Microwave-assisted synthesis of novel 4H-chromene derivatives bearing 2-aryloxyquinoline and their antimicrobial activity assessment

Article abstract of DOI:10.1007/s00044-012-0381-7

A new series of 4H-chromene derivatives 6a-x bearing 2-aryloxyquinoline nucleus have been synthesized under microwave irradiation by reaction of 2-aryloxyquinoline-3-carbaldehyde 3a-l, malononitrile 4, and compounds (Cyclohexanedione, Dimidone) 5a-b in th

Full text of DOI:10.1007/s00044-012-0381-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3831–3842
DOI 10.1007/s00044-012-0381-7
ORIGINAL RESEARCH
Microwave-assisted synthesis of novel 4H-chromene derivatives
bearing 2-aryloxyquinoline and their antimicrobial
activity assessment
•
Chetan B. Sangani Nimesh M. Shah
•
•
Manish P. Patel Ranjan G. Patel
Received: 4 January 2012 / Accepted: 27 November 2012 / Published online: 12 December 2012
Ó Springer Science+Business Media New York 2012
Abstract A new series of 4H-chromene derivatives
6a–x bearing 2-aryloxyquinoline nucleus have been syn-
thesized under microwave irradiation by reaction of 2-ary-
loxyquinoline-3-carbaldehyde 3a–l, malononitrile 4, and
compounds (Cyclohexanedione, Dimidone) 5a–b in the
presence of NaOH as the basic catalyst. All the compounds
were screened against three Gram-positive bacteria (Strep-
tococcus pneumoniae, Clostridium tetani, Bacillus subtilis),
three Gram-negative bacteria (Salmonella typhi, Vibrio
cholerae, Escherichia coli) and two fungi (Aspergillus
fumigatus, Candida albicans) using the broth microdilution
MIC (Minimum Inhibitory Concentration) method. Upon
study of the antimicrobial screening, it has been observed
that a majority of the compounds were found to be active
against C. tetani and B. subtilis as well as against C. albicans
as compared to the standard drugs.
believe that there is an urgent call for development of new
drugs with divergent and unique structure and with a prob-
ably unusual mechanism of action from that of existing first-
line drugs. Consequently, this spot of research is accorded an
immense significance and keeps attracting much attention of
an increasing number of medicinal chemists.
The chromene ring system is considered to be one of the
most imperative heterocycles in nature as it has the distinc-
tion of being the parent ring in countless derivatives of bio-
logic relevance. The current interest in 4H-chromene
derivatives arises from their potential application as anti-
microbial (Kuarm et al., 2011; Rai et al., 2010), anti-HIV
(Bhavsar et al., 2011; Park et al., 2008), anti-tubercular
(Kamdar et al., 2010), antioxidant (Singh et al., 2010),
anticancer (Raju et al., 2011), antitumor (Huang et al., 2009),
cytotoxic (Raj et al., 2010; Sabry et al., 2011), antidyslipi-
demic (Sashidhara et al., 2008), antileishmanial (Nazarian
et al., 2010), anti-inflammatory (Gebhardt et al., 2007), anti-
helicobacter pylori (Chimenti et al., 2007), and TNF-a
inhibitor agents (Cheng et al., 2003).
Keywords 2-Aryloxyquinoline ꢀ 4H-chromene ꢀ
One-pot reaction ꢀ In vitro antimicrobial activity
On the other hand, quinoline derivatives are a possessing
high activity profile due to their wide range of useful
biologic properties including antibacterial (Kalluraya et al.,
2008), antifungal (Rana et al., 2008), antimycobacterial
(Mital et al., 2006), antimalarial (Charris et al., 2005; Dave
et al., 2009), anti-inflammatory (Bava and Kumar, 2009),
and anticancer activities (Shi et al., 2008).
Introduction
The alarming increment in pathogenic resistance to existing
first-line standard drugs is a serious problem in antimicrobial
cure and necessitates continuing research into new classes of
antimicrobials (Woodford, 2003). Moreover, the progres-
sion of drug-resistant strains has contributed to the ineffi-
ciency of the straight antimicrobial therapy. This crops up an
enormous interest in antibacterial research and we strongly
A literature survey manifests that a number of 4H-
chromene derivatives have been synthesized using various
aldehydes (Thumar and Patel, 2011b; Mungra et al., 2011b;
Makawana et al., 2011; Kathrotiya and Patel, 2011a), but
there is not a single report where 2-aryloxyquinoline-3-
carbaldehyde is used.
C. B. Sangani ꢀ N. M. Shah ꢀ M. P. Patel ꢀ R. G. Patel (&)
Department of Chemistry, Sardar Patel University,
Vallabh Vidyanagar, Gujarat 388120, India
e-mail: patelranjanben@yahoo.com
The molecular manipulation of promising lead com-
pounds is still the chief approach to widen an area of
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Med Chem Res (2013) 22:3831–3842
medicine research. It involves an idea to merge the separate
pharmacophoric groups of analogous activity into one
compound, thus making structural changes in the biologic
activity. An attempt has been to undertake the synthesis of
chromene derivatives with the assumption that the assim-
ilation of more than one bioactive moiety into a single
scaffold may produce novel heterocycles with fascinating
antimicrobial activities to combat the infections of micro-
bial pathogens.
2011b). The required 2-chloro-3-formylquinoline 1a–c was
prepared by the Vilsmeier–Haack reaction according to the
literature procedure (Meth-Cohn and Bramha, 1978).
In the present study, 4H-chromene derivatives 6a–x have
been synthesized in moderate to good yield, i.e., 64–89 %,
by reaction of 2-aryloxyquinoline-3-carbaldehyde 3a–l,
malononitrile 4 and compounds 5a–b under microwave
irradiation in the presence of NaOH as a basic catalyst
(Scheme 1). The substitutions present on the compounds are
given in Table 1.
In light of the aforementioned facts, and as a prolon-
gation of our investigation on the synthesis of biologically
active heterocyclic compounds (Sangani et al., 2011, 2012;
Makawana et al., 2011a, b, c, d; Shah et al., 2012; Mungra
et al., 2011a, b; Ladani et al., 2010, 2011; Thumar
and Patel, 2011a, b, c, d; Kathrotiya and Patel, 2011a), we
were provoked to synthesize new aryloxyquinoline-based
4H-chromene derivatives and evaluate them as antimicro-
bial agents.
In accordance with the mechanism suggested in the lit-
erature (Makawana et al., 2011a), the first step of this process
may involve the Knoevenagel condensation of aldehyde and
malononitrile to give heterylidenenitrile derivatives fol-
lowed by Michael addition of 5a–b to heterylidenenitrile to
afford the title compounds 6a–x (Scheme 2).
The structures of all the newly synthesized compounds
1
were confirmed by FTIR, H NMR, 13C NMR, mass and
The conventional procedures are not found to be satis-
factory with regard to operational simplicity, effectiveness,
and yield. An alternative synthetic approach is microwave
irradiation (Mungra et al., 2011a, b; Makawana et al.,
2011a). In recent years, microwave irradiation has been
demonstrated not only to dramatically accelerate many
organic reactions, but also to improve yield and selectivity.
NaOH derives its remarkable ability to catalyze from its
strong base characteristic; it is also used as an eco-friendly
base. In connection with our earlier work on NaOH catal-
ysis with microwave irradiation (Makawana et al., 2011a),
we attempted same strategy to achieve novel 4H-chromene
derivatives of aryloxyquinoline.
elemental analysis. The IR spectrum of title compounds
6a–x confirms the presence of amino, cyano, carbonyl, and
ether groups due to the appearance of absorption bands at
around 3,400–3,460 & 3,290–3,340, 2,180–2,260, 1,650–
1
1,700, and 1,180–1,260 cm-1, respectively. Its H NMR
spectrum indicated the presence of one singlet in the range
d 4.60–4.80 ppm of –CH proton, and the disappearance of
a singlet at d 10.50 ppm of –CHO clearly confirmed the
cyclization of the Knoevenagel intermediate. Moreover,
multiplets in the range d 7.00–8.14 ppm appeared for
aromatic protons. In the 13C NMR spectral data of the title
compounds 6a–x, the most characteristic signal around d
32.25–40.50 ppm indicated the formation of a pyrane ring.
The signal at around d 56.05–57.50 ppm is assigned to
carbon attached with carbonitrile, while signals around d
106.10–165.97 and 196.20–196.60 ppm are attributed to all
the aromatic and carbonyl carbons, respectively, of com-
pounds 6a–x. The obtained elemental analysis values are in
good agreement with theoretic data. Further, the molecular
weight of selected compounds such as 6h and 6v was
confirmed by its mass spectral studies. Mass Spectroscopy
of the above-mentioned compounds showed a molecular
ion peak [M ? 1]? corresponding to exact mass. Mass
spectra of compound 6h gave a molecular ion peak at
m/z = 442.69 [M ? 1]? corresponding to molecular for-
mula C26H20FN3O3 and compound 6v gave a molecular ion
peak at m/z = 482.27 [M ? 1]? corresponding to molec-
ular formula C28H24FN3O3. All physical, analytical data as
well as spectroscopic characterization data of the synthe-
sized compounds 6a–x are given in the experimental sec-
tion. All the compounds were screened for their
antibacterial and antifungal activity and the results are
expressed in the form of MIC lg/mL.
The constitutions of all the products were confirmed using
1H NMR, 13C NMR, FTIR, and elemental analysis. All
synthesized compounds were screened for in vitro antimi-
crobial activity against eight human pathogens, of which
three are Gram-positive bacteria (Streptococcus pneumonia,
Clostridium tetani, Bacillus subtilis), three are Gram-negative
bacteria (Salmonella typhi, Vibrio cholerae, Escherichia
coli), and two are fungi (Aspergillus fumigatus, Candida
albicans), using the broth microdilution MIC (Minimum
Inhibitory Concentration) method (NCCLS, 2002).
Results and discussion
Chemistry
The key intermediate 2-aryloxyquinoline-3-carbaldehyde
3a–l was prepared by refluxing 2-chloro-3-formylquinoline
1a–c and various phenols in the presence of anhydrous
potassium carbonate in dry DMF for 3.5 h (Mungra et al.,
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Med Chem Res (2013) 22:3831–3842
3833
Scheme 1 General synthetic
route for the compounds 6a–x
Table 1 Substitution of compounds 6a–x
Compound
R1
R2
R3
Compound
R1
R2
R3
6a
6b
6c
6d
6e
6f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6m
6n
6o
6p
6q
6r
6s
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
OCH3
F
H
CH3
OCH3
F
H
H
H
H
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
H
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
H
CH3
OCH3
F
CH3
OCH3
F
6g
6h
6i
6t
H
6u
6v
6w
6x
H
6j
CH3
OCH3
F
CH3
OCH3
F
6k
6l
Scheme 2 Plausible
mechanistic pathway for
4H-chormene derivatives
Antimicrobial activity
Mueller–Hinton broth was used as the nutrient medium to
grow and dilute the compound suspension for the test
bacteria and Sabouraud Dextrose broth used for fungal
nutrition. Inoculum size for test strain was adjusted to 108
CFU [Colony Forming Unit] per milliliter by comparing
All the glass apparatus were sterilized before use. The
antimicrobial activity of all the synthesized compounds
was carried out by the broth microdilution method.
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Med Chem Res (2013) 22:3831–3842
the turbidity. The strains used for the activity were procured
from [MTCC—Microbial Type Culture Collection] the
Institute of Microbial Technology, Chandigarh. Each syn-
thesized compound was diluted obtaining 2,000 lg/mL
concentration, as a stock solution. The results are recorded
in the form of primary and secondary screening. The
compounds 6a–x were screened for their antibacterial
activity against S. pneumoniae (MTCC 1936), C. tetani
(MTCC 449), B. subtilis (MTCC 441), S. typhi (MTCC 98),
V. cholerae (MTCC 3906), and E. coli (MTCC 443) as well
as for antifungal activity against A. fumigatus (MTCC
3008) and C. albicans (MTCC 227) at concentrations of
1,000, 500, and 250 lg/mL as primary screening. DMSO
was used as the vehicle to get the desired concentrations of
compounds to test upon microbial strains. The compounds
found to be active in the primary screening were further
screened in a second set of dilution at concentrations of 200,
100, 62.5, and 50 lg/mL. 10 lL suspensions from each
well were further inoculated and growth was noted after 24
and 48 h. The lowest concentration, which showed no vis-
ible growth (turbidity) after spot subculture, was considered
as MIC for each compound. In the present study, ampicillin
and norfloxacin were used as standard antibacterial drugs,
whereas griseofulvin was used as the standard antifungal
drug. The protocols are summarized in Table 2.
whereas the analogs 6a (R1=H, R2=H, R3=H), 6r (R1=CH3,
R2=CH3, R3=CH3), and 6w (R1=OCH3, R2=OCH3, R3=CH3)
(MIC = 250 lg/mL) have shown comparable activity to
ampicillin (MIC = 250 lg/mL). Compounds 6f (R1=CH3,
R2=CH3, R3=H), 6k (R1=OCH3, R2=OCH3, R3=H), 6q
(R1=CH3, R2=H, R3=CH3), 6u (R1=OCH3, R2=H, R3=CH3),
and 6v (R1=OCH3, R2=CH3, R3=CH3) (MIC = 100 lg/mL)
are also found to be equally potent as compared to cipro-
floxacin (MIC = 100 lg/mL) against the same organism.
Toward S. pneumonia, the compound 6f (R1=CH3,
R2=CH3, R3=H) (MIC = 62.5 lg/mL) has shown better
activity, whereas 6c (R1=H, R2=OCH3, R3=H), 6i (R1=OCH3,
R2=H, R3=H), 6q (R1=CH3, R2=H, R3=CH3), and 6r
(R1=CH3, R2=CH3, R3=CH3) (MIC = 100 lg/mL) have
shown equal activity to ampicillin (MIC = 100 lg/mL).
Compound 6x (R1=OCH3, R2=F, R3=CH3) (MIC = 62.5
lg/mL) is found to be more potent, whereas 6a (R1=H,
R2=H, R3=H), 6d (R1=H, R2=F, R3=H), 6e (R1=CH3, R2=H,
R3=H), 6h (R1=CH3, R2=F, R3=H), and 6v (R1=OCH3,
R2=CH3, R3=CH3) (MIC = 100 lg/mL) have shown com-
parable activity to ampicillin (MIC = 100 lg/mL) when
employed to inhibit Gram-negative bacteria E. coli.
With regard to the activity against S. typhi, compounds 6h
(R1=CH3, R2=F, R3=H), 6q (R1=CH3, R2=H, R3=CH3), 6v
(R1=OCH3, R2=CH3, R3=CH3), and 6x (R1=OCH3, R2=F,
R3=CH3) (MIC = 100 lg/mL) show comparable activity to
ampicillin (MIC = 100 lg/mL). Toward V. cholerae, four
compounds 6c (R1=H, R2=OCH3, R3=H), 6f (R1=CH3,
R2=CH3, R3=H), 6i (R1=OCH3, R2=H, R3=H), and 6n
(R1=H, R2=CH3, R3=CH3) (MIC = 100 lg/mL) show
comparable activity to ampicillin (MIC = 100 lg/mL).
The examination of the data (Table 2) reveals that most of
the compounds showed excellent activity when compared
with standard antibacterial drugs Ampicillin, Ciprofloxacine,
Chlormphenicol, and Norfloxacine and antifungal drugs
Griseofulvin and Nystatin.
An examination of the antibacterial activity of 4H-chro-
mene derivatives 6a–x, assay indicated that among the
Gram-positive bacteria tested, two strains, namely B. subtilis
and C. tetani, showed relative high sensitivity toward the
tested compounds. In this view, against Gram-positive
bacteria B. subtilis, compounds 6c (R1=H, R2=OCH3,
R3=H), 6f (R1=CH3, R2=CH3, R3=H), 6h (R1=CH3, R2=F,
R3=H), 6i (R1=OCH3, R2=H, R3=H), 6q (R1=CH3, R2=H,
R3=CH3), 6r (R1=CH3, R2=CH3, R3=CH3), and 6x
(R1=OCH3, R2=F, R3=CH3) are found more potent than
ampicillin, whereas the analogs 6a (R1=H, R2=H, R3=H), 6d
(R1=H, R2=F, R3=H), 6g (R1=CH3, R2=OCH3, R3=H),
6j (R1=OCH3, R2=CH3, R3=H), 6o (R1=H, R2=OCH3,
R3=CH3), 6s (R1=CH3, R2=OCH3, R3=CH3) (MIC = 250
lg/mL) have shown comparable activity to ampicillin
(MIC = 250 lg/mL).
Against C. tetani compounds, 6f (R1=CH3, R2=CH3,
R3=H), 6k (R1=OCH3, R2=OCH3, R3=H), 6l (R1=OCH3,
R2=F, R3=H), 6m (R1=H, R2=H, R3=CH3), 6o (R1=H,
R2=OCH3, R3=CH3), 6q (R1=CH3, R2=H, R3=CH3), 6s
(R1=CH3, R2=OCH3, R3=CH3), 6u (R1=OCH3, R2=H,
R3=CH3), 6v (R1=OCH3, R2=CH3, R3=CH3), and 6x
(R1=OCH3, R2=F, R3=CH3) are found to be more potent,
Antifungal screening
Against fungal pathogen C. albicans, compounds 6o
(R1=H, R2=OCH3, R3=OCH3) (MIC = 100 lg/mL), 6p
(R1=H, R2=F, R3=CH3) (MIC = 200 lg/mL), 6d (R1=H,
R2=F, R3=H), 6f (R1=CH3, R2=CH3, R3=H), 6h (R1=CH3,
R2=F, R3=H), 6k (R1=OCH3, R2=OCH3, R3=H), 6m
(R1=H, R2=H, R3=CH3), 6q (R1=CH3, R2=H, R3=CH3), 6t
(R1=CH3, R2=F, R3=CH3), and 6w (R1=OCH3, R2=OCH3,
R3=CH3) (MIC = 250 lg/mL) are found to be more
potent, whereas compound 6a (R1=H, R2=H, R3=H), 6b
(R1=H, R2=CH3, R3=H), 6e (R1=CH3, R2=H, R3=H), 6g
(R1=CH3, R2=OCH3, R3=H), 6l (R1=OCH3, R2=F, R3=H),
6n (R1=H, R2=CH3, R3=CH3), 6u (R1=OCH3, R2=H,
R3=CH3), and 6x (R1=OCH3, R2=F, R3=CH3) (MIC = 500
lg/mL) are found to be equipotent to griseofulvin
(MIC =500 lg/mL). The remaining compounds showed
poor activity to inhibit the growth of bacterial pathogens
and are all less effective than standard drugs. From the
antimicrobial study of the title derivatives, it is interesting
to note that
a minor alteration in the molecular
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Med Chem Res (2013) 22:3831–3842
3835
Table 2 In vitro antimicrobial activity of 4H-chromene derivatives 6a–x
Gram-positive bacteria
Gram-negative bacteria
Fungal species
Compd Bs. MTCC 441 Ct. MTCC 449 Sp. MTCC 1936 Ec. MTCC 443 St. MTCC 98 Vc. MTCC 3906 Af. MTCC 3008 Ca. MTCC 227
Minimum inhibitory concentration (MIC) expressed in lg/ml
6a
6b
6c
6d
6e
6f
250
1,000
200
250
500
100
250
200
100
250
500
500
500
1,000
250
500
150
100
250
500
500
500
1,000
200
250
50
250
500
1,000
500
500
100
500
500
500
500
100
200
200
500
200
500
100
250
200
500
100
100
250
200
250
100
50
250
500
100
250
500
62.5
500
200
100
250
500
250
250
500
250
500
100
100
250
500
500
500
1,000
150
100
50
100
250
150
100
100
500
500
100
150
250
200
500
250
200
250
500
200
250
500
500
200
100
250
62.5
100
25
250
500
250
200
250
500
1,000
100
200
500
1,000
500
500
250
500
500
100
250
500
500
500
100
250
100
100
25
250
200
100
500
1,000
100
200
500
100
500
200
200
200
100
250
250
250
200
200
500
200
200
250
250
100
25
1,000
500
500
500
1,000
250
500
250
500
250
1,000
1,000
250
500
250
500
100
200
250
1,000
1,000
250
500
1,000
250
500
–
[1,000
[1,000
[1,000
500
6g
6h
6i
500
500
1,000
1,000
500
6j
6k
6l
500
6m
6n
6o
6p
6q
6r
6s
6t
[1,000
500
250
250
500
250
250
250
6u
6v
6w
6x
A
1,000
500
500
500
–
B
–
–
C
100
50
10
10
10
10
–
–
D
50
50
50
50
50
–
–
E
–
–
–
–
–
–
100
100
500
F
–
–
–
–
–
–
100
Bs.: Bacillus subtilis; Ct.: Clostridium tetani; Sp.: Streptococcus pneumoniae; Ec.: Escherichia coli; St.: Salmonella typhi; Vc.: Vibrio cholerae;
Af.: Aspergillus fumigatus; Ca.: Candida albicans; MTCC: Microbial Type Culture Collection; A: Ampicillin; B: Ciprofloxacin; C: Norfloxacin;
D: Chloramphenicol; E: Nystatin; F: Griseofulvin. ‘‘–’’ represents ‘‘not tested’’
The bold entries indicates that the compounds are either equipotent or more potent than the standard drug used
configuration of the investigated compounds may have a
pronounced effect on antimicrobial activity.
hydroxide were obtained from S. D. Fine Chem Ltd.,
Vadodara, Gujarat, India. Cyclohexanedione and dime-
done were obtained from Sigma-Aldrich. Solvents were
purified and dried before being used. The microwave-
assisted reactions are conducted in a ‘‘RAGA’s Modified
Electromagnetic Microwave System’’ whereby micro-
waves are generated by magnetron at a frequency of
2,450 MHz, having adjustable output power levels, i.e.,
10 levels from 140 to 700 Watts, and with an individual
sensor for temperature control (fiber optic is used as an
individual sensor for temperature control) with attach-
ment of reflux condenser with constant stirring (thus
Experimental
Chemistry
General procedures
Required acetic anhydride, substituted anilines, acetic
acid, malononitrile, phosphorous oxychloride, and sodium
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Med Chem Res (2013) 22:3831–3842
2-Amino-4-[2-(4-methylphenoxy)quinolin-3-yl]-5-oxo-
avoiding the risk of high pressure development). All
melting points were taken in open capillaries and are
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6b)
uncorrected. Thin-layer chromatography (TLC, on alu-
60
Yield 78 %, m.p. 268–269 °C, Anal. Calcd. for C26H21N3O3
(423.46 g/mol): C 73.74, H 5.00, N 9.92 % Found: C 74.00,
H 5.09, N 9.99 %. IR (KBr, cm-1): 3,395 and 3,300 (asym.
and sym. stretching of –NH2), 2,195 (–C:N stretching),
1,670 (–C=O str.), 1,205 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.90–2.26 (m, 4H, CH2), 2.43
(s, 3H, CH3), 4.62 (s, 1H, CH), 2.64 (m, 2H, CH2), 7.01–8.12
(m, 11H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
20.27 (CH2), 20.90 (CH3), 27.18 (CH2), 30.50 (CH), 36.90
(CH2), 56.18 (C–CN), 107.35, 120.19, 123.43, 126.40,
126.64, 127.21, 128.50, 128.83, 129.72, 132.05, 134.94,
138.18, 143.31, 153.17, 159.00, 159.81, 165.85 (Ar–C),
196.38 (C=O).
minum plates precoated with silica gel,
F
, 0.25 mm
254
thickness) (Merck, Darmstadt, Germany) was used for
monitoring the progress of all reactions and purity and
homogeneity of the synthesized compounds. UV radiation
and/or iodine were used as the visualizing agents. Ele-
mental analysis (% C, H, N) was carried out by Perkin-
Elmer 2400 series-II elemental analyzer (Perkin-Elmer,
USA) and all compounds are within 0.4 % of the theory
specified. The IR spectra were recorded in KBr on a
Perkin-Elmer Spectrum GX FT-IR Spectrophotometer
(Perkin-Elmer, USA) and only the characteristic peaks are
1
reported in cm-1. H-NMR and 13C-NMR spectra were
recorded in DMSO-d6 on a Bruker Avance 400F (MHz)
spectrometer (Bruker Scientific Corporation Ltd., Swit-
zerland) using solvent peak as the internal standard at 400
and 100 MHz, respectively. Chemical shifts are reported
in parts per million (ppm). Mass spectra were scanned on
a Shimadzu LCMS 2010 spectrometer.
2-Amino-4-[2-(4-methoxyphenoxy)quinolin-3-yl]-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6c)
Yield 80 %, m.p. 191–193 °C, Anal. Calcd. for C26H21N3O4
(439.46 g/mol): C 71.06, H 4.82, N 9.56 % Found: C 70.92,
H 4.67, N 9.35 %. IR (KBr, cm-1): 3,430 and 3,320 (asym.
and sym. stretching of –NH2), 2,200 (–C:N stretching),
1,655 (–C=O str.), 1,200 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.88–2.32 (m, 4H, CH2), 2.57
(m, 2H, CH2), 3.78 (s, 3H, OCH3), 4.78 (s, 1H, CH),
7.10–8.09 (m, 11H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 20.62 (CH2), 27.06 (CH2), 32.27 (CH), 36.86
(CH2), 55.88 (OCH3), 56.29 (C–CN), 106.60, 120.01,
123.62, 126.11, 126.90, 127.03, 128.44, 128.98, 129.77,
132.03, 135.12, 138.17, 143.13, 153.33, 159.21, 159.80,
163.87 (Ar–C), 196.91 (C=O).
General procedure for the synthesis of compounds 6a–x
2-Aryloxyquinoline-3-carbaldehyde 3a–l (10 mmol), mal-
ononitrile 4 (10 mmol), and Cyclohexanedione/Dimidone
5a–b (10 mmol) were thoroughly mixed in ethanolic NaOH
(5 mmol, 10 mL) and irradiated in a microwave oven at
350 W (50 % of output power) for 170–190 s. After the
completion of reaction (checked by TLC), the solution was
cooled to room temperature, the solid separated was filtered,
washed well with ethanol (10 mL), dried, and recrystallized
from chloroform to get the pure solid sample 6a–x. Physical,
analytical, and spectroscopic characterization data of the
compounds 6a–x are given hereafter.
2-Amino-4-(2-(4-fluorophenoxy)quinolin-3-yl)-5-oxo-
2-Amino-4-[2-phenoxyquinolin-3-yl]-5-oxo-5,6,7,8-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6d)
tetrahydro-4H-chromene-3-carbonitrile (6a)
Yield 66 %, m.p. 225–227 °C, Anal. Calcd. for C28H18
FN3O3 (427.43 g/mol): C 70.25, H 4.24, N 9.83 % Found:
C 70.42, H 4.59, N 9.61 %. IR (KBr, cm-1): 3,425 and
3,330 (asym. and sym. stretching of –NH2), 2,240 (–C:N
stretching), 1,660 (–C=O str.), 1,180 (C–O–C ether
Yield 73 %, m.p. 235–236 °C, Anal. Calcd. for C25H19N3O3
(409.44 g/mol): C 73.34, H 4.68, N 10.26 % Found: C 73.42,
H 4.44, N 10.55 %. IR (KBr, cm-1): 3,420 and 3,315 (asym.
and sym. stretching of –NH2), 2,215 (–C:N stretching),
1,710 (–C=O str.), 1,190 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.83–2.35 (m, 4H, CH2), 2.59 (m,
2H, CH2), 4.68 (s, 1H, CH), 7.12–8.02 (m, 12H, Ar–
H ? NH2). 13C NMR (100 MHz, DMSO-d6) d: 20.35
(CH2), 27.03 (CH2), 34.25 (CH), 36.74 (CH2), 56.25 (C–
CN), 112.48, 120.29, 123.47, 126.40, 126.77, 127.12,
128.24, 128.80, 129.93, 132.00, 135.06, 138.31, 143.35,
153.22, 159.18, 159.68, 164.27 (Ar–C), 196.52 (C=O).
1
stretching). H NMR (400 MHz, DMSO-d6): d 1.85–2.28
(m, 4H, CH2), 2.58 (m, 2H, CH2), 4.61 (s, 1H, CH),
7.05–8.10 (m, 11H, >Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 20.07 (CH2), 27.00 (CH2), 30.30 (CH), 36.79
(CH2), 56.73 (C–CN), 112.88, 120.13, 123.75, 125.96,
126.76, 127.14, 128.28, 128.78, 130.03, 132.21, 135.07,
138.31, 143.28, 153.20, 159.13, 159.83, 164.81 (Ar–C),
196.91 (C=O).
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Med Chem Res (2013) 22:3831–3842
3837
2-Amino-4-[6-methyl-2-phenoxyquinolin-3-yl]-
5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6e)
128.53, 128.93, 130.01, 132.16, 134.89, 138.30, 143.25,
153.15, 159.00, 159.81, 165.45 (Ar–C), 196.39 (C=O).
2-Amino-4-[6-methyl-2-(4-fluorophenoxy)quinolin-3-yl]-
5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6h)
Yield 76 %, m.p. 173–175 °C, Anal. Calcd. for C26H21N3O3
(423.46 g/mol): C 73.74, H 5.00, N 9.92 % Found: C 73.62,
H 4.96 N 10.11 %. IR (KBr, cm-1): 3,405 and 3,315 (asym.
and sym. stretching of –NH2), 2,180 (–C:N stretching),
1,680 (–C=O str.), 1,190 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.94–2.29 (m, 4H, CH2), 2.43
(s, 3H, CH3), 2.61 (m, 2H, CH2), 4.77 (s, 1H, CH), 7.12–7.99
(m, 11H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
20.25 (CH2), 21.49 (CH3), 27.14 (CH2), 31.86 (CH), 36.83
(CH2), 57.40 (C–CN), 113.07, 120.30, 123.62, 126.53,
126.94, 127.14, 128.23, 128.91, 129.77, 132.11, 135.04,
138.31, 143.28, 153.22, 159.21, 159.81, 165.80 (Ar–C),
196.40 (C=O).
Yield64 %, m.p.284–285 °C, Anal. Calcd. forC26H20FN3O3
(441.45 g/mol): C 70.74, H 4.57, N 9.52 % Found: C 70.58,
H 4.71, N 9.50 %. IR (KBr, cm-1): 3,435 and 3,320 (asym.
and sym. stretching of –NH2), 2,220 (–C:N stretching),
1,695 (–C=O str.), 1,235 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.92–2.33 (m, 4H, CH2), 2.44
(s, 3H, CH3), 2.58 (m, 2H, CH2), 4.66 (s, 1H, CH), 7.06–8.12
(m, 10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
20.31 (CH2), 21.38 (CH3), 27.08 (CH2), 32.27 (CH), 36.84
(CH2), 56.30 (C–CN), 112.44, 120.27, 123.53, 126.46,
126.81, 127.00, 128.55, 128.83, 129.93, 132.06, 134.97,
138.25, 143.20, 153.16, 159.04, 159.75, 165.86 (Ar–C),
196.50 (C=O). m/z = 442.69 [M ? 1]?
2-Amino-4-[6-methyl-2-(4-methylphenoxy)quinolin-
3-yl]-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6f)
2-Amino-4-[6-methoxy-2-phenoxyquinolin-3-yl]-
5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6i)
Yield 80 %, m.p. 263–265 °C, Anal. Calcd. for C27H23N3O3
(437.49 g/mol): C 74.12, H 5.30, N 9.60 % Found: C 74.22,
H 5.44, N 9.75 %. IR (KBr, cm-1): 3,430 and 3,295 (asym.
and sym. stretching of –NH2), 2,245 (–C:N stretching),
1,700 (–C=O str.), 1,215 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.84–2.25 (m, 4H, CH2), 2.42 (s,
3H, CH3), 2.47 (s, 3H, CH3), 2.55 (m, 2H, CH2), 4.73 (s, 1H,
CH), 7.04–8.06 (m, 10H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 20.42 (CH2), 20.86 (CH3), 21.37
(CH3), 27.19 (CH2), 34.45 (CH), 36.84 (CH2), 56.35
(C–CN), 106.10, 119.94, 122.93, 126.46, 126.80, 126.99,
128.54, 128.82, 129.90, 132.00, 134.89, 138.19, 143.17,
153.20, 159.00, 159.81, 164.07 (Ar–C), 196.58 (C=O).
Yield 67 %, m.p. 207–208 °C, Anal. Calcd. for C26H21N3O4
(439.46 g/mol): C 71.06, H 4.82, N 9.56 % Found: C 71.18,
H 5.00, N 9.38 %. IR (KBr, cm-1): 3,435 and 3,310 (asym.
and sym. stretching of –NH2), 2,210 (–C:N stretching),
1,665 (–C=O str.), 1,220 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.81–2.31 (m, 4H, CH2), 2.65
(m, 2H, CH2), 3.89 (s, 3H, OCH3), 4.70 (s, 1H, CH),
7.00–8.07 (m, 11H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 20.57 (CH2), 27.16 (CH2), 32.07 (CH), 36.80
(CH2), 55.93 (OCH3), 57.27 (C–CN), 112.55, 120.35,
123.71, 126.41, 126.86, 127.14, 128.24, 128.92, 130.02,
132.15, 134.83, 138.20, 143.21, 153.78, 158.98, 159.66,
164.97 (Ar–C), 196.55 (C=O).
2-Amino-4-[6-methyl-2-(4-methoxyphenoxy)quinolin-
3-yl]-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6g)
2-Amino-4-[6-methoxy-2-(4-methylphenoxy)quinolin-
3-yl]-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6j)
Yield 84 %, m.p. 167–168 °C, Anal. Calcd. for C27H23N3O4
(453.49 g/mol): C 71.51, H 5.11, N 9.27 % Found: C 71.39,
H 5.00, N 9.42 %. IR (KBr, cm-1): 3,450 and 3,310 (asym.
and sym. stretching of –NH2), 2,250 (–C:N stretching),
1,660 (–C=O str.), 1,250 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.85–2.30 (m, 4H, CH2), 2.45
(s, 3H, CH3), 2.60 (m, 2H, CH2), 3.76 (s, 3H, OCH3), 4.80
(s, 1H, CH), 7.15–8.10 (m, 10H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 20.20 (CH2), 21.43 (CH3), 27.11
(CH2), 33.37 (CH), 36.71 (CH2), 55.87 (OCH3), 56.19
(C–CN), 110.12, 120.31, 123.54, 126.40, 126.89, 127.01,
Yield 80 %, m.p. 290–291 °C, Anal. Calcd. for C27H23N3O4
(453.49 g/mol): C 71.51, H 5.11, N 9.27 % Found: C 71.62,
H 5.14, N 9.46 %. IR (KBr, cm-1): 3,415 and 3,290 (asym.
and sym. stretching of –NH2), 2,210 (–C:N stretching),
1,675 (–C=O str.), 1,185 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.90–2.27 (m, 4H, CH2), 2.44
(s, 3H, CH3), 2.59 (m, 2H, CH2), 3.86 (s, 3H, OCH3), 4.60 (s,
1H, CH), 7.14–8.10 (m, 10H, Ar–H ? NH2). 13C NMR
123

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Med Chem Res (2013) 22:3831–3842
(100 MHz, DMSO-d6) d: 20.26 (CH2), 20.88 (CH3), 27.20
(CH2), 33.71 (CH), 36.81 (CH2), 55.95 (OCH3), 56.05
(C–CN), 106.65, 120.38, 123.03, 126.12, 126.57, 127.12,
128.16, 128.76, 129.64, 132.13, 134.82, 138.13, 143.15,
153.00, 159.04, 159.80, 163.58 (Ar–C), 196.20 (C=O).
CH3) 2.16 (dd, 2H, CH2), 2.55 (s, 2H, CH2), 4.80 (s, 1H, CH),
7.17–8.10 (m, 12H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 27.65 (CH3), 28.78 (CH3), 32.26 (C), 39.61
(CH), 40.23 (CH2), 50.49 (CH2), 57.16 (C–CN), 111.40,
113.34, 120.12, 121.50, 121.82, 127.03, 128.30, 130.41,
133.64, 137.98, 139.00, 140.38, 152.06, 156.63, 158.51,
160.01, 163.83 (Ar–C), 196.32 (C=O).
2-Amino-4-[6-methoxy-2-(4-methoxyphenoxy)quinolin-
3-yl]-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6k)
2-Amino-4-[2-(4-methylphenoxy)quinolin-3-yl]-7,
7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (6n)
Yield 88 %, m.p. 184–185 °C, Anal. Calcd. for C27H23N3O5
(469.49 g/mol): C 69.07, H 4.94, N 8.95 % Found: C 69.14,
H 5.07, N 8.88 %. IR (KBr, cm-1): 3,405 and 3,300 (asym.
and sym. stretching of –NH2), 2,200 (–C:N stretching),
1,670 (–C=O str.), 1,170 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.87–2.34 (m, 4H, CH2), 2.56
(m, 2H, CH2), 3.77 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.63
(s, 1H, CH), 7.15–8.13 (m, 10H, Ar–H ? NH2). 13C NMR
(100 MHz, DMSO-d6) d: 20.01 (CH2), 27.07 (CH2), 34.44
(CH), 36.85 (CH2), 55.86 (OCH3), 55.90 (OCH3), 56.39
(C–CN), 111.96, 119.77, 123.42, 125.38, 126.73, 127.21,
128.63, 129.12, 130.01, 132.15, 135.02, 138.17, 143.25,
153.22, 159.00, 159.81, 162.11 (Ar–C), 196.37 (C=O).
Yield 65 %, m.p. 271–272 °C, Anal. Calcd. for C28H25N3O3
(451.52 g/mol): C 74.48, H 5.58, N 9.31 % Found: C 74.52,
H 5.64, N 9.47 %. IR (KBr, cm-1): 3,450 and 3,310 (asym.
and sym. stretching of –NH2), 2,205 (–C:N stretching),
1,650 (–C=O str.), 1,200 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.03 (s, 3H, CH3), 1.04 (s, 3H,
CH3) 2.11 (dd, 2H, CH2), 2.38 (s, 3H, CH3), 2.54 (s, 2H,
CH2), 4.78 (s, 1H, CH), 7.03–8.08 (m, 11H, Ar–H ? NH2).
13C NMR (100 MHz, DMSO-d6) d: 21.47 (CH3), 27.20
(CH3), 29.05 (CH3), 32.17 (C), 38.45 (CH), 40.35 (CH2),
50.46 (CH2), 56.41 (C–CN), 111.40, 113.76, 120.41, 121.47,
122.04, 127.11, 128.31, 130.45, 133.58, 137.87, 139.14,
140.48, 152.14, 156.83, 158.51, 159.87, 163.89 (Ar–C),
196.40 (C=O).
2-Amino-4-[6-methoxy-2-(4-fluorophenoxy)quinolin-
3-yl]-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6l)
2-Amino-4-[2-(4-methoxyphenoxy)quinolin-3-yl]-7,
7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (6o)
Yield70 %, m.p.276–278 °C, Anal. Calcd. forC26H20FN3O4
(457.45 g/mol): C 68.26, H 4.41, N 9.19 % Found: C 68.32,
H 4.63, N 9.49 %. IR (KBr, cm-1): 3,400 and 3,335 (asym.
and sym. stretching of –NH2), 2,190 (–C:N stretching),
1,700 (–C=O str.), 1,210 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.92–2.33 (m, 4H, CH2), 2.63
(m, 2H, CH2), 3.82(s, 3H, OCH3),4.65(s, 1H, CH), 7.01–8.07
(m, 10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
20.24 (CH2), 27.12 (CH2), 31.20 (CH), 36.76 (CH2), 55.89
(OCH3), 56.30 (C–CN), 112.11, 121.01, 123.24, 125.93,
127.15, 127.76, 128.02, 128.80, 129.88, 132.17, 136.02,
138.31, 143.81, 153.34, 159.00, 159.84, 165.88 (Ar–C),
196.50 (C=O).
Yield 74 %, m.p. 180–181 °C, Anal. Calcd. for C28H25N3O4
(467.52 g/mol): C 71.93, H 5.39, N 8.99 % Found: C 72.02,
H 5.58, N 9.21 %. IR (KBr, cm-1): 3,390 and 3,310 (asym.
and sym. stretching of –NH2), 2,200 (–C:N stretching),
1,705 (–C=O str.), 1,210 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 0.99 (s, 3H, CH3), 1.05 (s, 3H,
CH3) 2.14 (dd, 2H, CH2), 2.57 (s, 2H, CH2), 3.76 (s, 3H,
OCH3), 4.63 (s, 1H, CH), 7.11–7.97 (m, 11H, Ar–H ?
NH2). 13C NMR (100 MHz, DMSO-d6) d: 27.42 (CH3),
28.75 (CH3), 32.16 (C), 40.33 (CH2), 42.25 (CH), 50.53
(CH2), 55.88 (OCH3), 56.32 (C–CN), 108.78, 111.44,
120.41, 121.14, 121.82, 127.13, 128.31, 130.45, 133.86,
137.72, 139.16, 140.64, 152.11, 156.52, 158.32, 159.83,
162.78 (Ar–C), 196.42 (C=O).
2-Amino-4-[2-phenoxyquinolin-3-yl]-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (6m)
Yield 75 %, m.p. 245–246 °C, Anal. Calcd. for C27H23N3O3
(437.49 g/mol): C 74.12, H 5.30, N 9.60 % Found: C 74.31,
H 5.43, N 9.29 %. IR (KBr, cm-1): 3,420 and 3,300 (asym.
and sym. stretching of –NH2), 2,225 (–C:N stretching),
1,685 (–C=O str.), 1,205 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.05 (s, 3H, CH3), 1.06 (s, 3H,
2-Amino-4-[2-(4-fluorophenoxy)quinolin-3-yl]-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6p)
Yield70 %, m.p.253–254 °C, Anal. Calcd. forC27H22FN3O3
(455.48 g/mol): C 71.20, H 4.87, N 9.23 % Found: C 71.37,
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Med Chem Res (2013) 22:3831–3842
3839
H 4.96, N 9.44 %. IR (KBr, cm-1): 3,450 and 3,305 (asym.
and sym. stretching of –NH2), 2,235 (–C:N stretching),
1,685 (–C=O str.), 1,180 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.07 (s, 3H, CH3)
2.15 (dd, 2H, CH2), 2.49 (s, 2H, CH2), 4.67 (s, 1H, CH),
7.05–8.05 (m, 11H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 27.36 (CH3), 28.80 (CH3), 32.32 (C), 40.39
(CH2), 40.49 (CH), 50.45 (CH2), 56.18 (C–CN), 106.75,
110.95, 120.24, 121.44, 121.98, 126.94, 128.54, 130.31,
133.98, 138.02, 139.15, 140.78, 152.17, 156.86, 158.50,
160.01, 163.97 (Ar–C), 196.49 (C=O).
2-Amino-4-[6-methyl-2-(4-methoxyphenoxy)quinolin-3-yl]-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6s)
Yield 75 %, m.p. 280–281 °C, Anal. Calcd. for C29H27N3O4
(481.54 g/mol): C 72.33, H 5.65, N 8.73 % Found: C 72.10,
H 5.90, N 8.82 %. IR (KBr, cm-1): 3,410 and 3,320 (asym.
and sym. stretching of –NH2), 2,200 (–C:N stretching),
1,675 (–C=O str.), 1,200 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.01 (s, 3H, CH3), 1.04 (s, 3H,
CH3) 2.15 (dd, 2H, CH2), 2.44 (s, 3H, CH3), 2.55 (s, 2H,
CH2), 3.78 (s, 3H, OCH3), 4.72 (s, 1H, CH), 7.18–8.12
(m, 10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
21.39 (CH3), 27.31 (CH3), 28.30 (CH3), 32.22 (C), 39.48
(CH), 40.36 (CH2), 50.50 (CH2), 55.87 (OCH3), 57.10
(C–CN), 106.97, 111.36, 120.28, 121.23, 121.89, 127.16,
128.54, 130.32, 133.89, 138.05, 139.17, 140.65, 152.15,
156.87, 158.51, 159.89, 164.91 (Ar–C), 196.25 (C=O).
2-Amino-4-[6-methyl-2-phenoxyquinolin-3-yl]-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (6q)
Yield 87 %, m.p. 212–213 °C, Anal. Calcd. for C28H25N3O3
(451.52 g/mol): C 74.48, H 5.58, N 9.31 % Found: C 74.52,
H 5.70, N 9.33 %. IR (KBr, cm-1): 3,430 and 3,325 (asym.
and sym. stretching of –NH2), 2,185 (–C:N stretching),
1,655 (–C=O str.), 1,225 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.04 (s, 3H, CH3), 1.05 (s, 3H,
CH3) 2.12 (dd, 2H, CH2), 2.47 (s, 3H, CH3), 2.58 (s, 2H,
CH2), 4.69 (s, 1H, CH), 7.00–8.07 (m, 11H, Ar–H ? NH2).
13C NMR (100 MHz, DMSO-d6) d: 21.42 (CH3), 27.23
(CH3), 28.73 (CH3), 32.27 (C), 40.30 (CH2), 41.50 (CH),
50.51 (CH2), 57.17 (C–CN), 106.25, 111.49, 120.45, 121.63,
121.95, 126.94, 128.30, 130.34, 133.84, 137.83, 139.11,
140.52, 152.23, 156.87, 158.54, 159.68, 164.49 (Ar–C),
196.45 (C=O).
2-Amino-4-[6-methyl-2-(4-fluorophenoxy)quinolin-3-yl]-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6t)
Yield 67 %, m.p. 240–241 °C, Anal. Calcd. for
C28H24FN3O3 (469.51 g/mol): C 71.63, H 5.15, N 8.95 %
Found: C 71.46, H 5.26, N 9.13 %. IR (KBr, cm-1): 3,415
and 3,295 (asym. and sym. stretching of –NH2), 2,210
(–C:N stretching), 1,690 (–C=O str.), 1,175 (C–O–C
1
ether stretching). H NMR (400 MHz, DMSO-d6): d 0.96
(s, 3H, CH3), 1.03 (s, 3H, CH3) 2.10 (dd, 2H, CH2), 2.42
(s, 3H, CH3), 2.60 (s, 2H, CH2), 4.73 (s, 1H, CH),
7.05–8.11 (m, 10H, Ar–H ? NH2). 13C NMR (100 MHz,
DMSO-d6) d: 21.45 (CH3), 27.44 (CH3), 29.00 (CH3),
32.19 (C), 40.25 (CH2), 42.17 (CH), 50.41 (CH2), 57.50
(C–CN), 112.40, 112.43, 119.75, 121.23, 121.69, 127.14,
128.31, 130.42, 133.84, 138.11, 139.13, 140.60, 152.11,
156.81, 158.12, 160.04, 162.50 (Ar–C), 196.60 (C=O).
2-Amino-4-[6-methyl-2-(4-methylphenoxy)quinolin-
3-yl]-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6r)
Yield 82 %, m.p. 274–275 °C, Anal. Calcd. for C29H27N3O3
(465.54 g/mol): C 74.82, H 5.85, N 9.03 % Found: C 75.01,
H 5.74, N 8.91 %. IR (KBr, cm-1): 3,410 and 3,325 (asym.
and sym. stretching of –NH2), 2,220 (–C:N stretching),
1,665 (–C=O str.), 1,195 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 0.97 (s, 3H, CH3), 1.07 (s, 3H,
CH3) 2.16 (dd, 2H, CH2), 2.35 (s, 3H, CH3), 2.48 (s, 3H,
CH3), 2.56 (s, 2H, CH2), 4.66 (s, 1H, CH), 7.02–7.95
(m, 10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
20.96 (CH3), 21.38 (CH3), 27.28 (CH3), 28.75 (CH3), 32.35
(C), 40.15 (CH), 40.29 (CH2), 50.59 (CH2), 56.30 (C–CN),
106.69, 111.46, 119.88, 121.39, 121.64, 127.00, 128.31,
130.31, 133.82, 138.02, 139.15, 140.46, 152.11, 156.81,
158.51, 159.84, 163.83 (Ar–C), 196.50 (C=O).
2-Amino-4-[6-methoxy-2-phenoxyquinolin-3-yl]-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (6u)
Yield 73 %, m.p. 220–221 °C, Anal. Calcd. for C28H25N3O4
(467.52 g/mol): C 71.93, H 5.39, N 8.99 % Found: C 71.87,
H 5.57, N 9.13 %. IR (KBr, cm-1): 3,400 and 3,340 (asym.
and sym. stretching of –NH2), 2,205 (–C:N stretching),
1,680 (–C=O str.), 1,215 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.05 (s, 3H, CH3), 1.08 (s, 3H,
CH3) 2.19 (dd, 2H, CH2), 2.53 (s, 2H, CH2), 3.88 (s, 3H,
OCH3), 4.67 (s, 1H, CH), 7.06–8.03 (m, 11H, Ar–H ?
NH2). 13C NMR (100 MHz, DMSO-d6) d: 27.38 (CH3),
123

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Med Chem Res (2013) 22:3831–3842
28.47 (CH3), 32.23 (C), 38.67 (CH), 40.38 (CH2), 50.55
(CH2), 55.94 (OCH3), 57.21 (C–CN), 109.08, 111.37,
120.31, 121.61, 121.84, 126.24, 128.32, 130.33, 133.84,
137.83, 139.17, 140.55, 151.57, 156.80, 158.51, 160.13,
165.03 (Ar–C), 196.47 (C=O).
and 3,320 (asym. and sym. stretching of –NH2), 2,230
(–C:N stretching), 1,670 (–C=O str.), 1,225 (C–O–C ether
stretching). 1H NMR (400 MHz, DMSO-d6): d 1.00 (s, 3H,
CH3), 1.04 (s, 3H, CH3) 2.14 (dd, 2H, CH2), 2.51 (s, 2H,
CH2), 3.85 (s, 3H, OCH3), 4.75 (s, 1H, CH), 7.09–8.14
(m, 10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
27.66 (CH3), 28.69 (CH3), 32.25 (C), 40.27 (CH2), 39.49
(CH), 50.47 (CH2), 55.92 (OCH3), 56.49 (C–CN), 106.08,
111.28, 119.98, 121.38, 121.84, 127.12, 128.33, 130.09,
133.44, 137.95, 139.04, 140.33, 152.11, 156.83, 158.51,
160.00, 165.88 (Ar–C), 196.41 (C=O).
2-Amino-4-[6-methoxy-2-(4-methylphenoxy)quinolin-
3-yl]-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6v)
Yield 89 %, m.p. 199–201 °C, Anal. Calcd. for C28H27N3O4
(481.54 g/mol): C 72.33, H 5.65, N 8.73 % Found: C 72.40,
H 5.73, N 8.86 %. IR (KBr, cm-1): 3,430 and 3,320 (asym.
and sym. stretching of –NH2), 2,200 (–C:N stretching),
1,680 (–C=O str.), 1,250 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 0.98 (s, 3H, CH3), 1.04 (s, 3H,
CH3) 2.13 (dd, 2H, CH2), 2.33 (s, 3H, CH3), 2.55 (s, 2H,
CH2), 3.86 (s, 3H, OCH3), 4.62 (s, 1H, CH), 7.01–8.10 (m,
10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
20.89 (CH3), 27.43 (CH3), 28.77 (CH3), 32.26 (C), 40.31
(CH2), 40.47 (CH), 50.54 (CH2), 55.91 (OCH3), 56.18
(C–CN), 106.67, 111.36, 120.30, 121.52, 121.71, 127.07,
128.28, 130.25, 133.71, 137.94, 139.02, 140.41, 152.09,
156.72, 158.47, 159.92, 163.88 (Ar–C), 196.38 (C=O).
m/z = 482.27 [M ? 1]?
Conclusion
A series of some new 4H-chromene derivatives containing
2-aryloxyquinoline moiety 6a–x have been synthesized
through a facile one-pot multicomponent reaction by the
microwave irradiation method. This synthetic strategy
allows the construction of relatively complicated nitrogen-
and oxygen-containing heterocyclic system as well as the
introduction of various heteroaromatic substitutions into
4-positions of pyrane. It can be concluded from antimi-
crobial screening (Table 2), against a panel of human
pathogens, that many of the synthesized above derivatives
are found to be highly active, compared to standard drugs,
against B. subtilis and C. tetani bacterial pathogens.
The interesting point to be noted is that compounds 6f
(R1=CH3, R2=CH3, R3=H), 6q (R1=CH3, R2=H, R3=CH3),
and 6r (R1=CH3, R2=CH3, R3=CH3) having CH3 substituent
on all of the three positions R1, R2, and R3 or at any two
position are more or equally potent to ampicilin against the
three Gram-positive bacteria. Also, the compounds 6o
(R1=H, R2=OCH3, R3=CH3) and 6s (R1=CH3, R2=OCH3,
R3=CH3) having OCH3 substituent at R2 and CH3 substituent
at R3 are found active against Gram-positive bacteria.
Examination of the antifungal activity of the compounds
reveals that most of the compounds of the present series are
potent against C. albicans, but having poor activity against
A. fumigatus. It is worth mentioning that a minor change in
molecular configuration of these compounds profoundly
influences the activity. The present study throws light on
the identification of this new structural class as antimi-
crobials which can be of interest for further detailed pre-
clinical investigations.
2-Amino-4-[6-methoxy-2-(4-methoxyphenoxy)quinolin-
3-yl]-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6w)
Yield 87 %, m.p. 249–250 °C, Anal. Calcd. for C29H27N3O5
(497.54 g/mol): C 70.01, H 5.47, N 8.45 % Found: C 69.92,
H 5.64, N 8.70 %. IR (KBr, cm-1): 3,415 and 3,300 (asym.
and sym. stretching of –NH2), 2,190 (–C:N stretching),
1,695 (–C=O str.), 1,230 (C–O–C ether stretching). 1H NMR
(400 MHz, DMSO-d6): d 1.03 (s, 3H, CH3), 1.09 (s, 3H,
CH3) 2.20 (dd, 2H, CH2), 2.52 (s, 2H, CH2), 3.77 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 4.71 (s, 1H, CH), 7.08–8.08
(m, 10H, Ar–H ? NH2). 13C NMR (100 MHz, DMSO-d6) d:
27.38 (CH3), 28.71 (CH3), 32.30 (C), 39.30 (CH), 40.38
(CH2), 50.42 (CH2), 55.86 (OCH3), 55.86 (OCH3), 56.31
(C–CN), 112.37, 111.41, 120.42, 121.65, 122.04, 127.23,
128.33, 130.37, 133.44, 138.02, 139.34, 140.52, 152.23,
156.54, 158.51, 159.74, 165.70 (Ar–C), 196.49 (C=O).
2-Amino-4-[6-methoxy-2-(4-fluorophenoxy)quinolin-3-yl]-
7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitrile (6x)
Acknowledgments We are thankful to the Department of Chemis-
try, Sardar Patel University, for providing research facilities. We are
also thankful to the Vaibhav Analytical Laboratory, Ahmedabad, for
the FT-IR; the Sophisticated Instrumentation Centre for Applied
Research and Training (SICART), Vallabh Vidyanagar, for elemental
analysis; Oxygen Healthcare Research Pvt. Ltd., Ahmadabad, for
providing mass spectrometry facilities; and Microcare Laboratory,
Yield 70 %, m.p. 258–259 °C, Anal. Calcd. for
C28H24FN3O4 (485.51 g/mol): C 69.27, H 4.98, N 8.65 %
Found: C 69.36, H 4.86, N 8.73 %. IR (KBr, cm-1): 3,425
123

Med Chem Res (2013) 22:3831–3842
3841
Surat, for antimicrobial screening of the compounds reported herein.
One of the authors is grateful to UGC, New Delhi, for a Research
Fellowship in Sciences for Meritorious Students.
Makawana JA, Patel MP, Patel RG (2011b) Diversity-synthesis and
antimicrobial evaluation of new pyrano[4,3-b]pyran and pyr-
ano[3,2-c]chromene derivatives bearing 2-thio-phenoxyquinoline
nucleus. Arch Pharm Chem Life Sci. doi:10.1002/ardp.201100203
Makawana JA, Patel MP, Patel RG (2011c) Synthesis and in vitro
antimicrobial evaluation of penta-substituted pyridine deriva-
tives bearing the quinoline nucleus. Med Chem Res. doi:10.
1007/s00044-011-9568-6
Makawana JA, Patel MP, Patel RG (2011d) Synthesis and in vitro
antimicrobial activity of new 3-(2-morpholinoquinolin-3-yl)
substituted acrylonitrile and propanenitrile derivatives. Chem
Pap 65:700–706
Meth-Cohn O, Bramha NA (1978) A versatile new synthesis of
quinolines, thienopyridine and related fused pyridines. Tetrahe-
dron Lett 23:2045–2048
Mital A, Negi V, Ramachandran U (2006) Synthesis and antimyco-
bacterial activities of certain trifluoromethyl-aminoquinoline
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