antibacterial activity and antifungal activity
All of the synthesized compounds were tested for their anti-
bacterial and antifungal activity (MIC) in vitro by serial dilution
technique. Bacterial strains Staphylococcus aureus [ATCC-25923]
and Streptococcus pyogenes [MTCC-443] as Gram-positive,
Escherichia coli [ATCC-25922] and Pseudomonas aeruginosa
[MTCC-441] as Gram-negative and Aspergillus niger [MTCC-282]
as fungal strains were used for the in vitro studies. Ampicillin,
Ciprofloxacin, Nystatin, and Griseofulvin were use as standard
drugs. From the screening results, molecules 5e and 6e displayed
broad spectrum antimicrobial activity against the both Gram-
negative and Gram-positive bacteria compared with ampicillin
(Table 2). Compound 5e showed excellent activity against all
bacteria, whereas compound 5b showed excellent activity
against both of the Gram-positive bacteria. Compound 6e was
found significantly active against Gram-negative bacteria E. coli
compared with ampicillin. Remaining compounds showed good
to moderate activity against other bacteria compared with the
remaining standard drugs.
4.2.1. 2-Amino-4-(4-Methoxyphenyl)-4H-chromene-3-
carbonitrile (4a)
210 ꢁC (ethanol), White solid, Yield 80%, IR (KBr)
n
(cmꢂ1): 2843
(eOCH3), 3420 (eNH2), 2200 (eC^N), 1254 (CeOeC at pyran ring);
1H NMR (300 MHz, CDCl3)
d
(ppm): 3.81 (s, 3H, eOCH3), 5.16 (s, 1H,
pyran eCH), 7.17 (d, 2H, J ¼ 7.21 Hz, Ar-H), 7.22 (d, 2H, J ¼ 8.01 Hz, Ar-
H), 7.02 (d, 2H, J ¼ 7.41 Hz, Ar-H), 6.48e6.65 (t, 2H, Ar-H), 6.80 (s, 2H,
eNH2); m/z: 278.11 (100.0%), 279.11 (18.6%), 280.11 (2.2%); 13C NMR
(300 MHz, CDCl3)
d (ppm): 55.4 (eOCH3), 15.7 and 131.0 (C]C at
pyran ring), 180.4 (CeNH2), 30.68 (eCH at pyran ring), 80.20
(CeC^N),110.22(eC]N),119.4,120.2,129.3,128.6,129.1,130.2,132.0,
134.4,135.4,136.2 (10 aromatic carbons); Anal. Calcd. for C17H14N2O2:
C, 73.37; H, 5.07; N, 10.07. Found: C, 73.33; H, 5.09; N, 10.05.
4.2.2. 2-Amino-7-hydroxy-4-(4-methoxyphenyl)-4H-chromene-3-
carbonitrile (4b)
3. Conclusion
218 ꢁC (ethanol), White solid, Yield 80%, IR (KBr) (cmꢂ1): 2840
n
(eOCH3), 3390 (eNH2 stretching), 3220 (eOH), 2200 (eC^N), 1250
We report successful synthesis, antitubercular and antimicro-
bial activity of new pyrimidine and thiopyrimidine derivatives.
The assumed structures are confirmed by the IR, 1H NMR, 13C
NMR, Mass spectra and Elemental analysis. The antitubercular
activity study revealed that all the tested compounds showed
good to moderate antitubercular activities against M. tuberculosis
H37Rv. Antimicrobial activity of title compounds showed that
presence of hydroxy groups attached to phenyl ring to the chro-
mene ring of the title compounds is responsible for good anti-
microbial activity. 5, 6, 7, 8(aee) demonstrated more significant
antibacterial, antifungal and antitubercular activity than the
corresponding lead molecules. The field is further open for study
of these compounds with respect to toxicity, chronic toxicity,
pharmacokinetics and clinical studies to establish these molecules
as drugs in the market.
(CeOeC at pyran ring); 1H NMR (300 MHz, CDCl3)
d
(ppm): 3.84 (s,
3H, eOCH3), 5.14 (s, 1H pyran), 6.80 (s, 2H, eNH2), 7.02 (d, 2H,
J ¼ 7.39 Hz, Ar-H), 7.42 (d, 1H, J ¼ 8.74 Hz, Ar-H), 7.46 (d, 2H,
J ¼ 7.43 Hz, Ar-H), 7.56 (d, 2H, J ¼ 8.34 Hz, Ar-H), 7.66 (s,1H, eOH); m/
z: 294.10 (100.0%), 295.10 (19.2%), 296.11 (1.6%); 13C NMR (300 MHz,
CDCl3)
d (ppm): 55.8 (eOCH3), 151.25 (CeOH), 145 and 121 (C]C at
pyran ring), 177.4 (CeNH2), 29.68 (eCH at pyran ring), 79.5
(CeC^N), 111.22 (eC]N), 114.2, 114.5, 119.3, 128.6, 129.1, 130.2,
132.0, 134.4, 135.4 (9 aromatic carbons); Anal. Calcd. for C17H14N2O3:
C, 69.38; H, 4.79; N, 9.52. Found: C, 69.38; H, 4.79; N, 9.52.
4.2.3. 2-Amino-4-(4-methoxyphenyl)-4H-benzo[h]chromene-3-
carbonitrile (4c)
215 ꢁC (ethanol), White solid, Yield 90%, IR (KBr) (cmꢂ1): 2845
n
(eOCH3), 3410 (eNH2), 2197 (eC^N), 1254 (CeOeC at pyran ring);

N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
5059
Table 2
The in vitro antimicrobial activity (MIC,
mg/ml) of the synthesized compounds.
Compd.
The minimum inhibitory concentration (MIC)
Gram - ive
Gram þ ive
Antifungal
Escherichia coli
Pseudomonas aeruginosa
Streptococcus
Staphylococcus aureus
Aspergillus niger
[ATCC-25922]
[MTCC e 441]
pyogenes [MTCC e 443]
[ATCC-25923]
[MTCC e 282]
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8c
8d
500
250
500
150
250
250
125
500
250
125
500
500
250
250
62.5
250
250
500
250
125
250
250
500
500
125
25
500
250
1000
500
250
250
250
500
250
125
500
500
250
125
125
250
125
250
500
125
250
250
250
500
125
25
250
125
500
250
125
125
62.5
250
250
62.5
250
250
125
250
125
125
250
250
125
125
125
62.5
500
500
62.5
50
250
125
500
250
125
125
62.5
250
125
62.5
250
250
125
125
125
125
125
250
125
62.5
125
62.5
500
250
62.5
50
1000
500
500
1000
500
500
500
125
1000
250
1000
500
1000
1000
125
250
250
500
500
250
500
250
1000
1000
500
e
8e
Ciprofloxacin
Ampicillin
Nystatin
Greseofulvin
100
e
100
e
250
e
100
e
e
100
100
e
e
e
e
1H NMR (300 MHz, CDCl3)
d
(ppm): 3.85 (s, 3H, eOCH3), 5.13 (s, 1H,
J ¼ 7.49 Hz, Ar-H), 7.60 (t, 1H, Ar-H), 7.85 (t, 2H, Ar-H), 7.56 (d, 2H,
J ¼ 7.64 Hz, Ar-H at pyridine ring); m/z: 329.12 (100.0%), 330.12
(21.9%), 331.12 (2.9%), 330.11 (1.1%); 13C NMR (300 MHz, CDCl3)
pyran), 6.88 (s, 2H, eNH2), 7.25 (d, 2H, J ¼ 7.21 Hz, Ar-H), 7.32 (d, 2H,
J ¼ 8.02 Hz, Ar-H), 7.46 (d, 2H, J ¼ 7.41 Hz, Ar-H), 7.60 (d, 2H,
J ¼ 8.25 Hz, Ar-H), 7.66 (t, 2H, Ar-H); m/z: 328.12 (100.0%), 329.12
d
(ppm): 55.8 (OCH3), 151.0 and 122.0 (C]C at pyran ring), 178.4
(23.5%), 330.13 (2.9%); 13C NMR (300 MHz, CDCl3)
d
(ppm): 55.6
(CeNH2), 79.4 (CeC^N), 109.20 (eC]N), 45.0 (eCH at pyran ring),
120.1, 126.2, 133.9, 135.0 (carbons at pyridine ring), 150.0 (eC]N at
pyridine ring), 129.6, 128.2, 129.8, 130.9, 132.6, 134.9, 135.4, 136.2
(aromatic carbons); Anal. Calcd. for C20H15N3O2: C, 72.94; H, 4.52;
N, 12.76. Found: C, 72.93; H, 4.54; N, 12.75.
(eOCH3), 151.0 and 122.0 (C]C at pyran ring), 178.4 (CeNH2), 30.1
(eCH at pyran ring)00, 79.4 (CeC^N), 109.20 (eC]N), 118.0, 119.5,
121.2, 123.5, 125.9, 127.3, 128.6, 129.1, 130.2, 132.0, 134.4, 135.4,
136.2, 140.2 (14 aromatic carbons); Anal. Calcd. for C21H16N2O2: C,
76.81; H, 4.91; N, 8.53. Found: C, 76.82; H, 4.95; N, 8.50.
4.3. General preparation of 5-(4-methoxyphenyl)-1,5-dihydro-2H-
4.2.4. 3-Amino-1-(4-Methoxyphenyl)-1H-benzo[f]chromene-2-
substitutedchromeno[2,3-d]pyrimidine-2,4(3H)-dithione 5(aee)
carbonitrile (4d)
278 ꢁC (ethanol), Yellow solid, Yield 74%, IR (KBr) (cmꢂ1): 2841
n
A mixture of compound 4(aee) (2.0 mmol) and carbon disul-
phide (152.0 mg, 2.0 mmol) in pyridine (10 ml) were refluxed on
water bath for 6 h (Monitored by TLC). After completion of reaction,
the reaction mixture was cooled at room temperature then poured
in to ice cold water (50 ml) and neutralized with hydrochloric acid
(1:1). The separate product was filtered off, washed and recrys-
talized from ethanol.
(eOCH3), 3420 (eNH2 stretching), 2210 (eC^N) 1257 (CeOeC at
pyran ring); 1H NMR (300 MHz, CDCl3)
d
(ppm): 3.83 (s, 3H, eOCH3),
5.31 (s, 1H, pyran eCH), 7.20 (d, 2H, J ¼ 7.27 Hz, Ar-H), 7.36 (d, 2H,
J ¼ 8.0 Hz, Ar-H), 7.44 (d, 2H, J ¼ 7.4 Hz, Ar-H), 7.62 (d, 2H, J ¼ 8.2 Hz,
Ar-H), 7.80 (t, 2H, Ar-H), 6.9 (s, 2H, eNH2); m/z: 328.12 (100.0%),
329.12 (23.5%), 330.13 (2.9%); 13C NMR (300 MHz, CDCl3)
d (ppm):
55.6 (OCH3), 151.0 and 122.0 (C]C at pyran ring), 178.4 (CeNH2),
30.1 (eCH at pyran ring), 79.4 (CeC^N), 109.20 (eC]N), 118.0,
119.5,121.2,123.5,125.9,127.3,128.6,129.1,130.2,132.0,134.4,135.4,
136.2, 140.2 (14 aromatic carbons); Anal. Calcd. for C21H16N2O2: C,
76.81; H, 4.91; N, 8.53. Found: C, 76.82; H, 4.95; N, 8.51.
4.3.1. 5-(4-Methoxyphenyl)-1,5-dihydro-2H-chromeno[2,3-d]
pyrimidine-2,4(3H)-dithione (5a)
162e163 ꢁC (ethanol), Yellow solid, Yield 74%, IR (KBr) (cmꢂ1):
n
3337, 3212 (eNH stretching), 2843 (eOCH3), 1508, 1646, 1622 (eNH
bending), 1442, 1254 (CeOeC at pyran ring), 1307 (pC]S pyrimi-
dine dithione ring); 1H NMR (300 MHz, CDCl3)
d (ppm): 3.83 (s, 3H,
4.2.5. 2-Amino-4-(4-Methoxyphenyl)-4H-pyrano[3,2-h]quinoline-
3-carbonitrile (4e)
eOCH3), 4.71 (s, 1H, pyran eCH), 8.56 (s, 1H, eNH), 7.03 (d, 2H,
J ¼ 7.11 Hz, Ar-H), 7.12 (d, 2H, J ¼ 8.10 Hz, Ar-H), 7.22 (d, 2H,
J ¼ 7.43 Hz, Ar-H), 6.48e6.75 (t, 2H, Ar-H); m/z: 354.05 (100.0%),
355.05 (21.9%), 356.05 (9.9%), 356.06 (1.8%), 357.05 (1.8%); 13C NMR
270 ꢁC (ethanol), Yellow solid, Yield 85%, IR (KBr) (cmꢂ1): 2846
n
(eOCH3), 3390 (eNH2 stretching), 2200 (eC^N), 1253 (CeOeC at
pyran ring); 1H NMR (300 MHz, CDCl3)
d
(ppm): 3.81 (s, 3H,
eOCH3), 5.18 (s, 1H pyran eCH), 6.9 (s, 2H, eNH2), 7.34 (d, 2H,
J ¼ 7.20 Hz, Ar-H), 7.39 (d, 2H, J ¼ 8.08 Hz, Ar-H), 7.48 (d, 2H,
(300 MHz, CDCl3)
(eCH at pyran ring), 55.8 (eOCH3), 177.0, 194.9 (pC]S at
d (ppm): 150.7, 166.0 (CeOeC at pyran ring), 45.0

5060
N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
pyrimidine dithione ring), 118.0, 119.4, 120.2, 129.3, 128.6, 129.1,
130.2, 132.0, 134.4, 135.4, 136.2 (aromatic carbons); Anal. Calcd. for
C18H14N2O2S2 (354.45): C, 60.99; H, 3.98; N, 7.90. Found: C, 61.02; H,
3.96; N, 7.93%.
2H, J ¼ 8.09 Hz, Ar-H), 7.49 (d, 2H, J ¼ 7.33 Hz, Ar-H), 7.65 (t, 1H, Ar-
H), 7.68 (t, 2H, Ar-H), 8.27 (d, 2H, J ¼ 7.69 Hz, Ar-H at pyridine ring);
m/z: 405.06 (100.0%), 406.06 (25.5%), 407.06 (10.1%), 407.07 (2.5%),
408.06 (2.2%). 13C NMR (300 MHz, CDCl3)
d (ppm): 55.83 (eOCH3),
151.1, 169.0 (CeOeC at pyran ring), 44.0 (eCH at pyran ring), 178.2,
194.7 (pC]S at pyrimidine dithione ring), 120.1, 126.2, 133.9, 135.0
(carbons at pyridine ring), 150.0 (eC¼N at pyridine ring), 129.6,
128.2, 129.8, 130.9, 132.6, 134.9, 135.4, 136.2 (aromatic carbons);
Anal. Calcd. for C21H15N3O2S2 (405.49): C, 62.20; H, 3.73; N, 10.36.
Found: C, 62.22; H, 3.71; N, 10.39%.
4.3.2. 8-Hydroxy-5-(4-methoxyphenyl)-1,5-dihydro-2H-chromeno
[2,3-d]pyrimidine-2,4(3H)-dithione (5b)
181e183 ꢁC (ethanol), Yellow solid, Yield 81%, IR (KBr) (cmꢂ1):
n
3428, 3299 (eNH stretching), 2842 (eOCH3), 1510, 1637, 1625,
(eNH bending), 3200 (eOH), 1448, 1246 (CeOeC at pyran ring),
1315 (pC]S at pyrimidine dithione ring); 1H NMR (300 MHz,
CDCl3)
d
(ppm): 3.83 (s, 3H, eOCH3), 4.74 (s,1H, pyran eCH), 8.58 (s,
4.4. General preparation of 5-(4-methoxyphenyl)-3,5-dihydro-4H-
1H, eNH), 8.98 (s, 1H, eOH), 6.58 (d, 2H, J ¼ 7.45 Hz, Ar-H), 7.32 (d,
1H, J ¼ 8.89 Hz, Ar-H), 7.47 (d, 2H, J ¼ 7.42 Hz, Ar-H), 7.85 (d, 2H,
J ¼ 8.51 Hz, Ar-H); m/z: 370.04 (100.0%), 371.05 (19.7%), 372.04
(9.2%), 372.05 (2.8%), 371.04 (2.3%), 373.04 (1.9%); 13C NMR
substitutedchromeno[2,3-d]pyrimidine-4-one 6(aee)
A mixture of compound 4(aee) (2.0 mmol) and excess of formic
acid were refluxed on sand bath for 12 h (Monitored by TLC). After
completion of the reaction, solvent was distilled off under reduced
pressure and the solid thus obtained was purified by recrystalli-
zation from absolute ethanol to give compounds 6(aee).
(300 MHz, CDCl3)
d (ppm): 55.83 (eOCH3), 151.1, 168.0 (CeOeC at
pyran ring), 160.0 (CeOH), 43.1 (eCH at pyran ring), 177.5 and 194.7
(pC]S at pyrimidine dithione ring), 119.4, 120.2, 129.3, 128.6, 129.1,
130.2, 132.0, 134.4, 135.4, 136.2 (aromatic carbons); Anal. Calcd. for
C18H14N2O3S2 (370.45): C, 58.36; H, 3.82; N, 7.56. Found: C, 58.37;
H, 3.80; N, 7.53%.
4.4.1. 5-[4-Methoxyphenyl]-3,5-dihydro-4H-chromeno[2,3-d]
pyrimidine-4-one (6a)
154e156 ꢁC (ethanol), Cream solid, Yield 71%, IR (KBr) (cmꢂ1):
n
4.3.3. 7-(4-Methoxyphenyl)-7H-benzo[7, 8]chromeno[2,3-d]
3372 (eNH stretching), 1690 (pC]O), 2843 (eOCH3), 1610 (eC]N
at pyrimidine ring), 1515 (eNH bending), 1441, 1256 (CeOeC at
pyrimidine-8,10(9H,11H)-dithione (5c)
165e167 ꢁC (ethanol), Yellow solid, Yield 71%, IR (KBr)
n
(cmꢂ1):
pyran ring); 1H NMR (300 MHz, CDCl3)
d (ppm): 3.81 (eOCH3), 4.74
3455, 3343 (eNH stretching), 2839 (eOCH3), 1513,1648,1620 (eNH
bending), 1434, 1249 (CeOeC at pyran ring), 1303 (pC]S at
(s, 1H, pyran eCH), 7.92 (d, 1H, eNH at pyrimidine ring), 7.64 (d, 1H,
eCH at pyrimidine ring), 7.12 (d, 2H, J ¼ 7.23 Hz, Ar-H), 7.20 (d, 2H,
J ¼ 8.16 Hz, Ar-H), 7.37 (d, 2H, J ¼ 7.45 Hz, Ar-H), 6.83e6.90 (t, 2H,
Ar-H); m/z: 306.10 (100.0%), 307.10 (20.3%), 308.11 (1.8%); 13C NMR
pyrimidine dithione ring); 1H NMR (300 MHz, CDCl3)
d: 3.76 (s, 3H,
eOCH3), 4.77 (s, 1H, pyran eCH), 8.54 (s, 1H, eNH), 7.01 (d, 2H,
J ¼ 7.18 Hz, Ar-H), 7.21 (d, 2H, J ¼ 8.11 Hz, Ar-H), 7.60 (d, 2H,
J ¼ 7.46 Hz, Ar-H), 7.77 (d, 2H, J ¼ 8.29 Hz, Ar-H), 7.89 (t, 2H, Ar-H);
m/z: 404.07 (100.0%), 405.07 (24.1%), 406.06 (9.1%), 406.07 (3.7%),
(300 MHz, CDCl3)
d (ppm): 55.43 (eOCH3), 155.5, 152.9 (CeOeC at
pyran ring), 39.3 (eCH at pyran ring), 150.2 (eC]N at pyrimidine
ring), 162.1.0 (pC]O), 106.1, 108.5, 110.5, 113.6, 120.2, 123.3, 125.9,
128.4, 129.2, 130.3 (aromatic carbons); Anal. Calcd. for C18H14N2O3
(306.31): C, 70.58; H, 4.61; N, 9.15. Found: C, 70.60; H, 4.59; N,
9.16%.
405.06 (2.3%), 407.06 (2.3%); 13C NMR (300 MHz, CDCl3)
d (ppm):
55.76 (eOCH3), 152.1, 170.0 (CeOeC at pyran ring) 44.9 (eCH at
pyran ring), 177.5, 194.7 (pC]S at pyrimidine dithione ring), 119.4,
120.2, 123.9, 155, 129.3, 128.6, 129.1, 130.2, 132.0, 134.4, 135.4, 136.2
(aromatic carbons); Anal. Calcd. for C22H16N2O2S2 (404.50): C,
65.32; H, 3.99; N, 6.93. Found: C, 65.29; H, 4.03; N, 6.95%.
4.4.2. 8-Hydroxy-5-(4-methoxyphenyl)-3,5-dihydro-4H-chromeno
[2,3-d]pyrimidine-4-one (6b)
165e168 ꢁC (ethanol), White solid, Yield 55%, IR (KBr) (cmꢂ1):
n
4.3.4. 12-(4-Methoxyphenyl)-8,12-dihydro-9H-benzo[5,6]
3381 (eNH stretching), 1697 (pC]O stretching), 2840 (eOCH3),
1616 (eC]N at pyrimidine ring), 1511 (eNH bending), 1457, 1239
(CeOeC at pyran ring), 3200 (eOH); 1H NMR (300 MHz, CDCl3)
chromeno[2,3-d]pyrimidine-9,11(10H)-dithione (5d)
175e177 ꢁC (ethanol), Yellow solid, Yield 67%, IR (KBr) (cmꢂ1):
n
3432, 3339 (eNH stretching), 2844 (eOCH3), 1503, 1639, 1627
(eNH bending), 1436, 1266 (CeOeC at pyran ring), 1292 (pC]S at
d (ppm): 3.84 (eOCH3), 4.81 (s, 1H, pyran eCH), 8.12 (d, 1H, eNH at
pyrimidine ring), 7.50 (d, 1H, eCH at pyrimidine ring), 9.0 (s, 1H,
eOH), 6.77 (d, 2H, J ¼ 7.51 Hz, Ar-H), 7.19 (d, 1H, J ¼ 8.77 Hz, Ar-H),
7.24 (d, 2H, J ¼ 7.33 Hz, Ar-H), 7.30 (d, 2H, J ¼ 8.39 Hz, Ar-H); m/z:
322.10 (100.0%) 323.10(19.8%), 324.10 (2.8%); 13C NMR (300 MHz,
pyrimidine dithione ring); 1H NMR (300 MHz, CDCl3)
d (ppm): 3.84
(s, 3H, eOCH3), 4.74 (s, 1H, pyran eCH), 8.61 (s, 1H, eNH), 7.24 (d,
2H, J ¼ 7.28 Hz, Ar-H), 7.46 (d, 2H, J ¼ 8.19 Hz, Ar-H), 7.64 (d, 2H,
J ¼ 7.38 Hz, Ar-H), 7.72 (d, 2H, J ¼ 8.29 Hz, Ar-H), 8.20 (t, 2H, Ar-H);
m/z: 404.07 (100.0%), 405.07 (24.1%), 406.06 (9.1%), 406.07 (3.7%),
CDCl3) d (ppm): 55.42 (eOCH3) 156.5, 154.5 (CeOeC at pyran ring),
40.0 (eCH at pyran ring), 150.6 (eC]N at pyrimidine ring), 161.3
(pC]O), 162.6 (CeOH), 101.1, 108.5, 111.5, 123.6, 123.2, 125.3, 125.9,
128.4, 129.2, 130.3, 131.0 (aromatic carbons); Anal. Calcd. for
C18H14N2O4 (322.31): C, 67.07; H, 4.38; N, 8.69. Found: C, 67.09; H,
4.35; N, 8.72%.
405.06 (2.3%), 407.06 (2.3%); 13C NMR (300 MHz, CDCl3)
d (ppm):
55.84 (eOCH3), 152.1, 170.0 (CeOeC at pyran ring), 44.9 (eCH at
pyran ring), 177.5, 194.7 (pC]S at pyrimidine dithione ring), 119.6,
120.3, 123.9, 125.0, 129.1, 128.4, 129.4, 130.0, 132.2, 134.7, 135.5,
136.4 (aromatic carbons); Anal. Calcd. for C22H16N2O2S2 (404.50): C,
65.32; H, 3.99; N, 6.93. Found: C, 65.30; H, 4.02; N, 6.96%.
4.4.3. 7-(4-Methoxyphenyl)-7,9-dihydro-8H-benzo[7,8]chromeno
[2,3-d]pyrimidine-8-one (6c)
4.3.5. 7-(4-Methoxyphenyl)-7H-pyrimido[50,40:5,6]pyrano[3,2-h]
153e156 ꢁC (ethanol), Brown solid, Yield 64%, IR (KBr) (cmꢂ1):
n
quinoline-8,10(9H,11H)-dithione (5e)
3364 (eNH stretching), 1705 (pC]O), 2848 (eOCH3), 1602 (eC]N
at pyrimidine ring), 1523 (eNH bending), 1450, 1266 (CeOeC at
187e189 ꢁC (ethanol), Brown solid, Yield 59%, IR (KBr) (cmꢂ1):
n
3455, 3329 (eNH stretching), 2845 (eOCH3), 1519, 1640, 1631 (eNH
Bending), 1447, 1249 (CeOeC at pyran ring), 1313 (pC]S at
pyran ring); 1H NMR (300 MHz, CDCl3)
d (ppm): d 3.85 (eOCH3),
4.80 (s, 1H, pyran eCH), 8.10 (d, 1H, eNH at pyrimidine ring), 7.55
(d, 1H, eCH at pyrimidine ring), 6.50 (d, 2H, J ¼ 7.22 Hz, Ar-H), 6.87
(d, 2H, J ¼ 7.99 Hz, Ar-H), 6.99 (d, 2H, J ¼ 7.53 Hz, Ar-H), 7.14 (d, 2H,
J ¼ 8.25 Hz, Ar-H), 7.25 (t, 2H, Ar-H); m/z: 356.12 (100.0%), 357.12
pyrimidine dithione ring); 1H NMR (300 MHz, CDCl3)
d (ppm): 3.83
(s, 3H, OCH3), 4.78 (s, 1H pyran eCH), 8.26 (s, 1H, eNH), 7.30e7.56
(m, 3H, Ar-H at pyridine ring), 7.34 (d, 2H, J ¼ 7.21 Hz, Ar-H), 7.41 (d,

N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
5061
(24.1%), 358.12 (3.5%); 13C NMR (300 MHz, CDCl3)
d
(ppm): 55.44
322.11 (20.6%), 323.12 (2.5%); 13C NMR (300 MHz, CDCl3)
d
(ppm):
(eOCH3), 144.0e151.0 (CeOeC at pyran ring), 37.9 (eCH at pyran
ring), 151.8 (eC]N at pyrimidine ring), 161.2 (pC]O), 118.2, 120.7,
121.8, 122.6, 123.2, 125.8, 126.9, 127.4, 128.6, 129.9, 130.4, 130.2
(aromatic carbons); Anal. Calcd. for C22H16N2O3 (356.37): C, 74.15;
H, 4.53; N, 7.86. Found: C, 74.18; H, 4.55; N, 7.83%.
55.44 (eOCH3) 150.3, 148.9 (CeOeC at pyran ring), 33.8 (eCH at
pyran ring),163.3 (CeNH2), 162.5 (pC]O),122.5, 122.5, 123.6,124.2,
125.3, 127.9, 128.4, 129.2, 130.3, 131.0 (aromatic carbons); Anal.
Calcd. for C18H15N3O3 (321.33): C, 67.28; H, 4.71; N, 13.08. Calcd: C,
67.25; H, 4.74; N, 13.05%.
4.4.4. 12-(4-Methoxyphenyl)-10,12-dihydro-11H-benzo[5,6]
4.5.2. 4-Amino-8-hydroxy-5-(4-methoxyphenyl)-1,5-dihydro-2H-
chromeno[2,3-d]pyrimidine-11-one (6d)
chromeno[2,3-d]pyrimidine-2-one (7b)
155e157 ꢁC (ethanol), Yellow solid, Yield 68%, IR (KBr)
n
(cmꢂ1):
170e173 ꢁC (ethanol), Brown solid, Yield 75%, IR (KBr) (cmꢂ1):
n
3389 (eNH stretching), 2840 (eOCH3),1725 (pC]O),1618 (eC]N at
pyrimidine ring), 1522 (eNH bending), 1460, 1221 (CeOeC at pyran
3450 (eNH stretching at NH2), 1613, 1510 (eNH bending at eNH2),
3306 (eNH stretching at pyrimidine ring), 3215 (eOH), 2849
(eOCH3), 1667 (pC]O), 1580 (eC]N at pyrimidine ring), 1456, 1407
(CeN pyrimidine ring), 1437, 1265 (CeOeC at pyran ring); 1H NMR
ring); 1H NMR (300 MHz, CDCl3)
d (ppm): 3.80 (eOCH3), 4.85 (s, 1H,
pyran eCH), 8.15 (d,1H, eNH at pyrimidine ring), 7.52 (d,1H, eCH at
pyrimidine ring), 6.77 (d, 2H, J ¼ 7.21 Hz, Ar-H), 7.12 (d, 2H,
J ¼ 8.10 Hz, Ar-H), 7.44 (d, 2H, J ¼ 7.47 Hz, Ar-H), 7.45 (d, 2H,
J ¼ 8.26 Hz, Ar-H), 7.65 (t, 2H, Ar-H); m/z: 356.12 (100.0%), 357.12
(300 MHz, CDCl3) d (ppm): 3.79 (eOCH3), 4.76 (s,1H, pyran eCH), 8.0
(s, 2H, eNH2), 8.12 (s, 1H, eNH at pyrimidine ring), 9.09 (s, 1H, eOH),
6.85(d, 2H, J ¼ 7.44 Hz, Ar-H), 7.11 (d,1H, J¼ 8.77 Hz, Ar-H), 7.26 (d, 2H,
J ¼ 7.48 Hz, Ar-H), 7.30 (d, 2H, J ¼ 8.49 Hz, Ar-H); m/z: 337.11 (100.0%),
338.11 (19.8%), 339.11 (2.9%), 338.10 (1.1%); 13C NMR (300 MHz, CDCl3)
(24.1%), 358.12 (3.5%); 13C NMR (300 MHz, CDCl3)
d (ppm): 55.84
(eOCH3), 145.0, 151.0 (CeOeC at pyran ring) 37.6 (eCH at pyran
ring), 151.2 (eC]N at pyrimidine ring), 161.4 (pC]O), 118.2, 120.7,
121.8, 122.6, 123.2, 125.8, 126.9, 127.4, 128.6, 129.9, 130.4, 130.2
(aromatic carbons). Anal. Calcd. for C21H14N2O2 (356.37): C, 74.15; H,
4.53; N, 7.86. Found: C, 74.16; H, 4.56; N, 7.84%.
d
(ppm): 55.79 (eOCH3), 154.5, 136.2 (CeOeC at pyran ring), 34.4
(eCH at pyran ring), 164.6 (CeNH2), 161.3 (pC]O), 162.8 (CeOH),
100.2, 110.5, 111.5, 123.6, 123.2, 125.3, 125.9, 128.4, 129.2, 130.3, 131.0
(aromatic carbons); Anal. Calcd. for C18H15N3O4 (355.34): C, 60.09; H,
4.48; N, 12.46. Found: C, 60.05; H, 4.46; N, 12.49%.
4.4.5. 7-(4-Methoxyphenyl)-7,9-dihydro-8H-pyrimido[50,40:5,6]
pyrano[3,2-h]quinoline-8-one (6e)
4.5.3. 8-Amino-7-(4-methoxyphenyl)-7,11-dihydro-10H-benzo[7,8]
170e172 ꢁC (ethanol), Yellow solid, Yield 63%, IR (KBr)
n
(cmꢂ1):
chromeno[2,3-d]pyrimidine-10-one (7c)
3376 (eNH stretching),1730 (pC]O), 2842 (eOCH3),1601 (eC]N at
pyrimidine ring), 1504 (eNH bending), 1448, 1247 (CeOeC at pryan
172e175 ꢁC (ethanol), Green solid, Yield 68%, IR (KBr) (cmꢂ1):
n
3448 (eNH stretching at NH2), 1604, 1512 (eNH bending at eNH2),
3311 (eNH stretching at pyrimidine ring), 2839 (eOCH3), 1657 (pC]
O stretching), 1575 (eC]N at pyrimidine ring), 1444, 1416 (CeN at
pyrimidine ring), 1264 (CeOeC at pyran ring); 1H NMR (300 MHz,
ring); 1H NMR (300 MHz, CDCl3)
d (ppm): 3.84 (eOCH3), 4.92 (s, 1H,
pyran eCH), 8.10 (d, 1H, eNH at pyrimidine ring), 7.56 (d, 2H,
J ¼ 7.55 Hz, Ar-H at pyridine ring), 7.34e7.49 (m, 3H, Ar-H at pyridine
ring), 6.83 (d, 2H, J ¼ 7.29 Hz, Ar-H), 7.21(d, 2H, J ¼ 8.15Hz, Ar-H), 7.28
(d, 2H, J ¼ 7.41 Hz, Ar-H), 7.47 (t, 1H, Ar-H), 7.63 (t, 2H, Ar-H); m/z:
357.11 (100.0%), 358.11 (23.8%), 359.12 (3.1%); 13C NMR (300 MHz,
CDCl3)
d (ppm): 3.79 (eOCH3), 4.75 (s, 1H, pyran eCH), 8.05 (s, 2H,
eNH2), 8.16 (s, 1H, eNH at pyrimidine ring), 7.03 (d, 2H, J ¼ 7.28 Hz,
Ar-H), 7.18 (d, 2H, J ¼ 8.12 Hz, Ar-H), 7.44 (d, 2H, J ¼ 7.55 Hz, Ar-H),
7.69 (d, 2H, J ¼ 8.33 Hz, Ar-H), 7.89 (t, 2H, Ar-H); m/z: 371.13 (100.0%),
372.13 (24.1%), 373.13 (3.6%), 372.12 (1.1%); 13C NMR (300 MHz,
CDCl3) d (ppm): 55.84 (eOCH3), 162.2, 151.4 (CeOeC at pyran ring),
39.3 (eCH at pyran ring), 150.0 (eC]N at pyrimidine ring), 162.6
(pC]O), 120.1, 127.2, 135.2, 137.6 (carbons at pyridine ring), 150.7
(eC]N at pyridine ring),128.6,131.2,131.8,132.9,133.6,134.9,135.4,
136.2 (aromatic carbons); Anal. Calcd. for C21H15N3O3 (357.36): C,
70.58; H, 4.23; N, 11.76. Found: C, 70.61; H, 4.25; N, 11.74%.
CDCl3)
d (ppm): 55.79 (eOCH3), 136.0, 151.0 (CeOeC at pyran ring),
32.7 (eCH at pyran ring), 164.6 (CeNH2), 148.4 (pC]O), 123.2, 122.7,
123.8, 123.6, 124.2, 125.8, 126.9, 127.4, 128.6, 129.9, 130.4, 130.2
(aromatic carbons); Anal. Calcd. for C22H17N3O3 (371.38): C, 71.15; H,
4.61; N, 11.31. Found: C, 71.14; H, 4.63; N, 11.28%.
4.5. General preparation of 4-amino-5-(4-methoxyphenyl)-1,5-
dihydro-2H-substituted chromeno[2,3-d]pyrimidine-2-one 7(aee)
4.5.4. 11-Amino-12-(4-methoxyphenyl)-8,12-dihydro-9H-benzo
[5,6]chromeno[2,3-d]pyrimidine-9-one (7d)
A mixture of compound 4(aee) (2.0 mmol) and urea (120.0 mg,
2.0 mmol) with catalytic amount of sodium ethoxide in ethanol
(15 ml) was refluxed on water bath for 6e7 h (Monitored by TLC).
After completion of reaction, the reaction mixture was poured in
crushed ice (50 g) and neutralized by the diluted hydrochloric acid
(1:1). The separated product was collected by the filtration and
washed with water. The crude product was purified by crystalli-
zation from absolute ethanol 7(aee).
190e192 ꢁC (ethanol), Brown solid, Yield 74%, IR (KBr) (cmꢂ1):
n
3446 (eNH stretching at NH2), 1615, 1505 (eNH bending at eNH2),
3322 (eNH stretching at pyrimidine ring), 2850 (eOCH3), 1643
(pC]O), 1579 (eC]N at pyrimidine ring), 1452, 1419 (CeN at
pyrimidine ring), 1267 (CeOeC at pyran ring); 1H NMR (300 MHz,
CDCl3)
d (ppm): 3.85 (eOCH3), 4.78 (s, 1H, pyran eCH), 7.95 (s, 2H,
eNH2), 8.05 (s, 1H, eNH at pyrimidine ring), 6.89 (d, 2H, J ¼ 7.10 Hz,
Ar-H), 7.14 (d, 2H, J ¼ 8.11 Hz, Ar-H), 7.23 (d, 2H, J ¼ 7.39 Hz, Ar-H),
7.30 (d, 2H, J ¼ 8.29 Hz, Ar-H), 7.35 (t, 2H, Ar-H); m/z: 371.13 (100.0%),
372.13 (24.1%), 373.13 (3.6%), 372.12 (1.1%); 13C NMR (300 MHz,
4.5.1. 4-Amino-5-(4-methoxyphenyl)-1,5-dihydro-2H-chromeno
[2,3-d]pyrimidine-2-one (7a)
CDCl3) d (ppm): 55.79 (eOCH3), 136.0, 151.0 (CeOeC at pyran ring),
168e172 ꢁC (ethanol), Brown solid, Yield 58%, IR (KBr)
n
(cmꢂ1):
32.7 (eCH at pyran ring),164.6 (CeNH2),158.4 (pC]O),123.2,122.7,
123.8, 123.6, 124.2, 125.8, 126.9, 127.4, 128.6, 129.9, 130.4, 130.2
(aromatic carbons); Anal. Calcd. for C22H17N3O3 (371.38): C, 71.15; H,
4.61; N, 11.31. Found: C, 71.17; H, 4.64; N, 11.30%.
3446 (eNH stretching at NH2), 1605, 1509 (eNH bending at eNH2),
3301 (eNH stretching at pyrimidine ring), 2844 (eOCH3), 1653
(pC]O), 1579 (eC]N at pyrimidine ring), 1454, 1400 (CeN at
pyrimidine ring), 1448, 1260 (CeOeC at pyran ring); 1H NMR
(300 MHz, CDCl3)
d
(ppm): 3.84 (eOCH3), 4.84 (s, 1H, pyran eCH),
4.5.5. 8-Amino-7-(4-methoxyphenyl)-7,11-dihydro-10H-pyrimido
8.15 (s, 2H, eNH2), 8.21 (s, 1H, eNH at pyrimidine ring), 6.78 (d, 2H,
J ¼ 7.17 Hz, Ar-H), 7.26 (d, 2H, J ¼ 8.13 Hz, Ar-H), 7.45 (d, 2H,
J ¼ 7.52 Hz, Ar-H), 6.89e7.10 (t, 2H, Ar-H); m/z: 321.11 (100.0%),
[50,40:5,6]pyrano[3,2-h]quinoline-10-one (7e)
168e170 ꢁC (ethanol), Yellow solid, Yield 78%, IR (KBr) (cmꢂ1):
n
3446 (eNH stretching at NH2), 1614, 1508 (eNH bending at eNH2),

5062
N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
3313 (eNH stretching at pyrimidine ring), 2835 (eOCH3), 1649
(pC]O stretching), 1580 (eC]N at pyrimidine ring), 1455, 1405
(CeN at pyrimidine ring), 1250 (CeOeC at pyran ring); 1H NMR
4.6.3. 8-Amino-7-(4-methoxyphenyl)-7,11-dihydro-10H-benzo[7,8]
chromeno[2,3-d]pyrimidine-10-thione (8c)
178e179 ꢁC (ethanol), Green solid, Yield 75%, (KBr)
n
(cmꢂ1):
(300 MHz, CDCl3)
d
(ppm): 3.86 (eOCH3), 4.84 (s, 1H, pyran eCH),
3430 (eNH stretching at eNH2), 3315 (eNH stretching at pyrimi-
dine ring), 3050, 1610 (eNH bending at eNH2), 2840(eOCH3), 1570
(eC]N pyrimidine ring), 1505 (eNH bending at pyrimidine ring),
1450, 1250 (CeOeC at pyran ring),1185 (pC]S stretching); 1H NMR
8.24 (s, 2H, eNH2), 8.11 (s, 1H, eNH at pyrimidine ring), 6.83 (d, 2H,
J ¼ 7.26 Hz, Ar-H), 7.31 (d, 2H, J ¼ 8.10 Hz, Ar-H), 7.49 (d,
2H, J ¼ 7.49 Hz, Ar-H), 7.60 (t, 1H, Ar-H), 7.64 (t, 2H, Ar-H), 7.57 (d,
2H, J ¼ 7.63 Hz, Ar-H at pyridine ring); m/z: 372.12 (100.0%), 373.13
(23.0%), 374.13 (3.1%), 373.12 (1.5%); 13C NMR (300 MHz, CDCl3)
(300 MHz, CDCl3)
d (ppm): 3.75 (eOCH3), 4.80 (s, 1H, pyran eCH),
8.17 (s, 2H, eNH2), 8.10 (s, 1H, eNH at pyrimidine ring), 6.90 (d, 2H,
J ¼ 7.12 Hz, Ar-H), 7.28 (d, 2H, J ¼ 8.01 Hz, Ar-H), 7.36 (d, 2H,
J ¼ 7.48 Hz, Ar-H), 7.54 (d, 2H, J ¼ 8.23 Hz, Ar-H), 8.10 (t, 2H, Ar-H);
m/z: 387.10 (100.0%), 388.11 (24.1%), 389.10 (4.8%), 389.11 (3.4%),
d
(ppm): 55.87 (eOCH3), 136.9, 151.4 (CeOeC at pyran ring) 34.8
(eCH at pyran ring), 164.8 (CeNH2), 160.9 (pC]O), 119.6, 128.0,
135.8, 137.2 (carbons at pyridine ring), 150.0 (eC]N at pyridine
ring), 128.6, 131.2, 131.8, 132.9, 133.6, 134.9, 135.4, 136.2 (aromatic
carbons); Anal. Calcd. for C21H16N4O3 (372.37): C, 67.73; H, 4.33; N,
15.05. Found: C, 67.70; H, 4.31; N, 15.01%.
388.10 (1.9%), 390.10 (1.1%); 13C NMR (300 MHz, CDCl3)
d (ppm):
55.42 (eOCH3), 143.0, 149.2 (CeOeC at pyran ring), 34.8 (eCH at
pyran ring), 165.6 (CeNH2), 181.4 (pC]S), 119.2, 120.5, 123.5, 123.6,
123.2, 125.3, 125.9, 126.4, 126.6, 127.9, 128.4, 129.2, 130.3, 131.0
(aromatic carbons); Anal. Calcd. for C22H17N3O2S (387.45): C, 68.20;
H, 4.42; N, 10.85. Found: C, 68.17; H, 4.44; N, 10.84%.
4.6. General preparation of 4-amino-5-(4-methoxyphenyl)-1H-
substitutedchromeno[2,3-d]pyrimidine-2(5H)-thione 8(aee)
A mixture of compound 4(aee) (2.0 mmol) and thiourea
(152.0 mg, 2.0 mmol) with catalytic amount of sodium ethoxide in
ethanol (15 ml) was refluxed on water bath for 6e7 h (Monitored by
TLC). After completion of reaction, the reaction mixture was poured
in crushed ice (50 g) and neutralized by the diluted hydrochloric
acid (1:1). The separated product was collected by the filtration and
washed with water. The crude product was purified by crystalli-
zation from absolute ethanol 8(aee).
4.6.4. 11-Amino-12-(4-methoxyphenyl)-8,12-dihydro-9H-benzo
[5,6]chromeno[2,3-d]pyrimidine-9-thione (8d)
200e203 ꢁC (ethanol), Green solid, Yield 88%, (KBr)
n
(cmꢂ1):
3446 (eNH stretching at eNH2), 3050, 1605, (eNH bending at
eNH2), 3301 (eNH stretching at pyrimidine ring), 2844 (eOCH3),
1573 (eC]N pyrimidine ring), 1515 (eNH bending at pyrimidine
ring),1445,1250 (CeOeC at pyran ring),1180 (pC]S stretching); 1H
NMR (300 MHz, CDCl3)
d (ppm): 3.86 (eOCH3), 4.80 (s, 1H, pyran
eCH), 8.18 (s, 2H, eNH2), 8.10 (s, 1H, eNH at pyrimidine ring), 6.60
(d, 2H, J ¼ 7.29 Hz, Ar-H), 7.21 (d, 2H, J ¼ 8.10 Hz, Ar-H), 7.51 (d, 2H,
J ¼ 7.57 Hz, Ar-H), 7.66 (d, 2H, J ¼ 8.30 Hz, Ar-H), 7.90 (t, 2H, Ar-H);
m/z: 387.10 (100.0%), 388.11 (24.1%), 389.10 (4.8%), 389.11 (3.4%),
4.6.1. 4-Amino-5-(4-methoxyphenyl)-1H-chromeno[2,3-d]
pyrimidine-2(5H)-thione (8a)
185e187 ꢁC (ethanol), Cream solid, Yield 65%, IR (KBr) (cmꢂ1):
n
2846 (eOCH3), 3430 (eNH stretching at eNH2), 3034, 1613 (eNH
bending at eNH2), 3331 (eNH stretching at pyrimidine ring), 1573
(eC]N pyrimidine ring), 1505 (eNH bending at pyrimidine ring),
1454, 1250 (CeOeC at pyran ring),1180 (pC]S stretching); 1H NMR
388.10 (1.9%), 390.10 (1.1%); 13C NMR (300 MHz, CDCl3)
d (ppm):
55.41(eOCH3), 149.0, 150.2 (CeOeC at pyran ring), 35.9 (eCH at
pyran ring), 163.9 (CeNH2), 180.4 (pC]S), 123.2, 122.7, 128.8, 129.6,
130.2, 131.8, 132.9, 133.4, 133.6, 134.9, 135.4, 135.2, 135.3, 136.0
(aromatic carbons); Anal. Calcd. for C22H17N3O2S (387.45): C, 68.20;
H, 4.42; N, 10.85. Found: C, 68.18; H, 4.43; N, 10.87%.
(300 MHz, CDCl3)
d (ppm): 3.84 (eOCH3), 4.74 (s, 1H, pyran eCH),
8.14 (s, 2H, eNH2), 8.15 (s, 1H, eNH at pyrimidine ring), 7.11 (d, 2H,
J ¼ 7.25 Hz, Ar-H), 7.21 (d, 2H, J ¼ 8.10 Hz, Ar-H), 7.37 (d, 2H,
J ¼ 7.41 Hz, Ar-H), 6.83e6.97 (t, 2H, Ar-H); m/z: 337.09 (100.0%),
338.09 (21.6%), 339.08 (4.5%), 339.10 (1.8%); 13C NMR (300 MHz,
4.6.5. 8-Amino-7-(4-methoxyphenyl)-7,11-dihydro-10H-pyrimido
[50,40:5,6]pyrano[3,2-h]quinoline-10-thione (8e)
CDCl3)
d
(ppm): 55.46 (eOCH3), 153.3, 149.9 (CeOeC at pyran ring),
190e192 ꢁC (ethanol), Yellow solid, Yield 65%, (KBr) (cmꢂ1):
n
34.4 (eCH at pyran ring), 164.6 (CeNH2), 55.8 (eOCH3), 182.5 (pC]
S), 121.5, 122.2, 123.4, 125.1, 125.6, 128.2, 128.8, 129.3, 131.0, 131.3
(aromatic carbons); Anal. Calcd. for C18H15N3O2S (337.39): C, 64.08;
H, 4.48; N, 12.45. Found: C, 64.10; H, 4.47; N, 12.41%.
3438 (eNH stretching at eNH2), 3329 (eNH stretching at pyrimi-
dine ring), 3043, 2838(eOCH3), 1612 (eNH bending at NH2), 1576
(eC]N pyrimidine ring), 1506 (eNH bending at pyrimidine ring),
1454,1260 (CeOeC at pyran ring),1175 (pC]S Stretching); 1H NMR
(300 MHz, CDCl3)
d (ppm): 28.55(eOCH3), 4.81 (s, 1H, pyran eCH),
4.6.2. 4-Amino-8-hydroxy-5-(4-methoxyphenyl)-1,5-dihydro-2H-
8.10 (s, 2H, eNH2), 8.12 (s, 1H, eNH at pyrimidine ring), 6.82 (d,
2H, J ¼ 7.22 Hz, Ar-H), 7.25 (d, 2H, J ¼ 8.11 Hz, Ar-H), 7.38 (d, 2H,
J ¼ 7.58 Hz, Ar-H), 7.60 (t, 1H, Ar-H), 7.97 (t, 2H, Ar-H), 7.47 (d, 2H,
J ¼ 7.6 Hz, Ar-H at pyridine ring); m/z: 342.11 (100.0%), 343.12
(21.9%), 344.12 (2.7%), 343.11 (1.5%); m/z: 388.10 (100.0%), 389.10
(25.1%), 390.10 (5.5%), 390.11 (2.5%), 391.10 (1.1%); 13C NMR
chromeno[2,3-d]pyrimidine-2-thione (8b)
176e178 ꢁC (ethanol), Orange solid, Yield 71%, (KBr)
n
(cmꢂ1):
2855 (eOCH3), 3438, (eNH stretching at eNH2), 3030, 1610 (eNH
bending at eNH2), 3316 (eNH stretching at pyrimidine ring), 3210
(eOH), 1567 (eC]N pyrimidine ring), 1525 (eNH bending at
pyrimidine ring), 1452, 1250 (CeOeC at pyran ring), 1179 (pC]S
(300 MHz, CDCl3)
d (ppm): 55.44 (eOCH3),149.0e150.2 (CeOeC at
stretching); 1H NMR (300 MHz, CDCl3)
d
(ppm): 3.88 (eOCH3), 4.80
pyran ring) 36.8 (eCH at pyran ring), 164.9 (CeNH2), 180.7 (pC]S),
120.1, 122.2, 130.3, 134.5 (carbons at pyridine ring), 149.4 (eC]N at
pyridine ring), 129.6, 130.2, 131.8, 132.9, 133.6, 134.9, 135.4, 136.2
(aromatic carbons); Anal. Calcd. for C21H16N4O2S (388.44): C, 64.93;
H, 4.15; N, 14.42. Found: C, 64.90; H, 4.13; N, 14.39%.
(s, 1H, pyran eCH), 8.09 (s, 2H, eNH2), 8.22 (s, 1H, eNH at pyrim-
idine ring), 9.05 (s, 1H, eOH), 7.10 (d, 2H, J ¼ 7.56 Hz, Ar-H), 7.43 (d,
1H, J ¼ 8.89 Hz, Ar-H), 7.73 (d, 2H, J ¼ 7.33 Hz, Ar-H), 8.10 (d, 2H,
J ¼ 8.41 Hz, Ar-H); m/z: 353.08 (100.0%), 354.09 (19.8%), 355.08
(4.7%), 355.09 (2.6%), 354.08 (1.9%); 13C NMR (300 MHz, CDCl3)
d
(ppm): 55.40 (eOCH3), 154.5, 149.9 (CeOeC at pyran ring), 34.0
4.7. In vitro antibacterial and antifungal activity
(eCH at pyran ring), 164.6 (CeNH2), 180.4 (pC]S), 55.8 (OCH3),
162.9 (CeOH), 100.4, 100.5, 112.2, 123.2, 123.5, 125.8, 126.0, 128.4,
129.2, 130.3, 131.5 (aromatic carbons); Anal. Calcd. for C18H15N3O3S
(353.39): C, 61.18; H, 4.28; N, 11.89. Found: C, 61.21; H, 4.30; N,
11.92%.
A definition of the minimum inhibitory concentration MIC is “the
lowest concentrationwhich resulted in maintenance or reduction of
inoculums viability”. The determination of the MIC involves a semi
quantitative test procedure which gives an approximation to the

N.R. Kamdar et al. / European Journal of Medicinal Chemistry 45 (2010) 5056e5063
5063
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least concentration of antimicrobial agent needed to prevent
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Acknowledgements
The authors thank to Department of Chemistry, Veer Narmad
South Gujarat University, Surat, for providing laboratory facilities
and D. Rajani, Microcare Laboratory, Surat, for antitubercular and
antimicrobial activity. The authors also thank SAIF, Chandigarh for
analytical analysis.
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