Solvent-free synthesis and antibacterial studies of some quinolinones

Article abstract of DOI:10.1007/s00706-011-0608-1

Solvent-free, microwave-induced condensation of 2-aminoaryl alkyl ketones and ethyl 3-oxobutanoate in the presence of amberlite Na sr1L gave quinolinones in high yield when compared to other catalysts. Further, N-alkylation of the quinolinones was carried

Full text of DOI:10.1007/s00706-011-0608-1

Monatsh Chem (2012) 143:485–489
DOI 10.1007/s00706-011-0608-1
ORIGINAL PAPER
Solvent-free synthesis and antibacterial studies of some
quinolinones
•
Radhakrishnan Subashini Fazlur-Rahman Nawaz Khan
Received: 13 April 2010 / Accepted: 5 August 2011 / Published online: 3 September 2011
Ó Springer-Verlag 2011
Abstract Solvent-free, microwave-induced condensation
of 2-aminoaryl alkyl ketones and ethyl 3-oxobutanoate in
the presence of amberlite Na sr1L gave quinolinones in
high yield when compared to other catalysts. Further,
N-alkylation of the quinolinones was carried out effec-
tively with various halides using amberlite Na sr1L. An
N-alkylated quinolinone exhibited enhanced activities
against B. subtilis, E. coli, and P. aeruginosa, similar to
standard drug ampicillin. Two compounds showed effec-
tive activity against S. aureus, and one resulted in moderate
activity against E. coli.
highly functionalized quinolinone derivatives represents a
challenge in medicinal chemistry [4–6].
Various methodologies have been adopted for the syn-
thesis of quinolinones including Diels-Alder cyclization
[7], palladium catalysis [8], and nanoparticle mediation [9].
In this communication, an attempt at a green chemical
approach for the synthesis of quinolinones using catalysts
such as bentonite, amberlite, basic alumina, montmorilo-
nite-KSF, and montmorilonite-K10 is presented.
Interestingly, relatively better yield and in situ enhance-
ment in catalytic activity of cation exchange resin catalyst
were observed. For the first time, we are reporting am-
berlite Na sr1L as an efficient catalyst for a two-step
organic synthesis. In view of its inherent properties of ion
exchange resin reusability, greater selectivity, operational
simplicity, noncorrosiveness, commercial availability,
nontoxicity, economical and environmental friendliness,
and ease of isolation [10, 11], the current methodology
offers several advantages. The preliminary reaction of
solvent-free microwave irradiation in the synthesis of
quinolin-2(1H)-one is tabulated. The N-alkylation of the
synthesized quinolinones was explored (Scheme 1).
Keywords Antibacterial studies Á Quinolinones Á
Amberlite Na sr1L Á Microwave irradiation
Introduction
Quinolinones are important constituents of pharmacologi-
cally active agents [1] and are frequently recognized in the
structure of numerous naturally occurring alkaloids [2].
Functionalized quinolinones are attractive compounds for
drug discovery since many of them have been shown to
exhibit excellent biological activities [3, 4]. Quinolinones
have been explored as inhibitors of topoisomerase, gyrase,
and IMPDH and tested for anticancer activity in vitro and
for immunosuppressive properties [5]. Therefore, the
development of facile methodologies for the synthesis of
Results and discussion
A mixture of 2-amino-5-chlorobenzophenone (1a) and
ethyl 3-oxobutanoate (2) (1:1.5 molar ratio) was placed in
a beaker (neat conditions) and initially irradiated under
microwave. However, the reaction failed to obtain
3-acetyl-6-chloro-4-phenylquinolin-2(1H)-one (3a). An
attempt has been made to reduce the time and increase
the yield [12, 13] by performing the reaction in the
presence of amberlite Na sr1L under microwave irradia-
tion (65 W, 115 °C) for 4 min, which afforded 92.4%
R. Subashini Á F.-R. N. Khan (&)
Organic and Medicinal Chemistry Research Laboratory,
Organic Chemistry Division, School of Advanced Sciences,
VIT University, Vellore 632 014, India
e-mail: nawaz_f@yahoo.co.in
123

486
R. Subashini, F.-R. N. Khan
the 1H NMR spectrum, a singlet at d = 12.4 ppm is
accounted for by the NH proton of 3a, and disappearance
of this proton in 5a confirms N-alkylation of quinolin-
2(1H)-one.
Alternatively, the same reaction, when carried out in one
pot by mixing 2-aminobenzophenone, ethyl 3-oxobutanoate,
amberlite Na sr1L, and alkylating agent 4 and irradiating for
longer time, did not proceed.
In the conventional method, the first step of the reaction
(Scheme 1) was carried out using piperidine as a catalyst
for 6–7 h at 160–180 °C, and the second step was tested
with the use of K2CO3 in DMF at 60–70 °C for 4–5 h. In
these two steps the yield and purity of desired product were
very low. Hence, the green catalyst (amberlite Na sr1L),
which is a cation exchange resin, was explored and found
to play a vital role in both steps.
All the compounds 3a–3c and 5a–5g were tested for their
minimum inhibition concentrations (MIC) by dissolving in
100% DMSO to obtain a concentration range of 15.6, 31.2,
62.5, 125, 250, 500, 1,000, 5,000, and 10,000 lg/cm3 against
three Gram-negative and two Gram-positive bacteria.
Compound 5d exhibited good activity against B. subtilis, E.
coli, and P. aeruginosa, similar to the standard drug ampi-
cillin. Compounds 3a and 5a showed high activity against S.
aureus, and 5b showed moderate activity against E. coli. All
other compounds were almost inactive.
Fig. 1 Plausible mechanism of N-alkylation of quinolinone
yield. The optimization of the molar ratio of the reactants
1 and 2 has been made under the same conditions for
different reaction time periods (Table 1), which suggested
that prolonged reaction time resulted in a decrease in
yield and purity due to decomposition of the product.
During optimization studies (Table 2) involving selection
of the catalyst, time, and temperature, amberlite Na sr1L was
found to be more effective when compared to bentonite,
amberlite, basic alumina, montmorilonite-KSF, and mont-
morilonite-K10 in the synthesis of quinolin-2(1H)-ones
3a–3c (Table 3). The formation of the product was confirmed
by spectral analysis. Further amberlite Na sr1L was utilized
for the N-alkylation of 3a to 3-acetyl-6-chloro-1-methyl-4-
phenylquinolin-2(1H)-one (5a) (Scheme 1; Fig. 1). The IR
spectrum of 3a showed absorption bands referable to car-
bonyl groups and a broad NH absorption at 3,146 cm-1. In
Conclusion
A simple, useful, efficient, inexpensive, and green chemi-
cal approach for the preparation of quinolin-2(1H)-ones
3a–3c and N-alkylquinolin-2(1H)-ones 5a–5g using am-
berlite Na sr1L as a catalyst has been established. The
simple product isolation procedures as well as the easy
recovery and reuse of the natural resin are expected to play
an important role in development of the new method. The
Scheme 1
R
R'
O
O
R'
O
O
2
4
R
R
Amberlite Na sr1L
Amberlite Na sr1L
R'
MW, 4-5 min
MW, 4-5 min
N
H
N
NH2
O
R''
1a-1c
3a-3c
5a-5g
R
R'
R"
2
4
: Ethyl 3-oxobutanoate; : R''X
a
b
c
d
e
f
-Cl -Ph
-CH3
-CH3
-H
-H
-Ph
-CH3 -CH3
-Cl -Ph
-H -Ph
-Cl -Ph
-Ph
-C2H5
-C2H5
-CH2Ph
-CH2Ph
g
-H
123

Solvent-free synthesis, antibacterial studies of quinolinones
487
Table 1 Optimization of molar ratio of the reactants 1 and 2
Table 3 Comparison of the efficiency of amberlite Na sr1L
Sample number Molar ratio of
reactants
Time/min Product Yielda/%
Sample Catalyst
number
Amount/mg Time/min Yield/%
3a 5a
1a
2
1
2
3
4
5
6
Montmorillonite K-10 10
Amberlite 10
Montmorillonite KSF 10
15
20
15
10
20
4
0
0
0
1
2
1
1
1
1
1
1
1
1
1
1
1
30
8
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
61.3
62
32
1.1
1.2
1.3
1.4
1.5
1.5
1.5
1.6
1.7
55 49
82 84
48 51
92 91
3
8
67
Bentonite
10
10
10
4
8
75
Basic alumina
Amberlite sr1L Na
5
6
81
6
4
92.4
87.1
72
Effect of solid support for the synthesis of 3a and 5a under micro-
wave irradiation (temp = 115 °C, power = 65 W)
7
6
8
8
1
for H reference). Reactions were conducted in a micro-
9
4
93
10
4
93.5
wave oven model Biotage Initiator-Esp-EU-355301, 11,
355–43 W. Chemicals were purchased from Sd-fine (am-
berlite Na sr1L resin, brand name Rohm & Hass, type
strong acidic cation exchange resin in Na? form, size
0.7 mm) and Aldrich (aminobenzophenone, ethyl aceto-
acetate, and solvents) chemical companies.
Temp = 115 °C, power = 65 W
a
Isolated yield based on 1a, amberlite Na sr1L = 10 mg
Table 2 Optimization of catalyst concentration
Sample Reactant Amberlite Na Time/min Product Yield/
sr1L/mg
General procedure: synthesis of quinolin-2(1H)-ones
3a–3c
number
%
1
1a
1a
1a
1a
1a
1a
1a
3a
3a
3a
3a
3a
3a
3a
None
2
30
8
3a
3a
3a
3a
3a
3a
3a
5a
5a
5a
5a
5a
5a
5a
0
A mixture of 2-aminoaryl alkyl ketone 1 (1 mmol), ethyl
3-oxobutanoate (1.5 mmol), and 10 mg amberlite Na sr1L
was placed in a beaker and properly mixed with a glass rod
and then irradiated in a microwave oven at 115 °C and
65 W power for the specified time (Table 4). On comple-
tion, the reaction mixture was diluted with ethyl acetate,
and the catalyst was filtered off. The ethyl acetate layer was
washed with water followed by brine and dried over
anhydrous Na2SO4. The solvent was removed under vac-
uum to afford pure quinolin-2(1H)-one derivative.
2
70
73
79
82
91
92
75
78
82
84
91
90
92
3
4
8
4
6
8
5
8
8
6
10
12
2
4
7
4
8
10
10
10
9
9
4
10
11
12
13
14
6
8
10
12
14
4
4
Table 4 Synthesis of quinolinones
4
Reactant
Product
Conventional
Microwave
Time/min
1a (1 mmol) ? 2 (1.5 mmol), temp = 115 °C, power = 65 W
3a (1 mmol) ? 4 (1.5 mmol)
Time/h
Yield/%
Yield/%
1a
1b
1c
3a
3b
3c
3a
3b
3a
3b
3a
3b
3c
5a
5b
5c
5d
5e
5f
8
7
8
5
4
4
5
5
6
6
75
70
68
72
70
69
66
73
63
68
4
5
5
4
3
5
5
4
5
5
92.4
90.2
87.3
80
compounds 5d, 5a, 5b, and 3a showed good to moderate
activity.
89
88
Experimental
87
86
Melting points were determined using an Elchem Micro-
processor based DT apparatus. FT-IR spectra, as KBr
pellets, were recorded on a Nucon Infrared spectropho-
tometer. NMR spectra were recorded on a Bruker
400 MHz spectrometer in CDCl3 or DMSO-d6 (with TMS
84
5g
83
3a–3c: 1 (1 mmol) ? 2 (1.5 mmol)
5a–5g: 3 (1 mmol) ? 4 (1.5 mmol)
123

488
R. Subashini, F.-R. N. Khan
3-Acetyl-6-chloro-4-phenylquinolin-2(1H)-one (3a)
Yield 92%; m.p.: 272 °C (273–274 °C [12, 13]).
1H, J = 8 Hz, Ar–H), 7.57 (d, 1H, J = 8 Hz, Ar–H), 7.67
(t, 1H, J = 8 Hz, Ar–H), 7.90 (d, 1H, J = 8 Hz, Ar–H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 13.6, 23.7,
29.6, 119.8, 121.3, 124.2, 126.5, 128.3, 129.4, 133.4,
151.7, 161.3, 200.4 ppm; LC-MS: m/z = 216 (M ? 1).
3-Acetyl-4-phenylquinolin-2(1H)-one (3b)
Yield 90%; m.p.: 244 °C (247 °C [13]).
3-Acetyl-4-methylquinolin-2(1H)-one (3c)
Yield 87%; m.p.: 272 °C (278–280 °C [17]).
3-Acetyl-6-chloro-1-ethyl-4-phenylquinolin-2(1H)-one
(5d, C19H16ClNO2)
ꢀ
Yield 87%; m.p.: 132 °C; IR (KBr):m = 2,939, 1,705,
General procedure: synthesis of N-substituted
2-quinolinones 5a–5g
1
1,635 cm-1; H NMR (500 MHz, CDCl3): d = 1.40–1.44
(t, 3H, J = 10 Hz, N–CH2CH3), 2.23 (s, 3H, CH3), 4.38 (q,
2H, N–CH2CH3), 7.24 (d, 1H, J = 10 Hz, Ar–H), 7.29 (m,
2H, Ar–H), 7.41 (s, 1H, Ar–H), 7.49 (m, 3H, Ar–H), 7.55
(d, 1H, J = 10 Hz, Ar–H) ppm; 13C NMR (125 MHz,
CDCl3): d = 12.6, 31.3, 37.7, 115.6, 122.09, 127.8 (2C),
128.7 (C5), 129.0 (2C), 129.1 (2C), 131.2 (2C), 133.4,
137.1, 145.1, 158.5 (C=O), 201.3 (COCH3) ppm; EI-MS:
m/z = 326 (M ? 1); crystal structure see Ref. [18].
Quinolin-2(1H)-one
3
(1 mmol), alkyl halide
4
(1.5 mmol), and 10 mg amberlite Na sr1L were mixed
thoroughly and irradiated in a microwave oven at 115 °C
and 65 W power for the specified time (Table 4). On
completion, ethyl acetate was added to the reaction mix-
ture, and the granules of the catalyst were filtered. Then the
combined organic layer was washed with water and dried
over anhydrous Na2SO4. The solvent was recovered in
vacuum; the solid obtained was purified by column chro-
matography using petroleum ether:ethyl acetate (8.5:1.5) as
eluent to give the N-alkylated compounds 5a–5g in high
yield.
3-Acetyl-1-ethyl-4-phenylquinolin-2(1H)-one
(5e, C19H17NO2)
ꢀ
Yield 86%; m.p.: 122 °C; IR (KBr):m = 2,925, 1,707,
1
1,629 cm-1; H NMR (400 MHz, CDCl3): d = 1.43–1.45
(t, 3H, J = 8 Hz, N–CH2CH3), 2.22 (s, 3H, CH3), 4.41–
4.46 (q, 2H, CH2CH3), 7.14 (t, 1H, J = 8 Hz, Ar–H), 7.26
(m, 3H, Ar–H), 7.46 (m, 5H, Ar–H) ppm; 13C NMR
(100 MHz, CDCl3): d = 13.3, 31.7, 39.2, 118.5, 121.7
(2C), 123.7 (2C), 127.7, 128.4 (2C), 129.6, 131.9 (2C),
132.9, 136.8, 145.6, 159.1 (C=O), 200.9 (COCH3) ppm;
LC-MS: m/z = 292 (M ? 1).
3-Acetyl-1-methyl-6-chloro-4-phenylquinolin-2(1H)-one
(5a, C18H14ClNO2)
ꢀ
Yield 80%; m.p.: 142 °C; IR (KBr):m = 1,708, 1,634,
1,108 cm-1 1H NMR (400 MHz, CDCl3): d = 2.23 (s,
;
3H, CH3), 3.78 (s, 3H, N–CH3), 6.70 (d, 1H, J = 8 Hz,
Ar–H), 7.28 (t, 1H, J = 8 Hz, Ar–H), 7.36 (s, 1H, Ar–H),
7.50 (m, 4H, Ar–H) ppm; 13C NMR (100 MHz, DMSO-
d6): d = 27.2, 31.5, 121.9, 123.6 (2C), 124.7, 125.8, 126.4,
128.6 (2C), 129.1, 129.7, 133.3 (2C), 139.6, 149.8, 160.5
(C=O), 201.2 (COCH3) ppm; MS: m/z = 311 (M?).
3-Acetyl-1-benzyl-6-chloro-4-phenylquinolin-2(1H)-one
(5f, C24H18ClNO2)
ꢀ
Yield 84%; m.p.:160 °C; IR (KBr):m = 2,942, 1,708,
1,578 cm-1 1H NMR (300 MHz, CDCl3): d = 2.29 (s,
;
3H, CH3), 5.62 (s, 2H, N–CH2), 7.25 (d, 1H, J = 6 Hz,
Ar–H), 7.27 (s, 1H, Ar–H), 7.31 (m, 5H, –CH2–C6H5), 7.51
(m, 5H, Ar–H), 7.61 (d, 1H, J = 6 Hz, Ar–H) ppm; 13C
NMR (75 MHz, CDCl3): d = 27.2, 46.7, 121.9 (2C), 126.7
(3C), 127.2, 128.1 (2C), 128.9 (2C), 129.2 (2C), 131.3
(2C), 131.8, 133.4, 136.0, 147.3, 160.4 (C=O), 201.1
(COCH3) ppm; LC-MS: m/z = 388 (M ? 1).
3-Acetyl-1-methyl-4-phenylquinolin-2(1H)-one
(5b, C18H15NO2)
ꢀ
Yield 89%; m.p.: 168 °C; IR (KBr):m = 2,923, 1,707,
1,639 cm-1 1H NMR (400 MHz, CDCl3): d = 2.29 (s,
;
3H, CH3), 3.74 (s, 3H, N–CH3), 7.26 (t, 1H, J = 8 Hz,
CH), 7.28–7.49 (m, 5H, CH), 7.50–7.53 (m, 2H, CH),
7.54–7.56 (d, 1H, J = 8 Hz, CH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 25.9, 30.9, 120.6 (2C), 122.3
(2C), 123.7, 124.2, 126.2 (3C), 128.3 (2C), 133.5, 139.6,
151.8, 161.2 (C=O), 200.9 (COCH3) ppm; HRMS:
m/z = 276.5643 (M?).
3-Acetyl-1-benzyl-4-phenylquinolin-2(1H)-one
(5g, C24H19NO2)
ꢀ
Yield 83%; m.p.: 194 °C; IR (KBr):m = 2,922, 1,708,
1,633 cm-1 1H NMR (400 MHz, CDCl3): d = 2.24 (s,
;
3H, CH3), 5.58 (s, 2H, N–CH2), 7.12 (m, 4H, Ar–H), 7.33
(m, 5H, Ar–H), 7.45 (m, 5H, Ar–H) ppm; 13C NMR
(100 MHz, CDCl3): d = 31.5, 46.1, 120.8, 122.4, 124.6,
126.6 (2C), 126.8, 127.4, 127.8 (2C), 127.9, 128.4 (2C),
128.6 (2C), 128.8 (2C), 128.9, 129.1, 129.5, 147.0, 159.6
(C=O), 201.6 (COCH3) ppm; EI-MS: m/z = 354 (M ? 1).
3-Acetyl-1,4-dimethylquinolin-2(1H)-one
(5c, C13H13NO2)
ꢀ
Yield 88%; m.p.: 106–108 °C; IR (KBr):m = 2,922, 1,701,
1,633 cm-1 1H NMR (400 MHz, CDCl3): d = 2.33 (s,
3H, CH3), 2.43 (s, 3H, CH3), 3.62 (s, 3H, N–CH3), 7.33 (t,
;
123

Solvent-free synthesis, antibacterial studies of quinolinones
489
Table 5 Determination of minimum inhibitory concentration
Test organisms
MICa/lg cm-3
3a
3b
3c
5a
5b
5d
5f
5g
S
S. aureus
15.62
31.25
125
125
125
15.62
31.25
31.25
[200
31.25
[200
62.5
62.5
125
125
15.62
31.25
15.62
31.25
15.62
B. subtilis
E. coli
62.5
31.25
31.25
125
15.62
15.62
31.25
15.62
31.25
31.25
31.25
125
31.25
31.25
125
[200
31.25
31.25
15.62
31.25
62.5
K. pneumoniae
P. aeruginosa
31.25
125
125
[200
a
Control, DMSO
S Ampicillin
Determination of minimum inhibitory concentration
(MIC)
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Acknowledgments The authors thank VIT University Management
for their generous support and other facilities.
123