One-pot three-component protocol for the synthesis of indolyl-4H-chromene-3-carboxamides as antioxidant and antibacterial agents

Article abstract of DOI:10.1039/c7nj00980a

A series of newly synthesized 4-(1H-indol-3-yl)-2-methyl-N-phenyl-4H-chromene-3-carboxamide derivatives were achieved by one-pot reaction between salicylaldehydes, substituted acetoacetanilides, and indoles in methanol catalyzed by 1,4-diazabicyclo [2.2.2]octane (DABCO) (30 mol%) at room temperature. These chromene systems were constructed through Knoevenagel condensation followed by a nucleophilic substitution process. The valuable features of this protocol such as short reaction time, simple operational procedure, broad substrate scope, and high yield of products make it an efficient and promising synthetic strategy. For the first time, various substituted 4H-chromene-3-carboxamide derivatives using DABCO as a catalyst are reported. The synthesized compounds (4a-p) were evaluated in antioxidant and antibacterial studies. The derivatives 4c, 4d, 4k, 4l, and 4p showed good antioxidant activity. Among all the derivatives 4k, 4l, and 4p were found to be active against bacterial strains with MIC values ranging from 9.3 to 18.75 μg mL^-1.

Full text of DOI:10.1039/c7nj00980a

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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ARTICLE
One pot three component protocol for the synthesis of Indolyl-
H-chromene-3-carboxamides as antioxidant and antibacterial
agents
4
Received 00th January 20xx,
Accepted 00th January 20xx
a
*a
DOI: 10.1039/x0xx00000x
Chitreddy V Subbareddy , and Shanmugam Sumathi
a
www.rsc.org/
Department of Chemistry, VIT University, Vellore 632014, Tamilnadu, Vellore, India
Corresponding author: sumathishanmugam2003@gmail.com
*
A series of newly synthesized 4-(1H-indol-3-yl)-2-methyl-N-phenyl-4H-chromene-3-carboxamide derivatives were achieved
by one-pot reaction between salicylaldehydes, substituted acetoacetanilides and indoles in methanol catalyzed by 1,4-
diazabicyclo [2.2.2]octane (DABCO) (30 mol%) at room temperature. These chromene systems were constructed through
Knoevenagel condensation followed by nucleophilic substitution process. The valuable features of this protocol such as
short reaction time, simple operational procedure, broad substrate scope, and high yield of products make it an efficient
and promising synthetic strategy. For the first time, various substituted 4H-chromene-3-carboxamide derivatives using
DABCO as a catalyst are reported. The synthesized compounds (4a-p) were evaluated for their antioxidant and
antibacterial studies. The derivatives 4c, 4d, 4k, 4l, and 4p shown good antioxidant activity. Among all the derivatives 4k,
−
1
4
l, and 4p were found to be active against bacterial strains with MIC values ranging from 9.3 to 18.75 µg mL .
compound MX58151 was found to be potentially active for the
Introduction
2
treatment of drug resistant cancers. Compound EPC2407 is
8
Since past several decades, multicomponent reactions currently in phase I/II clinical trials as vascular disrupting anti-
1
-5
29
(
MCRs) have gained much importance in synthetic organic cancer drug for the treatment of advanced solid tumors.
chemistry towards the formation of C-C bonds by effectively Some of tetrahydro-4H-chromene derivatives act as
3
0
combining multiple reactants to yield the desired products in a antibacterial agents.
single step. These reactions offer a wide range of feasibilities potential inhibitor of human acute myeloid leukaemia cells.
HA14-1 was demonstrated as a
3
1
for the efficient building of highly complex molecules in a Among the various types of chromenes, chromene-3-
single step, thus avoiding difficult purification processes carboxamides acquired significant importance as one of the
6
-8
32-36
without the formation of significant side products. It has the privileged medicinal frameworks.
advantages of being operationally simple and atom
O
COOH
O
Ph
O
Cl
economical, and in recent times, it is observed that MCRs have
profoundly dominated the conventional synthetic
methodologies in terms of high selectivity and excellent
OH
CF3
N
N
H
H
O
O
O
O
O
Cl
O
SD-8381
anti-inflammatory
anti-helicobacter pylori activity
potent acetylcholinesterase
inhibitors
9
-15
yields.
O
Br
O
O
Br
NH
On the other hand, chromenes encompass a major class of
naturally occurring compounds and has attracted significant
EtO2C
CN
O
CN
CN
CN
OEt
1
6
H3C
interest owing to their utility as biologically active molecules
as well as commercial applications such as food additives,
N
O
NH2
H N
2
O
NH2
O
NH2
HA14-1
O
NH2
CH3
NH2
anti-HIV-1RT
MX58151
EPC2407
cosmetic
agents,
1
and
potential
biodegradable
Fig. 1. Some of the biologically important molecules
7,18
agrochemicals.
Chromene derivatives have attracted global
attention due to their wide range of biological properties such
Owing to the importance of these functionalized 4H-
chromene molecules in medicinal chemistry, a number of
and anti- synthetic protocols have been developed; amongst which
influenza activities. Naturally occurring chromenes are most of the methodologies suffered from certain
1
9
20
21
22
as anti-coagulant, anti-cancer, anti-fungal, anti-HIV,
2
3
24
25
anti-tumor,
anti-malarial,
anti-bacterial,
2
6
2
7
present in plants and have been used as valuable leads for disadvantages such as multiple synthetic steps, tedious
the design and synthesis of pharmacophores in medicinal reaction conditions, and use of expensive reagents. In this
chemistry and drug development. As shown in Figure 1, context, MCR approaches proved advantageous and several
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methods have been recently reported for the synthesis of between
2-hydroxy
benzaldehyde,
3-oxo-N-
chromene derivatives using different homogeneous or phenylbutanamide, and indole in the presence of several
3
7
38
39
40
heterogeneous, organic, inorganic, and nanomaterial
catalysts. Liu and Xu reported the synthesis of chromenes from the employment of 20 mol% of iodine (Table 1, Entry 1)
ketones and phenols using AuCl /3AgOTf-catalyst system in 1, afforded 4a only in 28% yield. When p-toluenesulfonic acid
-dichloroethane under reflux conditions. Wu and co- (PTSA, 30 %) was employed as Bronsted acid, 4a was formed in
workers reported the synthesis of chromenes from ketones 12% yield (Table 1, Entry 2). However, when ZnCl (20 mol %)
and phenols via metal-free domino reactions using TsOH·H and FeCl (20 mol %) were used as Lewis acid catalysts in
catalysts (Table 1). Initially, we selected iodine as catalyst and
3
4
1
2
2
2
O
3
4
2
as catalyst in hexane at 100°C in sealed tube. Wu et al. have ethanol, 4a was not obtained even after 24h (Table 1, Entries 3
synthesized chromenes by the condensation of acetophenone and 4). In the presence of Bronsted bases like triethylamine
and phenols catalysed by sulphuric acid under solvent free (TEA 30%), piperidine (30%), and Morpholine (30%), 4a was
43
conditions. Funabiki et al. also reported the acid catalysed produced in 42%, 38%, and 54% yield, respectively (Table 1,
synthesis of chromenes by tandem benzylation and cyclization Entries 5, 6, and 7). In contrast, 4a was not formed in the
of 1, 3-dicarbonyl compounds using benzylic alcohols as presence of inorganic base K
2
CO
3
as the catalyst (Table 1, Entry
4
alkylating agents. Li and co-workers reported Bi(OTf)
4
3
8). Upon using 20 mol% of DBU in ethanol for 12 h, we
catalysed synthesis of functionalized 4H-chromenes via MCR of obtained the desired product 4a, in low yield up to 25% (Table
ketoesters with 1, 3-dihydroxynaphthalenes, 2-naphthols, and 1, Entry 9). With 30 mol% of DMAP, 4H-chromene-3-
4
-naphthols. Jamal et al. reported the chromene synthesis carboxamide 4a was obtained in 52% yield (Table 1, Entry 10).
5
1
from commercially available substituted aldehydes, Nonetheless, the employment of 30 mol% of clay catalysts
malononitrile, and 2-naphthol under solvent-free condition at such as MKSF and MK-10 did not yield 4a, (Table 1, Entries 11
4
6
125 °C.
and 12).
The literature reports discussed in the aforementioned
section on the synthesis of chromene derivatives through MCR
pathways proved successful but suffered from several
limitations such as use of toxic metal catalysts, high
temperatures, harsh reaction conditions, and expensive
reagents/catalysts. Hence, there is an ample scope towards
the synthesis of chromene derivatives through MCR pathway
using an economic catalyst at ambient reaction conditions. To
the best of our knowledge, MCRs towards the synthesis of 4H-
chromenes are very limited in the literature so far. For
instance, three-component condensation reactions of
salicylaldehyde, 1, 3-cyclohexanediones, and nucleophiles are
Scheme 1. Synthesis of indolyl-4H-Chromene-3-carboxamides
In the presence of 30 mol% of L-proline, the product 4a
was obtained in 62% yield (Table1, Entry 13). DABCO is
considered to be an efficient and promising catalyst in terms of
4
7-49
known to successfully generate 4H-chromenes.
reported one-pot three-component reaction of
salicylaldehyde, malononitrile, and a nucleophile to generate a
Rai et al.
53,54
organic transformation reactions.
Amongst all the catalysts
a
employed, the reaction carried out using 30 mol% of DABCO at
room temperature in ethanol exhibited excellent catalytic
activity and afforded compound 4a in good yield up to 72%
(Table 1, Entry 14). Nevertheless, the same reaction catalysed
by DABCO when carried out under refluxing conditions did not
5
0
special class of 4H-chromenes. To our surprise, a MCR
involving salicylaldehyde, acetoacetanilide, and indole towards
the synthesis of chromene frameworks has not been reported
so far in the literature. On the other hand, 1, 4-diazabicyclo afford 4a even after 15h (Table 1, Entry 15).
2.2.2] octane (DABCO) is an economic and efficient organic
base which has been successfully used in diverse organic
[
a
5
1
Table 1. Optimization reaction conditions for the synthesis of 4a
reactions such as cross-coupling and cyclization of O-
b
5
2
Entry
Catalyst [mol %] Solvent Temp Time
Yield
alkynylaryl isocyanides. In this contribution, we report the
facile synthesis of 4H-chromene-3-carboxamide derivatives
through a one-pot MCR pathway at ambient temperature
using DABCO as a catalyst. We envisage that a molecular
scaffold containing chromene, indole, and carboxamide might
integrate the properties of all the three moieties in a single
nucleus resulting in the formation of an essential molecule of
biological interest.
[ºC]
(h)
(%)
1
2
3
4
5
6
7
I2 [20]
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
RT
RT
RT
RT
RT
RT
RT
24
24
24
24
24
24
24
28
12
─
PTSA [30]
2
ZnCl [20]
FeCl [20]
─
3
TEA [30]
42
38
54
Piperidine [30]
Morpholine
Results and Discussion
[
30]
CO
DBU [20]
8
9
K
2
3
[15]
EtOH
EtOH
RT
RT
12
12
─
To optimize the synthesis of 4H-chromene-3-
25
carboxamides, we first studied the three-component reaction
2
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1
0
1
2
3
4
5
6
7
8
DMAP [30]
MKSF [30]
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
MeOH
RT
RT
RT
RT
RT
12
24
24
15
3
52
─
Consequently, the product 5a was isolated through
recrystallization. Furthermore, the role of methanol as a
reactant for the formation of 5a was confirmed by the
1
1
1
1
1
1
1
1
MK-10 [30]
L-proline [30]
DABCO [30]
DABCO [30]
DABCO [40]
DABCO [30]
DABCO [30]
TBAB [10]
─
1
13
analytical data based on H NMR and C NMR experiments
Scheme 2). The purified intermediate 2-methoxy-2-methyl-N-
62
72
─
(
phenyl-2H-chromene-3-carboxamide was further reacted with
indole to afford the desired product, 4H-chromene-3-
carboxamide (4a) was synthesized. Interestingly, the product
Reflux 15
RT
RT
RT
3
72
75
90
2.5
2.5
4a was obtained with an increased yield up to 92% using less
catalyst loading (10 mol %) within 30 minutes as represented
in Scheme 3.
1
9
0
1
DABCO [40]
TBAB [10]
MeOH
EtOH
DMF
RT
RT
RT
2.5
2.5
12
90
82
─
NH
O
2
DABCO [30]
TBAB [10]
DABCO (10 %)
O
N
H
N
Methanol
RT, 30 min
O
H
N
O
5
H
2
DABCO [30]
TBAB [10]
a
3a
O
4
a
a
Reaction conditions: 2-Hydroxy benzaldehyde (1 mmol), Acetoacetanilide
1 mmol), indole (1 mmol) DABCO (30 mol %), TBAB (10 mol%) Methanol (5
Scheme 3. Synthesis of indolyl-4H-chromene-3-carboxamides
(
mL), RT, 2.5 h. Isolated yields.
b
a
Table 2. Synthesis of Indolyl-4H-chromene-3-carboxamides (4a-p)
It should be noted that no improvement in the yield was
observed when the reaction was carried out in ethanol at
room temperature with an increase in the catalyst (DABCO)
loading up to 40 mol% (Table1, Entry 19). Nonetheless, a slight
improvement in the yield of 4a up to 75% was noticed when
the reaction was carried out in methanol using 30 mol% of
DABCO catalyst (Table 1, Entry 17). The reactions were further
carried out in a combination of DABCO (30%) and TBAB (10%)
in different solvents such as methanol, ethanol, and DMF.
Interestingly, the reaction performed in methanol at room
temperature using dual catalyst combination afforded 4a up to
90% yield within 2.5 h (Table 1, Entry 18).
Scheme 2. Synthesis of 2-methoxy-2-methyl-N-phenyl-2H-chromene-3-
carboxamide and acetyl coumarins
Surprisingly, the same reaction carried out in the presence
of aprotic solvent, DMF at room temperature using 30 mol%
DABCO and 10 mol% TBAB as catalyst and co-catalyst,
respectively did not afford the desired product 4a (Table 1,
Entries 21). It could be understood that the presence of protic
solvent (alcohol) plays a vital role in the formation of products.
To further study the mechanism, we carried out a reaction
between salicylaldehyde and 3-oxo-N-phenylbutanamide
alone (without indole) in methanol at room temperature in the
presence of DABCO (30 %) and TBAB (10%) as catalyst system.
Surprisingly, the reaction was completed within 2 h and the
product was confirmed as 2-methoxy-2-methyl-N-phenyl-2H-
a
Reaction conditions: Substituted 2-Hydroxy benzaldehydes (1 mmol),
Acetoacetanilides (1 mmol), indoles (1 mmol) DABCO (30 mol %), TBAB (10
mol%) Methanol (5 mL), RT, 2.5 h; No column chromatography.
To prepare 4H-chromene-3-carboxamide derivatives 4a-4p
,
the reactions of salicylaldehydes 1a-1b, 3-oxo-N-
phenylbutanamides 2a-2d, and indoles 3a-3b were carried out
in methanol and the results are depicted in Table 2. The
reaction of 1a, 2a, and 3a was investigated in various alcohols
such as methanol, ethanol, n-propanol, i-propanol n-butanol, i-
butanol, 2-methoxy ethanol, and 2-ethoxy ethanol which
successfully afforded the corresponding 4H-chromene-3-
chromene-3-carboxamide (product 5a
)
(Scheme 2).
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carboxamide 4a in a range of 90-55% yield (Table S1). The carbonyl-group involves in the cyclization instead of keto carbonyl-
reactivity of the alcohols in these reactions is in the following group in the presence of aprotic solvent leading to the formation of
order: methanol > ethanol > n-propanol > i-propanol > n- acetyl coumarins (6) via elimination of amines.
butanol > i-butanol > 2-methoxy ethanol > 2-ethoxy ethanol. Fig 2. Plausible mechanism for the synthesis of 4H-chromene-3-
However, the reactions did not proceed in the presence of
long chain alcohols such as 1-pentanol, 1-hexanol, 1-decanol,
which could be attributed to the long alkyl chains.
To our surprise, the reaction carried out between
salicylaldehyde and acetoacetanilide in the aprotic solvent,
DMF at room temperature using DABCO and TBAB as catalyst
combination afforded acetyl coumarins, 6a instead of the 5a
(
2-methoxy-2-methyl-N-phenyl-2H-chromene-3-carboxamide).
This further confirms the vital role of protic solvent (methanol)
towards the generation of the desired intermediate, 5a
.
Encouraged by these interesting findings, we continued to
synthesize the coumarin derivatives (6a-e) to validate this
newly found methodology. All the synthesized 3-
acetylcoumarins are listed in Table 3.
carboxamides
Biological evaluation
All the synthesized compounds 4a-p were evaluated for their
biological activities, such as antioxidant and antibacterial
activities.
a
Table 3. Synthesis of 3-acetyl-2H-chromen-2-ones (6a-e)
b
Entry
R
R
1
Product
6a
Time (h) Yield (%)
DPPH radical scavenging activity
The radical scavenging activity of 4-(1H-indol-3-yl)-2-methyl-
N-phenyl-4H-chromene-3-carboxamide derivatives, (4a-p) was
performed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay.
DPPH is extensively used to evaluate the antioxidant activity of
natural products as well as synthetic organic compounds.
Reduction of DPPH radicals were observed by a decrease in
absorbance at 517 nm. Activity of compounds (4a-p) was
compared with commercially available antioxidant ascorbic
1
2
3
4
5
H
H
H
H
H
H
3
3
3
5
5
90
90
90
82
85
3-OMe
6b
5-Br
6c
N,N-Diethyl
1-hydroxy-2-
napthaldehyde
6d
6e
a
Reaction conditions: 2-Hydroxy benzaldehydes (1 mmol), Acetoacetanilide
(
1 mmol), DABCO (30 mol %), TBAB (10 mol%) DMF (2 mL), RT, 3-5h. acid. The IC50 values calculated for each compound and
b
Isolated yields.
ascorbic acid (standard) are represented in Table 4. The results
demonstrated that all compounds 4a-p showed good
antioxidant activity. From the DPPH results, among all the
Plausible mechanism
compounds, 4c, 4d, 4k, 4l and 4p showed good activity.
Here, the presence of protic solvent plays an important role in the
rearrangement and cyclization process of the intermediate prior to
its reaction with indole. It should be noted that in our previous
research work on the synthesis of chromenes using simple β-keto
esters, we have observed the formation of 1-(2-methoxy-2-methyl-
In-vitro antibacterial activity
Indolyl 4H-chromene-3-carboxamide derivatives 4a-p were
screened successfully for their in vitro studies against different
Gram-positive and Gram-negative bacterial strains using agar
well diffusion method. All the compounds 4a-p were evaluated
for MIC and data reveals that among all the derivatives
compound 4p showed excellent activity (MIC values ranging
between 9.3–18.75 µg mL−1) against all the bacterial strains.
However, compound 4k and 4l exhibited good activity (MIC
value 9.3 µg mL−1) against Staphylococcus aureus and
Micrococcus luteus. Compounds 4c and 4d shows moderate
inhibitory against Staphylococcus aureus (MIC value 18.75µg
mL-1) in comparison with that of ampicillin. The antibacterial
activity results are tabulated in Table 5.
2H-chromen-3-yl)ethan-1-one
and
1-(2-hydroxy-2-methyl-2H-
chromen-3-yl)ethan-1-one in protic (alcohol) and aprotic (DMF)
5
5
solvents, respectively. Nevertheless, in this contribution, the MCR
pathway using acetoacetanilide, salicylaldehyde, and indole
afforded 4H-chromene-3-carboxamides and acetyl coumarins in the
presence of protic (methanol) and aprotic (DMF) solvents,
respectively. Here, we speculate that the keto carbonyl-group
selectively participates in cyclization over amide carbonyl-group in
the presence of protic solvent to afford 2-methoxy-2-methyl-N-
phenyl-2H-chromene-3-carboxamide (5) via benzopyrylium cation
intermediate. Furthermore, the compound 5 reacts with indole in
the presence of DABCO to afford 4H-chromene-3-carboxamides, 4a
via elimination of methoxy group. On the other hand, the amide
4
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Table 4. Anti-oxidant activity of Indolyl 4H-chromene-3-carboxamides, (4a- as follows: s = singlet, d = doublet, t = triplet, q = quartet, m =
p) and standard by DPPH radical scavenging method.
multiplet and dd = doublet of doublet.
Entry Compounds
Conc.
IC50
µg/mL
5
0
75
100
125
General procedure for the synthesis of 4-(1H-indol-3-yl)-2-methyl-
N-phenyl-4H-chromene-3-carboxamide derivatives (4a–4p)
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
42.13
45.05
48.19
48.43
40.32
41.06
43.86
43.14
41.17
43.76
49.89
48.01
45.43
44.58
43.98
49.56
49.18
56.08
55.76
57.92
58.56
52.08
53.75
54.63
57.14
51.57
52.19
58.28
59.06
57.46
52.45
53.17
58.96
60.93
69.22 80.34 1.56
70.17 82.65 1.43
72.13 85.72 1.21
71.94 84.19 1.21
69.12 78.56 1.74
68.43 80.44 1.68
70.65 83.91 1.52
68.27 84.45 1.52
69.04 82.19 1.72
70.65 84.45 1.60
74.83 85.67 1.13
75.14 86.04 1.19
66.84 81.92 1.46
70.41 81.42 1.56
71.27 80.89 1.56
75.06 85.96 1.07
76.24 93.12 1.06
In
a
typical experiment the salicylaldehyde (1 mmol),
acetoacetanilide (1 mmol), methanol (5 mL) and DABCO (30%) were
placed in a 25ml round-bottomed flask and stirred for 5 min to
dissolve the reactants. To this reaction mixture indole was added
and continued stirring at room temperature for 2.5 h (monitored by
TLC). After the completion of the reaction, the solid product was
filtered and washed with methanol (2-3 times) to get the pure
products 4a-p without column chromatography. All the compounds
1
13
were characterized by (M.P, H NMR, C NMR and Mass) spectral
data.
1
0
1
2
3
4
5
6
7
4j
4k
4l
4m
4n
4o
4p
Ascorbic
acid
1
1
1
1
1
1
1
Biological evaluation
Antioxidant activity
The DPPH radical scavenging activity was carried out by the
56
reported method. When DPPH reacts with an oxidant substrate,
which can donate hydrogen, it is reduced. The changes in the colour
(
4
from deep violet to light yellow) of the standard and compounds
a-p were measured at 517 nm on UV-Vis light
Table 5. Antibacterial activity of Indolyl 4H-chromene-3-carboxamide
derivatives (4a-p
a
)
-1
Minimum inhibitory concentration (MIC) (in µg/mL )
Compound Staphylococcus aureus Bacillus subtilis
Micrococcus luteus
E.coli
klebsiella
pneumoniae
Pseudomonas
aeruginosa
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
37.50
37.50
18.75
18.75
>150
>75.0
>75.0
>75.0
>150
>75.0
9.3
>75.0
>75.0
>75.0
>75.0
>150
>150
>150
>150
>75.0
>75.0
18.75
18.74
>150
>150
>75.0
18.75
4.6
>150
>150
37.50
37.50
>150
>150
>150
>150
>150
>150
9.3
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
37.50
18.75
9.3
>150
>150
>150
>150
>150
>150
>150
>150
>300
>150
>75
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
>150
18.75
9.3
9.3
9.3
>75
>75.0
>75.0
75.0
9.3
4.6
>150
>150
>150
9.3
>150
>150
>75
9.3
4.6
ampicillin
4.6
spectrophotometer.
Stock solutions were prepared by dissolving 1 mg of compound
in 1 ml of ethanol. Then, different concentrations of the sample, 50,
Experimental section
7
5, 100, and 125 µg, were prepared by dissolving in 3 mL ethanol.
General information
The DPPH solution was prepared just before the UV measurements.
Then, 3 ml of the test sample and 1 ml of the DPPH solution were
mixed and placed for incubation for 30 min at room temperature.
The absorbance of incubated test solutions and control (without
sample) were measured at 517 nm. Ascorbic acid was used as the
standard. The experiment was carried out in triplicate. The IC50
values were calculated for each sample as well as standard is
represented in Table 4.
All the commercially available materials were purchased from
suppliers (Sigma-Aldrich, Alfa Aesar) and were used without further
purification and the reactions were monitored by TLC. All the
reactions were performed using oven dried glassware. Elchem
digital melting point apparatus was used for recorded the melting
1
13
points in open capillaries and are uncorrected. The H NMR and
C
NMR were obtained using a Bruker Avance-400 MHz spectrometer
in CDCl and DMSO-d solvent with TMS as the internal standard.
3
6
The radical scavenging activity was calculated by using formula:
% Inhibition = [AB – AA/AB] × 100
Chemical shift values (δ) were expressed in parts per million (ppm).
Coupling constants (J) are reported in Hertz (Hz). Abbreviations are
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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New Journal of Chemistry
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DOI: 10.1039/C7NJ00980A
ARTICLE
Journal Name
Where AB is the absorption of blank solution and AA is the 119.8, 119.3, 118.2, 117.6, 115.4, 113.7, 110.4, 110.0, 31.9, 17.6,
absorption of the test sample
11.2; HRMS: m/z calcd. For C26
-(1H-indol-3-yl)-2-methyl-N-(o-tolyl)-4H-chromene-3-
carboxamide 4c
White solid; mp: 108-110 °C; H NMR (400 MHz, DMSO-d ): δ 10.95
22 2 2
H N O 394.4740 found 394.4738.
4
In-vitro antibacterial studies
1
6
All the newly synthesized compounds were executed for their in
vitro antibacterial studies against Gram-positive organisms such as
Staphylococcus aureus ATCC 700699, B. subtilis MTCC 430 and
Micrococcus luteus MTCC 2470 and Gram negative organisms such
as Klebsiella ATCC 10273, Escherichia coli ATCC 11105 and
(
s, 1H, NH), 9.10 (s, 1H, NH), 7.51 (d, J = 8 Hz, 1H, ArH), 7.34 (d, J = 8
Hz, 1H, ArH), 7.27 (d, J = 2.4 Hz, 1H, ArH), 7.16 – 7.14 (m, 3H, ArH),
7
1
.11 – 7.01 (m, 6H, ArH), 6.95 (t, J = 3.2 Hz, 1H, ArH), 5.44 (s,
13
H,CH), 2.28 (s, 3H, CH ), 1.78 (s, 3H, CH ); C NMR (100 MHz,
3
3
57
6
DMSO-d ) δ 166.7, 149.8, 149.7, 137.1, 136.6, 132.8, 130.6, 129.7,
Pseudomonas aeruginosa MTCC 2453 by the agar well technique.
1
1
27.9, 126.2, 125.8, 125.7, 124.8, 124.1, 123.9, 123.8, 121.4, 119.2,
19.0, 118.9, 116.1, 111.9, 110.5, 33.4, 18.4, 17.8; HRMS: m/z calcd.
All the compounds were dissolved in DMSO and different
concentrations were made. After inoculation, wells were scooped
out with 3 mm sterile cork borer and the caps of the dishes were
For C H N O 394.4740 found 394.4739.
2
6
22
2
2
replaced. To every well different concentrations of test solutions 2-Methyl-4-(2-methyl-1H-indol-3-yl)-N-(o-tolyl)-4H-chromene-3-
were added. All the plates and controls were kept at 37 ºC for 24 h carboxamide 4d
incubator. Inhibition zones were measured, the diameter calculated
in millimetre and the corresponding results were presented.
Standard antibacterial ampicillin was used as reference
antibacterial substances, respectively for comparison.
1
White solid; mp: 116-118 °C; H NMR (400 MHz, DMSO-d
(
8
6
6
): δ 10.80
s, 1H, NH), 9.11 (s, 1H, NH), 7.30 (d, J = 7.6 Hz, 1H, ArH), 7.22 (d, J =
.0 Hz, 1H, ArH), 7.17 – 7.13 (m, 1H, ArH), 7.10 – 7.01 (m, 5H, ArH),
.96 – 6.90 (m, 3H, ArH), 6.85 (t, J = 7.4 Hz, 1H, ArH), 5.46 (s, 1H,
), 2.23 (s, 3H, CH
6
100 MHz, DMSO-d ) δ 166.3, 149.5, 148.0, 136.1, 135.2, 132.7,
13
CH), 2.39 (s, 3H, CH
3
3 3
), 1.71 (s, 3H, CH ); C NMR
(
1
1
For MIC determination, all the compounds were dissolved in DMSO
to get the concentrations of 4.6, 9.3, 18.75, 37.50, 75.0, 150, 300,
32.2, 130.1, 129.3, 127.3, 127.1, 125.7, 125.4, 123.9, 123.6, 119.8,
18.3, 117.7, 115.4, 113.7, 110.3, 109.7, 31.9, 17.7, 17.1, 11.4;
600 and 1200 µg/ml. Standard antibacterial ampicillin (standard)
HRMS: m/z calcd. For C27
H
24
N
2
O
2
408.5010 found 408.5008.
was also tested for the comparison. Serial dilutions of all the
synthesized compounds were performed by the modified agar well
diffusion method. Test organisms were lawn cultured on the MHA
plates. The agar surface was bored by using a sterilize cork borer.
The concentrations of the test cultures were seeded with a 100 µl
microbial suspension of 0.5 MacFarland density. The test plates
were incubated at 37 ºC for 24 h. The lowest concentration which
showed a clear zone of inhibition considered as MIC value of each
compound. Ampicillin was used as standard drug. Experiments were
repeated thrice and the minimum inhibitory values are represented
in Table 5.
4
-(1H-indol-3-yl)-2-methyl-N-(p-tolyl)-4H-chromene-3-
carboxamide 4e
1
White solid; mp: 122-124 °C; H NMR (400 MHz, DMSO-d
s, 1H, NH), 9.68 (s, 1H, NH), 7.45 – 7.40 (m, 3H, ArH), 7.30 (d, J = 8
Hz, 1H, ArH), 7.17 – 7.13 (m, 3H, ArH), 7.06 – 6.94 (m, 5H, ArH), 6.91
6
): δ 10.87
(
(
t, J = 7.2 Hz, 1H, ArH), 5.45 (s, 1H, CH), 2.21 (s, 3H, CH
3
), 2.21 (s, 3H,
) δ 166.5, 149.9, 149.6, 137.0,
1
3
CH
1
1
3
); C NMR (100 MHz, DMSO-d
6
32.6, 129.6, 129.3, 127.9, 126.2, 124.8, 124.1, 123.5, 121.3, 120.0,
19.1, 119.0, 116.1, 112.0, 111.0, 33.4, 20.8, 18.3; HRMS: m/z calcd.
For C26
H
22
N
2
O
2
394.4740 found 394.4738.
2
-Methyl-4-(2-methyl-1H-indol-3-yl)-N-(p-tolyl)-4H-chromene-3-
carboxamide 4f
Spectral data of synthesized compounds (4a-4p)
and (6a-6e)
1
White solid; mp: 122-124 °C; H NMR (400 MHz, DMSO-d
6
): δ 10.73
(
s, 1H, NH), 9.70 (s, 1H, NH), 7.40 (d, J = 8 Hz, 2H, ArH), 7.20 – 7.13
4-(1H-indol-3-yl)-2-methyl-N-phenyl-4H-chromene-3-carboxamide
(m, 3H, ArH), 7.06 (t, J = 6 Hz, 3H, ArH), 6.94 – 6.88 (m, 3H, ArH),
4
a
6.81 (t, J = 7.6 Hz, 1H, ArH), 5.52 (s, 1H, CH), 2.35 (s, 3H, CH ), 2.21
(s, 3H, CH ), 2.17 (s, 3H, CH ); C NMR (100 MHz, DMSO-d ) δ
3 3 6
3
1
3
1
White solid; mp: 144-146 °C; H NMR (400 MHz, DMSO-d
6
): δ 10.89
1
1
1
66.5, 150.0, 149.2, 137.0, 135.7, 132.5, 132.4, 129.8, 129.3, 127.9,
27.4, 124.4, 124.1, 120.3, 119.9, 118.7, 118.1, 115.9, 114.3, 110.9,
10.6, 32.4, 20.8, 18.1, 11.7; HRMS: m/z calcd. For C27H N O
24 2 2
(s, 1H, NH), 9.79 (s, 1H, NH), 7.55 (d, J = 7.6 Hz, 2H, ArH), 7.46 (d, J =
8
Hz, 1H, ArH), 7.31 - 7.23 (m, 3H, ArH), 7.19 - 7.15 (m, 3H, ArH),
7.07 - 6.95 (m, 4H, ArH), 6.92 (t, J = 7.6 Hz, 1H, ArH), 5.47 (s, 1H,
13
408.5010 found 408.5008.
3 6
CH), 2.22 (s, 3H, CH ); C NMR (100 MHz, DMSO-d ) δ 166.3, 149.4,
1
1
49.2, 139.0, 136.5, 129.2, 128.5, 127.4, 125.7, 124.3, 123.6, 123.2, N-(4-Chlorophenyl)-4-(1H-indol-3-yl)-2-methyl-4H-chromene-3-
23.0, 120.9, 119.5, 118.6, 118.5, 115.6, 111.5, 110.5, 32.9, 17.8; carboxamide 4g
HRMS: m/z calcd. For C25
H N
20 2
O
2
380.4470 found 380.4468.
1
6
White solid; mp: 140-142 °C; H NMR (400 MHz, DMSO-d ): δ 10.88
2
-Methyl-4-(2-methyl-1H-indol-3-yl)-N-phenyl-4H-chromene-3-
(s, 1H, NH), 9.93 (s, 1H, NH), 7.58 (d, J = 8.8 Hz, 2H, ArH), 7.43 (d, J =
8 Hz, 1H, ArH), 7.32 (t, J = 8.4 Hz, 3H, ArH), 7.19 – 7.13 (m, 3H, ArH),
7.07 (d, J = 8 Hz, 1H, ArH), 7.03 – 6.95 (m, 1H, ArH), 6.91 (t, J = 7.6
carboxamide 4b
1
White solid; mp: 140-142 °C; H NMR (400 MHz, DMSO-d
6
): δ 10.75
13
Hz, 1H, ArH), 5.46 (s, 1H, CH), 2.21 (s, 3H, CH
DMSO-d ) δ 166.9, 150.0, 149.8, 138.5, 137.0, 129.6, 129.1, 128.9,
27.9, 127.3, 126.1, 124.7, 124.2, 123.5, 121.5, 121.4, 120.3, 119.0,
16.6, 112.0, 110.8, 33.3, 18.3; HRMS: m/z calcd. For C25
3
); C NMR (100 MHz,
(s, 1H, NH), 9.80 (s, 1H, NH), 7.53 (d, J = 8.0 Hz, 2H, ArH), 7.26 (t, J =
6
7.9 Hz, 2H, ArH), 7.20 – 7.14 (m, 3H, ArH), 7.07 (d, J = 8.1 Hz, 1H,
1
1
ArH), 7.02 (t, J = 7.4 Hz, 1H, ArH), 6.94 (dd, J = 4.4, 8.0, 3H, ArH),
.81 (t, J = 7.6 Hz, 1H, ArH), 5.54 (s, 1H, CH), 2.36 (s, 3H, CH ), 2.18
) δ 166.2, 149.5, 148.8,
2 2
H19ClN O
6
3
1
3
414.8890 found 414.8897.
3 6
(s, 3H, CH ); C NMR (100 MHz, DMSO-d
139.0, 135.2, 131.9, 129.3, 128.5, 127.4, 126.9, 123.8, 123.7, 123.1,
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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New Journal of Chemistry
Page 7 of 10
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DOI: 10.1039/C7NJ00980A
Journal Name
ARTICLE
N-(4-Chlorophenyl)-2-methyl-4-(2-methyl-1H-indol-3-yl)-2-4H-
4-(1H-indol-3-yl)-8-methoxy-2-methyl-N-(p-tolyl)-4H-chromene-3-
chromene-3-carboxamide 4h
carboxamide 4m
1
1
White solid; mp: 126-128 °C: H NMR (400 MHz, DMSO-d ): δ 10.74 White solid; mp: 128-130 °C; H NMR (400 MHz, DMSO-d ): δ 10.87
6
6
(s, 1H), 9.95 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), (d, J = 1.6 Hz, 1H, NH), 9.67 (s, 1H, NH), 7.45 – 7.39 (m, 3H, ArH),
7
.17 – 7.13 (m, 3H), 7.07 (d, J = 8.4 Hz, 1H), 6.94 – 6.88 (m, 3H), 6.80 7.30 (d, J = 8 Hz, 1H, ArH), 7.16 (d, J = 2.4 Hz, 1H, ArH), 7.05 – 6.99
1
3
(t, J = 7.6 Hz, 1H), 5.52 (s, 1H),2.34 (s, 3H), 2.17 (s, 3H); C NMR (m, 3H, ArH), 6.92 – 6.83 (m, 3H, ArH), 6.71 (t, J = 1.2 Hz, 1H, ArH),
13
(100 MHz, DMSO-d ) δ 166.8, 150.0, 149.6, 138.5, 135.6, 132.4, 5.43 (s, 1H, CH), 3.82 (s, 3H, OCH ), 2.21 (s, 6H, (CH ) ); C NMR
6
3
3 2
6
129.8, 128.9, 127.9, 127.4, 127.1, 124.2, 121.3, 120.3, 118.8, 118.0, (100 MHz, DMSO-d ) δ 166.6, 149.7, 147.4, 139.4, 137.0, 136.9,
115.9, 114.1, 110.9, 110.3, 32.4, 18.1, 11.6; HRMS: : m/z calcd. For 132.6, 129.3, 126.2, 125.5, 123.7, 123.5, 121.3, 120.8, 120.7, 119.1,
C
26
H
21ClN
2
O
2
428.9160 found 428.9158.
-(1H-indol-3-yl)-8-methoxy-2-methyl-N-phenyl-4H-chromene-3-
carboxamide 4i
White solid; mp: 126-128 °C; H NMR (400 MHz, DMSO-d ): δ 10.87
119.1, 119.0, 110.9, 110.2, 56.0, 33.4, 20.8, 18.4; HRMS: m/z calcd.
For C H N O 424.5000 found 424.4998.
2
7
24
2
3
4
8-Methoxy-2-methyl-4-(2-methyl-1H-indol-3-yl)-N-(p-tolyl)-4H-
chromene-3-carboxamide 4n
1
6
1
(s, 1H, NH), 9.76 (s, 1H, NH), 7.53 (d, J = 8 Hz, 2H, ArH), 7.45 (d, J = 8 White solid; mp:140-142 °C; H NMR (400 MHz, DMSO-d
6
): δ 10.72
Hz, 1H, ArH), 7.29 – 7.21 (m, 3H, ArH), 7.16 (d, J = 2.4 Hz, 1H, ArH), (s, 1H, NH), 9.69 (s, 1H, NH), 7.39 (d, J = 8.4 Hz, 2H, ArH), 7.20 (t, J =
7
=
CH
.02 (td, J = 7.6, 4.4 Hz, 2H, ArH), 6.91 – 6.82 (m, 3H, ArH), 6.70 (d, J 11.2 Hz, 2H, ArH), 7.04 (d, J = 8 Hz, 2H, ArH), 6.92 (t, J = 7.6 Hz, 1H,
7.6 Hz, 1H, ArH), 5.43 (s, 1H, CH), 3.82 (s, 3H, OCH ), 2.21 (s, 3H, ArH), 6.85 – 6.78 (m, 3H, ArH), 6.50 (dd, J = 2, 2 Hz, 1H, ArH), 5.50
) δ 166.32, 149.3, 147.0, 139.0, (s, 1H, CH), 3.83 (s, 3H, OCH ), 2.34 (s, 3H, CH ), 2.21 (s, 3H, CH ),
); C NMR (100 MHz, DMSO-d ) δ 166.5, 149.3,
18.6, 118.5, 111.5, 110.3, 109.7, 55.5, 32.9, 17.9; HRMS: m/z calcd. 147.2, 139.5, 137.0, 135.6, 132.5, 132.3, 129.3, 127.5, 125.0, 123.6,
410.4730 found 410.4726. 120.9, 120.3, 119.9, 118.7, 118.3, 114.2, 110.9, 110.3, 110.1, 56.0,
2.4, 20.8, 18.1, 11.7; HRMS: m/z calcd. For C28 438.5270
3
1
3
3
); C NMR (100 MHz, DMSO-d
6
3
3
3
1
3
138.9, 136.4, 128.5, 125.7, 125.0, 123.2, 123.0, 120.8, 120.3, 119.5, 2.17 (s, 3H, CH
3
6
1
22 2 3
For C26H N O
3
26 2 3
H N O
8-Methoxy-2-methyl-4-(2-methyl-1H-indol-3-yl)-N-phenyl-4H-
found 438.5267.
chromene-3-carboxamide 4j
1
N-(4-Chlorophenyl)-4-(1H-indol-3-yl)-8-methoxy-2-methyl-4H-
chromene-3-carboxamide 4o
White solid; mp: 128-130 °C; H NMR (400 MHz, DMSO-d
(
(
6
): δ 10.74
s, 1H, NH), 9.80 (s, 1H, NH), 7.53 (d, J = 8 Hz, 2H, ArH), 7.26 – 7.16
m, 4H, ArH), 7.00 (t, J = 7.3 Hz, 1H, ArH), 6.93 (t, J = 7.5 Hz, 1H, White solid; mp: 118-120 °C; H NMR (400 MHz, DMSO-d
1
6
): δ 10.87
ArH), 6.86 (dt, J = 7.2, 7.2 Hz, 3H, ArH), 6.51 (dd, J = 7.0, 1.8, 1H, (s, 1H, NH), 9.92 (s, 1H, NH), 7.58 (d, J = 8.0 Hz, 2H, ArH), 7.44 (d, J =
ArH), 5.53 (s, 1H, CH), 3.84 (s, 3H, OCH ), 2.35 (s, 3H, CH ), 2.19 (s, 7.6 Hz, 1H, ArH), 7.31 (d, J = 7.6 Hz, 3H, ArH), 7.15 (s, 1H, ArH), 7.03
); C NMR (100 MHz, DMSO-d ) δ 166.2, 148.9, 146.8, (t, J = 7.2 Hz, 1H, ArH). 6.91 – 6.84 (m, 3H, ArH), 6.71 (d, J = 6.8 Hz,
39.0, 139.0, 135.1, 131.8, 128.5, 127.0, 124.5, 123.2, 123.1, 120.4, 1H, ArH), 5.44 (s, 1H, CH), 3.83 (s, 3H, OCH
19.8, 119.3, 118.3, 117.6, 113.7, 110.4, 109.8, 109.6, 55.5, 31.9, NMR (100 MHz, DMSO-d ) δ 166.9, 150.1, 147.5, 139.4, 138.5,
3
3
1
3
3
1
1
1
4
H, CH
3
6
1
3
3
3
), 2.22 (s, 3H, CH ); C
6
7.6, 11.2; HRMS: m/z calcd. For C27
24.4999.
H
24
N
2
O
3
424.5000 found 136.9, 129.1, 128.9, 127.2, 126.1, 125.4, 123.8, 123.5, 121.5, 121.4,
120.8, 120.3, 119.0, 112.0, 110.7, 110.3, 56.0, 33.4, 18.4; HRMS:
2 3
m/z calcd. For C26H21ClN O 444.9150 found 444.9148.
4-(1H-indol-3-yl)-8-methoxy-2-methyl-N-(o-tolyl)-4H-chromene-3-
carboxamide 4k
N-(4-Chlorophenyl)-8-methoxy-2-methyl-4-(2-methyl-1H-indol-3-
1
yl)-4H-chromene-3-carboxamide 4p
White solid; mp: 146-148 °C; H NMR (400 MHz, DMSO-d
(
6
): δ 10.94
1
s, 1H, NH), 9.08 (s, 1H, NH), 7.51 (d, J = 8 Hz, 1H, ArH), 7.34 (d, J = White solid; mp: 136-138 °C; H NMR (400 MHz, DMSO-d
6
): δ 10.73
8.4 Hz, 1H, ArH), 7.26 (d, J = 2.0 Hz, 1H, ArH), 7.16 (d, J = 7.3 Hz, 1H, (s, 1H, NH), 9.95 (s, 1H, NH), 7.56 (d, J = 8.8 Hz, 2H, ArH), 7.30 (d, J =
ArH), 7.11 – 7.01 (m, 4H, ArH), 6.95 – 6.83 (m, 3H,ArH), 6.73 (d, J = 9.2 Hz, 2H, ArH), 7.19 (t, J = 8.4 Hz, 2H, ArH), 6.92 – 7.78 (m, 4H,
6
CH
3
.4 Hz, 1H, ArH), 5.42 (s, 1H, CH), 3.83 (s, 3H, OCH ), 2.29 (s, 3H, ArH), 6.50 (dd, J = 1.6, 1.6 Hz, 1H, ArH), 5.51 (s, 1H, CH), 3.83 (s, 3H,
1
3
13
3
), 1.77 (s, 3H, CH
3
); C NMR (100 MHz, DMSO-d
6
) δ 166.2, OCH
3
3 3
), 2.33 (s, 3H, CH ), 2.18 (s, 3H, CH ); C NMR (100 MHz,
1
1
1
49.3, 147.0, 138.8, 136.5, 136.1, 132.3, 130.1, 125.7, 125.7, 125.3, DMSO-d ) δ 166.9, 149.7, 147.2, 139.5, 138.5, 135.6, 132.3, 128.9,
25.2, 125.0, 123.3, 123.1, 120.9, 120.4, 118.7, 118.5, 118.5, 111.4, 127.4, 127.1, 124.8, 123.8, 121.3, 120.9, 120.3, 118.8, 118.0, 114.1,
09.8, 109.7, 55.5, 33.0, 18.0, 17.3; HRMS: m/z calcd. For 110.9, 110.2, 110.1, 56.0, 32.4, 18.1, 11.6; HRMS: m/z calcd. For
6
C
27
H
24
N
2
O
3
424.5000 found 424.4998.
-Methoxy-2-methyl-4-(2-methyl-1H-indol-3-yl)-N-(o-tolyl)-4H-
chromene-3-carboxamide 4l
27 2 3
C H23ClN O 458.1397 found 458.1395.
8
3-Acetyl-2H-chromen-2-one 6a
1
Yellow solid; H NMR (400 MHz, CDCl
3
) δ 8.51 (s, 1H, ArH), 7.64-7.68
1
13
White solid; mp: 148-150 °C; H NMR (400 MHz, DMSO-d
6
): δ 10.80 (m, 2H, ArH), 7.33-7.390 (m, 2H, ArH), 2.73 (s, 3H, CH
s, 1H, NH), 9.13 (s, 1H, NH), 7.30 (d, J = 7.6 Hz, 1H, ArH), 7.22 (d, J = (100 MHz, CDCl ) δ 195.5, 159.2, 155.3, 147.5, 134.4, 130.2, 125.0,
3
); C NMR
(
3
8
6
Hz, 1H, ArH), 7.10-7.00 (m, 4H, ArH), 6.95 (t, J = 7.2 Hz, 1H, ArH), 124.5, 118.2, 116.7, 30.5; GC-MS (EI); 188.
.87 (dd, J = 8, 7.2 Hz, 3H, ArH), 6.52 (dd, J = 2, 2 Hz, 1H, ArH), 5.44
3
-Acetyl-8-methoxy-2H-chromen-2-one 6b
(s, 1H, CH), 3.84 (s, 3H, OCH
3
), 2.38 (s, 3H, CH
), C NMR (100 MHz, DMSO-d
3
), 2.23 (s, 3H, CH
3
),
1
1
3
Yellow solid; H NMR (400 MHz, CDCl ) δ 8.48 (s, 1H, ArH), 7.19-7.29
1
1
1
1
4
.69 (s, 3H, CH
3
6
) δ 166.3, 148.1,
3
13
(
m, 3H, ArH), 4.00 (s, 3H, OCH
MHz, CDCl ) δ 195.5, 158.7, 147.6, 147.0, 145.0, 124.8, 124.6, 121.3,
18.8, 115.9, 56.3, 30.5; GC-MS (EI); 218.
3 3
), 2.74 (s, 3H, CH ); C NMR (100
46.8, 139.0, 136.1, 135.2, 132.8, 132.1, 130.1, 127.1, 125.7, 125.5,
25.4, 124.5, 123.1, 120.4, 119.8, 118.3, 117.7, 113.7, 110.3, 109.6,
09.5, 55.5, 31.9, 17.7, 17.1, 11.4; HRMS: m/z calcd. For C28
38.5270 found 438.5267.
3
1
26 2 3
H N O
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ARTICLE
Journal Name
3
-Acetyl-6-bromo-2H-chromen-2-one 6c
10 G. Harichandran, P. Parameswari, M. Kanagaraj, P.
Shanmugam, Tetrahedron Lett., 2015, 56, 150.
1
Yellow solid; H NMR (400 MHz, CDCl
=
Hz, 1H,ArH), 2.72 (s, 3H, CH ); C NMR (100 MHz, CDCl ) δ 195.0,
3 3
3
) δ 8.40 (s, 1H, ArH), 7.78 (d, J
1
1 A. Viola, L. Ferrazzano, G. Martelli, S. Ancona, L. Gentilucci,
A. Tolomelli, Tetrahedron 2014, 70, 6781.
2 Hz, 2H, ArH), 7.72 (dd, J = 2.4, 2.4 Hz, 1H, ArH), 7.26 (d, J = 0.8
13
1
1
2 P. P. Ghosh and A. R. Das, J. Org. Chem., 2013, 78, 6170.
3 M. Gyuris, R. Madacsi, L. G. Puskas, G. K. Toth, J. Wolfling,
and I. Kanizsai, Eur. J. Org. Chem., 2011, 848.
158.5, 154.1, 145.9, 137.0, 132.2, 125.4, 119.7, 118.4, 117.5, 30.5;
GC-MS (EI); 267.
1
4 K. S. Pandit, R. V. Kupwade, P. V. Chavan, U. V. Desai, P. P.
Wadgaonkar, and K. M. Kodam, ACS Sustainable Chem. Eng.,
2016, 4, 3450.
3
-Acetyl-7-(diethylamino)-2H-chromen-2-one 6d
1
Yellow solid; H NMR (400 MHz, CDCl
3
) δ 8.43 (s, 1H, ArH), 7.38 (d, J
=
8.8 Hz, 1H, ArH), 6.60 (dd, J = 2.4, 2.4 Hz, 1H, ArH), 6.46 (d, J = 2.4 15 A. M. Shestopalov, Y. M. Litvinov, L. A. Rodinovskaya, O. R.
Hz, 1H, ArH), 3.43-3.48 (m, 4H, (CH
2
)
2
), 2.68 (s, 3H, CH
3
), 1.22 (t, J =
Malyshev, M. N. Semenova, and V. V. Semenov, ACS Comb.
Sci., 2012, 14, 484.
6 M. Costa, T. A. Dias, A. Brito, F. Proença, Eur. J. Med. Chem.,
1
3
6
1
.8 Hz, 6H, (CH ) ); C NMR (100 MHz, CDCl ) δ 195.7, 160.8, 158.7,
53.0, 147.8, 131.9, 116.1, 109.8, 108.1, 96.5, 45.1, 30.6, 12.4; GC-
3
2
3
1
1
2
016, 123, 487.
MS (EI); 256.
7 N. Vukovic, S. Sukdolak, S. Solujic, N. Niciforovic, Food
Chemistry., 2010, 120, 1011.
18 J. E. Hayes, P. Allen, N. Brunton, M. N. O. Grady, J. P. Kerry,
Food Chemistry., 2011, 126, 948.
9 I. Zghab, B. Trimeche, M. B. Mansour, M. Hassine, D.
Touboul, H. B. Jannet, Arab. J. Chem., 2013
0 M. Puppala, X. Zhao, D. Casemore, B. Zhou, G. Aridoss, S.
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Med.Chem., 1991, 26, 13.
3-Acetyl-2H-benzo[h]chromen-2-one 6e
1
Yellow solid; H NMR (400 MHz, CDCl ) δ 9.28 (s, 1H, ArH), 8.33 (d, J
3
=
8.4 Hz, 1H, ArH), 8.07 (d, J = 9.2 Hz, 1H, ArH), 7.90 (d, J = 8 Hz, 1H,
1
2
ArH), 7.72 (t, J = 8 Hz, 1H, ArH), 7.59 (t, J = 7.2 Hz, 1H, ArH), 7.44 (d,
1
3
J = 9.2 Hz, 1H, ArH), 2.78 (s, 3H, CH
3
); C NMR (100 MHz, CDCl
95.5, 159.4, 156.1, 143.2, 136.3, 130.2, 129.8, 129.2, 126.6, 122.4,
21.7, 116.5, 112.7, 30.6; GC-MS (EI); 238.
3
) δ
1
1
2
2 Y. Chen, M. Cheng, F-Q. Liu, P. Xia, K. Qian, D. Yu, Y. Xia,
Zheng-Yu. Yang, Chin-Ho. Chen, S. L. Morris-Natschke, Kuo-
Hsiung. Lee, Eur. J. Med. Chem., 2011, 46, 4924.
Conclusions
2
3 Y. Shu-Qiang, M. Shi, K. Ting-Ting, Z. Cheng-Mei, K. Han, B.
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4 R. Devakaram, D. S. Black, K. T. Andrews, G. M. Fisher, R. A.
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5 A. Kakanejadifard, F. Azarbani, N. Khosravani, B. Notash, J.
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6 O. S. Patrusheva, V. V. Zarubaev, A. A. Shtro, Y. R.
Orshanskaya, S. A. Boldyrev, I. V. Ilyina, S. Y. Kurbakova, D. V.
Korchagina, K. P. Volcho, N. F. Salakhutdinov, Bioorg. Med.
Chem. Lett., 2016, 24, 5158.
In conclusion, we have demonstrated a simple and efficient DABCO
catalysed reaction of salicylaldehydes, acetoacetanilides and
indoles, which provides a new route and easy access to the
synthesis of highly functionalized 4H-chromene-3-carboxamides at
room temperature in good to excellent yields. The present
methodology offers high yields, simple reaction conditions and easy
isolation of the products without column chromatography.
Moreover, among the screened 4H-chromene-3-carboxamides,
compound 4p was considerably promising and identified as a lead
compound showing good antioxidant and antibacterial activities.
2
2
2
2
2
7 T. C. Lima, A. D. C. Santos, D. T.M. Costa, R. J. Souza, A.
Barison, M. Steindel, M. W. Biavatti. Revista Brasileira de
Farmacognosia., 2015, 25, 7.
8 W. Kemnitzer, J. Drewe, S. Jiang, H. Zhang, Y. Wang, J. Zhao,
S. Jia, J. Herich, D. Labreque, R. Storer, K. Meerovitch, D.
Bouffard, R. Rej, R. Denis, C. Blais, S. Lamothe, G. Attardo, H.
Gourdeau, B. Tseng, S. Kasibhatla, and S. X. Cai. J. Med.
Chem., 2004, 47, 6299.
Acknowledgement
The authors thank VIT University, Vellore for providing research
facilities and acknowledges VIT-SIF for providing NMR facilities to
carry out this work.
2
3
3
9 S.X. Cai, J. Drewe, W. Kemnitzer, Anti-Cancer Agents Med.
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Graphical abstract
One pot three component protocol for the synthesis of Indolyl-4H-chromene-
-carboxamides as antioxidant and antibacterial agents
3
a
a
Chitreddy V Subbareddy and Shanmugam Sumathi*
a
Department of Chemistry, VIT University, Vellore 632014, Tamilnadu, Vellore, India
Corresponding authors: sumathishanmugam2003@gmail.com
*