Microwave-assisted synthesis of quinolone derivatives and related compounds

Article abstract of DOI:10.1002/jhet.430

(Chemical Equation Presented) The Gould-Jacob type of reaction for the synthesis of ethyl 5-ethyl-8-oxo-5,8-dihydro-[1,3]-dioxolo[ 4,5-g]quinoline-7- carboxylate 4 has been carried out conventionally by the condensation between N-ethyl-3,4-methylenedioxyaniline 1 and diethyl ethoxymethylenemalonate 2 gave the unsaturated ester 3 and thermal cyclization in refluxing diphenyl oxide gave quinolone ethyl ester 4 and the results obtained were compared with single step microwave irradiation under solvent free conditions for the synthesis of 4. The esters on basic hydrolysis formed free acid 5, which, upon treatment with thionyl chloride gave the acid chloride 6. Treatment of acid chloride with o-phenylenediamine, hydrazine hydrate, ammonia, urea, and thiourea gave the amides (7-11). CS₂ treatment in presence of KOH on 8 gave 12. We prepared 7-12 derivatives by conventional as well as microwave irradiation. These compounds have been characterized on the basis of IR, ¹H NMR, MS, and elemental analysis. All the compounds prepared herein were screened for their antibacterial activity. Compounds 4, 5 possess promising antibacterial activity and compound 8 showed significant antibacterial activity.

Full text of DOI:10.1002/jhet.430

1104
Microwave-Assisted Synthesis of Quinolone Derivatives
and Related Compounds
Vol 47
Suhas Pednekar and Anil Kumar Pandey*
Organic Chemistry Research Laboratory, Ramnarain Ruia College, Matunga, Mumbai-400019,
Maharashtra, India
*E-mail: pandeyanil20@yahoo.com
Received July 5, 2009
DOI 10.1002/jhet.430
Published online 16 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
The Gould-Jacob type of reaction for the synthesis of ethyl 5-ethyl-8-oxo-5,8-dihydro-[1,3]-diox-
olo[4,5-g]quinoline-7-carboxylate 4 has been carried out conventionally by the condensation between
N-ethyl-3,4-methylenedioxyaniline 1 and diethyl ethoxymethylenemalonate 2 gave the unsaturated ester
3 and thermal cyclization in refluxing diphenyl oxide gave quinolone ethyl ester 4 and the results
obtained were compared with single step microwave irradiation under solvent free conditions for the
synthesis of 4. The esters on basic hydrolysis formed free acid 5, which, upon treatment with thionyl
chloride gave the acid chloride 6. Treatment of acid chloride with o-phenylenediamine, hydrazine
hydrate, ammonia, urea, and thiourea gave the amides (7–11). CS2 treatment in presence of KOH on
8
gave 12. We prepared 7–12 derivatives by conventional as well as microwave irradiation. These
1
compounds have been characterized on the basis of IR, H NMR, MS, and elemental analysis. All the
compounds prepared herein were screened for their antibacterial activity. Compounds 4, 5 possess
promising antibacterial activity and compound 8 showed significant antibacterial activity.
J. Heterocyclic Chem., 47, 1104 (2010).
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September 2010 Microwave-Assisted Synthesis of Quinolone Derivatives and Related Compounds
1105
Scheme 1
INTRODUCTION
Nalidixic acid and its quinolone analogs for example
oxolinic acid, norfloxacin, pefloxacin, ciprofloxacin, and
ofloxacin have been used for treatment of various bacte-
rial infections (urology, ophthalmology) [1]. The
purpose of this investigation was to provide a novel
and more advantageous method that the synthesis of
5-ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g]quinoline-
7-carboxylic acid 5 and its chloride 6 and then different
derivatives of amides 7–12 by conventional as well as
microwaves irradiation and comparative study of both the
method have been carried out. The solvent free reactions
[2–6] under microwave condition are especially for provid-
ing an environmentally benign system. Thus microwave
assisted synthesis becomes a part of ‘‘Sustainable chemis-
try’’. Microwave accelerated organic synthesis is an
effective and an alternative route proposed during the last
decade due to drastic reduction in the reaction time, to min-
imize cumbersome work-up and better yield [7–10]. We
report herein the synthesis of quinolone derivatives and
related compounds using conventional as well as micro-
wave methodologies and comparative study of both the
method have been carried out. These compounds were
evaluated for antibacterial activity in vitro and in vivo in
comparison with nalidixic acid [11–14].
RESULTS AND DISCUSSION
The aim of this work was to synthesize 5-ethyl-8-
one 12 by conventional heating as well as under micro-
wave irradiation (Scheme 1). The comparison between
conventional and microwave methodologies has been
shown in Table 1. Compounds obtained from both meth-
ods were identical and were confirmed on the basis of
TLC, mp, elemental, and spectral analysis.
oxo-5, 8-dihydro-[1,3]dioxolo[4,5-g] quinoline -7- car-
boxylic acid (oxolinic acid) and its chloride 6 and
different derivatives of amides. In conventional method,
N-ethyl methylene dioxyaniline 1 was condensed with
EMME 2 at 130–140ꢀC for 1.5–2 h to obtain unsatu-
rated ester 3, which on thermal cyclization in boiling di-
phenyl oxide at 250ꢀC for 2–3 h provided quinolone
ethyl ester 4 in 70% overall yield on the basis of com-
pound 1. On the other hand, single step microwave
assisted reaction of 1 with EMME 2 without solvent
(Method B) provided identical compound 4 within 8–10
min in 88% overall yield (Scheme 1). Thus microwave
assisted synthesis quinolone ethyl ester 4 has remarkable
advantages over the conventional techniques because of
easier work up, better yield, rapid and solvent free
cleaner reaction. Compound 4 on hydrolysis gave com-
pound 5, which upon treatment with thionyl chloride
gave acid chloride 6. Treatment of this acid chloride 6
with o-phenylenediamine, hydrazine hydrate, ammonia
solution, urea, and thiourea gave the amides 7–11 and
Compound 8 when refluxed with ethanol and carbon
disulfide in presence of potassium hydroxide yielded the
corresponding 5-ethyl-7-(5-thioxo-4, 5-dihydro-[1,3,4]
oxadiazol-2-yl)-5-H-[1, 3] dioxolo [4, 5-g] quinolin-8-
In conclusion, we have developed a simple, fast, sol-
vent free, and high yielding method for the synthesis
quinolone derivatives and related compounds, in which
compounds 4 and 5 displayed very promising activity as
expected (in vitro as well as in vivo activity better than
the standard Nalidixic acid), whereas synthesized novel
compound 8 exhibited significant antibacterial activity.
Rest of the novel compounds displayed weak antibacterial
activity.
EXPERIMENTAL
Melting points were determined in open capillaries on a
¨
BUCHI melting point apparatus B-540 and are uncorrected.
Infrared (ir) spectra were recorded on a PerkinElmer paragon
1000 FTIR spectrophotometer (potassium bromide pellets).
The 1H NMR spectra were recorded on Varians 400 MHz
spectrophotometer in deuteriodimethyl sulfoxide using TMS as
internal standard and the chemical shifts are expressed in ppm.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1106
S. Pednekar and A. K. Pandey
Vol 47
Table 1
A comparison between conventional and microwave assisted synthesis of quinolone derivatives and related compounds.
Conventional (Method A)
Time (h)
Microwave (Method B)
Time [c] (min)
Compound no.
Yield (%)
Yield (%)
Melting point (ꢀC)
4
5
6
7
8
9
10
11
12
3
70
82
86
60
78
77
70
70
71
4
4
–
4
4
2
4
4
5
88
93
–
169–73
313–14
245–47
335–37
300–02
288–90
285–87
265–68
260–63
2
12
10
03
01
03
03
24
87
92
92
88
86
86
Mass spectral (MS) data were obtained using an Agilent
1100LC/MSD VL system (G1946C) with a 0.4 mL/min flow
rate using a binary solvent system of 95:5 metanol/water.
Microwave irradiation was carried out in modified microwave
oven fitted with a condenser BPL microwave oven, Model
BMO 700T, (2450 MHz, 700 W). The purity of compounds
was checked by TLC using silica gel G plates.
irradiation in Pyrex glass round bottle flask attached with air
condenser from outside with special arrangement for 3 min.
After cooling at room temperature, the reaction mixture was
acidified using concentrated HCl. The resulting precipitated
was filtered and washed with water, and recrystallized from
aqueous DMF to give 3.4 g (93%) of 5.
5-Ethyl-8-oxo-5,8-dihydro-[1,3]-dioxolo[4,5-g]quinoline -7-
carbonyl chloride (6). This compound was obtained in 86%
yield as a light brown solid (ref. [17,18]).
Synthesis of 5-ethyl-8-oxo-5, 8-dihydro-[1, 3] dioxolo[4, 5-
g] quinoline-7-carboxylic acid (5). Three step conventional
method A.
Step 1: 2-[(Benzo[1,3]dioxolo-5-yl-ethyl-amino)
5-Ethyl-5,8-dihydro-[1,3]dioxolo-5,8,13-triaza-benzo[5,6]cy-
clohepta[1,2-a]naphthalen-7-one(7). Method A. To a solu-
tion of 6 (0.28 g, 0.001 mol) in 10 mL of xylene was added
o-phenylenediamine (0.162 g, 0.0015 mol) and the reaction
mixture was refluxed for 8–10 h. The liberated water was
collected in Dean-Stark trap. After the mixture was cooled to
room temperature, the solid precipitated was filtered and
recrystallized from ethanol to afford 0.20 g (60%) of 7 as
dark yellow solid.
methylene]-malonic acid diethyl ester (3). A mixture of ben-
zo[1,3]dioxol-5yl-ethyl-amine 1 (3.30 g, 0.02 mol), diethyl
ethoxy methylenemalonate 2 (4.40 g, 0.02 mol), and diphenyl
oxide (10 mL) was heated at 130–140ꢀC for 1.5 h, and the
alcohol generated from reaction mixture was allowed to
escape. The reaction mixture was keep for further step.
Step 2: Ethyl 5-ethyl-8-oxo-5, 8-dihydro-[1,3]dioxolo [4, 5-
g] quinoline-7-carboxylate (4). 2-[(Benzo[1,3]dioxolo-5-yl-
ethyl-amino)-methylene]-malonic acid diethyl ester 3 (6.70 g)
was dissolved in boiling diphenyl oxide (10 mL) and heated at
250ꢀC for 1.5–2 h. The liberated alcohol was collected in a
Dean-Stark trap. Then the mixture was cooled to room temper-
ature, the resulting solid was filtered and washed with petro-
leum ether and dried in vacuo, yielding 4.1 g (70%) of (4), mp
169–173ꢀC (ref. [15], mp 172–173ꢀC).
Method B. To a solution of compound 6 (0.28 g, 0.001
mol), o-phenylenediamine (0.162 g, 0.0015 mol) in 10 mL of
xylene, acidic alumina (2 g) was added. The reaction mixture
was stirred well, air dried, and subjected to the MWI intermit-
tently at 30 s intervals for specified time (Table 1). On com-
pletion of reaction as monitored by TLC, the product was
extracted into ethanol (3 ꢁ 5 mL). Removal of solvent under
reduced pressure yielded the product, which was recrystalized
from ethanol to give 0.29 g (87%) of (7) as dark yellow solid.
mp 335–337ꢀC; IR (KBr): 3422, 3218, 2924, 2853, 1676,
1624, 1599, 1555, 1538, 1500, 1473, 1455, 1376, 1299, 1277,
Step 3: 5-Ethyl-8-oxo-5, 8-dihydro-[1, 3] dioxolo [4, 5-g]
quinoline-7- carboxylic acid (5). This compound was obtained
in 82% yield as a white solid, (ref. [16,17]).
Two step microwave assisted method B. Step 1: Ethyl 5-
ethyl-8-oxo-5, 8-dihydro-[1, 3] dioxolo [4, 5-g] quinoline-7-
carboxylate (4). A neat mixture of benzo[1,3]dioxol-5yl-ethyl-
amine 1 (3.30 g, 0.02 mol) and diethyl ethoxymethylenemalo-
nate 2 (4.40 g, 0.02 mol) was taken in an open Pyrex tube and
subjected to microwave irradiation in domestic microwave
oven (BPL, BMO 700T) at an output of about 700 watts for
specified time given in (Table 1). Progress of reaction was
monitored through TLC at an interval of 45 sec. On comple-
tion, the reaction mixture was allowed to cool at room temper-
ature; the resulting solid was filtered and washed with petro-
leum ether and dried in vacuo, to give 5.1 g (88%) of 4.
mp 169–173ꢀC (ref. [15], mp 172–173ꢀC).
1
1254, 1202, 1032 cmꢂ1; H NMR (DMSO-d6): d 1.39 (t, 3H),
4.70 (q, 2H), 6.43 (s, 2H), 7.08–7.21 (m, 3H) 7.56 (d, d 1H),
7.85 (s, 1H), 8.75 (s, 1H), 9.10 (s, 1H), 10.50 (s, 1H); MS
(ESI, m/z):334 [MþH]þ. Anal.Calcd. For C19H15N3O3: C,
68.46; H, 4.54; N, 12.61. Found: C, 68.76; H, 4.36; N, 12.54.
5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g] quinoline -7-
carbohydrazide (8). Method A. To a solution of 6 (0.42 g,
0.0015 mol) dissolved in 10 mL of ethanol was added hydra-
zine hydrate (2.5 mL). The mixture was stirred for 1 h at
room temperature, and then poured into water. The precipitate
was collected by filtration and recrystallized from ethanol to
give 0.32 g (78%) of 8 as yellow solid.
Method B. To a solution of compound 6 (0.42 g, 0.0015
mol) and hydrazine hydrate (2.5 mL) in ethanol (10 mL)
acidic alumina (2 g) was added. The reaction mixture was
stirred well, air dried, and subjected to MWI intermittently at
30 s intervals for specified time (Table 1). On completion of
Step 2: 5 - Ethyl-8-oxo-5, 8-dihydro-[1, 3] dioxolo [4, 5-g]
quinoline-7- carboxylic acid (5). A neat mixture of ethyl 5-
ethyl-8-oxo-5, 8-dihydro-[1, 3] dioxolo [4, 5-g] quinoline -7-
carboxylate 4 (4.0 g, 0.014 mol) was dissolved in 20 mL of
10% NaOH. The reaction mixture was subjected to microwave
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Microwave-Assisted Synthesis of Quinolone Derivatives and Related Compounds
1107
reaction, as monitored by TLC the product was extracted into
ethanol (3 ꢁ 5 mL). Removal of solvent under reduced pres-
sure yielded the product, which was recrystallized from etha-
nol to give 0.38 g (92%) of 8 as yellow solid.
1037, 1017 cmꢂ1 1H NMR (DMSO-d6): d 1.42 (t, 3H), 4.66
;
(q, 2H), 6.35 (s, 2H), 7.74 (s, 1H), 8.26 (s, 1H), 9.11 (s, 1H),
15.62 (s,1H); MS (ESI, m/z):302[MþH]þ.Anal.Calcd. For
C14H11N3O3S: C, 55.80; H, 3.68; N, 13.95. Found: C, 55.70;
H, 3.88; N, 14.05.
mp 300–302ꢀC; IR (KBr): 3400, 3245, 2986, 1647, 1618,
1592, 1506, 1474, 1375, 1269, 1256, 1238, 1197, 1038 cmꢂ1
;
5-Ethyl -7-(5-thioxo-4, 5-dihydro-[1, 3, 4] oxadiazol-2-yl)-
5-H-[1, 3] di-oxolo [4, 5-g] quinolin-8-one (12).
MS (ESI, m/z):276 [MþH]þ. Anal. Calcd. For C13H13N3O4: C,
56.72; H, 4.76; N, 15.27. Found: C, 56.87; H, 4.56; N, 15.54.
5-Ethyl-8-oxo-5,8-dihydro-[1,3]dioxolo[4,5-g] quinoline-7-
carboxamide (9). Method A. This compound was obtained
in 77% yield as a white solid (ref. [19]).
Method
A. A mixture of 8 (0.30 g, 0.0011 mol), CS2 (0.68 g, 0.009
mol), and KOH (0.22 g, 0.004 mol) in ethanol 30 mL was
heated under reflux for 10 h, cooled to room temperature, and
diluted with water (4 mL) was heated under reflux until the
evolution of H2S had ceased. The reaction mixture was cooled
to room temperature, and poured into water and acidification
with HCl. The resulting precipitated was filtered and washed
with water and recrystallized from methanol to give 0.25 g
(71%) of 12.
Method B. To a solution of (8) (0.30 g, 0.0011 mol), CS2
(0.68 g, 0.009 mol) and KOH (0.22 g, 0.004 mol) in ethanol
20 mL dissolved in water (4 mL) were added. The reaction
mixture was subjected to microwave irradiation in a Pyrex
glass round bottle flask attached with water condenser from
outside with special arrangement for 4 min (Table 1). On com-
pletion of reaction, as monitored by TLC the reaction mixture
was cooled to room temperature and poured into water and
acidification with HCl. The resulting precipitated was filtered
and washed with water and recrystallized from methanol to
give 0.3 g (86%) of 12.
mp 260–263ꢀC; IR (KBr): 3442, 3171, 3050, 2901,
1650,1621, 1595, 1519, 1483, 1392, 1269, 1255, 1230,
1197,1039 cmꢂ1 1H NMR (DMSO-d6): d 1.35 (t, 3H), 4.40
;
(q, 2H), 6.19 (s, 2H), 7.48 (s, 1H), 7.52 (s, 1H) 8.58 (s, 1H),
11.26 (s, 1H); MS (ESI, m/z):318 [MþH] þ. Anal.Calcd. for
C14H11N3O4S: C, 52.99; H, 3.49; N, 13.24. Found: C, 52.88;
H, 3.36; N, 13.54.
Caution: Although we did not have any accident in this
work, it is highly recommended that the reaction should be
performed in an efficient hood.
In vitro antibacterial activity. Minimal inhibitory concen-
trations (MICs) were determined by means of an agar dilution
method, using Mueller Hinton agar plates containing a series
of twofold dilutions of drug. Overnight cultures in Mueller
Hinton broth were used for precultures of tested strains. MICs
were determined after overnight incubation at 37ꢀC, with an
inoculum equivalent to 1:100 dilution of an 18 h culture in
Mueller Hinton broth (about108 cells/mL). Each inoculum was
seeded onto agar plates by using an inoculum-replicating appa-
ratus and transferred by a 0.005 mL (about 104 cells) cali-
brated loop. The MIC was the lowest drug concentration that
inhibited the development of visible growth on agar plate.
The in vivo antibacterial activities of drugs were determined
in the systemic infections of mice with bacteria. Ten female
Swiss albino mice weighing 18 to 22 g were used for each
dose level. Microorganisms grown on Mueller Hinton agar
plates were suspended in physiological saline solution. Mice
were intraperitoneally challenged with bacteria. Mice infected
with Escherichia coli ML 4707 were treated at 1 h after infec-
tion. Mice infected with Klebsiella pneumoniae ML 4730 and
Proteus morganii ML 4731 were treated, respectively, at 1, 6,
and 24 h and then immediately and at 3 h after infection.
Drugs to be tested were administered PO. The total number of
surviving mice was recorded 1 week after infection, and the
Method B. To a solution of 6 (0.28 g, 0.001 mol), ammonia
solution (5 mL) in ethanol, basic alumina (2 g) was added.
The reaction mixture was stirred well, air dried, and subjected
to MWI intermittently at 30 s intervals for specified time
(Table 1). On completion of reaction, as monitored by TLC
the product was extracted into ethanol (3 ꢁ 5 mL). Removal
of solvent under reduced pressure yielded the product which
was recrystallized from ethanol to give 0.24 g (92%) of 9 as a
white solid. mp 334–336ꢀC; (lit. ref. [19] 336ꢀC).
6-Ethyl-6H-8, 10-dioxa-1, 3, 6 triaza-cyclopenta [b] phen-
anthrene-2, 4-dione (10). Method A. A mixture of 6 (0.28
g, 0.001 mol), urea (0.1 g, 0.002 mol), 5% aq. KOH (2 mL)
and methanol (10 mL) was refluxed for 2 h and cooled. The
precipitate obtained after dilution with water was filtered,
washed with water, and recrystallized from methanol to give
0.20 g (70%) of 10 as a white solid.
Method B. To a solution of compound 6 (0.28 g, 0.001
mol), urea (0.1 g, 0.002 mol) in methanol (10 mL), 5% aq
KOH (2 mL), and basic alumina 2 g was added. The reaction
mixture was stirred well, air dried, and subjected to MWI
intermittently at 30 s intervals for specified time (Table 1). On
completion of reaction, as monitored by TLC the product was
extracted into ethanol (3 ꢁ 5 mL). Removal of solvent under
reduced pressure yielded the product which was recrystallized
from methanol to give 0.25 g (88%) of 10 as a white solid.
mp 285–287ꢀC; IR (KBr): 3431, 2926,2853,1721, 1685,
1658, 1604, 1574, 1557, 1508, 1472, 1416, 1335, 1292, 1251,
1216, 1181, 1114, 1084,1024 cmꢂ1 1H NMR (DMSO-d6): d
;
1.42 (t, 3H), 4.66 (q, 2H), 6.35 (s, 2H), 7.74 (s, 1H), 8.26 (s,
þ
1H), 9.11 (s, 1H), 15.62 (s, 1H); MS (ESI, m/z):286 [MþH]
.
Anal.Calcd. For C14H11N3O4: C, 58.95; H, 3.89; N, 14.73.
Found: C, 58.85; H, 3.95; N, 14.85.
6-Ethyl – 2- thioxo-2, 6 dihydro-3H-8, 10-dioxa-1, 3, 6 tri-
aza-cyclopenta [b] phenanthrene - 4-one (11). Method A. A
mixture of 6 (0.28 g, 0.001 mol), thiourea (0.15 g, 0.002 mol),
5% aq. KOH (2 mL), and methanol (10 mL) was refluxed for
2 h and cooled. The precipitate obtained after dilution with
water was filtered, washed with water, and recrystallized from
methanol to give 0.21 g (70%) of 11 as a white solid.
Method B. To a solution of 6 (0.28 g, 0.001 mol), thiourea
(0.15 g, 0.002 mol) in methanol (10 mL), 5% aq KOH 2 mL,
and basic alumina 2 g was added. The reaction mixture was
stirred well; air dried, and subjected to MWI intermittently at
30 s intervals or specified time (Table 1).On completion of
reaction, as monitored by TLC, the product was extracted into
ethanol (3 ꢁ 5 mL). Removal of solvent under reduced pres-
sure yielded the product, which was recrystallized from metha-
nol to give 0.26 g (86%) of 11 as a white solid.
mp 265–268ꢀC; IR (KBr): 3401, 3061, 2363, 1708, 1629,
1553, 1499, 1471, 1433, 1396, 1370, 1272, 1250, 1221, 1166,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1108
S. Pednekar and A. K. Pandey
Vol 47
[4] Harmonised Integrated Classification System for Human
Health and Environmental Hazards of Chemical Substances and Mix-
tures; OECD Series on Testing and Assessment Number 33; ENV/JM/
MONO(2001)6; OECD: Paris, 2001.
Table 2
Biological activity.
Compound no.
MIC (lg/mL)
ED50(PO) (mg/kg bw)
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4
5
7
8
9
10
11
12
16
0.5
30
4.7
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256
<4
>50
15
>512
256
256
256
4.0
>50
>50
>50
>50
12.5
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Nalidixic acid
[11] CLSI. CLSI document M2-A7, Wayne, PA, 2001.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet