One-pot synthesis and antimicrobial activity of novel quinolone heterocyclic derivatives

Article abstract of DOI:10.1002/jhet.501

A series of novel quinolone heterocyclic derivatives from natural amino acid were synthesized in one-pot method, which is very beneficial for the industrial operation to save manufacturing costs. These new compounds were characterized by ¹H NMR

Full text of DOI:10.1002/jhet.501

November 2010
One-Pot Synthesis and Antimicrobial Activity of Novel
Quinolone Heterocyclic Derivatives
1411
Hui Zheng, Juan Liu, and Pengfei Zhang*
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University,
Hangzhou, 310036, China
*E-mail: chxyzpf@hotmail.com
Received January 27, 2010
DOI 10.1002/jhet.501
Published online 30 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel quinolone heterocyclic derivatives from natural amino acid were synthesized in
one-pot method, which is very beneficial for the industrial operation to save manufacturing costs. These
1
new compounds were characterized by H NMR, 13C NMR, infrared spectrum, mass spectrum, and ele-
mental analysis. The preliminary bioassays results revealed that they had certain antimicrobial activity
against Bacillus subtilis and Staphylococcus aureus.
J. Heterocyclic Chem., 47, 1411 (2010).
INTRODUCTION
natural amino acid salts were designed and prepared
according to this method. The title compounds were char-
Interests in heterocycle compounds [1], especially quin-
olone heterocyclic compounds, have flourished for many
years, largely as a result of the wide spread use on anti-
asthmatic, anti-bacterial, anti-malarial, tyrosine-kinase
PDGF-RTK inhibitor agent, etc. [2]. Because of such a
wide range of applicability in medicine and bioorganic
chemistry, there has been increasing interests in exploring
new quinolone heteocyclic compounds to enrich this do-
main [3]. Enlightened and encouraged by the bioactivity
of quinolone heterocyclic compounds and the abundant
existence of amino acid in nature, we attempt to introduce
amino acid piece into quinolone heterocycle and wish to
discover some new bioactive compounds.
1
acterized by H NMR, 13C NMR, infrared spectrum, mass
spectrum, and elemental analysis. To investigate their pre-
liminary antimicrobial bioactivities, these compounds
were screened by Bacillus subtilis, Staphylococcus aureus,
Aspergillus fumigatus, and Candida albicans. The prelimi-
nary bioassays results revealed that they had certain bacte-
ricidal activity against Bacillus subtilis and Staphylococ-
cus aureus. The synthetic routes are shown in Figure 1.
RESULTS AND DISCUSSION
Chemistry. As part of our ongoing interests to find
new quinolone heterocyclic derivatives, we try to obtain
the quinolone compounds via intramolecular cyclization
reaction, which contain natural amino acid piece at N1-
position of quinolone heterocyclic ring. We selected the
2,4,5-trifluoro-3-methoxybenzoic acid 1 as started materi-
als to synthesize quinolone derivatives 6. At first, we syn-
thesized compounds 6 step by step from 1 to 5 with com-
plicated post-treatment and purification in each step. Inter-
estingly, when we attempt to synthesize compounds 5
from compound 1 in one-pot to cut off much troublesome
separation and purification in the middle process we found
the whole reaction goes well. So a facile and simple rout
Generally, there are several steps and much compli-
cated post-treatment and purification process to synthesize
the quinolone and fluoroquinolone derivatives, such as 4-
oxoquinoline, 8-nitrofluoro-quinolone, and other quinolone
derivatives [4–7]. Therefore, we wish to develop a concise
route with simple post-treatment to synthesize a series of
novel quinolone heterocyclic compounds. Fortunately,
when we use one-pot method to synthesize compounds 5
from compound 1, the whole reaction goes well and
smoothly. This method is very beneficial for the industrial
operation to save time and manufacturing costs. Herein a
series of novel quinolone heterocyclic derivatives from
C
V
2010 HeteroCorporation

1412
H. Zheng, J. Liu, and P. Zhang
Vol 47
Figure 1. (a) SoCl2; (b) (E)-ethyl 3-(dimethylamino)acrylate; (c) Amino acid ethyl ester hydrochloride; (d) K2CO3; (e) Hydrolysis; (f) Merge step
(a), (b), and (c) to open-pot, and no individual separation.
for the synthesis of compound 5 in one-pot way without
any separation was developed, which is very beneficial
for the industrial operation to save manufacturing costs.
The structures of quinolone heterocyclic compounds
Staphylococcus aureus and nearly have no activity
against Aspergillus fumigatus and Candida albicans.
The detail results are listed in Table 1.
From the preliminary biological results, all the new
compounds have certain antibacterial and antifungal bio-
activity, which intrigued us to study its QSAR further
and synthesize higher activity compound, the in-depth
research work is undergoing.
1
of 6a–6f were confirmed by IR, H NMR, 13C NMR,
MS, and elemental analysis. The infrared spectra of all
compounds showed easily distinguishable carboxylic
group stretching at 1789–1799 cmꢀ1 and 1721–1747
cmꢀ1 because of the two kind of carboxylic groups. In
1H NMR spectrum, two kind of carboxylic group signals
appear between 13.42–13.73 ppm and 14.42–14.58 ppm,
which demonstrate the existence of amino acids and
quinolone cycle. In 13C NMR spectrum, the typical sig-
nals of carboxylic group and aromatic ring appear
between 164.47–176.71 ppm and 102.85–158.97 ppm,
which reveal the existence of the quinolone cycle.
In conclusion, we have developed a simple one-pot
way of preparing quinolone heterocyclic compounds and
synthesized a series of novel quinolone heterocyclic
derivatives from natural amino acid. This method facili-
tates the industrial operation to save manufacturing
costs. The preliminary bioassays results reveal that they
have certain antimicrobial activity against Bacillus subti-
lis and Staphylococcus aureus.
Biological activities. All the title compounds were
tested preliminarily for their antibacterial and antifungal
activity. From the screening results, all the title com-
pounds have certain activity against Bacillus subtilis and
EXPERIMENTAL
All the reagents were purchased commercially and used
without further purification. The melting point was determined
Table 1
The preliminary antimicrobial activity of title compounds.
Conc. (mg/mL)
6a
6b
6c
6d
6e
6f
Bacillus subtilis
1
0.95a
0.60
0.75
0.65
–
0.70
0.60
–
0.85
0.65
–
0.70
–
0.80
0.65
–
1.20
0.75
–
0.90
0.75
0.60
1.10
1.00
0.85
1.25
0.60
–
0.95
0.65
–
0.2
0.2
1
b
–
Staphylococcus aureus
0.85
0.60
–
0.2
0.1
–
a Diameter of inhibition zone (cm).
b No inhibition.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
One-pot Synthesis and Antimicrobial Activity of Novel
Quinolone Heterocyclic Derivatives
1413
Table 2
OCH3), 5.37 (s, 2H, CH2), 8.03–8.07 (m, 1H, ArH), 9.01 (s,
1H, C¼¼CH), 13.42 (br s, 1H, COOH), 14.55 (br s, 1H,
COOH); 13C NMR (DMSO-d6, 100 MHz): d 59.33, 63.59,
Chemical structure, yields, and melt point of the synthesized
compounds.
2
3
107.56, 107.21 (d, JCAF ¼ 17.8 Hz), 122.90 (d, JCAF ¼ 7.20
3
2
Compound
R
H
Yield (%)
M. P (ꢁC)
Hz), 131.86 (d, JCAF ¼ 3.39 Hz), 140.64 (d, JCAF ¼ 11.7
1
2
Hz), 147.45 (dd, JCAF ¼ 107.2 Hz, JCAF ¼ 15.4 Hz), 149.96
1
2
6a
6b
52
52
258–260
251–253
(dd, JCAF ¼ 104.1 Hz, JCAF ¼ 15.6 Hz), 153.57, 165.50,
169.37, 176.43; MS (70 eV): m/z (%) ¼ 313 (Mþ); Anal.
Calcd. for C13H9F2NO6: C, 49.85; H, 2.90; N, 4.47; Found: C,
50.01; H, 4.45; N, 4.51.
6c
50
310–312
1-(1-Carboxy-2-methylpropyl)-6,7-difluoro-8-methoxy-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (6b). IR (KBr)
v: 3488, 2981, 2898, 1795, 1726, 1631, 1573, 1499, 1378,
1
1216, 1058 cmꢀ1; H NMR (DMSO-d6, 400 MHz): d 0.82 (d,
6d
6e
49
52
284–286
162–164
J ¼ 7.20 Hz, 6H, CH3), 2.11–2.14 (m, 1H, CH), 3.68–3.70 (m,
1H, CH), 4.21 (s, 3H, OCH3), 8.01–8.04 (m, 1H, ArH), 9.12
(s, 1H, C¼¼CH), 13.73 (br s, 1H, COOH), 14.52 (br s, 1H,
COOH); 13C NMR (DMSO-d6, 100 MHz): d 21.71, 22.18,
2
29.42, 61.56, 68.51, 108.22, 109.43 (d, JCAF ¼ 15.6 Hz),
3
3
6f
48
195–197
121.75 (d, JCAF ¼ 5.62 Hz), 132.13 (d, JCAF ¼ 4.2 Hz),
2
1
141.21 (d, JCAF ¼ 14.6 Hz), 146.13 (dd, JCAF ¼ 108.3 Hz,
2JCAF ¼ 14.3 Hz), 148.68 (dd, JCAF ¼ 107.5 Hz, JCAF
¼
1
2
15.1 Hz), 152.98, 164.67, 169.66, 175.13; MS (70 eV): m/z
(%) ¼ 355 (Mþ); Anal. Calcd. for C16H15F2NO6: C, 54.09; H,
4.26; N, 3.94; Found: C, 54.12; H, 4.19; N, 4.01.
using a XT-4 melting-point apparatus and uncorrected. IR spec-
tra were recorded on a Bruker Equinox-55 spectrophotometer
using KBr discs in the 4000–400 cmꢀ1 region. The 1H NMR
and 13C NMR data were obtained on a Bruker AC-400 (400
MHz) instrument in DMSO-d6 using TMS as internal standard.
Chemical shifts (d) are expressed in ppm and coupling con-
stants J are given in Hz. Mass spectra were obtained on a Agi-
lent 5973N mass spectrometer operating at 70 eV by electron
ionization technique (EI/MS). Elemental analyses were per-
formed on an EA-1110 instrument.
1-(1-Carboxy-3-methylbutyl)-6,7-difluoro-8-methoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (6c). IR (KBr) v: 3482,
2959, 2852, 1789, 1721, 1631, 1557, 1499, 1348, 1210, 1078
1
cmꢀ1; H NMR (DMSO-d6, 400 MHz): d 0.87 (d, J ¼ 7.20 Hz,
6H, CH3), 1.36–1.42 (m, 1H, CH), 2.11–2.15 (m, 1H, CH2),
3.81–3.83 (m, 1H, CH), 4.36 (s, 3H, OCH3), 8.63–8.67 (m, 1H,
ArH), 9.07 (s, 1H, C¼¼CH), 13.62 (br s, 1H, COOH), 14.58 (br s,
1H, COOH); 13C NMR (DMSO-d6, 100 MHz): d 22.25, 23.19,
2
26.22, 29.57, 62.96, 71.55, 102.73, 107.60 (d, JCAF ¼ 15.8 Hz),
3
3
General synthesis procedure of compound 6a is described
below and other compounds were synthesized in similar way.
The chemical structure, yields, and melt points of the synthe-
sized compounds are listed in Table 2.
128.08 (d, JCAF ¼ 4.2 Hz), 139.11 (d, JCAF ¼ 4.8 Hz), 142.94
2
1
2
(d, JCAF ¼ 15.2 Hz), 145.39 (dd, JCAF ¼ 108.3 Hz, JCAF
¼
1
2
14.6 Hz), 148.84 (dd, JCAF ¼ 108.1 Hz, JCAF ¼ 14.2 Hz),
153.29, 165.82, 171.79, 176.71; MS (70 eV): m/z (%) ¼ 369
(Mþ); Anal. Calcd. for C17H17F2NO6: C, 55.29; H, 4.64; N, 3.79;
Found: C, 55.38; H, 4.52; N, 3.92.
1-(Carboxymethyl)-6,7-difluoro-8-methoxy-4-oxo-1,4-dihy-
droquinoline-3-carboxylic acid (6a). 2,4,5-trifluoro-3-methox-
ybenzoic acid 4.12 g (0.02 mol) was dissolved in thionyl chlo-
ride 22 mL in a 50 mL round-bottomed flask, stirring and
reflux for 3 h, removing the superfluous SOCl2 on a rotary
evaporator. (E)-ethyl-3-(dimethylamino) acrylate 2.86 g (0.02
mol) was added dropwise to the toluene solution of above
leavings with stirring at 40–50ꢁC, monitoring with TLC [PE/
EA ¼ 1/1 (v/v)] to the end of reactants, adding amino acid
ethyl ester hydrochloride (0.02 mol) directly and stirring for
about 5–8 h at room temperature, checking the reaction via
TLC, then potassium carbonate 4.14 g (0.03 mol) was added
and stirring for 8–10 h at 100ꢁC. When the reaction was com-
plete (determined by TLC), the mixture was acidified with
diluted hydrochloride acid (5%) to PH ¼ 2–3. The reaction
mixture was poured into separatory funnel and separated. The
organic layer was concentrated under reduced pressure and the
residual was chromatographed on silica gel (PE/EA¼2/1 (v/v))
to give compound 5, which was added to the 20% sulfuric
acid solution, refluxing for about 6–8 h, cooled to room tem-
perature and filter. The filter cake was crystallized using 20%
alcohol aqueous solution to afford compounds 6a. IR (KBr) v:
3493, 2981, 2809, 1799, 1746, 1632, 1581, 1484, 1348, 1215,
1-(1-Carboxy-2-methylbutyl)-6,7-difluoro-8-methoxy-4-
oxo-1,4-dihydroquinoline-3-carboxylic acid (6d). IR (KBr)
v: 3491, 2965, 2851, 1798, 1742, 1656, 1581, 1498, 1346, 1213,
;
1078 cmꢀ1 1H NMR (DMSO-d6, 400 MHz): d 0.74–0.79 (m,
6H, CH3), 0.88–0.95 (m, 2H, CH2), 2.01–2.05 (m, 1H, CH),
3.89–3.92 (m, 1H, CH), 4.23 (s, 3H, OCH3), 8.00–8.05 (m, 1H,
ArH), 9.18 (s, 1H, C¼¼CH), 13.53 (br s, 1H, COOH), 14.49 (br s,
1H, COOH); 13C NMR (DMSO-d6, 100 MHz): d 11.74, 13.77,
2
25.55, 38.01, 65.82, 67.97, 102.85 (d, JCAF ¼ 19.1 Hz), 109.68,
3
3
129.76 (d, JCAF ¼ 5.6 Hz), 139.05 (d, JCAF ¼ 6.4 Hz), 142.12
2
1
2
(d, JCAF ¼ 17.1 Hz), 147.92 (dd, JCAF ¼ 108.2 Hz, JCAF
¼
1
2
12.2 Hz), 149.15 (dd, JCAF ¼ 109.1 Hz, JCAF ¼ 14.8 Hz),
158.97, 165.62, 171.12, 176.55; MS (70 eV): m/z (%) ¼ 369
(Mþ); Anal. Calcd. for C17H17F2NO6: C, 55.29; H, 4.64; N, 3.79;
Found: C, 55.31; H, 4.59; N, 3.77.
1-(Carboxy(phenyl)methyl)-6,7-difluoro-8-methoxy-4-oxo-
1,4-dihydroquinoline-3-carboxylic acid (6e). IR (KBr) v:
3495, 2926, 2809, 1796, 1746, 1632, 1581, 1484, 1348, 1259,
;
1105 cmꢀ1 1H NMR (DMSO-d6, 400 MHz): d 4.11 (s, 3H,
OCH3), 4.33 (s, 1H, CH), 7.49–7.54 (m, 5H, ArH), 8.06–8.08
(m, 1H, ArH), 9.05 (s, 1H, C¼¼CH), 13.56 (br s, 1H, COOH),
1062 cmꢀ1 1H NMR (DMSO-d6, 400 MHz): d 4.02 (s, 3H,
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1414
H. Zheng, J. Liu, and P. Zhang
Vol 47
14.42 (br s, 1H, COOH); 13C NMR (DMSO-d6, 100 MHz): d
pound, three replicate trials were conducted against each
organism.
2
62.75, 69.83, 107.31 (d, JCAF ¼ 18.2 Hz), 109.78, 123.34,
3
129.39, 130.21 (d, JCAF ¼ 5.7 Hz), 131.22, 132.44, 133.03,
3
2
133.41, 140.78 (d, JCAF ¼ 5.2 Hz), 141.06 (d, JCAF ¼ 16.4
Acknowledgments. The authors are grateful to Zhejiang Provin-
cial Natural Science Foundation of China (No. Y4090052) and
National Science and Technology Ministry of China (No.
2007BAI34B05) for providing financial support.
1
2
Hz), 148.12 (dd, JCAF ¼ 108.8 Hz, JCAF ¼ 13.6 Hz), 149.47
1
2
(dd, JCAF ¼ 107.6 Hz, JCAF ¼ 12.2 Hz), 150.69, 165.14,
168.89, 176.32; MS (70 eV): m/z (%) ¼ 389 (Mþ); Anal.
Calcd. for C19H13F2NO6: C, 58.62; H, 3.37; N, 3.60; Found:
C, 58.71; H, 3.39; N, 3.71.
1-(1-Carboxy-2-phenylethyl)-6,7-difluoro-8-methoxy-
4-oxo-1,4-dihydroquinoli-ne-3-carboxylic acid (6f). IR
(KBr) v: 3495, 2958, 2868, 1798, 1747, 1617, 1568, 1474,
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;
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet