Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino Annulated Analogues of Azepinones

Article abstract of DOI:10.1002/jhet.3260

Starting from dimedone, two methodologies for synthesizing novel quinolino annulated azepinones have been reported. The protocol involves azepinone synthesis by the action of a newly synthesized organocatalyst derived from the reaction of TCT and DMF on o

Full text of DOI:10.1002/jhet.3260

Month 2018 Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino
Annulated Analogues of Azepinones
*
Deepika Arora,
Jaya Dwivedi,
Sakshi Arora, Sudesh Kumar, and Dharma Kishore
Department of Chemistry, Banasthali Vidyapith, Banasthali, Rajasthan 304022, India
*E-mail: deepika.arora92@gmail.com
Received January 25, 2018
DOI 10.1002/jhet.3260
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Starting from dimedone, two methodologies for synthesizing novel quinolino annulated azepinones have
been reported. The protocol involves azepinone synthesis by the action of a newly synthesized
organocatalyst derived from the reaction of TCT and DMF on oxime derivatives (5 and 9), which were ob-
tained by the reaction of acridine dione derivatives (4 and 8) with hydroxylamine hydrochloride. The deriv-
atives 4 and 8 were obtained by the reaction of 1 with anthranilic acid 2 and isatoic anhydride 7, respectively.
The synthesis of all the compounds was confirmed initially by TLC followed by spectral analysis through IR,
1H NMR, 13C NMR, mass spectrometry, and elemental analysis. The results that emanated on the evaluation
of the antibacterial activity of azepinones against two Gram-positive and two Gram-negative test organisms
using disc diffusion method have also been discussed. Compounds 6c, 6d, 6e, 10c, and 10e have been found
to display better inhibitory activity than standard drugs streptomycin and tetracycline. The minimum inhib-
itory concentration and IC50 values for the compounds under study as well as of standard drugs were calcu-
lated. The maximum inhibition by bacterial strains was observed at 150 μg/mL.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
using mefloquine for a prolonged time has been rarely
found to cause neuropsychiatric effects [6]. Despite a large
number of quinoline nucleus-based drugs, that is,
ciprofloxacin, sparfloxacin, ofloxacin, norfloxacin, and
gatifloxacin, have been available for treatment of various
infections, efforts have been made to improve the
pharmacokinetic profile and therapeutic index and to
remove the side effects caused due to these and antibiotics.
This situation forces to the search for new antimicrobials.
Quinoline, being significantly important for treatment of
various infectious diseases, has been selected in this
communication for synthesis of novel quinolino
annulated azepinone derivatives followed by their
antibacterial drug designing under in vitro conditions
with an effort to provide better treatment of various
pathogenic microorganisms.
The onset of new epidemic diseases and the renaissance of
several microbes that had been controlled coupled with the
increase in microbial resistance have necessitated the
requisition of development of new antimicrobials. Various
heterocyclic compounds show antimicrobial potential, and
among them quinoline nucleus forms the most desirable
motifs having prominent antimicrobial activity [1].
Quinoline and its derivatives, chiefly quinolones, are
medicinally important, as they show immense
pharmacological activities like antimicrobial [2], anticancer
[3], antiviral [4], and anti-inflammatory [5]. For instance,
antibiotic chloroquine is used in the treatment of malaria. It
is also reported that chloroquine is used in treating
amoebic liver abscess and some major autoimmune
disorders like rheumatoid arthritis and lupus erythematosus.
The utilization of drugs to cure diseases caused by the
microbes has been increased so much that the microbes
have become resistant to them. The dangerous effects of
drug molecules on human life include hypersensitivity,
immune suppression, and allergic reactions. For example,
RESULTS AND DISCUSSION
Synthetic route shown in Scheme 1 was followed to
accomplish the preparation of target compounds 6(a–e)
© 2018 Wiley Periodicals, Inc.

D. Arora, J. Dwivedi, S. Arora, S. Kumar, and D. Kishore
Vol 000
Scheme 1. Synthesis of quinolino annulated analogues of azepinones.
Table 1
and 10(a–e). The acridones 4 [7] and 8 [8,9] were
synthesized according to the reported procedures in the
literature. At room temperature, the synthesized acridone
(4 or 8) was stirred with hydroxylamine hydrochloride in
water and in the presence of Hyamine catalyst to obtain
the corresponding oximes (5 or 9), respectively. The rate
of reaction was also found to be significantly affected by
the amount of catalyst used and the temperature at which
the reaction was carried out. Various concentrations of
catalyst were loaded on to substrate out of which
60 mol% was found to be optimum as shown in Table 1.
The rate and yield of reaction remain unchanged on
increasing the amount of catalyst while it decreased on
decreasing catalyst concentration. Similarly, stirring at
higher or lower temperature led to the formation of
undesired products or left the reaction incomplete. Thus,
60 mol% Hyamine at room temperature under aqueous
conditions was chosen as the optimum reaction
conditions. Further, the effect of various solvents in the
transformation was also evaluated. It was found that
solvents like CHCl3, CH3CN, EtOH, and EtOH–H2O
Effect of various concentration of Hyamine catalyst on the synthesis of 5
and 9.
S. No.
Catalyst (mol%)
Time (min)
Yield (%)
1
2
3
4
5
6
No
30
40
50
60
70
65
71
82
78
55
60
19
62
69
87
99
97
took much more time for the completion of reaction and
still no desired product was formed. The transformation
occurred in least amount of time when the catalyst was
applied under aqueous conditions. The complete
illustration of effect of different reaction conditions on
yield of reaction has been depicted in Table 2.
The generated oxime (5 or 9) upon subsequent addition
of a newly synthesized organocatalyst derived from the
reaction of TCT and DMF underwent Beckmann
rearrangement to produce the corresponding quinolino
Journal of Heterocyclic Chemistry
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Month 2018
Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino
Annulated Analogues of Azepinones
Table 2
appearance of signal at 7.19–8.08 ppm due to the four
Effect of various reaction conditions on yield of reaction.
aromatic protons, at 1.91 ppm due to NH protons, and at
160.76 and 195.85 ppm due to C of two C¼O groups
further confirmed its formation. In the same way, the
appearance of absorption band at 3273, 1671, and
919 cmꢀ1 due to OH, C¼N, and N–O stretching,
respectively, and at 4.39 ppm due to OH protons marked
the formation of compound 5a or 9a. Similarly, the
formation of compound 6a or 10a was ascertained
through IR spectra, which showed absorption bands at
3565 cmꢀ1 due to NH stretching, doublet at 1700–
1648 cmꢀ1 due to overlapping of amide I and amide II
bands, and at 1338 cmꢀ1 due to amide III band. The
study of NMR again contributed to its formation by
displaying peaks at 11.12 ppm due to NH protons of
amide group and at 161.85 ppm due to C of amide
group. The compounds 6b and 10b displayed peaks
similar to 6a and 10a, respectively, except the presence
of an additional absorption band at 753 cmꢀ1 due to C–
Cl stretching was observed. On similar grounds, the
remaining compounds 6c–6e and 10c–10e were
interpreted. The latter compounds displayed different
absorption bands in IR due the the substitution of their
aromatic ring with different groups such as the following:
An absorption band at 685 cmꢀ1 was observed because
of C–Br stretching in 6c and 10c, while the formation of
compounds 6d and 10d was ascertained by the
appearance of absorption bands at 1530 and 1349 cmꢀ1
due to asymmetric and symmetric stretching of NO2. The
compounds 6e and 10e were confirmed by 1219 cmꢀ1
(asym. Str. of C–O–C) and 1016 cmꢀ1 (sym. Str. of C–
O–C) absorption bands in addition to the presence of tall
singlet at 3.73 ppm (–OCH3). The isotopic peaks were
observed in the mass spectrum of compounds 6b–6c and
10b–10c. A little variation in the 1H and 13C NMR
values of aromatic ring was observed in compounds 6b–
6e and 10b–10e again because of the attachment of
different groups.
S. No.
Reaction conditions
Yield (%)
A
B
C
D
E
F
G
H
I
Solvent free, no catalyst, r.t.
CHCl3, Hyamine, reflux
CHCl3, Hyamine, r.t.
CH3CN, Hyamine, reflux
CH3CN, Hyamine, r.t.
EtOH, Hyamine, reflux
EtOH, Hyamine, r.t.
H2O, Hyamine, reflux
H2O, Hyamine, r.t.
EtOH–H2O, Hyamine, reflux
EtOH–H2O, Hyamine, r.t.
Solvent-free, Hyamine, r.t.
10
29
62
33
55
38
69
20
99
52
78
80
J
K
L
annulated azepinones (6 or 10), respectively. The
Beckmann rearrangement usually involves the use of
harmful acids, so alternative pathways have been
searched where it is carried out under moderate
conditions [10]. Recently, the use of organocatalysts has
attracted the attention of the researchers because of their
efficiency, good catalytic activity, and easy method of
their handling during the operation of the process of
rearrangement. In this category of catalysts, the cyanuric
chloride (2,4,6-trichloro-1,3,5-triazine, TCT) has emerged
as one of the highly active, first [11–13] organocatalyst in
effecting the Beckmann rearrangement.
In the present communication, it has been found that the
synthesized organocatalyst has a mild effect and it gives
product with high purity unlike other catalysts that are
rather strong acids or bases. Besides requiring high
temperature, the latter reactions also produce huge
amounts of hazardous by-products [14,15]. Synthesis of
nylon-6 from ϵ-caprolactam is one such example that
employs the use of fuming sulfuric acid and produces
ammonium sulfate as by-product [16,17].
It was found out that the reaction worked equally well
with all the substituents whether electron releasing or
electron withdrawing. Scheme
2
summarizes the
Biological studies.
Followed by synthesis, the novel
optimization study of the synthesis of oximes 5 and 9 and
their further conversion into azepinones 6 and 10,
respectively. A probable mechanism for the synthesis of
quinolino annulated azepinones has been described in
Scheme 3.
The synthesis of quinolino annulated analogues of
azepinones 6 and 10 was confirmed initially via thin-
layer chromatography (TLC) and finally through spectral
and elemental analyses. During spectral analysis, the
authors depicted some distinctive peaks characteristic of
particular groups, such as the following: The IR spectra
illustrate the presence of absorption band at 3359 cmꢀ1
due to NH stretching, and a twin peak at 1673 cmꢀ1 and
1646 cmꢀ1 due to C¼O stretching respectively denoted
the formation of compound 4a or 8a. Besides IR, the
azepinones were evaluated for their efficiency against two
Gram-positive, that is, Staphylococcus aureus and
Bacillus subtilis, and two Gram-negative, that is,
Escherichia coli and Enterobacter cloacae, test
organisms by employing disc diffusion method and
taking 50, 100, and 150 μg/mL concentrations of the test
compounds. Streptomycin and tetracycline were taken as
standard. Streptomycin was put in the Petri plates
containing test compounds 6a to 6e containing S. aureus
and E. coli test organisms and test compounds 10a to 10e
containing B. subtilis and E. cloacae test organisms.
Tetracycline was put in the Petri plates containing test
compounds 6a to 6e containing B. subtilis and E. cloacae
test organisms and test compounds 10a to 10e containing
S. aureus and E. coli test organisms. The results of MIC
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Arora, J. Dwivedi, S. Arora, S. Kumar, and D. Kishore
Vol 000
Scheme 2. Optimization study of the synthesized products. [Color figure can be viewed at wileyonlinelibrary.com]
and IC50 screening are summarized in Table 3 and
Figure 1, respectively.
These novel derivatives demonstrated varying
Compound 10a being unsubstituted and compound 10d
bearing nitro group at 9 position showed remarkable
activity against S. aureus, whereas the unsubstituted
compound 6a showed moderate activity against
antibacterial activities against different
strains.
Journal of Heterocyclic Chemistry
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Month 2018
Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino
Annulated Analogues of Azepinones
Scheme 3. Mechanism for the synthesis of quinolino annulated azepinones. [Color figure can be viewed at wileyonlinelibrary.com]
Table 3
chlorine atom and nitro group at 9 position showed
good antibacterial activity against B. subtilis.
Compounds 10a, 10c, and 10e showed moderate
antibacterial activity. In the same way, compounds 10a
and 10d in case of E. coli and compound 6a in case of
E. cloacae depicted significant antibacterial activity. In
case of S. aureus, compounds 6c and 10e showed MIC
of 15 μg/mL, which means it was more potent than
standard drug streptomycin. In a similar way, in case of
B. subtilis, compound 6d bearing nitro group at 8
position showed MIC of 10 μg/mL and depicted it to
be more potent than standard drugs streptomycin
(40 μg/mL) and tetracycline (30 μg/mL). Compounds 6c
and 10c bearing chlorine atom at positions 8 and 9
respectively showed significant MIC (05 and 01 μg/mL,
respectively) than standard streptomycin (55 μg/mL) and
tetracycline (25 μg/mL). In the same way, compounds
6c and 6e showed significant MIC (10 and 20 μg/mL,
respectively) as compared with standard streptomycin
(20 μg/mL) and tetracycline (55 μg/mL).
Minimum inhibitory concentration in μg/mL against S. aureus, B. subtilis,
E. coli, and E. cloacae bacterial strains.
Products
S. aureus
B. subtilis
E. coli
E. cloacae
6a
6b
6c
6d
6e
10a
10b
10c
10d
10e
Streptomycin
Tetracycline
Control
30
80
15
120
35
80
55
25
145
15
20
50
-
100
155
105
10
45
35
100
90
60
75
40
15
90
05
55
25
70
20
01
110
35
55
25
-
90
100
10
115
20
60
25
185
25
40
20
55
-
30
-
S. aureus. In case of B. subtilis, compound 6b bearing
chlorine atom at position depicted significant
antibacterial activity. Compounds 10b and 10d bearing
8
Journal of Heterocyclic Chemistry
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D. Arora, J. Dwivedi, S. Arora, S. Kumar, and D. Kishore
Vol 000
Figure 1. IC50 values of synthesized azepinones. [Color figure can be viewed at wileyonlinelibrary.com]
CONCLUSIONS
assigned to the molecules. All the bacterial strains were
procured from MTCC, Chandigarh, India.
Synthetic protocols conceived in the present work
provided an elegant heteroannulation of the quinoline
ring with dimedone to produce the corresponding
azepinone analogues of biological interest. In vitro
evaluation of newly synthesized compounds revealed an
improved therapeutic effectiveness as compared with the
parent drugs. Some derivatives showed equipotent
antibacterial activities against the selected strains.
Experimental data reveal that the synthesized novel
derivatives of quinolino annulated azepinones have
remarkable antibacterial potential.
Chemistry. General procedure for the preparation of
6-substituted-3,3-dimethyl-3,4-dihydro-2H,10H-acridine-1,9-
dione (4) [7]. The acridone 4 was prepared according
to the protocol given in the literature in which
anthranilic acid 2 (0.1 mol, 13.7 g) on reaction with 1
(0.1 mol, 14.0 g) in the presence of absolute alcohol
(4.6 mL) gave enamine 3, which upon dehydration
with sulfuric acid (9.8 mL) underwent cyclization to
form acridone 4.
Spectral data of compound 4a. 3,3-Dimethyl-3,4-dihydro-
2H,10H-acridine-1,9-dione.
Yield: 98% (yellow solid
powder), mp 343–345°C, IR νmax (KBr, in cmꢀ1): 3359,
3132, 1673, 1646, 1610, 1348; 1H NMR (400 MHz;
DMSO-d6, δ): 1.10 (6H, s, 2CH3), 1.91 (1H, s, NH),
2.51–2.59 (2H, m, CH2), 3.45–3.65 (2H, m, CH2),
7.19–8.08 (4H, m, Ar–CH); 13C NMR (75 MHz, CDCl3):
21.89, 25.67, 43.94, 53.29, 120.31, 128.30, 129.33,
132.08, 137.26, 138.91, 152.22, 155.46, 160.76, 195.85;
EXPERIMENTAL
General. All the chemicals and solvents used in this
study were laboratory grade and procured from E. Merck
(Germany), Sigma-Aldrich, Alfa Aeaser, Molychem, and
Loba. All the solvents were distilled and dried before use.
The compounds were synthesized using feasible proce-
dures reported in the literature. Before analysis, the synthe-
sized compounds were purified through column
chromatography. The TLC plates (Silica Gel G) were used
to confirm the purity of commercial grade reagents and the
synthesized compounds. The IR spectra of synthesized
compounds were obtained on a PerkinElmer IR spectro-
MS (EI): m/e
= 241.26 [M+]; Anal. Calcd for
C15H15NO2: C, 74.67; H, 6.27; N, 5.81; O, 13.26. Found:
C, 74.69; H, 6.23; N, 5.79; O, 13.23.
General
7-substituted-3,3-dimethyl-3,4-dihydro-2H,10H-acridine-
1,9-dione (8) [8,9]. Dimedone 1 (15 mmol, 210 mg)
procedure
for
the
preparation
of
and sodium hydride (15 mmol, 360 mg) upon distillation
were stirred in 40-mL DMF for 10 min followed by
heating at 50°C for 6 min. The second step involved
stirring along with heating at 90–100°C for 4 h after the
addition of isatoic anhydride 7 (14 mmol, 228 mg) in the
reaction mixture. DMF was then distilled off, and water
(50 mL) and acetic acid (pH 5) were then added in the
obtained residue. The product was then precipitated out
and filtered through suction. The washing of precipitate
was performed with ethanol, and recrystallization was
performed with DMF.
1
photometer (KBr pellet). H NMR and 13C NMR spectra
were recorded using Bruker AVANCE II 400 NMR spec-
trometer, and chemical shifts are expressed as δ (ppm)
using tetramethylsilane as an internal standard and CDCl3
or DMSO as a solvent, from SAIF/CIL, Punjab University,
Chandigarh. Signal multiplicities are represented by s (sin-
glet), d (doublet), t (triplet), m (multiplet), and q (quartet).
Mass spectra of compounds were recorded on Waters, Q-
TOF Micromass (LC–MS) mass spectrometer from
SAIF/CIL, Punjab University, Chandigarh. The microanal-
Spectral data of compound 8b. 7-Chloro-3,3-dimethyl-
1
ysis and spectral (IR, H NMR, and MS) data of all the
3,4-dihydro-2H,10H-acridine-1,9-dione.
Yield:
95%
compounds were found to be consistent to the structures
(yellow solid powder), mp 302–306°C, IR νmax (KBr, in
Journal of Heterocyclic Chemistry
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Month 2018
Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino
Annulated Analogues of Azepinones
cmꢀ1): 3370, 3132, 1684, 1646, 1620, 1317, 800; 1H NMR
(400 MHz; DMSO-d6, δ): 1.12 (6H, s, 2CH3), 1.91 (1H, s,
NH), 2.61–2.68 (2H, m, CH2), 3.42–3.63 (2H, m, CH2),
7.05–8.17 (3H, m, Ar–CH); 13C NMR (75 MHz, CDCl3):
21.47, 23.96, 49.63, 59.08, 121.72, 129.01, 129.34,
130.17, 133.58, 146.29, 149.32, 149.67, 163.63, 195.11;
MS (EI): m/e = 277.45 (1) [M+2], 275.45 (3) [M+];
Anal. Calcd for C15H14ClNO2: C, 65.34; H, 5.12; Cl,
12.86; N, 5.08; O, 11.61. Found: C, 65.31; H, 5.09; Cl,
12.82; N, 5.09; O, 11.60.
m, CH2), 2.59–2.72 (2H, m, CH2), 4.39 (1H, s, OH),
7.16–8.01 (4H, m, Ar–CH); 13C NMR (75 MHz, CDCl3):
21.36, 39.38, 46.11, 58.09, 120.53, 128.34, 129.37,
132.83, 137.67, 141.01, 144.64, 145.37, 170.98, 190.87;
MS (EI): m/e
= 256.23 [M+]; Anal. Calcd for
C15H16N2O2: C, 70.29; H, 6.29; N, 10.93; O, 12.48.
Found: C, 70.27; H, 6.27; N, 10.96; O, 12.46.
7-Bromo-3,3-dimethyl-3,4-dihydro-2H,10H-acridine-1,9-
dione-1-oxime (9c). Yield: 84% (yellow solid powder),
mp 292–294°C, IR νmax (KBr, cmꢀ1): 3370, 3260, 3020,
1
1682, 1673, 1593, 1372, 938, 685; H NMR (400 MHz;
General
6-substituted-3,3-dimethyl-3,4-dihydro-2H,10H-acridine-
1,9-dione-1-oxime (5) and
7-substituted-3,3-dimethyl-3,4-dihydro-2H,10H-acridine-
1,9-dione-1-oxime (9). The reaction involved the
stirring of mixture of dione 4 (2 mmol, 482 mg) and
hydroxylamine hydrochloride (2.5 mmol, 174 mg) in
water (4 mL) in the presence of Hyamine (60 mol%).
TLC was performed to check the completion of reaction.
As the precipitate came in the reaction mixture, it was
filtered out and dried to obtain the pure oxime 5. Same
procedure was applied in the preparation of 9 from 8.
procedure
for
the
preparation
of
DMSO-d6, δ): 1.13 (6H, s, 2CH3), 1.95 (1H, s, NH),
2.09–2.31 (2H, m, CH2), 2.61–2.80 (2H, m, CH2), 4.46
(1H, s, OH), 7.03–8.51 (3H, m, Ar–CH); 13C NMR
(75 MHz, CDCl3): 23.49, 33.92, 43.17, 59.66, 122.54,
131.35, 132.05, 136.52, 137.61, 143.28, 149.77, 152.22,
160.94, 198.71; MS (EI): m/e = 336.9 (1) [M+2], 334.9
(1) [M+]; Anal. Calcd for C15H15BrN2O2: C, 53.75; H,
4.51; Br, 23.84; N, 8.36; O, 9.55. Found: C, 53.72; H,
4.52; Br, 23.85; N, 8.34; O, 9.54.
7-Methoxy-3,3-dimethyl-3,4-dihydro-2H,10H-acridine-1,9-
dione-1-oxime (9e). Yield: 93% (yellow solid powder),
mp 352°C, IR νmax (KBr, cmꢀ1): 3375, 3267, 2843,
2815, 1678, 1675, 1583, 1386, 1210, 1036, 948; 1H
NMR (400 MHz; DMSO-d6, δ): 1.08 (6H, s, 2CH3),
1.87 (1H, s, NH), 2.03–2.21 (2H, m, CH2), 2.57–2.79
(2H, m, CH2), 3.73 (3H, s, OCH3), 4.39 (1H, s, OH),
7.01–7.99 (3H, m, Ar–CH); 13C NMR (75 MHz,
CDCl3): 24.28, 36.85, 49.23, 52.47, 79.66, 121.39,
130.13, 130.46, 132.17, 136.23, 141.56, 143.87,
153.20, 167.29, 193.47; MS (EI): m/e = 286.53 [M+];
Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34; N,
9.78; O, 16.76. Found: C, 67.11; H, 6.31; N, 9.75;
O, 16.75.
Spectral data of some representative drugs. 6-Chloro-3,3-
dimethyl-3,4-dihydro-2H,10H-acridine-1,9-dione-1-oxime
(5b). Yield: 85% (yellow solid powder), mp 319°C, IR
νmax (KBr, cmꢀ1): 3386, 3200, 3010, 1680, 1673,
1
1592, 1380, 942, 750; H NMR (400 MHz; DMSO-d6,
δ): 1.12 (6H, s, 2CH3), 1.94 (1H, s, NH), 2.12–2.32
(2H, m, CH2), 2.63–2.72 (2H, m, CH2), 4.43 (1H, s,
OH), 7.23–8.12 (3H, m, Ar–CH); 13C NMR (75 MHz,
CDCl3): 23.02, 31.38, 42.91, 52.36, 120.71, 124.84,
127.14, 130.03, 138.44, 140.59, 148.13, 149.35,
165.49, 198.04; MS (EI): m/e = 292.45 (1) [M+2],
290.45 (3) [M+]; Anal. Calcd for C15H15ClN2O2: C,
61.97; H, 5.20; Cl, 12.19; N, 9.64; O, 11.01. Found:
Synthesis of organocatalyst.
The first step for the
synthesis of organocatalyst was the addition of DMF
(2 mL) on TCT (1.84 g, 0.01 mol). The temperature of
the reaction mixture was maintained at 25°C. As the
white solid was obtained, TLC was taken to ensure that
TCT and DMF have completely reacted to synthesize the
organocatalyst.
C, 61.99; H, 5.22; Cl, 12.16; N, 9.63; O, 11.04.
3,3-Dimethyl-6-nitro-3,4-dihydro-2H,10H-acridine-1,9-
dione-1-oxime (5d). Yield: 79% (yellow solid powder),
mp 324–326°C, IR νmax (KBr, cmꢀ1): 3380, 3210, 3023,
1685, 1652, 1581, 1522, 1378, 1340, 932; 1H NMR
(400 MHz; DMSO-d6, δ): 1.14 (6H, s, 2CH3), 1.97 (1H,
s, NH), 2.19–2.40 (2H, m, CH2), 2.68–2.80 (2H, m,
CH2), 4.46 (1H, s, OH), 7.76–8.69 (3H, m, Ar–CH); 13C
NMR (75 MHz, CDCl3): 24.98, 36.13, 46.45, 56.24,
120.11, 129.65, 129.93, 135.63, 139.04, 148.43, 152.34,
152.71, 163.86, 192.65; MS (EI): m/e = 301.44 [M+];
Anal. Calcd for C15H15N3O4: C, 59.79; H, 5.02; N,
13.95; O, 21.24. Found: C, 59.81; H, 5.05; N, 13.92; O,
General procedure for the synthesis of 8-substituted-4,4-
dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-b]quinoline-
2,11-dione (6) and 9-substituted-4,4-dimethyl-1,4,5,6-
tetrahydro-3H-azepino[3,2-b]quinoline-2,11-dione
(10).
The synthesized organocatalyst was subsequently
added to the mixture of oxime 5 (1 mmol, 256 mg) in
DMF (1.5 mL). The reaction mixture was then stirred till
precipitate was obtained. TLC was performed to confirm
the synthesis of azepinone. The reaction work up was
performed through ice in which residue obtained was
filtered. The precipitate obtained was dried and
recrystallized in ethanol to give 6. Same procedure was
applied in the preparation of 10 from 9.
21.26.
3,3-Dimethyl-3,4-dihydro-2H,10H-acridine-1,9-dione-1-
oxime (9a).
Yield: 99% (yellow solid powder), mp
330°C, IR νmax (KBr, cmꢀ1): 3379, 3273, 3010, 1676,
1
1671, 1583, 1375, 919; H NMR (400 MHz; DMSO-d6,
δ): 1.10 (6H, s, 2CH3), 1.92 (1H, s, NH), 2.06–2.26 (2H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Arora, J. Dwivedi, S. Arora, S. Kumar, and D. Kishore
Vol 000
Spectral data of some representative drugs. 4,4-Dimethyl-
1,4,5,6-tetrahydro-3H-azepino[3,3-b]quinoline-2,11-dione (6a
or 10a). Yield: 90% (yellow solid powder), mp 361–
8-Methoxy-4,4-dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-
b]quinoline-2,11-dione (6e).
Yield: 81% (yellow solid
powder), mp 393–395°C, IR νmax (KBr, cmꢀ1): 3560,
3360, 3052, 2848, 1670, 1642, 1611, 1557, 1372, 1332,
1219, 1016; 1H NMR (400 MHz; DMSO-d6, δ): 1.09
(6H, s, 2CH3), 1.92 (1H, s, NH), 2.51–2.60 (2H, m,
CH2), 3.20–3.43 (2H, m, CH2), 3.73 (3H, s, OCH3),
7.09–7.99 (3H, m, Ar–CH), 11.10 (1H, s, NH); 13C
NMR (75 MHz, CDCl3): 29.63, 37.68, 43.62, 54.15,
65.94, 121.65, 125.90, 129.36, 129.96, 136.72, 139.11,
142.42, 146.65, 166.28, 194.43; MS (EI): m/e = 286.49
[M+]; Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34;
N, 9.78; O, 16.76. Found: C, 67.10; H, 6.38; N, 9.72; O,
16.71.
363°C, IR νmax (KBr, cmꢀ1): 3565, 3447, 3029, 1700,
1648, 1617, 1578, 1395, 1338; 1H NMR (400 MHz;
DMSO-d6, δ): 1.08 (6H, s, 2CH3), 1.91 (1H, s, NH),
2.50–2.58 (2H, m, CH2), 3.18–3.38 (2H, m, CH2),
7.19–8.08 (4H, m, Ar–CH), 11.12 (1H, s, NH); 13C
NMR (75 MHz, CDCl3): 27.80, 31.84, 47.25, 53.27,
123.18, 128.10, 128.14, 132.07, 136.65, 146.70, 148.79,
149.88, 161.85, 197.17; MS (EI): m/e = 272.22 [M+];
Anal. Calcd for C15H16N2O2: C, 70.29; H, 6.29; N,
10.93; O, 12.48. Found: C, 70.26; H, 6.25; N, 10.95;
O, 12.46.
8-Chloro-4,4-dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-b]
9-Chloro-4,4-dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-b]
quinoline-2,11-dione (6b).
Yield: 79% (yellow solid
quinoline-2,11-dione (10b).
Yield: 76% (yellow solid
powder), mp 381°C, IR νmax (KBr, cmꢀ1): 3560, 3377,
3062, 1684, 1646, 1617, 1573, 1383, 1337, 753; 1H
NMR (400 MHz; DMSO-d6, δ): 1.09 (6H, s, 2CH3),
1.94 (1H, s, NH), 2.60–2.69 (2H, m, CH2), 3.17–3.32
(2H, m, CH2), 7.26–8.01 (3H, m, Ar–CH), 11.10 (1H,
s, NH); 13C NMR (75 MHz, CDCl3): 26.71, 33.67,
44.09, 53.19, 120.71, 124.44, 127.74, 130.01, 138.49,
145.98, 149.57, 149.97, 167.43, 196.77; MS (EI):
m/e = 292.45 (1) [M+2], 290.45 [M+]; Anal. Calcd for
C15H15ClN2O2: C, 61.97; H, 5.20; Cl, 12.19; N, 9.64;
O, 11.01. Found: C, 61.93; H, 5.18; Cl, 12.22; N, 9.62;
O, 11.04.
powder), mp 381°C, IR νmax (KBr, cmꢀ1): 3560, 3377,
3062, 1684, 1646, 1617, 1573, 1383, 1337, 753; 1H
NMR (400 MHz; DMSO-d6, δ): 1.09 (6H, s, 2CH3), 1.94
(1H, s, NH), 2.60–2.69 (2H, m, CH2), 3.17–3.32 (2H, m,
CH2), 7.05–8.17 (3H, m, Ar–CH), 11.10 (1H, s, NH);
13C NMR (75 MHz, CDCl3): 26.71, 33.67, 44.09, 53.19,
121.11, 122.47, 131.39, 132.66, 140.62, 145.36, 145.98,
149.57, 167.43, 196.77; MS (EI): m/e = 292.45 (1) [M
+2], 290.45 [M+]; Anal. Calcd for C15H15ClN2O2: C,
61.97; H, 5.20; Cl, 12.19; N, 9.64; O, 11.01. Found: C,
61.93; H, 5.18; Cl, 12.22; N, 9.62; O, 11.04.
9-Bromo-4,4-dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-b]
quinoline-2,11-dione (10c).
Yield: 71% (yellow solid
8-Bromo-4,4-dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-b]
quinoline-2,11-dione (6c).
Yield: 75% (yellow solid
powder), mp 365°C, IR νmax (KBr, cmꢀ1): 3573, 3378,
3062, 1674, 1639, 1627, 1576, 1380, 1333, 685; 1H
NMR (400 MHz; DMSO-d6, δ): 1.10 (6H, s, 2CH3),
1.96 (1H, s, NH), 2.62–2.73 (2H, m, CH2), 3.20–3.43
(2H, m, CH2), 7.03–8.51 (3H, m, Ar–CH), 11.14 (1H,
s, NH); 13C NMR (75 MHz, CDCl3): 24.39, 32.43,
42.82, 63.74, 116.23, 121.92, 129.23, 133.78, 137.29,
138.79, 141.41, 145.64 162.64, 198.27; MS (EI):
m/e = 336.89 (1) [M+2], 334.89 (1) [M+]; Anal. Calcd
for C15H15BrN2O2: C, 53.75; H, 4.51; Br, 23.84; N,
8.36; O, 9.55. Found: C, 53.72; H, 4.48; Br, 23.87; N,
8.34; O, 9.52.
powder), mp 365°C, IR νmax (KBr, cmꢀ1): 3573, 3378,
3062, 1674, 1639, 1627, 1576, 1380, 1333, 685; 1H
NMR (400 MHz; DMSO-d6, δ): 1.10 (6H, s, 2CH3), 1.96
(1H, s, NH), 2.62–2.73 (2H, m, CH2), 3.20–3.43 (2H, m,
CH2), 7.29–8.06 (3H, m, Ar–CH), 11.14 (1H, s, NH);
13C NMR (75 MHz, CDCl3): 24.39, 32.43, 42.82, 63.74,
123.87, 127.17, 127.46, 128.03, 130.82, 138.79, 140.32,
141.41, 162.64, 198.27; MS (EI): m/e = 336.89 (1) [M
+2], 334.89 (1) [M+]; Anal. Calcd for C15H15BrN2O2: C,
53.75; H, 4.51; Br, 23.84; N, 8.36; O, 9.55. Found: C,
53.72; H, 4.48; Br, 23.87; N, 8.34; O, 9.52.
4,4-Dimethyl-8-nitro-1,4,5,6-tetrahydro-3H-azepino[3,2-b]
4,4-Dimethyl-9-nitro-1,4,5,6-tetrahydro-3H-azepino[3,2-b]
quinoline-2,11-dione (6d).
Yield: 63% (yellow solid
quinoline-2,11-dione (10d).
Yield: 59% (yellow solid
powder), mp 388–390°C, IR νmax (KBr, cmꢀ1): 3573,
powder), mp 388–390°C, IR νmax (KBr, cmꢀ1): 3573,
3369, 3060, 1676, 1634, 1614, 1562, 1530, 1386, 1336,
1349; H NMR (400 MHz; DMSO-d6, δ): 1.08 (6H, s,
3369, 3060, 1676, 1634, 1614, 1562, 1530, 1386, 1336,
1349; H NMR (400 MHz; DMSO-d6, δ): 1.08 (6H, s,
1
1
2CH3), 2.01 (1H, s, NH), 2.69–2.80 (2H, m, CH2),
3.26–3.41 (2H, m, CH2), 7.73–8.62 (3H, m, Ar–CH),
11.18 (1H, s, NH); 13C NMR (75 MHz, CDCl3): 23.92,
34.92, 47.68, 54.38, 125.42, 129.15, 129.55, 132.79,
135.23, 142.76, 146.83, 149.04, 161.69, 195.72; MS
(EI): m/e = 301.92 [M+]; Anal. Calcd for C15H15N3O4:
C, 59.79; H, 5.02; N, 13.95; O, 21.24. Found: C, 59.76;
H, 5.05; N, 13.98; O, 21.23.
2CH3), 2.01 (1H, s, NH), 2.69–2.80 (2H, m, CH2),
3.26–3.41 (2H, m, CH2), 7.91–9.49 (3H, m, Ar–CH),
11.18 (1H, s, NH); 13C NMR (75 MHz, CDCl3): 23.92,
34.92, 47.68, 54.38, 115.31, 122.56, 123.36, 132.26,
146.83, 149.04, 151.23, 159.29, 161.69, 195.72; MS
(EI): m/e = 301.92 [M+]; Anal. Calcd for C15H15N3O4:
C, 59.79; H, 5.02; N, 13.95; O, 21.24. Found: C, 59.76;
H, 5.05; N, 13.98; O, 21.23.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Organocatalyzed Synthesis and Antibacterial Activity of Novel Quinolino
Annulated Analogues of Azepinones
9-Methoxy-4,4-dimethyl-1,4,5,6-tetrahydro-3H-azepino[3,2-
b]quinoline-2,11-dione (10e).
measured to determine the antibacterial activity. Each
test was performed in triplicates [21].
Calculation of minimum inhibitory concentration and
Yield: 80% (yellow solid
powder), mp 393–395°C, IR νmax (KBr, cmꢀ1): 3560,
3360, 3052, 2848, 1670, 1642, 1611, 1557, 1372, 1332,
1219, 1016; 1H NMR (400 MHz; DMSO-d6, δ): 1.09
(6H, s, 2CH3), 1.92 (1H, s, NH), 2.51–2.60 (2H, m,
CH2), 3.20–3.43 (2H, m, CH2), 3.73 (3H, s, OCH3),
7.01–7.99 (3H, m, Ar–CH), 11.10 (1H, s, NH); 13C
NMR (75 MHz, CDCl3): 29.63, 37.68, 43.62, 54.15,
65.94, 101.66, 106.95, 133.43, 136.27, 139.11, 142.19,
146.65, 150.48 166.28, 194.43; MS (EI): m/e = 286.49
[M+]; Anal. Calcd for C16H18N2O3: C, 67.12; H, 6.34;
N, 9.78; O, 16.76. Found: C, 67.10; H, 6.38; N, 9.72; O,
16.71.
IC50.
After measuring zone of inhibition, the values
of MIC and IC50 were calculated for which serial
dilution method was adopted. It depicted the minimum
concentration, where no microbial growth was
observed. A stock solution of 3 mg/mL of each
compound was prepared in DMSO and further diluted
to obtain a final concentration ranging from 200 to
0.05 μg/mL. Microorganisms were then added to each
dilution in a 1:1 ratio. The prepared test tubes were
then incubated for 24
h
at 27°C. The lowest
concentration where no growth of microorganisms was
observed was noted as MIC. Dose–response curves
were computed to obtain the concentrations where 50%
inhibition of bacteria growth (IC50) was observed. For
some compounds, streptomycin was used as a standard,
and for some other compounds, tetracycline was used
as standard.
Biological evaluation. Antibacterial assay.
Disc
diffusion method [18,19] was adopted to assess the
antibacterial potential of the synthesized compounds
under in vitro conditions against randomly chosen
bacterial strains, namely, S. aureus, B. subtilis (Gram
positive), and E. cloacae, E. coli (Gram negative),
taking streptomycin and tetracycline as standard. The
MIC and IC50 values of all the synthesized compounds
and of the standard drugs were determined.
Disc diffusion assay. The biological assay started with
the synthesis of nutrient agar media. The latter was
autoclaved and put (approx. 40 mL) in different Petri
plates and left undisturbed for some time to let it
settle down and get solidified. With the help of
micropipette approx. 100 μL bacteria was put in the
center of each Petri plate, which was spread on the
entire Petri plate with the help of an L-shaped glass
rod. The Petri plates were then bored to produce four
Acknowledgment. The authors are thankful to Prof. Aditya
Shastri, Vice Chancellor, Banasthali University, for providing
support and facilities to our work.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Arora, J. Dwivedi, S. Arora, S. Kumar, and D. Kishore
Vol 000
[19] Sharshira, E. M.; Hamada, N. M. M. Molecules 2012, 17,
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SUPPORTING INFORMATION
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Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet