A Convenient Synthesis of Bipyrido-Fused Coumarins and Their Biological Evaluation

Article abstract of DOI:10.1002/jhet.3672

A convenient and efficient strategy has been devised for the synthesis of bipyrido-fused coumarins employing Kr?hnke's pyridine synthesis approach. In the present work, 4-hydroxycoumarins 1a–d were reacted with appropriate chalcones 2a–c to afford desired

Full text of DOI:10.1002/jhet.3672

Month 2019
A Convenient Synthesis of Bipyrido-Fused Coumarins and Their
Biological Evaluation
Rakesh R. Giria*
b
and Dinkar I. Brahmbhatt
a
Department of Chemistry, S.P.T. Arts and Science College, Godhra 389001, Gujarat, India
b
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar 388120, Gujarat, India
*
E-mail: drrakeshgiri@gmail.com
Received April 13, 2019
DOI 10.1002/jhet.3672
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A convenient and efficient strategy has been devised for the synthesis of bipyrido-fused coumarins
employing Kröhnke’s pyridine synthesis approach. In the present work, 4-hydroxycoumarins 1a–d were
reacted with appropriate chalcones 2a–c to afford desired bipyridyl-fused coumarins 3a–l. The structures
1
13
of all the newly synthesized compounds 3a–l were ascertained by IR, H NMR, C NMR, mass spectral
data, and elemental analyses. The compounds were further evaluated for their antimicrobial response against
representative panel of pathogens, and the results thus obtained were compared with those of standard drugs.
Few of the derivatives 3c, 3f, and 3i exhibited promising potency.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
vigorous reaction condition, and lower yield, and also the
reported methods have very limited scope of introducing
substitution in coumarin ring or pyridine ring.
Coumarin derivatives, natural as well as synthetic, belong
to a cardinal class of heterocycles that possess a diverse
range of applications. Coumarins, along with possessing
varied biological activities such as antidepressant [1],
anticancer [2], antibacterial [3], anti-HIV [4], and anti-
inflammatory [5] activities, also have been extensively
studied for their other applications such as photochemical
Earlier, we have reported the synthesis of bipyridyl-
substituted coumarins [27–29] and pyrido-fused
coumarins [30,31]. Therefore, in continuation of our
effort to synthesize new heterocycles and study their
biological responses, herein, we report the synthesis of 2-
aryl-4-(pyridin-4-yl)-5H-chromeno[4,3-b]pyridin-5-one
(3a–l) (bipyrido-fused coumarins) and their antimicrobial
activity.
[
6], chemiluminescence [7], growth regulators in plant [8],
cosmetics [9], laser dyes, nonlinear optical chromophores,
fluorescent whiteners, fluorescent probes, polymers,
optical recording, and solar energy collectors [10,11].
Among coumarin derivatives, pyrido-fused coumarins
constitute an important category that is known to have
properties such as wound healing [12], anti-allergic [13],
anticoagulant [14], antidiabetic [15], and analgesic [16]
properties. During our literature survey, we came to know
that bipyridine moieties are components of molecules
that are of varied applications such as in supramolecular
chemistry [17], photocatalysis [18], nonlinear optical
chromophore [19], fungicidal activity [20], and cardiotonic
drugs [21]. Despite possessing such astonishing properties,
no attempt has been made to synthesize compounds
having both these scaffolds, namely, pyrido-fused
coumarins and bipyridines. An earlier report on the
synthesis of pyrido-fused coumarin [22–26] suffers from
several shortcomings such as operational complexity,
RESULTS AND DISCUSSION
The required α,β-unsaturated carbonyls (chalcones)
2a–c were prepared by aldol condensation of appropriate
acetophenone and 4-formyl pyridine. These chalcones
were then reacted with appropriate 4-hydroxycoumarin
1a–d in the presence of ammonium acetate and acetic
acid to afford the target compounds 3a–l (Scheme 1) in
55–67% yield (Table 1). A plausible mechanism for the
synthesis of title compounds 3a–l is depicted in
Scheme 2. The structures of all compounds 3a–l were
1
13
established on the basis of IR, H-NMR, C NMR, and
selected mass spectral data.
The IR spectra of compounds 3a–l showed the
À1
characteristic band between 1728 and 1738 cm
for
©
2019 Wiley Periodicals, Inc.

R. R. Giri and D. I. Brahmbhatt
Vol 000
Scheme 1. Synthesis strategy for the target compounds 3a–l.
3
d and 3e became merged with other aromatic protons
Table 1
and hence could not be assigned separately. The signals
Physicochemical parameters of synthesized derivatives 3a–l.
for C ′–H and C ′–H appear in most downfield regions
2
6
Yield
(%)
Melting
point (°C)
owing to their attachment to the carbons that are
Compound
R
R
1
R
2
directly attached to N ′. The signals for C –H, C ″–H,
1
10
2
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
CH
CH
CH
H
H
H
H
CH
CH
CH
H
H
H
CH
OCH
Cl
CH
3
OCH
Cl
CH
3
OCH
Cl
3
64
67
63
59
57
61
55
62
64
58
62
63
263–264
246
223–225
199–201
179
185–187
277
219–221
271–273
245
and C ″–H appear in the downfield region owing to the
6
3
3
3
3
peri effect of N .
1
13
In the C NMR spectra of compounds 3a–l, the
coumarin carbonyl carbons, appeared as the most
deshielded signal between 160.61 and 162.75 δ. The
signals for other aromatic carbons were observed
between 105.24 and 162.11 δ. The compounds having
3
3
3
3
3
3
j
Cl
Cl
Cl
CH
3
methyl (CH ) group exhibited the corresponding signal
3
k
l
H
H
OCH
Cl
250–252
229
between 15.60 and 21.61 δ, and those bearing
methoxyl (OCH3) functionality depicted
a
signal
between 55.36 and 55.52 δ.
+
coumarin carbonyl stretching. The band observed
between 1581 and 1601 cm was assigned to aromatic
The mass spectrum of compound 3a showed M peak
at 364 (100%) m/z (%) along with other fragment
peaks at 336 (17%), 321 (2%), 182 (11%), 91 (4%),
44 (4%), and so on. The appearance of molecular ion
peak at 364 mass unit supports the structure of
compound 3a.
À1
C═C stretching. The stretching band for C═N was
À1
observed between 1528 and 1547 cm . The bands for
aliphatic and aromatic C–H stretchings were observed
À1
between 2921–2939 and 3031–3043 cm , respectively.
À1
The band observed between 814 and 832 cm
was
Evaluation of antimicrobial activity.
All compounds
assigned to C–H bending of p-disubstituted benzene ring.
The H NMR spectra of compounds 3a–l exhibited a
doublet of doublet integrating for one proton between
3a–l were assayed for their in vitro antimicrobial activity
against Gram-positive bacteria [viz. Bacillus subtilis
1
(MTCC 441) and Staphylococcus aureus (MTCC 96)]
7
.58 and 8.01 δ was attributed to C –H. The signal
and Gram-negative bacteria [viz. Escherichia coli
(MTCC 443) and Salmonella typhimurium (MTCC 98)]
and antifungal activity against Aspergillus niger (MTCC
282) and Candida albicans (MTCC 227) by broth
1
0
for C ″–H and C ″–H appeared as doublet integrating
2
6
for two proton between 7.69 and 8.24 δ. The most
deshielded doublet observed between 8.63 and 8.80 δ,
integrating for two protons, was assigned to C ′–H and
2
dilution method [32].
C ′–H. The other aromatic protons resonated between
6
The antimicrobial activity results presented in Table 2
6
.59 and 7.74 δ. The compounds bearing CH3 group
reveal that compound 3f [minimum inhibitory
concentration (MIC) = 100 μg/mL] and compounds
3c and 3i (MIC = 125 μg/mL) showed admirable
activity against B. subtilis than did ampicillin
(MIC = 250 μg/mL). Compounds 3a, 3c, and 3d
gave singlet for methyl between 2.41 and 2.75 δ.
Similarly, compounds bearing methoxyl (OCH3)
functionality exhibited a singlet around 3.9 δ. The
signals for C –H, C ″–H, and C ″–H of compounds
10
2
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient and Convenient Synthesis of Hither to Unreported Bipyrido Fused
Coumarins 3a-l has been Carried Out and Screened for Their Biological Activities
Scheme 2. Plausible mechanism for the synthesis of compounds 3a–l.
Table 2
Antimicrobial activity data for compounds 3a–l.
Minimum Inhibitory Concentration (μg/mL)
Gram +ve bacteria
B.s. S.a.
Gram Àve bacteria
E.c. S.t.
125
Fungi
Compound
A.n.
C.a.
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
250
250
125
250
250
100
200
250
125
250
250
200
250
50
100
200
100
100
250
200
250
200
125
200
200
250
250
50
250
250
200
100
200
100
250
250
200
200
250
250
100
50
>1000
1000
500
>1000
250
>1000
500
>1000
500
1000
250
>1000
—
>1000
500
200
250
100
100
200
200
250
125
250
200
250
100
50
500
500
1000
1000
250
>1000
250
>1000
>1000
>1000
—
j
k
l
Ampicillin
Chloramphenicol
Ciprofloxacin
Norfloxacin
Gentamicin
Griseofulvin
Nystatin
—
—
—
—
100
100
—
—
—
—
500
100
50
50
25
25
100
1
10
0.25
10
10
0.05
5
—
—
—
—
—
—
—
—
B.s., Bacillus subtilis; S.a., Staphylococcus aureus; E.c., Escherichia coli; S.t., Salmonella typhi; A.n., Aspergillus niger; C.a., Candida albicans.
(
MIC = 100 μg/mL) and 3i (MIC = 125 μg/mL) exerted
found to be more potent against S. aureus than ampicillin
(MIC = 250 μg/mL).
excellent activity against S. aureus than did ampicillin
(
MIC = 250 μg/mL).
Compounds 3g and 3l (MIC = 200 μg/mL) showed
Compounds 3a, 3b, 3d, 3e, 3h, 3j, and 3k
(MIC = 250 μg/mL) were found to be equipotent against
B. subtilis, while compounds 3e, 3g, and 3l
(MIC = 250 μg/mL) exhibited equal activity against
better activity against B. subtilis, whereas compounds 3b,
f and 3h, and 3j and 3k (MIC = 200 μg/mL) were
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. R. Giri and D. I. Brahmbhatt
Vol 000
S. aureus than ampicillin. Compounds 3d and 3e
General procedure for synthesis of 2-aryl-4-(pyridin-4-yl)-
H-chromeno[4,3-b]pyridin-5-one (3a–l).
4
5
An appropriate
-hydroxycoumarin 1a–d (0.005 mol) was taken in
(MIC = 100 μg/mL) and compounds 3d and 3f
MIC = 100 μg/mL) were found to be equipotent to
(
ampicillin against E. coli and Salmonella typhi,
respectively.
glacial acetic acid (15 mL). To this solution,
ammonium acetate (0.05 mol) was added, and then a
solution of appropriate 3-(pyridin-4-yl)-1-aryl-prop-2-en-
1-one 2a–c (0.005 mol) in acetic acid (15 mL) was
added while stirring at ambient temperature. The
reaction mixture was further stirred for 30 min and
then refluxed in an oil bath at 140°C. The progress of
reaction was monitored by thin-layer chromatography. It
was then allowed to come to ambient temperature and
poured into ice-cold water (75 mL). The gummy mass
obtained was extracted with chloroform (3 × 30 mL).
The combined chloroform extract was washed with
10% sodium bicarbonate solution (3 × 20 mL) and
then with water (3 × 20 mL). It was then dried over
anhydrous sodium sulfate. The removal of chloroform
under vacuum gave a solid product. This was further
purified by column chromatography using silica gel and
ethyl acetate–pet.ether (60:80) (2:8) as an eluent. Thus,
2-aryl-4-(pyridin-4-yl)-5H-chromeno[4,3-b]pyridin-5-one
Compounds 3g and 3i (MIC = 250 μg/mL) depicted
better activity than did griseofulvin (MIC = 500 μg/mL),
whereas compounds 3b, 3c, and 3d were found to be
equipotent to griseofulvin (MIC = 500 μg/mL) against
C. albicans. None of the tested compounds were found to
possess better activity against A. niger than were standard
drugs.
All compounds 3a–l possess promising antibacterial
activity against Gram-positive bacteria B. subtilis and
S. aureus. By examining the antimicrobial data, it has
been observed that the derivatization of the parent
molecule altered the antimicrobial potency of the
synthesized analogues.
The observation indicates that varying the substitution
on coumarin ring did not affect the antibacterial activity
to a remarkable extent, but as the substitution on
pendant phenyl ring was altered, a drastic change in
antibacterial potency was observed. For example, when
CH3 group was replaced with OCH3 group, the
antibacterial potency varied but to a smaller extent.
When the CH3 was replaced by Cl group, the
antibacterial potency enhanced markedly. In fact,
(
3a–l) (bipyridyl-fused coumarins) were obtained as
white to pale yellow solid, which were recrystallized
from chloroform–hexane.
4-(Pyridin-4-yl)-2-p-tolyl-5H-chromeno[4,3-b]pyridin-5-one
(3a). IR (KBr) (ν): 3031 (Ar C–H), 2921 (Ali.C–H),
compounds 3c, 3f, and 3i (R = Cl) emerged as most
1728 (C═O), 1581 (C═C), 1534 (C═N), 819 (p-
2
À1
1
proficient members of the series. It can be concluded
that introducing an electron-withdrawing group in
pendant phenyl ring enhances the antibacterial activity
against the Gram-positive bacterial stains.
disubstituted benzene ring) cm ; H NMR (CDCl
(ppm): 2.49 (s, 3H, CH ), 7.35–7.71 (m, 8H, Ar–H),
7.86 (dd, 1H, J = 1.6 and 8.0 Hz, C10–H), 8.20 (d,
2H, J = 8.0 Hz, C ″–H and C ″–H), 8.76 (d, 2H,
J = 4.4 Hz, C ′–H and C
(ppm): 21.48 (CH ), 112.43 (C), 116.90 (CH), 119.53
(C), 121.77 (CH), 122.79 (CH), 124.64 (CH), 125.60
) δ
3
3
2
6
13
Among all the tested compounds, compounds 3c, 3f, and
2
′–H); C NMR (CDCl ) δ
6 3
3i were found to be the most proficient members of the
3
series.
(
(
CH), 127.73 (CH), 129.86 (CH), 132.44 (CH), 134.45
C), 141.71 (C), 147.71 (C), 149.45 (CH), 152.03 (C),
EXPERIMENTAL SECTION
152.89 (C), 153.15 (C), 159.35 (C), 161.53 (CO of
coumarin); MS m/z (%): 364 [M+]. Anal. Calcd. for
All the melting points were determined on μThermoCal
C
24
H
16
N
2
O
2
: C (79.11), H (4.43), N (7.69); found:
1
0 apparatus. All the IR spectra (KBr disc) were recorded
C (79.08), H (4.47), N (7.74).
1
on Shimadzu FT-IR 8400-S spectrometer. H NMR and
2
-(4-Methoxyphenyl)-4-(pyridin-4-yl)-5H-chromeno[4,3-b]
1
3
C NMR spectra were recorded on Bruker Avance 400
spectrometer (Bruker Corp., Billerica, MA) operating at
pyridin-5-one (3b). IR (KBr) (ν): 3038 (Ar C–H), 2932
(Ali.C–H), 1730 (C═O), 1589 (C═C), 1536 (C═N), 827
(p-disubstituted benzene ring) cm ; H NMR (CDCl ) δ
1
13
À1
1
4
00 MHz for H NMR and 100 MHz for C NMR.
3
The chemical shift (δ) is reported in ppm using
(ppm): 3.93 (3H, s, OCH ), 7.04–7.68 (8H, m, Ar–H),
3
DMSO-d as a solvent and calibrated standard solvent
7.78 (1H, dd, J = 1.6 and 8.4 Hz, C –H), 8.19 (2H, d,
6
10
signal. Mass spectra were recorded on Shimadzu QP
J = 8.8 Hz, C ″–H and C ″–H), 8.76 (2H, concealed d,
C ′–H and C ′–H); C NMR (CDCl ) δ (ppm): 55.52
2 6 3
2
6
13
2010 spectrometer (Shimadzu Corp., Kyoto, Japan).
Elemental analysis was carried out on PerkinElmer 2400
C-H-N-S-O Analyzer Series-II. The precursors 4-
hydroxycoumarin [31] 1a–d and 3-(pyridin-4-yl)-1-aryl-
prop-2-ene-1-ones [27] 2a–c were prepared according to
literature procedures.
(OCH ), 111.32 (C), 114.52 (CH), 118.10 (CH), 119.02
3
(CH), 122.26 (C), 122.98 (CH), 124.75 (CH), 126.68
(CH), 128.95 (C), 129.44 (CH), 132.44 (C), 135.43 (CH),
141.52 (C), 148.27 (C), 149.08 (CH), 151.81 (C), 155.09
(C), 160.39 (C), 161.27 (CO of coumarin). Anal. Calcd.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient and Convenient Synthesis of Hither to Unreported Bipyrido Fused
Coumarins 3a-l has been Carried Out and Screened for Their Biological Activities
for C H N O : C (75.78), H (4.24), N (7.36); found: C
(CH), 121.21 (C), 122.52 (CH), 124.03 (C), 125.14 (C),
128.43 (CH), 129.50 (CH), 130.17 (C), 131.22 (CH),
24 16 2 3
(
75.82), H (4.29), N (7.40).
2
-(4-Chlorophenyl)-4-(pyridin-4-yl)-5H-chromeno[4,3-b]
1
(
37.09 (CH), 137.64 (C), 145.31 (C), 148.61 (C), 150.11
CH), 151.88 (C), 152.48 (C), 161.22 (C), 162.75 (CO
of coumarin). Anal. Calcd. for C H ClN O :
pyridin-5-one (3c). IR (KBr) (ν): 3041 (Ar C–H), 2931
(
(
(
Ali.C–H), 1736 (C═O), 1593 (C═C), 1528 (C═N), 832
24
15
2 2
À1
1
p-disubstituted benzene ring) cm ; H NMR (CDCl ) δ
3
C (72.27), H (3.79), N (7.02); found: C (72.32), H
3.82), N (6.97).
ppm): 7.34–7.69 (8H, m, Ar–H), 7.74 (1H, dd, J = 1.6
(
and 10.0 Hz, C –H), 8.15 (2H, d, J = 8.0 Hz, C ″–H
10
2
7
-Methyl-4-(pyridin-4-yl)-2-p-tolyl-5H-chromeno[4,3-b]
and C ″–H), 8.80 (2H, d, J = 5.6 Hz, C ′–H and C ′–H);
6
2
6
pyridin-5-one (3g). IR (KBr) (ν): 3042 (Ar C–H), 2932
(Ali.C–H), 1735 (C═O), 1593 (C═C), 1533 (C═N),
1
3
C NMR (CDCl ) δ (ppm): 111.93 (C), 117.03 (CH),
3
À1
1
119.76 (C), 121.86 (CH), 122.71 (CH), 124.66
8
20 (p-disubstituted benzene ring) cm
;
H NMR
(
(
CH), 126.17 (CH), 127.75 (CH), 130.11 (CH), 132.52
CH), 135.53 (C), 142.22 (C), 147.89 (C), 149.61 (CH),
(
CDCl ) δ (ppm): 2.47 and 2.71 (6H, two s, 2 × CH ),
3
3
7
.32–7.64 (7H, m, Ar–H), 8.01 (1H, concealed dd,
151.94 (C), 153.19 (C), 154.47 (C), 160.21 (C), 162.42
C –H), 8.12 (2H, d, J = 8.0 Hz, C ″–H and C ″–H),
1
0
2
6
13
(
CO of coumarin). Anal. Calcd. for C H ClN O :
2
3
13
2
2
8.76 (2H, d, J = 5.2 Hz, C ′–H and C ′–H); C NMR
2 6
C (71.79), H (3.41), N (7.28); found: C (71.83), H (3.38),
N (7.33).
(
(
(
(
CDCl ) δ (ppm): 15.98 (CH ), 21.48 (CH ), 119.46
3 3 3
CH), 122.18 (C), 122.88 (CH), 124.21 (CH), 124.24
CH), 127.56 (C), 127.79 (CH), 129.84 (CH), 133.96
C), 136.39 (CH), 138.28 (C), 141.73 (C), 148.08 (C),
9
-Methyl-4-(pyridin-4-yl)-2-p-tolyl-5H-chromeno[4,3-b]
pyridin-5-one (3d). IR (KBr) (ν): 3043 (Ar C–H), 2939
(
(
(
(
Ali.C–H), 1734 (C═O), 1598 (C═C), 1536 (C═N), 824
1
1
49.25 (CH), 151.89 (C), 153.58 (C), 157.83 (C),
60.72 (C), 161.21 (CO of coumarin). Anal. Calcd. for
À1
1
p-disubstituted benzene ring) cm ; H NMR (CDCl ) δ
3
ppm): 2.46 and 2.47 (6H, two s, 2 × CH ), 7.35–8.20
3
C H N O : C (79.35), H (4.79), N (7.40); found: C
25 18 2 2
10H, m, Ar–H), 8.76 (2H, d, J = 5.6 Hz, C ′–H and
2
(79.39), H (4.83), N (7.37).
13
C ′–H); C NMR (CDCl ) δ (ppm): 20.88 (CH ), 21.50
6
3
3
2
-(4-Methoxyphenyl)-7-methyl-4-(pyridin-4-yl)-5H-
(
CH ), 117.88 (CH), 119.38 (CH), 122.82 (CH), 126.05
3
chromeno[4,3-b]pyridin-5-one (3h). IR (KBr) (ν): 3032 (Ar
C–H), 2938 (Ali.C–H), 1737 (C═O), 1599 (C═C), 1537
(CH), 127.76 (CH), 129.87 (CH), 133.79 (C), 134.38 (C),
1
(
1
34.54 (C), 134.68 (C), 136.71 (CH), 141.65 (C), 141.84
C), 147.95 (C), 149.33 (CH), 152.01 (C), 152.04 (C),
53.30 (C), 160.61 (CO of coumarin). Anal. Calcd. for
C H N O : C (79.35), H (4.79), N (7.40); found:
À1
1
(C═N), 829 (p-disubstituted benzene ring) cm
;
H
NMR (CDCl ) δ (ppm): 2.71 (3H, s, CH ), 3.92 (3H, s,
3
3
OCH ), 7.05–7.64 (7H, m, Ar–H), 8.01 (1H, concealed
3
2
5 18 2 2
dd, C –H), 8.21 (2H, d, J = 9.2 Hz, C ″–H and C ″–H),
1
0
2
6
C (79.40), H (4.83), N (7.37).
13
8
.76 (2H, concealed d, C ′–H and C ′–H); C NMR
2 6
2
-(4-Methoxyphenyl)-9-methyl-4-(pyridin-4-yl)-5H-
(
CDCl ) δ (ppm): 15.98 (CH ), 55.49 (OCH ), 114.49
3 3 3
chromeno[4,3-b]pyridin-5-one (3e). IR (KBr) (ν): 3041 (Ar
C–H), 2931 (Ali.C–H), 1731 (C═O), 1597 (C═C), 1547
(CH), 118.98 (CH), 122.22 (C), 122.88 (CH), 124.16
À1
1
(CH), 124.23 (CH), 127.49 (C), 129.53 (CH), 134.87 (C),
36.31 (CH), 139.55 (C), 141.02 (C), 145.77 (C), 148.13
C), 149.27 (CH), 153.58 (C), 160.33 (C), 161.28 (C),
162.30 (CO of coumarin). Anal. Calcd. for C25
C (76.13), H (4.60), N (7.10); found: C (76.10), H
(C═N), 832 (p-disubstituted benzene ring) cm
;
H
1
(
NMR (CDCl ) δ (ppm): 2.41 (3H, s, CH ), 3.92 (3H, s,
3
3
OCH ), 7.04–8.28 (10H, m, Ar–H), 8.75 (2H, concealed
3
1
3
H N O :
18 2 3
d, C ′–H and C ′–H); C NMR (CDCl ) δ (ppm):
2
6
3
2
1
1
1
1
1
1.52 (CH ), 55.36 (OCH ), 108.14 (CH), 114.62 (CH),
3 3
(4.56), N (7.15).
20.03 (CH), 121.49 (C), 122.40 (CH), 123.73 (C),
23.77 (C), 124.02 (C), 128.68 (CH), 131.61 (CH),
36.85 (CH), 141.52 (C), 145.36 (C), 149.51 (C),
50.34 (CH), 151.93 (C), 160.98 (C), 162.11 (C),
62.72 (CO of coumarin). Anal. Calcd. for C H N O :
2-(4-Chlorophenyl)-7-methyl-4-(pyridin-4-yl)-5H-
chromeno[4,3-b]pyridin-5-one (3i). IR (KBr) (ν): 3034 (Ar
C–H), 2928 (Ali.C–H), 1738 (C═O), 1596 (C═C), 1534
À1
1
(C═N), 826 (p-disubstituted benzene ring) cm
;
H
2
5 18 2 3
NMR (CDCl ) δ (ppm): 2.75 (3H, s, CH ), 7.33–7.69
C (76.13), H (4.60), N (7.10); found: C (76.09), H
4.57), N (7.15).
3
3
(7H, m, Ar–H), 8.01 (1H, concealed dd, C –H), 8.24
10
(
(
2H, d, J = 8.8 Hz, C ″–H and C ″–H), 8.76 (2H,
2
-(4-Chlorophenyl)-9-methyl-4-(pyridin-4-yl)-5H-
2
6
13
chromeno[4,3-b]pyridin-5-one (3f). IR (KBr) (ν): 3037 (Ar
C–H), 2928 (Ali.C–H), 1736 (C═O), 1601 (C═C), 1543
concealed d, C ′–H and C ′–H); C NMR (CDCl ) δ
2 6 3
(ppm): 15.60 (CH ), 112.00 (C), 119.48 (CH), 122.15
3
À1
1
(C═N), 829 (p-disubstituted benzene ring) cm
;
H
(C), 124.36 (CH), 127.58 (C), 129.13 (CH), 129.35 (CH),
131.79 (C), 133.96 (CH), 135.15 (C), 135.35
(CH), 136.56 (CH), 137.55 (C), 147.72 (C), 149.38 (CH),
152.34 (C), 153.56 (C), 159.33 (C), 161.17 (CO of
coumarin). Anal. Calcd. for C H ClN O : C (72.27),
NMR (CDCl ) δ (ppm): 2.46 (3H, s, CH ), 7.13–7.68
3
3
(7H, m, Ar–H), 7.92 (1H, dd, J = 1.6 and 7.6 Hz,
C –H), 8.06 (2H, d, J = 8.4 Hz, C ″–H and C ″–H),
1
0
2
6
1
3
8
.78 (2H, d, J = 6.0 Hz, C ′–H and C ′–H); C NMR
2 6
24 15
2 2
(
CDCl ) δ (ppm): 21.61 (CH ), 107.37 (CH), 118.12
H (3.79), N (7.02); found: C (72.31), H (3.84), N (6.97).
3
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. R. Giri and D. I. Brahmbhatt
Vol 000
8
9
-Chloro-4-(pyridin-4-yl)-2-p-tolyl-5H-chromeno[4,3-b]
10 CFU/mL (colony-forming unit) per milliliter well];
pyridin-5-one (3j). IR (KBr) (ν): 3033 (Ar C–H), 2925
that is, inoculum size for test strain was adjusted to
8
(
(
Ali.C–H), 1732 (C═O), 1585 (C═C), 1539 (C═N), 825
1
0 CFU/mL by comparing the turbidity (turbidimetric
À1
1
p-disubstituted benzene ring) cm ; H NMR (CDCl )
method). Similarly, fungi were inoculated on Sabouraud
dextrose broth; the procedures of inoculum
3
δ (ppm): 2.47 (3H, s, CH ), 7.34–7.74 (7H, m, Ar–H),
3
7
.87 (1H, dd, J = 1.6 and 8.0 Hz, C –H), 8.11 (2H, d,
10
standardization were also similar. Dimethyl sulfoxide
(DMSO) was used as diluent to obtain desired
concentration of synthesized compounds and standard
drugs to test upon standard microbial strains; that is,
the compounds were dissolved in DMSO, and the
solutions were diluted with a culture medium. Each
compound and standard drugs were diluted obtaining
2000 μg/mL concentration, as a stock solution. By
further progressive dilutions with the test medium, the
required concentrations were obtained for primary and
secondary screening. In the primary screening 1000,
500, and 250 μg/mL concentrations of the synthesized
compounds were taken. The active compounds found in
this primary screening were further diluted to obtain
J = 8.4 Hz, C ″–H and C ″–H), 8.78 (2H, d,
J = 5.2 Hz, C ′–H and C ′–H); C NMR (CDCl ) δ
2
6
1
3
2
6
3
(
(
(
ppm): 21.49 (CH ), 119.74 (CH), 122.77 (CH), 123.17
C), 126.06 (CH), 126.97 (CH), 127.79 (CH), 129.91
CH), 130.62 (C), 133.57 (C), 135.49 (CH), 136.36 (C),
3
1
1
39.37 (C), 142.13 (C), 147.47 (C), 149.39 (CH),
52.15 (C), 153.40 (C), 157.86 (C), 161.05 (CO
of coumarin). Anal. Calcd. for C H ClN O :
C (72.27), H (3.79), N (7.02); found: C (72.24), H
2
4
15
2 2
(3.82), N (7.08).
9-Chloro-2-(4-methoxyphenyl)-4-(pyridin-4-yl)-5H-
chromeno[4,3-b]pyridin-5-one (3k).
IR (KBr) (ν): 3041
Ar C–H), 2926 (Ali.C–H), 1731 (C═O), 1588 (C═C),
(
À1
1
529 (C═N), 818 (p-disubstituted benzene ring) cm ;
2
00, 100, 62.5, 50, 25, 12.5, and 6.25 μg/mL
1
H NMR (CDCl ) δ (ppm): 3.87 (3H, s, OCH ), 6.59–
3
3
concentrations for secondary screening to test in a
second set of dilution against all microorganisms.
Briefly, the control tube containing no antibiotic is
immediately subcultured (before inoculation) by
spreading a loopful evenly over a quarter of a plate of
medium suitable for the growth of the test organism.
The tubes are then put for incubation at 37°C for 24 h
for bacteria and 48 h for fungi. Growth or a lack of
growth in the tubes containing the antimicrobial agent
was determined by comparison with the growth control,
indicated by turbidity. The lowest concentration that
completely inhibited visible growth of the organism
was recorded as the MIC (μg/mL); that is, the amount
of growth from the control tube before incubation
7.28 (7H, m, Ar–H), 7.58 (1H, concealed dd, C –H),
10
7.69 (2H, d, J = 8.8 Hz, C ″–H and C ″–H), 8.63 (2H,
2
6
1
3
d, J = 4.8 Hz, C ′–H and C ′–H); C NMR (CDCl ) δ
2
6
3
(ppm): 55.47 (OCH ), 105.24 (CH), 114.51 (CH),
3
1
1
1
1
1
19.84 (CH), 121.33 (C), 122.30 (CH), 123.56 (C),
23.91 (C), 123.94 (C), 128.62 (CH), 131.49 (CH),
36.73 (CH), 141.52 (C), 145.27 (C), 149.45 (C),
50.27 (CH), 151.85 (C), 161.03 (C), 162.02 (C),
62.63 (CO of coumarin). Anal. Calcd. for
C H ClN O : C (69.49), H (3.64), N (6.75); found: C
2
4
15
2 3
(69.53), H (3.59), N (6.79).
9-Chloro-2-(4-chlorophenyl)-4-(pyridin-4-yl)-5H-
chromeno[4,3-b]pyridin-5-one (3l). IR (KBr) (ν): 3036 (Ar
C–H), 2924 (Ali.C–H), 1732 (C═O), 1582 (C═C), 1535
(which represents the original inoculum) is compared.
À1
1
(C═N), 814 (p-disubstituted benzene ring) cm
;
H
A set of tubes containing only seeded broth and the
solvent controls were maintained under identical
conditions so as to make sure that the solvent had no
influence on strain growth. The protocols were
summarized in Table 2 as the MIC (μg/mL).
NMR (CDCl ) δ (ppm): 6.64–7.55 (7H, m, Ar–H), 7.67
3
(2H, d, J = 8.4 Hz, C ″–H and C ″–H), 7.91 (1H,
2 6
concealed dd, C –H), 8.64 (2H, d, J = 5.6 Hz, C ′–H
and C ′–H); C NMR (CDCl ) δ (ppm): 106.39 (CH),
10
2
13
6
3
1
1
1
1
20.16 (CH), 121.08 (C), 122.45 (CH), 123.96 (C),
25.07 (C), 128.31 (CH), 129.43 (CH), 130.07 (C),
31.14 (CH), 137.06 (CH), 137.61 (C), 145.20 (C),
48.42 (C), 150.03 (CH), 151.77 (C), 152.36 (C), 161.10
CONCLUSION
(
C), 162.59 (CO of coumarin). Anal. Calcd. for
In conclusion, we reported convenient and efficient
synthesis of some new bipyridyl-fused coumarins. The
adopted strategy gave the target compounds in better
yields than did earlier reported methods. The
antimicrobial assay of the synthesized compounds
showed good-to-moderate activity. The compounds not
only can serve as lead for novel biologically potent
agents with varied mechanism of action but also can find
application in other fields as well, such as photochemistry
and nonlinear optical chromophores.
C H Cl N O : C (65.89), H (2.88), N (6.68); found: C
2
3
12
2 2 2
(65.94), H (2.92), N (6.73).
In vitro evaluation of antimicrobial activity. The MICs
of synthesized compounds were carried out by broth
microdilution method. Bacterial strains were primarily
inoculated into Mueller–Hinton agar, and after
overnight growth, a number of colonies were directly
suspended in saline solution until the turbidity matched
the turbidity of the McFarland standard [approximately
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
An Efficient and Convenient Synthesis of Hither to Unreported Bipyrido Fused
Coumarins 3a-l has been Carried Out and Screened for Their Biological Activities
Acknowledgment. The authors are thankful to the Head of the
Department of Chemistry, Sardar Patel University, for providing
basic research amenities.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet