Modified Pyridine-Substituted Coumarins: A New Class of Antimicrobial and Antitubercular Agents

Article abstract of DOI:10.1080/00397911.2014.963875

Some new biologically potent coumarin derivatives 7a-f, 8a-f, and 9a-f bearing modified pyridine moieties (indeno[1,2-b]pyridine, 4-azaphenanthrene and benzofuro [3,2-b]pyridine) at the sixth position were designed and synthesized. All the synthesized com

Full text of DOI:10.1080/00397911.2014.963875

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Modified Pyridine-Substituted
Coumarins: A New Class of Antimicrobial
and Antitubercular Agents
Rakesh R. Giria, Hemali B. Lada, Varun G. Bhilaa, Chirag V. Patela &
D. I. Brahmbhatta
a Department of Chemistry, Sardar Patel University, Vallabh
Vidyanagar, Gujarat, India
Accepted author version posted online: 10 Oct 2014.Published
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online: 13 Dec 2014.
To cite this article: Rakesh R. Giri, Hemali B. Lad, Varun G. Bhila, Chirag V. Patel & D. I. Brahmbhatt
(2015) Modified Pyridine-Substituted Coumarins: A New Class of Antimicrobial and Antitubercular
Agents, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 45:3, 363-375, DOI: 10.1080/00397911.2014.963875
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Synthetic Communications1, 45: 363–375, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2014.963875
MODIFIED PYRIDINE-SUBSTITUTED COUMARINS: A
NEW CLASS OF ANTIMICROBIAL AND
ANTITUBERCULAR AGENTS
Rakesh R. Giri, Hemali B. Lad, Varun G. Bhila,
Chirag V. Patel, and D. I. Brahmbhatt
Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar,
Gujarat, India
GRAPHICAL ABSTRACT
Some new biologically potent coumarin derivatives 7a–f, 8a–f, and 9a–f bearing modified
pyridine moieties (indeno[1,2-b]pyridine, 4-azaphenanthrene and benzofuro [3,2-b]
pyridine) at the sixth position were designed and synthesized. All the synthesized
compounds were assayed for their antimicrobial efficiency against Staphylococcus
aureus, Bacillus subtilis, Escherichia coli, Salmonella typhi, Candida albicans, and
Aspergillus niger. Most of the compounds showed appreciable antimicrobial activity
against the tested strains. Compounds 8b, 8c, 9b, 9d, and 9f emerged as most proficient
members of the series. The antitubercular activity for all the synthesized compounds was
performed against Mycobacterium tuberculosis H37Rv. Compounds 8f, 9b, and 9f
exhibited promising antitubercular activity. Consequently, synthesized derivatives were
found to be worthy of further investigation.
Keywords Antimicrobial activity; antitubercular activity; coumarins; Krohnke’s
reaction; modified pyridines
Received July 1, 2014.
Address correspondence to D. I. Brahmbhatt, Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar 388120, Gujarat, India. E-mail: drdib317@gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
363

364
R. R. GIRI ET AL.
INTRODUCTION
Tuberculosis (TB), a contagious disease caused by the infection with
Mycobacterium tuberculosis, remains a major global health problem. According
to the world Health Organization (WHO), there were almost 9 million new cases
and 1.4 million TB deaths reported worldwide in 2011.[1] TB is a global health
emergency because of the increase in the secondary infections and/or coinfection
in immunocompromised patients such as those infected with HIV and the emerg-
ence of Mycobacterium tuberculosis multidrug-resistant (MDR) and extensively
drug-resistant (XDR) strains.[2] Consequently, the development of new affordable
drugs with novel mechanisms of action and shorter and simpler regimens capable
of effectively treating MDR-TB and XDR-TB is of great importance. At the
moment there are a worryingly low number of potential new chemical entities
in the TB drug pipeline. Therefore, the current situation necessitates the
development of new antitubercular entities to end the scourge of this debilitating
disease.
For decades, various heterocyclic-bearing coumarin derivatives have been
exploited by medicinal chemists to achieve desirable biological properties such as
anti-inflammatory,[3] antibacterial,[4] antioxidant,[5] anticoagulant,[6] anti-HIV,[7]
antihyperlipidemic,[8] and antitumor[9] activities. Among the heterocyclic-
substituted coumarins, pyridine-substituted coumarins constitute an elite class of
compounds as they exhibit important biological activities such as central nervous
system depressant,[10] antifungal,[11] and antibacterial[12] activities. On the other
hand, there are reports that heterocycles bearing pyridine and modified pyridine
moieties (i.e., cyclopenta[b]pyridine, 5,6,7,8-tetrahydroquinoline, indeno[1,2-b]
pyridine, azaphenanthrene, benzofuro[3,2-b]pyridine) display important biological
properties such as cytotoxicity,[13,14] calcium antagonistic,[15] bovine liver
glutathione-S-transferase inhibitory,[16] wound healing,[17] in vitro antioxidant,[17]
antimicrobial,[18,19]
antituberculor.[22]
cyclooxygenase-2
inhibitor,[20]
antiallergic,[21]
and
In spite of displaying such astonishing biological activities, no significant
efforts hitherto have been made to synthesize a heterocycle incorporating both of
these biolabile nuclei and to study its biological properties. The hybridization of
the distinct pharmacophores of two different biologically active compounds in a
single molecular scaffold has been a key approach to design molecules with
synergistic properties of both the pharmacophores.
These findings prompted us to design and synthesize molecules that include
both coumarin and modified pyridine in a single molecular frame. Consequently,
herein we report the synthesis and antimicrobial and antitubercular evaluation of
some new 6-modified pyridine substituted coumarins 7a–f, 8a–f, and 9a–f with
the anticipation that integration of these two bioactive moieties into a single
scaffold may lead to novel heterocycles with fascinating antimicrobial and
antitubercular activities. All the synthesized compounds 7a–f, 8a–f, and 9a–f were
characterized by infrared (IR), 1H NMR, 13C NMR (APT), and elemental analysis.
Representative compounds 7a, 8a, and 9a were also characterized by mass spectral
analysis.

MODIFIED PYRIDINE-SUBSTITUTED COUMARINS
365
RESULTS AND DISCUSSION
Chemistry
The strategy acquired for the synthesis of the key precursors and target
compounds 7a–f, 8a–f, and 9a–f is depicted in Scheme 1.
Scheme 1. General pathway for the synthesis of key precursors and 4-methyl-3-phenyl-6-(4-aryl-5H-indeno
[1,2-b]pyridin-2-yl)coumarins 7a–f, 4-methyl-3-phenyl-6-(1-phenyl-9,10-dihydro-4-aza-phenanthren-3-yl)
coumarins 8a–f, 4-methyl-3-phenyl-6-(4-phenyl-benzofuro[3,2-b] pyridin-2-yl)coumarins 9a–f. Reagents
and reaction conditions: (a) 10% ethanolic KOH, rt, 5 h; (b) Hg(OAc)2, pyridine, reflux, 15 min; and (c)
NH4OAc, AcOH, reflux, 12 h.

366
R. R. GIRI ET AL.
The mechanism for the formation of compounds 7a–f, 8a–f, and 9a–f is
shown in Scheme 2. The reaction proceeds via Michael addition by the nucleophilic
attack of active methylene group of 6 at a,b-unsaturated carbonyl functionality of
2a–f, 3a–f, and 5a–f to afford 1,5-dicarbonyl intermediate, which in the presence
of ammonia gets cyclized to give the target compounds 7a–f, 8a–f, and 9a–f.
See Table 1 for their physical characteristics.
The structures of all the newly synthesized compounds were confirmed by
1
FT-IR, H NMR, 13C NMR (APT), and elemental analysis. Mass spectra were
recorded for representative compounds 7a, 8a, and 9a.
=
=
In the IR spectra of compounds 7a–f, the bands for aromatic C C and C N
stretching were observed around 1608 and 1641 cm−1 respectively. A sharp band
observed around 1708 cm−1 was attributed to C O stretching of d-lactone ring.
=
1
The H NMR spectra of compounds 7a–f exhibited a singlet around d 2.49 corre-
sponding to methyl group protons. The two CH2 protons appeared as a singlet
around d 4.03. A multiplet was observed between d 7.06 and 7.71 for aromatic pro-
tons. The C0ꢀH showed a concealed doublet of a doublet around d 8.28. The C7-H
appeared as9a doublet of a doublet at around d 8.33 and C5-H appeared as a doublet
around d 8.54. The 13C NMR (APT) spectra are in well agreement with the structures
assigned. The signals for CH3 and CH2 appeared around d 16.80 and 34.50 respect-
ively. The CO of d-lactone showed signal around d 161.55. Other aromatic carbons
exhibited signals between d 111.45 and 161.49. The IR spectra of compounds 8a–f
Scheme 2. Mechanism for the formation of compounds 7a–f, 8a–f, and 9a–f.

367

368
R. R. GIRI ET AL.
exhibited bands around 1541 and 1610 cm−1, which were attributed to aromatic C N
=
=
=
and C C stretching respectively. The band for C O stretching of d-lactone was
observed around 1718 cm−1. In 1H NMR spectra, the methyl group protons exhibited
a singlet around d 2.47. The four protons attached to C9 and C100 appeared as a multi-
0
plet around d 2.95. A multiplet was observed between d 6.96 and 7.65 due to aromatic
protons. A doublet of a doublet around d 8.36 and a doublet around d 8.53 were
0
observed for C7-H and C5-H respectively. The C5 -H exhibited a concealed doublet
of a doublet around d 8.57. The 13C NMR (APT) spectra showed signal for CH3
0
0
around d 16.80. The signals for C9 and C10 appeared around d 25.35 and 28.11
respectively. The CO of d-lactone exhibited a signal around d 162.40 while the aro-
matic carbon signals appeared between d 111.20 and 161.47. In the IR spectra of com-
=
=
=
pounds 9a–f and the aromatic C N and C C stretching bands were observed around
1465 and 1608 cm−1 respectively. The C O stretching band of d-lactone appeared
around 1714 cm−1. The 1H NMR spectra showed a singlet around d 2.49 for three pro-
tons of methyl group. The aromatic protons exhibited a multiplet between d 6.98 and
8.42. A doublet of doublet around d 8.36 and a concealed doublet around d 8.44
0
appeared, which were attributed to C7-H and C9 -H respectively. The C5-H showed
a doublet around d 8.62. In the 13C NMR (APT) the CH3 signal appeared around
d 16.85. The signal for CO appeared around d 161.32 while other aromatic carbons
exhibited signals between d 112.19 and 161.52. In case of the compounds 7a, 7c, 9a,
9d, and 6f, the 13C APT spectra showed one signal less than expected. The lack of
one signal may be due to overlapping of two carbon signals, which may have identical
chemical shifts. In 13C-APT spectrum of compounds 7f, 8f, and 9f, the three sets of
1
2
3
carbon appear as doublets due to the JC-F, JC-F, and JC-F couplings respectively
and consequently the number of signals is three more than expected.
The obtained elemental analyses are in good agreement with the proposed
structures. The mass spectra of representative compounds (i.e., compounds 7a, 8a,
and 9a) gave expected M+ peak corresponding to their molecular weight. The
physical characteristics of all the derivatives are shown in Table 1.
Biological Results
Antimicrobial activity. The MICs of synthesized compounds were deter-
mined by broth microdilution method as recommended by National Committee for
Clinical Laboratory Standards (NCCLS).[23] Antibacterial activity was screened
against two Gram-positive (Bacillus subtilis MTCC 441, Staphylococcus aureus
MTCC 96) and two Gram-negative (Escherichia coli MTCC 443, Salmonella typhi
MTCC 98) bacteria using ampicillin, chloramphenicol, and ciprofloxacin as standard
antibacterial drugs. Antifungal activity was screened against two fungal species
(Aspergillus niger MTCC 282, Candida albicans MTCC 227) where griseofulvin and
nystatin were used as standard antifungal drugs. The minimum inhibition concen-
tration (MIC) values were determined in terms of µg/mL (Table 2).
Compound 9d (MIC ¼ 25 µg/mL) exhibited excellent activity against Salmonella
typhi compared to ampicillin (MIC ¼ 100 µg/mL) and chloramphenicol (MIC ¼ 50 µg/
mL) and was equipotent to ciprofloxacin (MIC ¼ 25 µg/mL). Compounds 8b and 9f
(MIC ¼ 62.5 µg/mL) also showed appreciable activity against Salmonella typhi com-
pared to ampicillin (MIC ¼ 100 µg/mL) and comparable activity to chloramphenicol

MODIFIED PYRIDINE-SUBSTITUTED COUMARINS
369
Table 2. In vitro antimicrobial activity of synthesized coumarin derivatives 7a–f, 8a–f, and 9a–f MICs,
µg/mL
Gram-positive bacteria
Gram-negative bacteria
Fungi
B.S. MTCC
441
S.A.
MTCC 96
E.C. MTCC
443
S.T.
MTCC 98
C.A.
MTCC 227
A.N.
MTCC 282
Compound
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
200
500
500
200
100
62.5
100
62.5
100
500
500
250
100
125
200
125
500
125
250
50
250
500
250
200
125
100
125
125
100
500
500
250
125
62.5
125
100
250
200
250
50
62.5
250
500
100
500
500
250
100
62.5
200
100
62.5
100
62.5
100
125
250
50
125
250
500
200
500
500
200
62.5
125
200
100
100
125
100
125
25
200
62.5
100
50
25
n.t.
n.t.
500
500
>1000
1000
1000
250
>1000
500
250
1000
1000
1000
500
>1000
1000
>1000
250
200
>1000
>1000
>1000
500
>1000
>1000
1000
500
>1000
500
250
>1000
500
n.t.
250
1000
1000
1000
200
n.t.
n.t.
n.t.
100
500
9e
9f
Ampi.
Chlo.
Cipr.
Gris.
Nyst.
100
50
25
n.t.
n.t.
n.t.
n.t.
100
100
50
n.t.
n.t.
50
n.t.
n.t.
Notes. B.S., Bacillus subtilis; S.A., Staphylococcus aureus; E.C., Escherichia coli; S.T., Salmonella typhi; A.
N., Aspergillus niger; C.A., Candida albicans; MTCC, microbial type culture collection; Ampi., ampicillin;
Chlo., chloramphenicol; Cipr., ciprofloxacin; Gris., griseofulvin; Nyst., nystatin; and n.t., not tested.
(MIC ¼ 50 µg/mL). Against Escherechia coli, compounds 9f (MIC ¼ 50 µg/mL) and 8c,
8f, and 9b (MIC ¼ 62.5 µg/mL) exerted significant activity compared to ampicillin
(MIC ¼ 100 µg/mL) and chloramphenicol (MIC ¼ 50 µg/mL). Against Bacillus subtilis,
compounds 7f and 8b (MIC ¼ 62.5 µg/mL), 7e, 8a, 8c, and 9a (MIC ¼ 100 µg/mL), and
9b, 9d, and 9f (MIC ¼ 125 µg/mL) demonstrated excellent activity compared to ampi-
cillin (MIC ¼ 250 µg/mL). Against Staphylococcus aureus, compounds 9b (MIC ¼
62.5 µg/mL), 7f, 8c, and 9d (MIC ¼ 100 µg/mL), and 7e, 8a, 8b, 9a, and 9c (MIC ¼
125 µg/mL) showed excellent activity compared to ampicillin (MIC ¼ 250 µg/mL).
Compounds 7d and 9f (MIC ¼ 200 µg/mL) depicted better activity while
compounds 7c, 8f, and 9e (MIC ¼ 250 µg/mL) were equipotent to ampicillin (MIC ¼
250 µg/mL) against Staphylococcus aureus. Against Bacillus subtilis, compounds 7a,
7d, and 9c (MIC ¼ 200 µg/mL) showed better activity, whereas compound 8f (MIC ¼
250 µg/mL) was found to be equipotent to ampicillin (MIC ¼ 250 µg/mL). Against
Escherechia coli, compounds 7d, 8b, 8e, 9a, and 9c (MIC ¼ 100 µg/mL) were found
equipotential to ampicillin (MIC ¼ 100 µg/mL). Compounds 8e, 8f, and 9b (MIC ¼
100 µg/mL) were found equipotent to ampicillin (MIC ¼ 100 µg/mL) against
Salmonella typhi.

370
R. R. GIRI ET AL.
Compounds 7f, 8c, and 9b (MIC ¼ 250 µg/mL) and 9f (MIC ¼ 200 µg/mL)
showed excellent activity against Candida albicans compared to greseofulvin
(MIC ¼ 500 µg/mL). Compounds 7a, 7b, 8b, and 9a (MIC ¼ 500 µg/mL) showed
comparable activity to greseofulvin. None of the compounds showed appreciable
activity against Aspergillus niger.
Antituberculosis activity. The in vitro antitubercular activity of all the
newly synthesized compounds was determined by using Lowenstein–Jensen medium
(conventional method) against Mycobacterial tuberculosis H37Rv strain as described
by Rattan.[24] The observed results are presented in Table 3 in the form of inhibition
(%), relative to that of standard antitubercular drugs isoniazid and rifampicin.
Compounds demonstrating more than 90% inhibition in the primary screening were
retested at lower concentration (MIC) in a Lowenstein–Jensen medium and evalu-
ated for their MIC values. Three compounds exhibiting more than 90% inhibition
were again screened to get their MIC values (Table 4).
The encouraging results of the antimicrobial screening prompted us to screen
the title compounds for their in vitro antitubercular activity. The antitubercular
activity was performed against Mycobacterium tuberculosis H37Rv. The results are
summarized in Table 3.
Among the compounds screened for antitubercular activity, compounds 9f
(MIC ¼ 62.5 µg/mL), 8f (MIC ¼ 100 µg/mL), and 9b (MIC ¼ 125 µg/mL) were found
to possess the greatest potency against Mycobacterium tuberculosis with 95, 93, and
92% inhibition respectively (Table 4). Other derivatives showed moderate to poor
antitubercular activity. Compounds 9b, 9d, and 9f showed comparable activity to
Table 3. In vitro antituberculosis activity (percent
inhibition) of compounds 7a–f, 8a–f, and 9a–f against
M. tuberculosis H37Rv (at concentration 250 µg/mL)
Compound
Inhibition (%)
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
8f
9a
9b
9c
9d
40
51
35
49
12
65
27
53
47
39
44
93
70
92
81
62
64
95
99
98
9e
9f
Isoniazid
Rifampicin

MODIFIED PYRIDINE-SUBSTITUTED COUMARINS
371
Table 4. In vitro antituberculosis activity of title compounds exhibiting
greater inhibition against M. tuberculosis H37Rv (MICs, µg/mL)
Compound
Inhibition (%)
MIC (µg/mL)
8f
9b
9f
93
92
95
98
99
100
125
62.5
40
Rifampicin
Isoniazid
0.20
the standard drug. Alas, other derivatives showed moderate to poor antituberculosis
activity.
CONCLUSION
The present study reports the successful synthesis of a new series of coumarin
derivatives bearing biologically active modified pyridine entities (viz., indeno[1,2-b]
pyridine, 4-azaphenanthrene, and benzofuro[3,2-b]pyridine). The synthesized com-
pounds were screened for their antimicrobial and antitubercular activities. The
screening results revealed that all the compounds exhibited moderate to excellent
activities against all the pathogenic strains. Upon varying the substitution on aryl ring
appended to the pyridine ring and modifying the nature of pyridine moiety, the activi-
ties changed drastically. Compounds 8b, 8c, 9b, 9d, and 9f displayed excellent antibac-
terial activity. Compounds 8f, 9b, and 9f demonstrated good antitubercular activity.
Consequently, the compounds proved to be worthy for further modifications to
obtain more efficacious antibacterial and antimycobacterial compounds.
EXPERIMENTAL
All reactions were performed with commercially available reagents used with-
out further purification. All reactions were monitored by thin-layer chromatography
(TLC, on aluminium plates coated with silica gel 60 F254, 0.25 mm thickness, Merck)
carried on fluorescent-coated plates and detection of the components was made by
exposure to iodine vapors or ultraviolet (UV) light. Melting points were determined
on µThermocal 10 apparatus and are uncorrected. IR spectra were recorded on
Shimadzu FT-IR 8400-S spectrometer using potassium bromide pellets in the range
4000–400 cm−1 and frequencies of only characteristic peaks are expressed in cm−1
.
1H and 13C NMR spectra were recorded in CDCl3 on a Bruker Avance 400 F
(MHz) spectrometer (Bruker Scientific Corporation Ltd., Switzerland) using residual
solvent signal as an internal standard at 400 and 100 MHz respectively. Chemical
shifts were reported in parts per million (ppm). Mass spectra were scanned on a
Shimadzu LCMS 2010 spectrometer (Shimadzu, Tokyo, Japan). Elemental analyses
were performed by Perkin-Elmer 2400 series II elemental analyzer (Perkin-Elmer,
USA) and all compounds are within 0.4% of the theoretical compositions.
The precursors 2-arylidine-1-indanones[25] 2a–f, 2-arylidine-1-tetralones[18]
3a–f, 2-arylidine aurones[20] 5a–f, and 4-methyl-3-phenyl-6-coumarinoyl methyl
pyridinium salt[26] 6 were prepared according to the literature procedures. The target

372
R. R. GIRI ET AL.
compounds 7a–f, 8a–f, and 9a–f were synthesized by reacting 4-methyl-3-phenyl-6-
coumarinoyl methyl pyridinium salt with 2-arylidene-1-indanones 2a–f,
6
2-arylidene-1-tetralones 3a–f, and 2-arylidene aurones 5a–f respectively under
Krohnke’s reaction condition[27] in good yield (Table 1). The formation of pyridine
ring in the target compounds proceeded via Krohnke’s reaction mechanism.
General Procedure for the Synthesis of 4-Methyl-3-phenyl-6-(4-aryl-
5H-indeno[1,2-b]pyridin-2-yl)coumarins 7a–f
A solution of 4-methyl-3-phenyl-6-coumarinoyl methyl pyridinium salt 6
(0.003 mol) in glacial acetic acid (50 mL) was taken in a round-bottom flask. To this
ammonium acetate (0.03 mol) and appropriate 2-arylidene-1-indanone 2a–f
(0.003 mol) was added with stirring. The stirring was further continued for 45 min
and then the reaction mixture was refluxed for 12 h. The reaction mixture was allowed
to cool to room temperature and poured into ice-cold water. It was then extracted with
chloroform (3 × 30 mL). The chloroform extract was washed with water (2 × 20 mL)
and then dried over anhydrous Na2SO4. The removal of chloroform under reduced
pressure gave the crude product, which was subjected to column chromatography
using ethyl acetate–petroleum ether (1:4) as eluent to obtain pure product 7a–f.
4-Methyl-3-phenyl-6-(4-phenyl-5H-indeno[1,2-b]pyridin-2-yl)
coumarin (7a)
IR (KBr, nmax, cm−1): 700 and 746(C-H bending of mono substituted benzene
=
=
=
ring), 1439 (C N aromatic stretching), 1612 (C C aromatic stretching), 1709 (C O
d-lactone stretching), 2919 (C-H aliphatic stretching), 3052 (C-H aromatic stretch-
1
0
ing); H NMR (400 MHz, CDCl3, d): 2.48 (3H, s, CH3), 4.04 (2H, s, C5 protons),
0
7.28–7.71(15H, m, Ar-H), 8.29 (1H, concealed dd, C9 -H), 8.33 (1H, dd, J ¼ 2.0
and 8.8 Hz, C7-H), 8.52 (1H, d, J ¼ 2.0 Hz, C5-H); 13C NMR (100 MHz, CDCl3,
d): 16.80 (CH3), 34.45 (CH2), 117.14 (CH), 117.93 (CH), 120.78 (C), 121.40 (CH),
123.86 (CH), 125.06 (CH), 127.32 (CH), 127.54 (C), 128.23 (CH), 128.25 (CH),
128.46 (CH), 128.77 (CH), 128.98 (CH), 129.01 (CH), 130.11 (CH), 130.17 (CH),
133.30 (C), 134.51 (C), 136.09 (C), 138.65 (C), 140.86 (C), 144.20 (C), 146.73 (C),
147.97 (C), 153.12 (C), 155.59 (C), 161.35 (d-lactone CO). Anal. calcd. for
C34H23NO2: C, 85.51; H, 4.85; N, 2.93%. Found: C, 85.38; H, 5.01; N, 2.87%.
General Procedure for the Synthesis of 4-Methyl-3-phenyl-6-(1-
phenyl-9,10-dihydro-4-azaphenanthren-3-yl)coumarins 8a–f
A solution of 4-methyl-3-phenyl-6-coumarinoyl methyl pyridinium salt 6
(0.003 mol) in glacial acetic acid (50 mL) was taken in a round-bottom flask. To this
ammonium acetate (0.03 mol) and appropriate 2-arylidene-1-tetralone 3a–f (0.003 mol)
was added with stirring. The stirring was further continued for 45 min and then the reac-
tion mixture was refluxed for 12 h. The reaction mixture was allowed to cool to room
temperature and was poured into ice-cold water. It was then extracted with chloroform
(3 × 30 mL). The chloroform extract was washed with water (2 × 20 mL) and then dried
over anhydrous Na2SO4. The removal of chloroform under reduced pressure gave the

MODIFIED PYRIDINE-SUBSTITUTED COUMARINS
373
crude product, which was subjected to column chromatography using ethyl acetate–
petroleum ether (1:4) as eluent to obtain pure product 8a–f.
4-Methyl-3-phenyl-6-(1-phenyl-9,10-dihydro-4-azaphenanthren-3-yl)
coumarin (8a)
IR (KBr, nmax, cm−1): 700 and 752 (C-H bending of mono substituted benzene
=
=
=
ring), 1544 (C N aromatic stretching), 1608 (C C aromatic stretching), 1721 (C O
d-lactone stretching), 2919 (C-H aliphatic stretching), 3053 (C-H aromatic stretch-
1
0
ing); H NMR (400 MHz, CDCl3, d): 2.47 (3H, s, CH3), 2.89–3.00 (4H, m, C9
0
and C10 protons), 7.27–7.65 (15H, m, Ar-H), 8.37 (1H, dd, J ¼ 1.6 and 8.4 Hz,
C7-H), 8.53 (1H, d, J ¼ 1.6 Hz, C5-H), 8.58 (1H, concealed dd, C5 -H); 13C NMR
0
(100 MHz, CDCl3, d): 16.81 (CH3), 25.30 (CH2), 28.11 (CH2), 117.12 (CH),
119.66 (CH), 120.69 (C), 123.39 (CH), 125.61 (CH), 127.14 (CH), 127.52 (CH),
127.63 (C), 128.21 (CH), 128.25 (CH), 128.40 (C), 128.45 (CH), 128.58 (CH),
128.78 (CH), 129.32 (CH), 129.90 (CH), 130.10 (CH), 134.53 (C), 134.96 (C),
135.91 (C), 138.31 (C), 139.14 (C), 147.95 (C), 149.62 (C), 152.85 (C), 153.00 (C),
153.11 (C), 160.92 (d-lactone CO). Anal. calcd. for C35H25NO2: C, 85.52; H, 5.13;
N, 2.85%. Found: C, 85.38; H, 5.18; N, 2.81%.
General Procedure for the Synthesis of 4-Methyl-3-phenyl-6-(4-
phenylbenzofuro[3,2-b]pyridin-2-yl)coumarins 9a–f
A solution of 4-methyl-3-phenyl-6-coumarinoyl methyl pyridinium salt 6
(0.003 mol) in glacial acetic acid (50 mL) was taken in a round-bottom flask. To this
ammonium acetate (0.03 mol) and appropriate 2-arylidene aurone 5a–f (0.003 mol)
were added with stirring. The stirring was further continued for 45 min, and then
the reaction mixture was refluxed for 12 h. The reaction mixture was allowed to cool
to room temperature and was poured into ice-cold water. It was then extracted with
chloroform (3 × 30 mL). The chloroform extract was washed with water (2 × 20 mL)
and then dried over anhydrous Na2SO4. The removal of chloroform under reduced
pressure gave the crude product, which was subjected to column chromatography
using ethyl acetate–petroleum ether (1:4) as eluent to obtain pure product 9a–f.
4-Methyl-3-phenyl-6-(4-phenylbenzofuro[3,2-b]pyridin-2-yl)coumarin
(9a)
IR (KBr, nmax, cm−1): 700 and 752 (C-H bending of mono substituted benzene
=
=
=
ring), 1464 (C N aromatic stretching), 1609 (C C aromatic stretching), 1715 (C O
d-lactone stretching), 2921 (C-H aliphatic stretching), 3055 (C-H aromatic stretching);
1H NMR (400 MHz, CDCl3, d): 2.47 (3H, s, CH3), 7.29–7.71 (15H, m, Ar-H), 8.29
0
(1H, dd, J ¼ 1.6 and 8.4 Hz, C7-H), 8.35 (1H, concealed dd, C9 -H), 8.55 (1H, d,
J ¼ 1.6 Hz, C5-H); 13C NMR (100 MHz, CDCl3, d): 16.82 (CH3), 117.21 (CH),
117.96 (CH), 120.82 (C), 121.45 (CH), 123.93 (CH), 125.11 (CH), 127.37 (CH),
127.58 (C), 128.24 (CH), 128.29 (CH), 128.49 (CH), 128.86 (CH), 129.00 (CH),
129.08 (CH), 130.14 (CH), 130.21 (CH), 133.33 (C), 134.54 (C), 136.11 (C), 138.69
(C), 140.93 (C), 144.25 (C), 146.77 (C), 147.97 (C), 153.17 (C), 155.65 (C), 161.51

374
R. R. GIRI ET AL.
(d-lactone CO). Anal. calcd. for C33H21NO3: C, 82.66; H, 4.41; N, 2.92%. Found: C,
82.49; H, 4.32; N, 2.81%.
ACKNOWLEDGMENT
The authors are thankful to the head, Department of Chemistry, Sardar Patel
University, for providing the basic research amenities.
FUNDING
This work was supported by the University Grants Commission, India
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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