Microwave Synthesis of Fused Pyrans by Humic Acid Supported Ionic Liquid Catalyst and Their Antimicrobial, Antioxidant, Toxicity Assessment, and Molecular Docking Studies

Article abstract of DOI:10.1002/jhet.3465

A series of fused quinolinyl and quinolonyl pyrans were synthesized via a one-pot reaction of quinolinyl and quinolonyl carbaldehydes, malononitrile, and a 1,3-diketone. The reactions were catalyzed by a new humic acid supported 1-butyl-3-methyl imidazoli

Full text of DOI:10.1002/jhet.3465

Month 2019
Microwave Synthesis of Fused Pyrans by Humic Acid Supported Ionic
Liquid Catalyst and Their Antimicrobial, Antioxidant, Toxicity Assess-
ment, and Molecular Docking Studies
a
b
c
a
a
Muthu Thangaraj,
Bibhuti Ranjan, Ramesh Muthusamy, Arul Murugesan, and Robert Moonsamy Gengan *
a
Department of Chemistry, Faculty of Applied Sciences, Durban University of Technology, Durban 4001, South Africa
b
Department of Biotechnology and Food Technology, Faculty of Applied Sciences, Durban University of Technology,
Durban 4001, South Africa
c
Department of Pharmaceutical Analysis and Quality Assurance, Omega College of Pharmacy, Edulabad, Ghatkesar,
Telangana 501 301, India
*
E-mail: genganrm@dut.ac.za
Received June 11, 2018
DOI 10.1002/jhet.3465
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of fused quinolinyl and quinolonyl pyrans were synthesized via a one-pot reaction of quinolinyl
and quinolonyl carbaldehydes, malononitrile, and a 1,3-diketone. The reactions were catalyzed by a new hu-
mic acid supported 1-butyl-3-methyl imidazolium thiocyanate ionic liquid under microwave irradiation con-
ditions. Antimicrobial, antioxidant, and toxicity studies displayed various biological activities depending on
structure of the pyrans.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
2-amino-4H-pyrans are used as photoactive materials
12], pigments [13], and potentially biodegradable
[
Six-membered heterocyclic compounds containing
oxygen, such as pyrans, constitute an important class of
natural and synthetic products that plays a fundamental
role in bio-organic chemistry and continues to attract
research interest [1,2]. The fused pyrans are biologically
interesting compounds that display antimicrobial [3],
antifungal [4], antitumor [5], anticoagulant, diuretic,
spasmolytic, and anti-anaphylactic activities [6–9].
Furthermore, 4H-pyrans are building blocks for
some important natural products [10,11]. A number of
agrochemicals [14]. Because they possess unique
pharmacological properties, new methodologies for the
synthesis of these compounds have emerged. The
simplest synthesis involves a three-component coupling
of an aromatic aldehyde, malononitrile, and 1,3-diketones.
Quinoline and its annulated derivatives are highly
valuable compounds because of their wide applications as
drugs and pharmaceuticals [15,16]. The fused pyran is an
important class of compounds that constitute the basic
frameworks of a number of alkaloids of biological
©
2019 Wiley Periodicals, Inc.

M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
During the past two decades, a rapidly growing
awareness to environmental issues has catalyzed the thirst
for greener and more sustainable technologies in the
chemical industry. Ionic liquids (ILs), which consist of
cations and anions with low melting points and very low
vapor pressures, [25–27] are in great demand as an
application in green synthesis. Many different ILs have
been prepared and used as solvents and modified
catalysts. Homogeneous catalysts in ILs usually provide
the advantages of high catalytic activity and good
selectivity; however, their widespread usage is associated
with some drawbacks such as difficult product isolation
and recovery of the catalyst as well as high cost of ILs
and their unstudied toxicological properties. Fortunately,
ILs in heterogeneous form overcome these drawbacks
and moreover, supported solid catalysts with ILs combine
the benefits of ILs and heterogeneous catalysis such as
good stability of catalytically active species, ease of
handling, simple separation, and recycling. In this
context, ILs are now widely used for immobilization of
homogeneous catalysts [28–31].
The cationic parts of most ILs are organic-based
moieties such as imidazolium ions, and the anionic parts
can be organic or inorganic and include entities such as
thiocyanates, humic substances, nitrates, and acetates.
The supported ILs phase catalysis concept is based on a
classical homogeneous catalyst that is dissolved in a thin
film of ILs that is further dispersed over the high internal
surface of porous support. In supported ILs phase
materials, the dissolved catalyst still acts microscopically
as homogeneously dissolved metal complex in its
uniform ILs environment while macroscopically dry solid
form that can be recycled easily. Humic acid is a typical
Figure 1. Examples of pyran molecules with biological activities. [Color
figure can be viewed at wileyonlinelibrary.com]
significance [17]. Figure 1 shows few examples of fused
pyran molecules with biological activities [17]. Therefore,
considerable efforts are invested in their synthesis [18]
thereby resulting in a large number with important
medicinal benefits.
Heterocyclic sulfur-containing molecules have broad
application in organic and medicinal chemistry [19]:
β-mercapto diketones, as a typical example, display
remarkable pharmacological properties such as a diuretic
and HIV protease inhibitory [20–23]. Recently, several
multicomponent reactions, related to sulfur, have been
described [24]. Kornienko and Magedov reported [24] a
one-pot synthesis of heterocyclic privileged medicinal
scaffolds by using malononitrile with aldehydes and
thiols, in ethanol, catalyzed by triethylamine.
Figure 2. The proposed interaction of HASIL. HASIL, humic acid supported 1-butyl-3-methyl imidazolium thiocyanate. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
In this study, humic acid (HA) supported 1-butyl-3-
methyl imidazolium thiocyanate (HASIL) catalyst is used
for the synthesis of novel fused quinoline and quinolonyl
pyrans.
RESULTS AND DISCUSSION
Firstly, a new HASIL material was synthesized by stirring
an ethanolic mixture of 1-butyl-3-methylimidazolium
thiocyanate IL ([bmim]SCN) and HA under inert
atmosphere for 10 h followed by reflux. The solvent was
removed in vacuo to produce an off-white powder that was
treated with a solution of HA and copper acetate to produce
the catalyst, after work-up of the reaction content. The
proposed possible interaction of copper, HA, and [bmim]
SCN [33,34] is shown in Figure 2. The synthesized novel
catalyst was analyzed using various techniques including
powder X-ray diffraction, scanning electron microscopy
(SEM), energy dispersive X-ray spectroscopy, transmission
electron microscopy, thermogravimetric analysis (TGA),
differential scanning calorimetry (DSC), and Fourier-
transform infrared spectroscopy (FTIR).
Figure 3. The powder X-Ray Diffraction pattern for HASIL. HASIL,
humic acid supported 1-butyl-3-methyl imidazolium thiocyanate. [Color
figure can be viewed at wileyonlinelibrary.com]
support material that catalyzes several reactions [32]: it
enhances the basic nature of the catalyst and provides a
heterogenic system. Heterogeneous catalytic systems
display advantages including larger interfacial reaction
area, ease of product separation, cost-effectiveness,
recyclability, and environmental friendliness.
The X-ray diffraction pattern in the 2θ range from
10°C to 70°C of HASIL (Fig. 3) exhibits very small
Figure 4. SEM images of the humic acid supported ionic liquid catalyst. SEM, scanning electron microscopy.
Journal of Heterocyclic Chemistry
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M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
Figure 5. EDX spectra and elemental mapping of HASIL. EDX, energy-dispersive X-ray spectroscopy; HASIL, humic acid supported 1-butyl-3-methyl
imidazolium thiocyanate. [Color figure can be viewed at wileyonlinelibrary.com]
diffuse peaks with a few intense peaks, implying its
non-crystalline nature. This behavior is consistent with
the behavior observed in the case of humic substances
from other sources [35,36]. The weaker diffraction lines
of HASIL exhibit the humic particles are coated
with ILs. The diffraction reflection observed at around
observed. The small particles suggest high metal
adsorption [38] is promoted: Cu can form bridges with
the carboxyl groups of HA, interact by chemisorption
with oxidized carbon atoms, and form coordination
compounds [39] with other functional groups of humic
substances, such as hydroxyl, phenol, carboxyl, and
methoxy functional groups. Compacted microaggregates
are found in HASIL. The aggregation phenomenon is
important to the transport of metal ions in natural
environments [40]. The HA substances in general form
thin thread and net-like structures that grow into larger
38.5°, 45°, 56°, and 62.5° corresponds to (002), (111),
(200), and (113) of Bragg’s reflection for cubic structure
of copper [37].
Figure 4A, B, C, and D provides the SEM images of
HASIL where small particles at 20, 10, 2, and 1 μm are
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
Figure 6. TEM images of HASIL and particle histogram. HASIL, humic acid supported 1-butyl-3-methyl imidazolium thiocyanate; TEM, transmission
electron microscopy. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 5 depicts a spectrum acquired from the SEM
images of HASIL, revealing the existence of elements
such as carbon, oxygen, copper, and gold. The copper
peaks were obtained at 1.4 and 1.8 KeV. The elemental
mapping is obtained while running Energy-Dispersive X-
Ray Spectroscopy spectrum. The appearance of Au peaks
is because of the coating of sample with conducting
material (Au) to reflect electrons (sputter coating).
The size and morphology of HASIL were obtained by
transmission electron microscopy (Fig. 6). The images
reveal the formation of maximum number of particles
with an average size of 166 nm followed by 250 nm (size
variation: ±14 nm calculated by ImageJ, see particle
histogram) with an initial process of particle sinterization.
The entire HASIL particles contained aggregates with no
uniform size and fractal feature. Few of the individual
Figure 7. TGA curve of HASIL. HASIL, humic acid supported 1-butyl-
HASIL particles are ellipsoidal in shape (Fig. 6A and C).
The smallest particles visible are ~83 nm in size (Fig. 6
histogram).
3
-methyl imidazolium thiocyanate; TGA, thermogravimetric analysis.
[Color figure can be viewed at wileyonlinelibrary.com]
The TGA curve (Fig. 7) shows that in the temperature
range 25°C to 500°C mass losses of HASIL reach about
60% that are most likely caused by destruction of the
organic components and condensation of hydroxyl groups
at high temperatures [42]. The appearance of a mass loss
rings and sheets with increasing humic and cationic
concentrations [41]. The cationic concentrations are
because of the IL, [bmim]SCN.
Journal of Heterocyclic Chemistry
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M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
the appearance of ions corresponding to phenolic and
carboxylic groups of HA [42]. Almost similar
temperature range of 244.6°C to 390.6°C was observed
in the literatures for [bmim]SCN that confirmed the
strong interaction of IL with HA [43].
The DSC method is convenient for such studies as it is a
rapid technique to give characteristic curves, whose
variation in enthalpy is associated with phase changes in
mineral or soil organic matter, reflecting events related to
structures and chemical compositions [44–46]. The areas
under the DSC curves were divided into two groups
representing different degrees of resistance to thermal
oxidation: (a) temperature range (230–338°C), mostly
attributable to labile organic matter, mainly compromising
phenolic hydrates and other aliphatic compounds.
Nevertheless, decarboxylation and dehydration (removal
of OH groups during the formation of interaction between
HA and [bmim]SCN) should be considered and (b)
temperature at 35–175°C, mostly attributable to organic
matter, such as polyphenols and polycondensed aromatic
substances including HA, humin, and black carbon
Figure 8. DSC curve of HASIL. DSC, thermogravimetric analysis;
HASIL, humic acid supported 1-butyl-3-methyl imidazolium thiocyanate.
[Color figure can be viewed at wileyonlinelibrary.com]
[47,48]. The following parameters were also determined:
temperature of maximum combustion peaks in the DSC
curves was observed at 230°C and 338°C with two
exothermic peaks and is shown in Figure 8, respectively.
The FTIR spectra (Fig. 9) of HASIL exhibit a strong
ꢀ
1
stretching band at 3289 cm that is assigned to the OH
stretch of HA. The other absorption observed frequencies
ꢀ
1
(
cm ) at 1210 for C─N, 1652 for C═O, 1487 for C═C,
055 for ─C─O and bending frequencies 1742 for
N─H, 1368 for ─C─H, and 754 for ─CH═CH. The
1
Figure 9. FTIR spectrum of HASIL. FTIR, Fourier-transform infrared;
HASIL, humic acid supported 1-butyl-3-methyl imidazolium thiocyanate.
ꢀ
1
FTIR of HASIL shows absorption bands at 557 cm for
ꢀ
1
[Color figure can be viewed at wileyonlinelibrary.com]
Cu─O and 437 cm
for Cu─N. This confirms the
formation of ─C═N─Cu. A strong stretching vibration
ꢀ
1
at 110°C is because of the presence of water molecule. As
we can see, the main decomposition process starts near
band is observed at 937 cm
for ─N─O─Cu. This
confirms the formation of ─N─O─Cu bond [49]. These
results suggest that Cu was adsorbed on the bulk material
of HA. The procedure adopted for the preparation of
230°C and practically ends to 320°C with a mass loss
range 50–60%. The decomposition can be determined by
Scheme 1. Synthesis of 2-methoxy quinoline-3-carbaldehyde and 2-oxo-1,2-dihydropyridine-3-carbaldehyde derivatives [50]. [Color figure can be
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
HASIL, where the hydroxyl and carboxylic groups are
present in their dissociated form, could create favorable
conditions for strong interactions with the positive
charges of IL.
After the successful characterization, the HASIL activity
was investigated in a one-pot three-component synthesis of
quinolinyl pyran derivatives. At first, 2-chloroquinoline-
synthesized by stirring a mixture of dimethylformamide
and POCl3 at 0–5°C followed by refluxing with the
corresponding acetanilides at 80–90°C using the Vilsmeier–
Haack reaction [50]. Thereafter, the desired starting
material 2-methoxy quinoline-3-carbaldehyde was obtained
from the reaction of K CO3 with 2-chloroquinoline-
2
3-carbaldehyde in methanol (Scheme 1). The quinolone
starting material 2-oxo-1,2-dihydropyridine-3-carbaldehyde
derivatives were prepared from the reaction of glacial
3-carbaldehyde, 2-chloro-6-methylquinoline-3-carbaldehyde,
and 2-chloro-7-fluoroquinoline-3-carbaldehyde were
Scheme 2. Synthesis of quinolinyl-4H-pyrans in the presence of HASIL under microwave irradiation. HASIL, humic acid supported 1-butyl-3-methyl
imidazolium thiocyanate. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 3. Synthesis of quinolonyl-4H-pyrans in the presence of HASIL under microwave irradiation (4i and 4j). HASIL, humic acid supported 1-butyl-
3
-methyl imidazolium thiocyanate. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
CH COOH with 2-chloro-7-fluoroquinoline-3-carbaldehyde
and quinolinyl proton singlet C4 at δ 7.91. The dimedone
3
and 2-chloro-6-methylquinoline-3-carbaldehyde.
The three-component reaction was explored from an
equivalent mixture of 2-methoxy quinoline-3-carbaldehyde
protons (CH ) showed a quartets at δ 2.48 and δ 2.22 for
2
0
0
13
C8 -H and C6 -H, respectively. The C-NMR spectrum
0
of 4a showed the carbonyl group C5 (C═O) at δ 195.9.
(
(
1 mmol), malononitrile (1 mmol), and dimedone
1 mmol) in the absence of catalyst in ethanol as medium
The methoxy group C9 (OCH ) was assigned to δ 53.4.
3
0
0
The methyl carbon C9 at δ 27.0 and C10 methyl carbon
0
under reflux conditions. Thin-layer chromatography
TLC) was used to monitor the progress of the reaction.
at δ 29.3 were observed. The carbon C6 (CH ) showed a
2
0
(
peak at δ 50.5, and C8 showed a peak at δ 40.7. The CH
(C4 ) carbon showed a peak at δ 32.1, and the
0
There was no products obtained until 24 h.
Thereafter, HASIL was used to carry out the reaction
with the same equimolar ratio of the substrates as
described earlier. TLC analysis showed a new spot
thereby indicating a promising reaction. After 3 h, the
mixture was worked-up and the solid was purified by
column chromatography using a ethyl acetate : petroleum
ether (1:3) solvent system. The obtained yield was 52%.
A repeat of the experimental under microwave (MW)
irradiation with the power set at 120 W for reaction times
of 5, 8, 10, 12, and 15 min, separately, was investigated.
A maximum yield of 97% of 4a was obtained in 10 min.
Hence, MW irradiation became the method of choice for
the synthesis of new fused quinolinyl and quinolonyl
pyrans (Schemes 2 and 3). The structure was confirmed
carbonitrile CN was observed at δ 111.8. The pyran ring
0
carbon atoms C3 at δ 60.8 and in the same pyran ring,
0
0
C2 at δ 160.1 and C8b at δ 158.6, were observed. The
0
dimedone carbonyl carbon C7 was identified at δ 32.7.
The quinolinyl carbon C3 was observed at δ 125.2 and
C═N in the quinolinyl ring showed a peak at δ 162.9 and
1
C4 showed a peak at δ 137.8. The selected H-NMR and
13
C-NMR chemical shifts of 4a are shown in Figure 10.
The structure was further confirmed on the basis of 2D
13
1
NMR spectral studies. The C, H-COSY correlation of
carbon signals at δ 137.8, 129.2, 127.6, 126.6, 125.3,
124.0, 53.4, 50.5, 40.7, 32.1, 29.3, and 27.0 were
0
0
0
0
assigned to C4, C7, C5, C8, C6, C4b , C9, C6 , C8 , C4 ,
0
0
C10 , and C9 , respectively. The carbon signal at δ 137.8
was because of the quinolinyl carbon (C4), and the
spectrum is shown in Figure S4.
The H, H-COSY spectrum of 4a revealed the
correlation between quartet of C6 (CH ) proton at δ 2.22
1
13
by FTIR, H-NMR, C-NMR, and elemental analysis.
1
13
Fourier-transform infrared, H-NMR, and
C-NMR
1
1
chemical shifts of quinolinyl pyrans. The FTIR spectrum
ꢀ
1
0
of 4a shows stretching frequencies (cm ) at 2253 for
C≡N, 1571 for C═N, 1216 for C─N, 2970 for CH, 1637
2
0
0
and singlet of CH (C9 ) proton δ 1.05. The C9 (CH )
proton at δ 1.05 correlated with quartet of C6 (CH )
3
3
0
for C═C, 1752 for C═O, 2940 for OCH , and 3028 for
3
2
1
NH. The H-NMR spectrum of 4a showed six singlets
for CH (C4 ) at δ 4.68, NH (C12 ) at δ 4.59, methyl
proton broad singlet (CH , C10 ) at δ 1.44, broad singlet
of (CH , C9 ) at δ 1.05, broad singlet of OCH at δ 4.08,
proton at δ 2.22 (Fig. S5).
0
0
1
1
The H, H-NOESY spectrum revealed the singlet
2
0
protons (NH ) at δ 4.59 was coupled with a quartet of
3
2
0
0
C6 (CH ) at δ 2.22 (Fig. S6).
3
3
2
1
13
Figure 10. Selected H-NMR and C-NMR chemical shifts for 4a. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
Figure 11. Selected HMBC correlation spectrum of 4a. HMBC, heteronuclear multiple bond correlation. [Color figure can be viewed at
wileyonlinelibrary.com]
Table 1
Table 2
Effect of solvents on the synthesis of quinolinyl pyrans .
a
Selected heteronuclear multiple bond correlations of 4a.
b
Entry
1
Protons
Correlated carbons
Entry
Solvent
Time (min)
Yield (%)
0
0
0
C4 -H (s, 1H) at
δ 4.68 ppm
C3 (60.83), C11 (111.83),
1
2
3
4
5
6
Acetonitrile
Dichloromethane
Ethanol
Methanol
Water
Ethanol–water
15
15
10
15
20
15
73
71
97
88
35
40
0
C3 (125.28), C5 (195.94),
0
and C4b (124.08)
0
2
3
4
5
6
7
C4-H (s, 1H) at
δ 7.91 ppm
C6 -H (q, 2H) at
δ 2.22 ppm
C8 -H (q, 2H) at
δ 2.48 ppm
C9 -H (brs, 3H) at
δ 1.05 ppm
C10 -H (brs, 3H) at
δ 1.44 ppm
C4-H (s, 1H) at δ
C4 (32.17), C5 (127.60),
and C2 (163.92)
0
0
0
C7 (32.77), C8 (40.79),
0
and C5 (195.94)
a
0
0
0
Reaction conditions: aldehyde (1 mmol), malononitrile (1 mmol), 1,3-
C7 (32.77), C6 (50.58),
0
diketone (1 mmol), and HASIL (10 mol%) were added to the ethanol as
solvent (15 mL) under microwave irradiation (120 W) at room
temperature.
and C2 (160.15)
0
C2 (162.93)
b
Isolated yields.
0
0
0
C7 (32.77), C8 (40.79),
0
and C6 (50.58)
0
0
0
C4 (32.17), C5 (127.60),
coupled with C3 of pyran ring carbon at δ 60.8 and C11
carbonitrile CN carbon at δ 111.8, quinolinyl carbon C3
at δ 125.2 and dimedone carbons C5 at δ 195.9 and C4b
7.91 ppm
and C2 (162.93)
0
0
The heteronuclear multiple bond correlation (HMBC)
at δ 124.0.
0
0
spectrum (Fig. S7) of 4a shows the long-range
This correlation of C4 -H to the pyran ring carbon (C3 ),
carbonitrile carbon (C11 ), quaternary carbon (C3) of
0
0
correlations as follows: the proton C4 -H (CH) group was
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M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
0
Table 3
at δ 160.1. The C9 -H (CH ) was coupled with C2 at δ
3
0
0
0
Effect of optimization of HASIL catalyst.
162.9. The C10 -H was coupled with C7 at δ 32.7, C8 at
δ 40.7, and C6 (CH ) carbon at δ 50.5. The quinolinyl
proton C4-H was coupled with C4 (CH) carbon at δ 32.1,
quinolinyl carbons (C5) at δ 127.6, and C2 at δ 162.9. The
selected HMBC correlations of 4a are shown in Table 1.
Based on the aforementioned spectral details and its
elemental analysis (Anal. Calcd for C H N O : C,
0
a
2
Entry
Catalyst
Mol %
Time (min)
Yield (%)
0
1
2
3
4
5
HA
25
5
10
15
20
20
15
10
15
15
Trace
71
97
90
90
HASIL
HASIL
HASIL
HASIL
22 21 3 3
a
70.38; H, 5.64; N, 11.19; %. Found: C, 70.36; H, 5.65;
Isolated yield.
N, 11.20; %), the structure was confirmed as 2-amino-
4
-(2-methoxyquinolin-3-yl)-7,7-dimethyl-5-oxo-5,6,7,8-
0
0
quinoline ring, and carbons C5 and C4b of dimedone
tetrahydro-4H-chromene-3-carbonitrile (4a).
0
indicated that the three groups were attached to C4 (CH).
Thus, it was evident that three different moieties were
bonded to a common carbon (C4 ) and hence added
valuable information to 4a. The selected H-NMR, C-
NMR, and HMBC chemical shifts are shown in Figure 11.
The C4-H, quinoline proton was coupled with C4 at δ
2.1, quinolinyl carbons (C5) at δ 127.6, and (C2) at δ
63.9. The C6 -H of dimedone was coupled with C7 at δ
To determine the effect of solvents and the efficiency of
the catalyst, the synthesis of 4a was selected as model
reaction. Solvents such as acetonitrile, DCM, ethanol,
ethanol, water, and ethanol–water were used for
optimizing the suitable solvent. It was found that ethanol
showed a crucial effect on the reaction yield (97%). The
yield decreased to 35% when altering the solvents, and
the low yield resulted from some unreacted substances
(Table 2, entry 5).
When the same substrate mixture was reacted in the
presence of HASIL (5 mol %), the isolated yield of 4a
was 71%. In another attempt, a trace amount of product
was obtained while HA used as a catalyst (Table 3, entry
1). It was found that in the presence of (10 mol %)
HASIL, the yield of 4a substantially increased to 97%
within 10 min (Table 3, entry 3). However, on further
increasing the amount of HASIL to 15 mol % and
0
1
13
0
3
1
3
0
0
0
0
0
2.7, C8 (40.7), and C5 (195.9). The C8 -H proton was
coupled with C7 at δ 32.7, C6 (CH ) at δ 50.5, and C2
0
0
0
2
Table 4
Effect of microwave (MW) irradiation on the synthesis of quinolinyl
a
pyran .
b
Entry
Power (W)
Time (min)
Yield (%)
1
2
3
4
5
6
Without MW (r.t)
Without MW (90°C)
24 h
3 h
20
10
15
38
52
75
97
90
90
2
0 mol %, no improvements in the yield (90%) were
100
120
150
200
observed (Table 3, entries 4 and 5). This shows that the
best yield of 4a was obtained when HASIL is taken at
1
0 mol %, respectively.
15
To report the effect of MW irradiation and to evaluate
a
Reaction conditions: aldehyde (1 mmol), malononitrile (1 mmol), 1,3-
diketone (1 mmol), and HASIL (10 mol%) were added to the ethanol as
solvent (15 mL).
and compare normal refluxing with MW assisted method,
various conventional and unconventional conditions were
screened. The results are listed in Table 4. Without MW,
b
Isolated yields.
Figure 12. Recyclability of HASIL. HASIL, humic acid supported 1-butyl-3-methyl imidazolium thiocyanate. [Color figure can be viewed at
wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
Table 5
Effect of optimization of reported catalysts with HASIL catalyst.
Entry
Catalyst
Temp (°C)
Time
Yield (%)
References
1
2
3
4
5
6
7
8
9
Montmorillonite K10
125
85
80
125
100
125
125
100
120
80
100
80
90
110
110
110
110
110
80
30 min
25 min
90 min
300 min
40 min
240 min
180 min
300 min
10 min
2 h
30 min
40 min
2 h
25 min
20 min
20 min
25 min
30 min
10 min
96
97
88
87
95
90
78
87
89
90
97
95
97
52
50
53
55
61
97
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
-
4 3
Fe (HSO )
Zwitterionic salt
Iodine
TCT
p-TSA
K
5
CoW12
[FemSILP]-L-Prolinate
[TEBSA][HSO
[bmim][PF
2
O40.3H O
4
]
10
11
12
13
14
15
16
17
18
19
6
]
[DMAP-PEG1000-DIL][BF
4
]
ꢀ
[PhNMe
DABCO
AlCl
CuBr
2 2 2
CH NMe ]Cl
3
-
-
-
-
ZnCl
2
B (OH)
3
FeCl
HASIL
3
This work
4
a was formed in the presence of HASIL under stirring at
catalytic efficiency of recycled HASIL, five successive
cycles of the model reaction were run under optimal
conditions. The activity of the catalyst did not show any
significant decrease in the yields after five successive
runs for the model reaction. It was found that the catalyst
displayed good recyclability (Fig. 12).
room temperature after 24 h. Also the reaction at 90°C
and without MW irradiation, the observed yield was 38–
5
effect of MW irradiation of different powers was
investigated. It was observed that the irradiation power of
2% within 3 h (Table 4, entries 1 and 2). Moreover, the
1
20 W at 110°C afforded the best yield of 4a, with 97%
The catalyst was further compared with previously
reported catalysts (Table 5, entries 1–13), and the results
are tabulated. In addition, Lewis acids such as AlCl3,
isolated yield after 10 min (Table 4, entry 4). It was
found that the MW condition can raise the rate of the
reaction without harmful to the environment and
therefore reduced the energy consumption.
The HASIL was separated by simple filtration from the
reaction mixture and it was washed with MeOH followed
by acetone and dried in an oven at 100°C. Furthermore,
the reusability of HASIL was screened. To investigate the
ZnCl , and CuBr were investigated for their catalytic
2
activity; however, these Lewis acids proved to be
ineffective for the reaction. The reaction with B (OH)3
and FeCl was also attempted, but the desired product
3
was obtained in poor yield (Table 5, entries 14–18). The
catalysts including montmorillonite K10, Fe (HSO ) ,
4
3
Table 6
Synthesis of quinolinyl and quinolonyl pyrans by using HASIL under MW conditions.
a
Entry
Aldehydes
NO
1,3-Diketones
Product
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
C
11
H
9
2
C
8
C
8
C
6
H
12
H
12
H
10
O
2
O
2
O
3
C
C
C
22
28
20
H
21
H
25
H
19
N
N
N
3
O
3
O
3
O
3
3
4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
10
10
10
12
15
12
14
15
12
15
12
10
10
10
97
96
96
90
88
89
92
87
90
85
89
93
95
93
17
C H
13NO
2
C
C
11
H
H
9
NO
NO
2
11
9
2
C
C
3
H
H
3
NO
NOS
2
S
C
17
H
12
N
4
O
3
S
C
11
H
8
N
O
2 4
3
3
2
C
17
H
11
N
5
O
4
S
2
C
11
C
11
C
11
C
10
H
8
H
8
H
8
H
6
FNO
FNO
FNO
FNO
2
2
2
2
C
C
8
H
H
12
O
O
2
C
C
C
C
C
C
C
C
22
H
H
20FN
18FN
3
O
O
3
6
10
3
20
3
4
C
H
3 3
NO
2
S
17
21
18
22
H
H
H
H
11FN
18FN O
4 3
O S
C
8
H
12
O
2
3 3
10
11
12
13
14
C
11
H
9
NO
ClNO
2
C
4
H
4
N
2
O
3
13
N
5
O
4
C
11
H
8
C
8
C
8
C
6
H
12
H
12
H
10
O
2
O
2
O
3
20ClN
3
O
2
C
C
C
12
H
12
H
12
H
11NO
11NO
11NO
2
2
2
23
H
H
23
N
N
3
O
O
3
21
21
3
4
C
H
3 3
NOS
2
C
18
H
14
N
4
O
2
S
2
a
Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
Scheme 4. Plausible mechanism for HASIL promoted synthesis of quinolinyl pyrans. HASIL, humic acid supported 1-butyl-3-methyl imidazolium
thiocyanate. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 13. Growth inhibition of some bacterial strains caused by: (A) positive (ciprofloxacin) and negative (DMSO) control, (B) different derivatives of
the quinolinyl pyrans. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
TCT, [DMAP-PEG1 -DIL][BF ], [PhNMe CH NMe ]
000
4
2
2
2
ꢀ
Cl , and DABCO offered more than 90% yield;
however, they had drawbacks of long reaction times. It
was deduced that the present protocol, with the aid of
HASIL, was better than other reported protocols with
respect to time, temperatures, and yields. Thus, the one-
pot multicomponent synthesis of new quinolinyl pyrans
was successfully synthesized by using HASIL under MW
and characterized. A total of 14 compounds were
1
synthesized successfully (Table 6). The FTIR, H-NMR,
and C-NMR for all the synthesized compounds (4a–4n)
13
are available in the Supporting Information.
Mechanism.
Humic acid,
material, is able to catalyze the condensation of cyclic-
,3-diketones with aromatic aldehydes, and the products
a well-known cheap
1
are formed with comparatively high yields [32]. The
weak Van der Waals interaction and electrostatic
interaction of [bmim]SCN IL [43] might be responsible
for the catalytic activity.
A plausible mechanism is presented in Scheme 4.
Herein, the active methylene group of malononitrile 2
attacks the carbonyl carbon of aldehyde 1 and undergoes
Knoevenagel condensation to form 3 with loss of water.
The methine carbon of the Knoevenagel product 3 is then
activated by HASIL and it reacts with C─H activated
compound 4 by a Michael addition to produce the
intermediate 5. Thereafter, 5 undergoes intramolecular
cyclization to afford 6 followed by tautomerism, to
produce the quinolinyl pyran 7.
Antimicrobial studies. In vitro antibacterial properties of
the quinolinyl and quinolonyl pyrans.
The antibacterial
efficacy was evaluated for quinolinyl-4H-pyrans (QPs) and
quinolonyl-4H-pyrans (QOPs) by determining the zone of
inhibition against a range of Gram-positive (Bacillus
cereus, Enterococcus faecalis, and Staphylococcus aureus)
Figure 14. Quinolinyl pyrans (4a, 4d, 4g, 4h, 4j, 4l, 4m, and 4n) toxicity
assay at different intervals by Artemia salina. [Color figure can be viewed
at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
Table 8
4l shows potential toward Gram-positive and Gram-
negative bacteria. Fluorinated quinolinyl pyran 4g and
methyl QPs 4m condensed from ethyl acetoacetate show
potential toward Gram-negative. Thus, the core structure
of quinoline and sulfur heterocyclic system from
quinolinyl pyrans show crucial activity confirming the
microbial effects of quinoline and sulfur heterocycles
[3,15,19].
Molecular docking scores of quinolinyl pyran derivatives.
Entry
Molecule
Absolute energy LibDock score
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
43.92
67.44
59.67
47.82
58.46
43.95
66.08
38.40
61.69
56.36
41.66
49.82
67.50
51.36
83.08
96.69
88.08
74.59
91.58
85.14
90.51
96.30
88.41
78.97
79.23
92.11
96.96
82.32
86.55
176.61
Antioxidant
scavenging activity of the quinolinyl-4H-pyrans and
quinolonyl-4H-pyrans.
studies. 2,2-Diphenyl-1-picrylhydrazyl
The 2,2-diphenyl-1-picrylhydrazyl
10
11
12
13
14
15
(DPPH) radical scavenging assay is used for initial
screening of the compounds for their antioxidant activity
[51]. An antioxidant assay was conducted for all QP
derivatives and it was found that 4b, 4d, 4e, 4f, 4g, 4h, 4l,
4m, and 4n are effective DPPH scavenging agents.
Toxicity assessment studies. Toxicity assessment of the
Reference ligand
quinolinyl-4H-pyrans and quinolonyl-4H-pyrans.
Brine
and Gram-negative (Escherichia coli) bacteria (Fig. 13). It
is found that 4a, 4d, 4h, 4g, and 4m had preferential
activity toward all Gram-positive species tested (Fig. 13).
Moreover, compound 4j and 4n shows activity toward
S. aureus only. Interestingly, compound 4l shows their
potential against all species tested (Table 7).
Quinolinyl-4H-pyrans that containing methoxy
quinolines 4a, 4m, and 4n, sulfur heterocycles 4d and 4h
and fluorinated quinolines 4g and 4h and QOP containing
quinolonyl ring and methyl group 4j showed remarkable
potential effects toward Gram-positive bacteria.
Interestingly, QP that contains methoxy and methyl group
shrimp is one of the most valuable test organisms
available for preliminary assessment of toxicity [52].
Therefore, the toxicity of all compounds at different
intervals, which is having activity toward Gram-positive
or Gram-negative or both species, was evaluated. Among
all the compounds tested, 4d, 4g, 4l, 4m, and 4n have
mortality rate below 50% (Fig. 14), which suggest that
these compounds are safe for further biological
applications because less than 50% of brine shrimp
mortality rate is considered as safe [53].
Molecular docking studies. The biological importance
of quinolinyl pyran derivatives was assessed based on
Figure 15. Ligand binding mode of 4l inside Mtb DNA gyrase. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
molecular docking. The crystal structure of Mtb gyrase
PDB ID: 4PLB) was used to determine the antibacterial
activity of quinolinyl pyran derivatives [54]. The three
dimensional structure of Mtb gyrase was prepared in
Chimera software package to carry out molecular docking
analysis was conducted with a Philips PW 1050
diffractometer set at 1 min with a scanning step size of
0.02 from 40 to 100 2 using monochromated CoKα
irradiation. Data were captured with a sietonics 122D
automated microprocessor linked to diffractometer. A Carl
Zeiss Ultra Plus scanning electron microscope with
energy-dispersive X-ray spectroscopy detector was used.
The TGA and DSC analyses were conducted with TA
instruments. Melting points were determined by Stuart
SMP10 and are uncorrected. The IR spectra were recorded
on Perkin Elmer 537 spectrophotometer instrument, using
ATR disc, and the absorption frequencies were expressed
(
[55]. The ligands (QPs) were built in Chem3D
Biodraw and were energetically minimized by MM2
method integrated with the same software. Further,
ligands were prepared in for ionization, conformation,
and stereoisomers in Discover Studio software packages
[56]. Then, molecular docking was conducted using
LibDock module of Discovery Studio software packages
around the bound ligand. The docking pose of the ligands
was ordered based on LibDock score (Table 8). The
ligands were docked with the scores varying from 74.59
to 96.96 kcal/mol. The molecules 4a, 4f, 4g, 4k, and 4l
show higher binding affinity with the LibDock scores of
ꢀ
1
1
13
as νmax cm
,
H-NMR and C-NMR spectra were
recorded on BRUKER 400 MHz spectrometer using
tetramethylsilane as an internal standard. The chemical
shift values are recorded on δ scale, and the coupling
constants (J) are in hertz. The progress of the reaction was
monitored by TLC using aluminum plates with silica gel
(Sigma-Aldrich and Fluka). Silica gel (60–120 mesh) was
purchased from Sigma-Aldrich and used as adsorbent for
column chromatography. The elemental analyses
96.69, 92.11, 91.58, 90.51, 96.96, and 96.30,
respectively, toward Mtb gyrase. Figure 15 shows the
binding interaction of ligand 4l inside Mtb DNA gyrase
that strengthens the antimicrobial activity of 4l.
(C, H, N) were obtained from a Perkin Elmer precisely
2
400 analyzer.
CONCLUSION
General procedure for the synthesis of humic acid
supported 1-butyl-3-methyl
catalyst.
imidazolium
A mixture of [bmim]SCN (5 mmol) in
thiocyanate
In conclusion, a very simple, energy efficient, and
conveniently practical method was developed for easy
access to a wide range of pharmaceutically interesting
functionalized quinolinyl and quinolonyl pyrans with
catalytic amounts of HASIL. The reaction is a one-pot
tandem Knoevenagel-cyclocondensation of aldehydes,
malononitrile, and 1,3-diketones in ethanol at room
temperature. Furthermore, seven QPs and one QOPs
showed good potential against B. cereus, E. faecalis,
S. aureus, and E. coli whilst nine QPs showed
antioxidant properties. The brine shrimp test showed
five QPs with mortality rate less than 50% until 48 h.
Molecular docking showed one QP has remarkable
interaction with Mtb DNA gyrase. Mild reaction
conditions, excellent yields, operational simplicity, clean
reaction profiles, energy efficiency, and high atom
economy as well as the use of inexpensive and
environmentally benign catalyst are the key advantages
of the present method of synthesis. Moreover, the
reusability of the catalyst is an added advantage to this
protocol.
methanol (10 mL) and HA (5 g) was taken in a round-
bottomed flask (100 mL) and stirred at room
temperature for 10 h under inert atmosphere and then
dried under reduced pressure until free-flowing powder
was obtained. In another round-bottomed flask (100 mL),
[bmim]SCN (10 mmol) and copper acetate (0.5 mmol)
were dissolved in methanol (10 mL) and stirred for
5 min. Thereafter, the HA pretreated with IL was
suspended in this solution and the mixture was refluxed
for 10 h under inert atmosphere. Then, solvent was
evaporated under reduced pressure to get free-flowing
powder. Then, it was dried in an oven at 200°C for 5 h to
afford the HASIL catalyst.
Typical procedure for the synthesis of quinolinyl and
quinolonyl pyrans.
Catalytic amount (10 mol %) of
HASIL was added to a mixture of aldehyde (1 mmol)
and malononitrile (1 mmol) in ethanol (15 mL) followed
by the addition of 1,3-diketone (1 mmol). The reaction
tube was placed into a CEM MW discover synthesizer
and irradiated at 120 W with the temperature of 110°C
for 10 min. The progress of the reaction was monitored
by TLC. After the completion of the reaction, the catalyst
was separated by simple filtration. The solvent was
evaporated under reduced pressure, and the crude product
was purified by column chromatography using silica as
adsorbent from eluent (ethyl acetate : petroleum ether,
50%). The crystallization of the product was performed
in ethanol to yield the pure product.
EXPERIMENTAL
Material and methods. All chemicals were purchased
from Sigma-Aldrich and used without further purification.
Solvents used were of synthesis grade. CEM discover
MW reactor was used for reaction. The X-ray diffraction
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
1
3
Antibacterial activity of the quinolinyl and quinolonyl
pyran derivatives. Bacterial strains.
CH3). C-NMR: (100 MHz, CDCl ) δ ppm 195.9, 162.9,
3
The antibacterial
160.1, 158.6, 137.8, 129.2, 127.6, 126.6, 126.6, 125.3,
125.2, 124.0, 111.8, 60.8, 53.4, 50.5, 40.7, 32.7, 32.1,
29.3, 27.0. Elemental Analysis: Anal. Calcd for
C H N O : C, 70.38; H, 5.64; N, 11.19; %. Found: C,
efficacy of each synthesized compound was assessed
using four bacterial strains. Two strains of each Gram-
positive (B. cereus, S. aureus, and E. faecalis) and Gram-
negative (E. coli) bacteria were selected. The bacterial
strains were provided from the culture collection of
Department of Biotechnology and Food Technology,
Durban University of Technology, South Africa.
2
2 21 3 3
70.36; H, 5.65; N, 11.20; %.
2-Amino-7,7-dimethyl-5-oxo-4-(2-(o-tolyloxy)quinolin-3-yl)-
,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4b). Yellow
solid, mp = 209–211°C; IR νmax (cm ): IR νmax (cm ):
5
ꢀ
1
ꢀ1
2
246 C≡N, 1577 C═N, 1207 C─N, 2924 CH, 1631
1
Inoculum preparation.
Each bacterial strain was
C═C, 1751 C═O, 3327 NH. H-NMR: (400 MHz,
subcultured overnight at 37°C on Mueller–Hilton agar
plate. Further, bacterial cultures were grown in Mueller–
Hilton broth at 37°C, 200 rpm in order to attain the
DMSO-d ) δ ppm 8.69 (1H, s, Ar─H), 8.05 (2H, d,
J = 7.84 Hz, Ar─H), 7.92 (2H, d, J = 8.32 Hz, Ar─H),
6
8
7
.84 (2H, td, J = 1.36 Hz, Ar─H), 7.63 (2H, td,
J = 1.04 Hz, Ar─H), 5.21 (1H, s, CH), 4.98 (2H, s,
NH ), 3.01 (3H, brs, CH ), 2.70 (2H, q, J = 17.88 Hz,
), 2.41 (2H, q, J = 16.16 Hz, CH ), 1.14 (3H, brs,
C-NMR: (100 MHz,
) δ ppm 195.6, 169.0, 154.5, 145.5, 140.6,
viable count of approximately 10 cfu/mL.
Antibacterial activity. The agar well diffusion method
was used to evaluate the antimicrobial activity of each
2
3
8
compound. Hundred microliter of ~10 cfu/mL bacterial
CH
CH
2
2
13
suspension was plated on Mueller–Hinton Agar plates. A
well of 6 mm diameter was made using a sterile cork
borer, and 30 μL of each compound (3 mg/mL) was
added in each well and kept at 37°C for 16 h. The assays
were carried out in triplicate. Ciprofloxacin (3 mg/mL)
), 1.12 (3H, brs, CH ).
3 3
DMSO-d
6
131.5, 128.0, 127.5, 126.6, 126.6, 113.8, 112.8, 112.6,
107.2, 49.6, 40.4, 40.0, 39.8, 39.6, 39.4, 39.2, 38.8, 33.2,
31.7, 30.5, 28.9, 27.1, 26.0. Elemental Analysis: Anal.
was used as positive control and DMSO (100%) as a
negative control.
Antioxidant assays of the quinolinyl and quinolonyl pyran
Calcd for C28H N O : C, 74.48; H, 5.58; N, 9.31; %.
25 3 3
Found: C, 74.47; H, 5.59; N, 9.33; %.
Methyl
6-amino-5-cyano-4-(2-methoxyquinolin-3-yl)-2-
derivatives.
The antioxidant ability of the quinolinyl
methyl-4H-pyran-3-carboxylate (4c).
Yellow solid,
ꢀ
1
pyran derivatives was determined by the decolorization of
methanol solution of DPPH. Hundred microliter of each
compound was added separately to 1 mL of 0.1-mM
DPPH solution, and change in color was observed at
regular intervals. Rutin hydrate was used as the positive
control and methanol (95%) as negative control.
mp = 209–211°C; IR νmax (cm ): 2254 C≡N, 1552
C═N, 1226 C─N, 2970 CH, 1672 C═C, 1722 C═O,
1
2876 OCH
, 3361 NH. H-NMR: (400 MHz, DMSO-d
)
6
3
δ ppm 8.92 (1H, s, Ar─H), 8.21 (1H, d, J = 6.40 Hz,
Ar─H), 7.78 (1H, dd, J = 2.52 Hz, Ar─H), 7.52 (1H, dt,
J = 1.12 Hz, Ar─H), 7.30 (1H, t, J = 5.56 Hz, Ar─H),
Toxicity assessment. The brine shrimp larvae (Artemia
salina) were hatched in sea water for 24–48 h prior to
being used in the test. An aliquot of 5 mL sea water
containing 10 brine shrimp was added to each vial and
supplemented with different derivatives of quinolinyl
pyran. Each derivative concentrations of 300 μg was used
in individual vial. Brine shrimp death was observed at
regular intervals in order to find the toxic nature of each
compound.
6.98 (2H, brs, NH
OCH ), 2.59 (2H, q, J = 13.52 Hz, CH
CH ), 1.23 (3H, s, CH
) δ ppm 165.4, 158.4, 156.5, 144.8, 128.3, 127.1,
126.7, 119.6, 107.2, 60.1, 57.2, 40.0, 39.8, 39.6, 39.0,
38.8, 38.7, 30.6, 18.0, 13.6. Elemental Analysis: Anal.
2
), 4.59 (1H, s, CH), 3.76 (3H, s,
), 1.95 (3H, s,
). C-NMR: (100 MHz, DMSO-
3
2
13
3
3
d
6
Calcd for C20
H N O : C, 65.74; H, 5.24; N, 11.50; %.
19 3 4
Found: C, 65.76; H, 5.26; N, 11.51; %.
5
-Amino-7-(2-methoxyquinolin-3-yl)-2-oxo-3,7-dihydro-2H-
pyrano[2,3-d]thiazole-6-carbonitrile (4d).
mp = 218–220°C; IR νmax (cm ): 2191 C≡N, 1604
C═N, 1215 C─N, 2970 CH, 1654 C═C, 1751 C═O,
Yellow solid,
Synthesis of quinolinyl and quinolonyl pyrans (4a–4n) by
using humic acid supported 1-butyl-3-methyl imidazolium
thiocyanate under microwave conditions. 2-Amino-4-(2-
methoxyquinolin-3-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
ꢀ1
1
2
863 OCH , 714 C─S, 2596 S─H, 3393 NH. H-NMR:
3
4
H-chromene-3-carbonitrile (4a).
Pale yellow crystals,
(400 MHz, DMSO-d ) δ ppm 10.25 (2H, s, NH ), 8.41
6
2
ꢀ
1
mp = 182–184°C; IR νmax (cm ): 2253 C≡N, 1571
C═N, 1216 C─N, 2970 CH, 1637 C═C, 1752 C═O,
2
ppm 7.91 (1H, s, Ar─H), 7.79 (1H, d, J = 8.32 Hz,
Ar─H), 7.65 (1H, d, J = 1.4 Hz, Ar─H), 7.58 (1H, td,
J = 1.24 Hz, Ar─H), 7.38 (1H, td, J = 8.28 Hz, Ar─H),
(1H, s, Ar─H), 7.79 (1H, d, J = 7.44 Hz, Ar─H), 7.56
(1H, t, J = 7.12 Hz, Ar─H), 7.34 (1H, d, J = 8.28 Hz,
Ar─H), 7.17 (1H, t, J = 7.24 Hz, Ar─H), 5.13 (1H, s,
1
940 OCH , 3028 NH. H-NMR: (400 MHz, CDCl ) δ
3
3
13
NH), 4.42 (1H, s, CH), 2.51 (3H, s, OCH
). C-NMR:
3
(100 MHz, CDCl ) δ ppm 159.8, 159.8, 153.1, 150.7,
3
145.8, 136.8, 136.7, 134.4, 134.2, 134.1, 129.7, 127.7,
126.7, 125.1, 125.1, 124.5, 124.5, 124.3, 120.8, 120.8,
118.2, 118.1, 114.8, 114.6, 113.1, 113.1, 63.6, 63.5,
63.3, 63.2, 54.0, 49.3, 47.8, 16.4, 16.4, 16.2, 16.1.
4
.68 (1H, s, CH), 4.59 (2H, brs, NH ), 4.08 (3H, brs,
2
OCH ), 2.48 (2H, q, J = 1.04 Hz, CH ), 2.22 (2H, q,
J = 18 Hz, CH ), 1.14 (3H, brs, CH ), 1.05 (3H, brs,
3
2
2
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
ꢀ
1
Elemental Analysis: Anal. Calcd for C H N O S: C,
Brown solid, mp = 205–207°C; IR νmax (cm ): 2252
C≡N, 1557 C═N, 1292 C─N, 2917 CH, 1621 C═C,
1
7 12 4 3
57.95; H, 3.43; N, 15.90; %. Found: C, 57.97; H, 3.44;
N, 15.92; %.
1690 C═O, 2849 OCH , 693 C─S, 2606 S─H, 1393
3
1
5
-Amino-7-(2-methoxy-6-nitroquinolin-3-yl)-2-thioxo-3,7-
C─F, 3362 NH. H-NMR: (400 MHz, CDCl ) δ ppm
3
dihydro-2H-pyrano[2,3-d]thiazole-6-carbonitrile
Brown solid, mp = 249–251°C; IR νmax (cm ): 2254
C≡N, 1588 C═N, 1047 C─N, 2880 CH, 1608 C═C,
(4e).
8
.42 (1H, s, NH), 8.35 (1H, d, J = 3.12 Hz, Ar─H), 8.17
2H, s, NH ), 7.80 (1H, d, J = 5.68 Hz, Ar─H), 7.68
ꢀ
1
(
2
(
1H, t, J = 7.08 Hz, Ar─H), 7.42 (1H, t, J = 7.24 Hz,
1
709 C═O, 2944 OCH , 2602 S─H, 1268 C═S, 650
13
3
Ar─H), 4.91 (1H, s, CH), 2.25 (3H, s, OCH ). C-NMR:
3
1
C─S, 3232 NH. H-NMR: (400 MHz, DMSO-d ) δ ppm
6
(
100 MHz, CDCl ) δ ppm 206.9, 163.5, 147.9, 147.8,
45.9, 142.3, 137.9, 129.1, 122.8, 121.3, 113.8, 32.9,
2.9, 32.7, 30.9, 22.2, 13.7. Elemental Analysis: Anal.
Calcd for C H FN O S: C, 55.13; H, 2.99; N, 15.13;
3
8
.15 (1H, s, NH), 7.78 (1H, s, Ar─H), 7.65 (2H, d,
J = 10.24 Hz, Ar─H), 7.55 (1H, d, J = 8.44 Hz, Ar─H),
.80 (2H, brs, NH ), 4.25 (1H, s, CH), 4.03 (3H, s,
1
3
6
2
17
11
4 3
13
OCH3). C-NMR: (100 MHz, CDCl ) δ ppm 150.2,
3
%
. Found: C, 55.15; H, 2.98; N, 15.15; %.
2
1
1
1
2
50.1, 147.0, 146.9, 145.3, 145.1, 139.3, 137.8, 137.7,
30.7, 129.2, 129.1, 129.1, 128.0, 127.9, 127.3, 127.2,
19.9, 114.4, 110.6, 63.9, 63.9, 63.5, 63.4, 52.5, 51.0,
1.5, 16.4, 16.4, 16.1, 16.1, 16.0. Elemental Analysis:
-Amino-4-(7-fluoro-2-oxo-1,2-dihydroquinolin-3-yl)-7,7-
dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
ꢀ
1
(4i).
Pale yellow, mp = 129–131°C; IR νmax (cm ):
2183 C≡N, 1572 C═N, 1152 C─N, 2979 CH, 1679
1
Anal. Calcd for C H N O S : C, 49.39; H, 2.68; N,
C═C, 1722 C═O, 1098 C─F, 3446 NH. H-NMR:
1
7 11 5 4 2
1
6.94; %. Found: C, 49.41; H, 2.70; N, 16.96; %.
(400 MHz, DMSO-d ) δ ppm 8.69 (1H, s, NH), 8.40
6
2
-Amino-4-(7-fluoro-2-methoxyquinolin-3-yl)-7,7-dimethyl-
(1H, s, Ar─H), 8.10–8.04 (1H, m, J = 6.24 Hz, Ar─H),
5
-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4f).
7
.73 (2H, s, NH ), 7.50 (1H, t, J = 5.84 Hz, Ar─H), 7.42
2
ꢀ
1
White solid, mp = 195–197°C; IR νmax (cm ): 2181
(1H, s, Ar─H), 4.09 (1H, s, CH), 2.70–2.57 (2H, m,
C≡N, 1602 C═N, 1135 C─N, 2970 CH, 1638 C═C,
J = 17.92 Hz, CH ), 2.40–2.28 (2H, m, J = 16.20 Hz,
2
1
1678 C═O, 2653 OCH , 1007 C─F, 3368 NH. H-
19
3
CH ), 1.25 (3H, s, CH ), 1.05 (3H, s, CH ). F-NMR:
2
3
3
NMR: (400 MHz, DMSO-d ) δ ppm 8.03 (1H, s, Ar─H),
13
6
(
(
400 MHz, DMSO-d ) δ ppm ꢀ108.37.
C-NMR:
6
7
.96 (1H, t, J = 6.44 Hz, Ar─H), 7.46 (1H, d,
J = 2.52 Hz, Ar─H), 7.33 (1H, t, J = 6.20 Hz, Ar─H),
.01 (2H, brs, NH ), 4.52 (1H, s, CH), 3.96 (3H, s,
100 MHz, CDCl ) δ ppm 195.6, 191.2, 161.9, 140.5,
3
1
1
1
38.1, 130.1, 126.3, 126.1, 123.9, 122.4, 121.0, 120.5,
19.0, 117.6, 109.3, 108.7, 108.5, 96.6, 37.7, 29.0, 24.8,
9.8, 13.8, 13.7. Elemental Analysis: Anal. Calcd for
7
2
OCH ), 2.49 (2H, q, J = 17.80 Hz, CH ), 2.24 (2H, q,
J = 16.04 Hz, CH ), 1.04 (3H, s, CH ), 0.96 (3H, s,
CH3). C-NMR: (100 MHz, CDCl ) δ ppm 155.6, 148.5,
3
2
2
3
C H FN O : C, 66.48; H, 4.78; N, 11.08; %. Found: C,
21
18
3 3
13
3
6
6.50; H, 4.79; N, 11.10; %.
1
1
5
46.4, 146.3, 137.3, 129.2, 129.0, 123.0, 123.0, 122.9,
22.9, 119.7, 118.5, 114.0, 63.6, 63.5, 63.3, 63.2, 58.3,
6.8, 16.4, 16.3, 16.2, 16.1. F-NMR: (400 MHz,
7
-Amino-5-(6-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2,4-
dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
1
9
carbonitrile (4j). Brown solid, mp = 237–239°C; IR νmax
ꢀ
1
CDCl ) ꢀ107.33. Elemental Analysis: Anal. Calcd for
(cm ): 2222 C≡N, 1572 C═N, 1217 C─N, 2925 CH,
3
1
C H FN O : C, 67.17; H, 5.12; N, 10.68; %. Found: C,
1651 C═C, 1750 C═O, 3026 NH. H-NMR: (400 MHz,
2
2
20
3 3
6
7.19; H, 5.14; N, 10.70; %.
DMSO-d ) δ ppm 12.20 (1H, s, NH), 10.78 (1H, s, NH),
6
Ethyl-6-amino-5-cyano-4-(7-fluoro-2-methoxyquinolin-3-yl)-
9.42 (1H, s, NH), 8.12 (1H, s, Ar─H), 7.55 (1H, d,
J = 1.44 Hz, Ar─H), 7.46 (2H, t, J = 8.44 Hz, Ar─H),
7.29 (2H, s, NH ), 4.44 (1H, s, CH), 2.36 (3H, brs, CH ).
2
-methyl-4H-pyran-3-carboxylate (4g).
Yellow solid,
ꢀ
1
mp = 191–193°C; IR νmax (cm ): 2229 C≡N, 1580
C═N, 1219 C─N, 2919 CH, 1614 C═C, 1708 C═O,
2
3
13
C-NMR: (100 MHz, CDCl ) δ ppm 159.8, 159.8,
3
1
1021 C─F, 3400 NH. H-NMR: (400 MHz, DMSO-d ) δ
6
145.9, 145.9, 144.5, 144.3, 136.7, 136.6, 129.7, 129.1,
127.7, 126.8, 125.1, 125.1, 124.3, 123.2, 120.6, 120.6,
114.7, 63.6, 63.5, 63.4, 63.3, 53.9, 49.6, 48.1, 16.4, 16.4,
16.1, 16.1. Elemental Analysis: Anal. Calcd for
C H N O : C, 59.50; H, 3.61; N, 19.28; %. Found: C,
ppm 8.87 (1H, s, Ar─H), 8.59 (1H, s, Ar─H), 8.02 (1H,
d, J = 8.04 Hz, Ar─H), 7.83 (2H, s, NH ), 7.54 (1H, t,
J = 2.88 Hz, Ar─H), 4.43 (1H, s, CH), 4.07 (3H, s,
OCH ), 3.91–3.89 (2H, m, J = 16.88 Hz, CH ), 2.50
2
3
2
18 13 5 4
1
3
(3H, s, CH ), 2.39 (3H, s, CH ). C-NMR: (100 MHz,
59.52; H, 3.63; N, 19.30; %.
3
3
CDCl ) δ ppm 176.0, 176.0, 156.2, 155.4, 155.3, 151.5,
2-Amino-4-(2-chloro-6-methylquinolin-3-yl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4k).
Yellow solid, mp = 187–189°C; IR νmax (cm ): 2227
3
1
1
1
51.4, 139.2, 134.2, 126.2, 125.9, 125.8, 123.2, 119.5,
18.3, 112.3, 64.0, 63.9, 63.9, 63.8, 45.6, 44.0, 29.6,
6.4, 16.4, 16.3, 16.2, 14.1. Elemental Analysis: Anal.
ꢀ
1
C≡N, 1562 C═N, 1216 C─N, 2923 CH, 1657 C═C,
1
1
751 C═O, 733 C─Cl, 3039 NH. H-NMR: (400 MHz,
Calcd for C H FN O : C, 62.66; H, 4.73; N, 10.96; %.
20
18
3 4
DMSO-d ) δ ppm 11.38 (2H, s, NH ), 7.71 (1H, d,
Found: C, 62.68; H, 4.75; N, 10.95; %.
6
2
5
-Amino-7-(7-fluoro-2-methoxyquinolin-3-yl)-2-oxo-3,7-
J = 3.2 Hz, Ar─H), 7.47 (1H, s, Ar─H), 7.35–7.32 (1H,
dihydro-2H-pyrano[2,3-d]thiazole-6-carbonitrile (4h).
t, J = 2.52 Hz, Ar─H), 7.30–7.27 (1H, d, J = 5.56 Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Thangaraj, B. Ranjan, R. Muthusamy, A. Murugesan, and R. M. Gengan
Vol 000
Ar─H), 4.51 (1H, s, CH), 2.52 (3H, brs, CH ), 2.39 (2H, q,
Elemental Analysis: Anal. Calcd for C H N O S : C,
56.53; H, 3.69; N, 14.65; %. Found: C, 56.55; H, 3.71;
N, 14.67; %.
3
18 14 4 2 2
J = 16.25 Hz, CH ), 2.25 (2H, q, J = 12.36 Hz, CH ), 1.32
2
2
1
3
(
3H, s, CH ), 0.92 (3H, s, CH ). C-NMR: (100 MHz,
3 3
CDCl ) δ ppm 176.2, 176.2, 156.2, 155.3, 155.2, 145.2,
3
1
1
1
45.0, 133.8, 129.3, 125.9, 125.4, 123.4, 120.0, 119.1,
18.2, 114.0, 63.8, 63.7, 63.5, 63.4, 46.2, 44.6, 30.9,
6.4, 16.3, 16.2, 16.2. Elemental Analysis: Anal. Calcd
Acknowledgments. We are grateful to the National Research
Foundation (NRF) and Durban University of Technology
(
DUT) (grant number MT21356991) for funding this project.
for C H ClN O : C, 67.09; H, 5.12; N, 10.67; %.
22
20
3 2
Found: C, 67.10; H, 5.14; N, 10.69; %.
2
-Amino-4-(2-methoxy-6-methylquinolin-3-yl)-7,7-dimethyl-
REFERENCES AND NOTES
5
-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4l).
Yellow solid, mp = 174–176°C; IR νmax (cm ): 2223
ꢀ
1
[1]
Abe, I.; Oguro, S.; Utsumi, Y.; Sano, Y.; Noguchi, H. J Am
C≡N, 1579 C═N, 1236 C─N, 2840 CH, 1614 C═C,
Chem Soc 2005, 127, 12709.
1
[2] Sibi, M. P.; Zimmerman, J. J Am Chem Soc 2006, 128, 13346.
1
697 C═O, 2970 OCH , 3446 NH. H-NMR: (400 MHz,
3
[3] Hussein, A. H. M.; Gad-Elkareem, M. A.; El-Adasy, A. B. A.;
CDCl ) δ ppm 7.72 (1H, s, Ar─H), 7.60 (1H, d,
3
Khames, A. A.; Othman, I. M. Int J Org Chem 2012, 2, 341.
J = 8.48 Hz, Ar─H), 7.39 (1H, s, Ar─H), 7.32 (1H, dd,
[4] Chattapadhyay, T. K.; Dureja, P. J. Agri and Food Chem 2006,
4, 2129.
5
J = 1.60 Hz, Ar─H), 4.68 (2H, brs, NH ), 4.54 (1H, s,
2
[5] Wang, T.; Liu, J.; Zhong, H.; Chen, H.; Lv, Z.; Zhang, Y.;
CH), 3.98 (3H, s, OCH ), 2.37 (3H, s, CH ), 2.34 (2H, q,
3
3
Zhang, M.; Geng, D.; Niu, C.; Li, Y.; Li, K. Bioorg Med Chem Lett
2011, 21, 3381.
[6] DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J.
W.; Pippin, D. A. Chem & High Throughput Screen 2004, 7, 473.
J = 12.20 Hz, CH ), 2.17 (2H, q, J = 16.44 Hz, CH ),
2
2
1
3
1
.02 (3H, s, CH ), 0.93 (3H, s, CH ).
C-NMR:
3
3
(
100 MHz, CDCl ) δ ppm 196.0, 162.9, 159.7, 158.7,
3
[
7] Safari, J.; Zarnegar, Z.; Heydarian, M. Bull Chem Soc Japan
012, 85, 1332.
[8] Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur J Med
Chem 1993, 28, 517.
1
1
2
44.0, 137.2, 133.5, 131.2, 126.7, 126.3, 125.3, 125.3,
19.0, 111.8, 60.4, 53.3, 50.5, 40.7, 32.6, 32.1, 29.2,
7.0, 21.2. Elemental Analysis: Anal. Calcd for
2
[9] Heravi, M. M.; Baghernejad, B.; Oskooie, H. A. J Chin Chem
C H N O : C, 70.93; H, 5.95; N, 10.79; %. Found: C,
2
3 23 3 3
Soc 2008, 55, 659.
7
0.95; H, 5.96; N, 10.81; %.
[10] Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. J. Chem
Soc, Chem Comm 1988, 17, 1202.
Ethyl-6-amino-5-cyano-4-(2-methoxy-6-methylquinolin-3-
yl)-2-methyl-4H-pyran-3-carboxylate (4m).
Brown solid,
[11] Singh, K.; Singh, J.; Singh, H. Tetrahedron 1996, 52, 14273.
[12] Armesto, D.; Horspool, W. M.; Martin, N.; Ramosand, A.;
Seoane, C. J Organomet Chem 1989, 54, 3069.
ꢀ
1
mp = 188–190°C; IR νmax (cm ): 2338 C≡N, 1512
C═N, 1240 C─N, 2917 CH, 1627 C═C, 1697 C═O,
[13] Maleki, B.; Sheikh, S. Org Preparation and Pro Int 1989,
1
2
879 OCH , 3233 NH. H-NMR: (400 MHz, DMSO-d )
47, 368.
3
6
[14] Kumar, D.; Reddy, V. B.; Sharad, S.; Dube, U.; Kapur, S. Eur
δ ppm 8.30 (1H, s, Ar─H), 7.46 (1H, d, J = 3.12 Hz,
Ar─H), 7.11 (2H, dt, J = 10.20 Hz, Ar─H), 7.05 (2H,
brs, NH ), 4.17 (1H, s, CH), 2.49 (3H, s, OCH ), 2.06
J Med Chem 2009, 44, 3805.
[15] (a) Elderfield, R. C. Heterocyclic Compounds; John Wiley:
2
3
New York, London, 1960; (b) Wright, C. W.; Addae-Kyereme, J.; Breen,
A. G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gökçek, Y.; Kendrick, H.;
Phillips, R. M.; Pollet, P. L. J Med Chem 2001, 44, 3187; (c) Sahu, N.
P.; Pal, C.; Mandal, N. B.; Banerjee, S.; Raha, M.; Kundu, A. P.; Basu,
A.; Ghosh, M.; Roy, K.; Bandyopadhyay, S. Bioorg Med Chem 2002,
(
2H, q, J = 16.04 Hz, CH ), 1.48 (3H, s, CH ), 1.02 (3H,
2 3
1
3
s, CH ), 0.94 (3H, s, CH ). C-NMR: (100 MHz,
3
3
CDCl ) δ ppm 165.0, 163.0, 160.3, 150.6, 145.7, 142.9,
3
1
2
0, 1687; (d) Bringmann, G.; Reichert, Y.; Kane, V. V. Tetrahedron
004, 60, 3539; (e) Kouznetsov, V. V.; Méndezand, L. Y. V.; Gómez,
1
1
3
36.0, 135.3, 130.5, 130.4, 129.9, 129.1, 128.1, 127.4,
26.8, 125.4, 124.0, 120.5, 103.4, 62.0, 61.0, 60.8, 53.5,
3.6, 13.8, 13.4. Elemental Analysis: Anal. Calcd for
C. M. M. Curr Org Chem 2005, 9, 141.
[16] Peters, W.; Richards, W. H. G. Antimalarial Drug II; Springer
Verlag: Berlin Heidelberg, New York, Tokyo, 1984.
C H N O : C, 66.48; H, 5.58; N, 11.08; %. Found: C,
2
1 21 3 4
[17] (a) Corral, R. A.; Orazi, O. O. Tetrahedron Lett 1967, 8, 583;
6
6.50; H, 5.59; N, 11.10; %.
(b) Sekar, M.; Prasad, K. R. J Nat Prod 1998, 61, 294; (c) Puricelli, L.;
5
-Amino-7-(2-methoxy-6-methylquinolin-3-yl)-2-thioxo-3,7-
Innocenti, G.; Monache, G. D.; Caniato, R.; Filippini, R.; Cappelletti, E.
M. Nat Prod Lett 2002, 16, 95; (d) Marco, J. L. Mini-Rev Med Chem
2003, 3, 518; (e) Pandit, K. S.; Chavan, P. V.; Desai, U. V.; Kulkarni,
M. A.; Wadgaonkar, P. P. New J Chem 2015, 39, 4452.
dihydro-2H-pyrano[2,3-d]thiazole-6-carbonitrile (4n).
Brown solid, mp = 198–200°C; IR νmax (cm ): 2226
C≡N, 1557 C═N, 1229 C─N, 2927 CH, 1688 C═C,
ꢀ
1
[18] Morel, A. F.; Larghi, E. L. Tetrahedron Asymmetry 2004, 15, 9.
1
751 C═O, 2826 OCH , 1074 C═S, 615 C─S, 2511
3
[19] (a) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic
Synthesis; Academic Press: New York, 1994; (b) Nudelman, A. The
Chemistry of Optically Active Sulfur Compounds; Gordon and Breach:
New York, 1984; (c) Chatgilialoglu, C.K.; Asmus, D. Springer: New
York, 1991.
1
S─H, 3407 NH. H-NMR: (400 MHz, DMSO-d ) δ ppm
6
1
2.07 (1H, brs, NH), 8.49 (1H, s, Ar─H), 7.82 (1H, d,
J = 5.88 Hz, Ar─H), 7.74 (2H, dd, J = 3.96 Hz, Ar─H),
.46 (2H, brs, NH ), 4.69 (1H, s, CH), 3.63 (3H, s,
7
[20] Bicking, J. B.; Holtz, W. J.; Watson, L. S.; Cragoe, E. J. Jr. J
Med Chem 1976, 19, 530.
2
1
3
OCH ), 2.39 (3H, s, CH ). C-NMR: (100 MHz, CDCl3)
3
3
[21] Ghosh, A. K.; Thompson, W. J.; McKee, S. P.; Duong, T. T.;
δ ppm 190.4, 189.3, 135.2, 134.9, 128.9, 126.6, 115.7,
7.4, 47.0, 46.4, 40.9, 32.4, 31.4, 29.6, 29.2, 27.4, 20.9.
Lyle, T. A.; Chen, J. C.; Darke, P. L.; Zugay, J. A.; Emini, E. A. J Med
Chem 1993, 36, 292.
7
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Fused Pyrans by HASIL and Their Antimicrobial, Antioxidant,
Toxicity Assessment, and Molecular Docking Studies
[
22] Inomata, K.; Barragué, M.; Paquette, L. A. The J Org Chem
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2
1
005, 70, 533.
[23] Yamauchi, M.; Katayama, S.; Watanabe, T. Synthesis 1982,
1, 935.
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Phar Sciences 2015, 23, 20.
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[53] Meyer, B. N.; Ferrigni, N. R.; Putnam, J. E.; Jacobsen, L. B.;
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Meinke, P. T.; Olsen, D.; Lagrutta, A.; Bradley, P.; Lu, J.; Patel, S.
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[
[
26] Weingärtner, H. Angew Chem Int Ed 2008, 47, 654.
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3
772.
[
[
28] Mehnert, C. P. Chem Eur J 2005, 11, 50.
29] Riisagera, A.; Fehrmanna, R.; Haumannb, M.; Wasserscheidb,
[55] Pettersen, E. F.; Goddard, T. D.; Huang, C. C.; Couch, G. S.;
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[
[
30] Gu, Y.; Li, G. Adv Synth Catal 2009, 351, 817.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet