Synthesis of 4-Hydroxyquinolin-2(1H)-one analogues and 2-substituted quinolone derivatives

Article abstract of DOI:10.1002/jhet.5570380109

A versatile synthetic method for preparing 4-hydroxyquinolone and 2-substituted quinolone compounds from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well known ethyl acetoacetate synthesis, malonic ester s

Full text of DOI:10.1002/jhet.5570380109

Jan-Feb 2001
Synthesis of 4-Hydroxyquinolin-2(1H)-one Analogues
and 2-Substituted Quinolone Derivatives
61
Jae-Chul Jung, Young-Jo Jung and Oee-Sook Park*
Department of Chemistry, College of Natural Sciences, Chungbuk National
University, Cheongju 361-763, Chungbuk, Korea
Received May 16, 2000
A versatile synthetic method for preparing 4-hydroxyquinolone and 2-substituted quinolone compounds
from simple benzoic acid derivatives was demonstrated. The synthetic strategies involve the use of well
known ethyl acetoacetate synthesis, malonic ester synthesis and reductive cyclization. The key intermediates
were keto esters 4a-e, which could be transformed to 4-hydroxyquinolones 5a,b or 2-substituted quinolone
ethyl esters 6a-c depending on the reaction conditions. 4-Hydroxyquinolone analogues were prepared and
investigated for N-methyl-D-aspartate (NMDA) activity in vitro. Among these derivatives, 6,7-difluoro-3-
nitro-4-hydroxyquinolin-2(1H)-one (9) exhibited moderate activity.
J. Heterocyclic Chem., 38, 61 (2001).
Many 4-hydroxyquinolone compounds are useful
4a-e in excellent yields. In this condensation reaction, we
found that magnesium ethoxide was the most effective
among bases such as sodium ethoxide, sodium hydride and
potassium t-butoxide. The keto diesters 4a,b were
smoothly transformed to 4-hydroxyquinolone compounds
5a,b by reductive ring closure over palladium-on-charcoal
with sodium borohydride under akaline reduction
condition. Whereas, the diketo esters 4c-e were converted
to N-hydroxy-2-substituted quinolone compounds 6a-c
using the mild catalytic hydrogenation over palladium-on-
charcoal in ethanol at room temperature (Scheme 1).
intermediates for biologically active substances [1] and
many industrial products such as dye stuffs [2] and
herbicides [3]. Recent reports [4] describe novel class of
4-hydroxyquinolone derivatives, i.e., 4-hydroxy-3-
arylquinolin-2(1H)-one and 4-hydroxy-3-nitroquinolin-
2(1H)-one as potent and selective N-methyl-D-aspartate
(NMDA) receptor glycine site antagonist after oral
administration. Many of these compounds have been
derived from the 4-hydroxyquinolin-2(1H)-one nucleus.
A variety of routes for the synthesis of 4-hydroxy-
quinolone compounds have been reported in the literature
[5-8]. Most of these methods have been based on the
cyclization of malondianilides with aluminium trichloride
[9] or poly phosphoric acid [10], which afforded the
corresponding 4-hydroxyquinolone compounds in poor to
moderate yields and made the product isolation
considerably difficult. Our need for rapid access to
4-hydroxyquinolone compounds for large scale syntheses
for 2-substituted quinolone compounds, prompted us to
explore new methodology for the synthesis of these
compounds.
The present paper describes a convenient method for the
preparing 4-hydroxyquinolones 5a,b and 2-substituted
quinolone compounds 6a-c. The synthetic strategies involve
the use of well known ethyl acetoacetate synthesis, malonic
ester synthesis [11] and reductive cyclization. Several
derivatives of 4-hydroxyquinolone and 2-substituted
quinolone were also prepared by simple method from
4-hydroxyquinolones 5a,b and 2-substituted (methyl or
phenyl) quinolones 6a-c. These compounds were evaluated
for N-methyl-D-aspartate (NMDA) glycine binding site
activity and antibacterial activity in vitro, respectively.
We have used 4,5-difluorobenzoic acid as starting
material, which was nitrated to give 4,5-difluoro-2-
nitrobenzoic acid (2b). Acids 2a,b were treated with
thionyl chloride to give acid chlorides, which were
subsequently treated with the anion of diethyl malonate,
ethyl acetoacetate or phenyl acetoacetate to give keto esters
i) HNO /H SO ; ii)SOCl , urea/toluene; iii) Mg, EtOH/toluene; iv) NaBH ,
3
2
4
2
4
Pd-C, NaOH (aq), 1,4-dioxane; v) H , Pd-C, EtOH, 1 bar.
2

62
J.-C. Jung, Y.-J. Jung and O.-S. Park
Vol. 38
i) p-TsOH/H O; ii) H , Pd-C, EtOH; iii) HNO /AcOH; iv) NaBH , Pd-C, NaOH (aq), 1,4-dioxane; v) 3 N HCl (aq)/EtOH; vi) POCl /EtN; vii) NH OH
2
2
3
4
3
4
The treatment of diethyl 3,4-difluoro-2-nitrobenzoyl-
malonate (4b) with p-toluenesulfonic acid gave the
ethyl 3,4-difluoro-2-nitrobenzoylacetate (7), which was
used without further purification for the next step. In
this decarboxylation reaction, we found that p-toluene-
sulfonic acid gave the best yield among acids or base
such as 10% sulfuric acid, 10% hydrochloric acid or
15% sodium hydroxide. Reductive cyclization of 7 with
catalytic hydrogenation over palladium-on-charcoal in
ethanol proceeded smoothly to afford 6,7-difluoro-4-
hydroxyquinolin-2(1H)-one (8) in 96% yield.
Compound 8 was nitrated with a mixture of nitric acid
and acetic acid to produce 6,7-difluoro-3-nitro-4-
hydroxyquinolin-2(1 H)-one (9). Chlorination of
compound 9 with phosphoryl chloride in the presence of
triethylamine gave 6,7-difluoro-2,3,4-trichloro-
quinoline (10) in good yield. The compound 5b was
treated with concentrated ammonium hydroxide to give
the 6,7-difluoro-4-hydroxyquinolin-2(1H)-3-carbox-
amide (11) [12a,b] in 75% yield (Scheme 2).
On the other hand, the compounds 6b,c were readily
reduced to ethyl 6,7-difluoro-2-(methyl or phenyl)-4-
oxoquinoline-3-carboxylates (12a,c) using sodium hydro-
sulfite in aqueous ethanol in near quantitative yield.
Table
In Vitro Antibacterial Activity of 2-Substituted Quinoline Compounds
Minimum Inhibitory Concentrations (MICs, µg/ml) [a]
Organism
14a
14b
14c
14d
NFLX [b]
Streptococcus pyogenes 308 A
Streptococcus pyogenes 77 A
Streptococcus faccium MD 8b
Staphylococcus aureus SG 511
Staphylococcus aureus 285
Staphylococcus aureus 503
Escherichia coli 078
Escherichia coli DC 0
Escherichia coli DC 2
Escherichia coli TEM
Escherichia coli 1507 E
Pseudomonas aeruginosa 9027
Pseudomonas aeruginosa 1592 E
Pseudomonas aeruginosa 1771
Pseudomonas aeruginosa 1771 M
Salmonella typhimurium
Klebsiella oxytoca 1082 E
Klebsiella aerogenes 1522 E
Enterobacter cloacae P 99
Enterobacter cloacae 1321 E
1.6
6.3
0.8
1.6
3.2
6.3
6.3
6.3
3.2
3.2
1.6
6.3
6.3
3.2
3.2
6.3
3.2
6.3
6.3
6.3
3.2
1.6
0.8
1.6
1.6
3.2
6.3
3.2
1.6
3.2
6.3
6.3
3.2
6.3
6.3
3.2
3.2
3.2
6.3
6.3
1.6
3.2
1.6
6.3
0.8
3.2
6.3
6.3
3.3
6.3
3.2
3.2
6.3
3.2
6.3
6.3
6.3
6.3
6.3
6.3
3.2
3.2
1.6
1.6
1.6
0.8
3.2
6.3
6.3
3.2
6.3
6.3
6.3
3.2
6.3
6.3
6.3
3.2
6.3
3.2
1.6
1.6
3.2
0.06
0.8
0.4
0.8
0.01
0.8
0.16
0.4
0.1
0.2
0.02
0.1
0.02
0.4
0.63
0.4
0.8
[a] Standard microdilution techniques, [13a,b]. [b] Norfloxacin.

Jan-Feb 2001
Synthesis of 4-Hydroxyquinolin-2(1H)-one Analogues
63
EXPERIMENTAL
Reactions requiring anhydrous conditions were performed
with the usual precautions for rigorous exclusion of air and
moisture. Tetrahydrofuran and diethyl ether were distilled from
sodium benzophenone ketyl prior to use. Thin layer chroma-
tography (tlc) was performed on precoated silica gel
60 F plates from EM reagents and visualized with 254-nm uv
254
light or ceric sulfate-ammoniummolybdate-sulfuric acid spray.
Flash chromatography was carried out on silica gel 60 (E. M.
Merck, particle size 0.040~0.063 mm, 230~400 mesh ASTM).
1
13
H nmr and C nmr spectra were recorded on a Brucker DPX
300 at 300 MHz and 76 MHz, respectively. The chemical shifts
were reported in parts per million (ppm) downfield from
tetramethylsilane, and J-values were in Hz. Infrared spectra (ir)
were obtained on a Jasco FT/IR-300E spectrometer. Mass spectra
(ms) were recorded on a Shimadzu-LKB 9000 GC/MS system.
High resolution mass spectra (hrms) were obtained on a JEOL
JMS-HX-110A/110A high resolution mass spectrometer.
Elemental analyses were performed on a CE instruments Model
1110 elemental analyzer. All compounds has analytical results
within ±0.4% of their theoretical values. All mps were
uncorrected. When necessary, chemicals were purified according
to the reported procedure [16].
All cultures were stored as frozen stock. The MICs
determinations; a broth microdilution method [13a,b] was used to
quantitate antibacterial activity for these compounds. The
antibacterial activity was determined by agar dilution assay using
a multipoint inoculator. The test compounds were dissolved and
incorporated by the two fold dilution method in the agar medium.
Bacterial inocula, coming from overnight broth and containing
i) Na S O , EtOH/H O; ii) 2 N NaOH (aq) or LiOH/THF; ii) piperazine
or N-methylpiperazine/pyridine
2
2
4
2
Compounds 12a,c were hydrolyzed with aqueous
sodium hydroxide or lithium hydroxide in tetrahydrofuran
and then acidified with 2N hydrochloric acid to give the
6,7-difluoro-2-methyl or phenyl-4-oxoqinoline-3-
carboxylic acids 13a,c. Acids 13a,c were treated with
anhydrous piperazine or N-methylpiperazine in pyridine
according to the reported method [14-15] to yield 6-fluoro-
2-(methyl or phenyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl
or N-methyl-piperazinyl)quinoline-3-carboxylic acids
7
10 colony-forming units per point, were inoculated by
multipoint inoculator. Bacterial growth was observed after 18
hours of incubation at 37°. The lowest concentration of test
compounds that completely inhibited growth was considered to
be the minimum inhibitory concentrations (MICs).
4,5-Difluoro-2-nitrobenzoic Acid (2b).
1
14a-d, respectively (Scheme 3). Spectral data ( H nmr,
A solution of nitric acid (70%, 9.9 g, 110 mmoles) in
concentrated sulfuric acid (11.4 g, 110 mmoles) was added
dropwise to a solution of 3,4-difluorobenzoic acid (15.8 g,
100 mmoles) in 60 ml of concentrated sulfuric acid at 10° for
1 hour. The reaction mixture was stirred at room temperature for
3 hours and diluted with 120 ml of ice water in an ice-salt bath.
The product was collected by filtration, washed with water and
cold ethanol. The pale yellow solid was dried at 40° for 16 hours
to give 17.5 g (86%) of 2b, mp 158-159° (ref [17a,b], 152-154°);
13
C nmr, ir, ms) of all the prepared compounds are in
accordance with the proposed compounds.
The minimum inhibitory concentrations (MICs) of
14a-d against six Gram-positive bacteria and fourteen
Gram-negative bacteria compared to those of
norfloxacin, in vitro are listed in Table. Interestingly,
these compounds showed better antibacterial activities
against Gram-positive bacteria than Gram-negative
bacteria. The affinity of the prepared 4-hydroxy-
quinolone analogues such as 5b, 6b, 8-10 and 11 for the
N-methyl-D-aspartate receptor glycine binding site was
-1
ir (potassium bromide); 3310, 1716, 1540, 1438, 1196, 660 cm ;
1
H nmr (acetone-d ): δ 10.05 (br s, 1H), 8.14 (dd, 1H, J = 7.19,
6
13
Hz, J = 3.66 Hz), 7.93 (dd, 1H, J = 8.00 Hz, J = 4.34 Hz); C nmr
(acetone-d ): δ 164.3, 152.8, 152.0, 146.1, 125.7, 120.2, 115.5.
6
3
measured by inhibition of [ H]MDL 105,519 binding to
General Procedure for the Preparation of Keto Esters (4a-e).
rat brain cortical membranes. Among these compounds,
6,7-difluoro-3-nitro-4-hydroxyquinolin-2(1H)-one (9)
Thionyl chloride (60.3 mmoles) was added to a well stirred
suspension of compound 2 (50.2 mmoles) and urea (0.3 g) in
40 ml of anhydrous toluene. The reaction mixture was heated in
an oil bath at 100° for 3 hours, then cooled to room temperature.
The mixture of compound 3 (50.2 mmoles), magnesium
(53.4 mmoles), ethanol (165.0 mmoles), carbon tetrachloride
(1.1 ml) and 80 ml of anhydrous toluene was stirred at room
temperature for 1 hour and refluxed for 1 hour. The reaction
exhibited the most potent activity (IC : 3.9 µM).
50
In conclusion, the operational simplicity, inexpensive
and readily available materials and high yields can make
this procedure a useful and alternative to the currently
available methods. It is also applicable to industrial scale
preparation.

64
J.-C. Jung, Y.-J. Jung and O.-S. Park
Vol. 38
mixture was cooled to 5°. The former solution was cannulated
into the latter. The resulting reaction mixture was stirred at room
temperature for 30 minutes and then 20 ml of 10% hydrochloric
acid was added. The mixture was extracted with ether, and the
combined organic extracts were washed with brine, dried and
concentrated at reduced pressure.
Ethyl 4-hydroxyquinolin-2(1H)-3-carboxylate (5a).
To a solution of keto diester 4a (3.1 g, 10.0 mmoles) in
dioxane (45 ml) was added 20% aqueous sodium hydroxide
(10 ml) and 10% palladium-on-charcoal (0.4 g) at room
temperature. The mixture was stirred for 20 minutes and then
added dropwise to a solution of sodium borohydride (0.7 g, 18
mmoles) in water (5 ml). The reaction mixture was stirred at
room temperature under hydrogen gas for 30 minutes and filtered
through Celite. The filtrate was concentrated to remove dioxane
and then the residue was acidified with 10% hydrochloric acid to
give a pale yellow solid, which was recrystallized from ethanol to
give 1.6 g (70%) of 5a, mp 300° (dec, ref [19], 304°); ir
Diethyl 2-nitrobenzoylmalonate (4a).
This compound was obtained in 99% yield as a beige liquid
(ref [18]), ir (chloroform); 3428, 2964, 1726, 1702, 1455, 1196
-1 1
cm ; H nmr (deuteriochloroform): δ 14.53 (br s, 1H), 7.82-7.46
(m, 3H), 7.38 (d, 1H, J = 7.06 Hz), 4.18 (q, 2H, J = 7.12 Hz), 4.10
(q, 2H, J = 7.14 Hz), 1.26 (t, 3H, J = 7.12 Hz), 1.11 (t, 3H, J =
-1
1
potassium bromide); 3320-3084, 1711, 1412, 1144 cm ; H nmr
13
7.14 Hz); C nmr (deuteriochloroform): δ 176.1, 169.7, 166.2,
(dimethyl sulfoxide-d ): δ 12.64 (br s, 1H), 8.22-8.01 (m, 3H),
6
152.3, 133.9, 130.6, 126.8, 125.1, 119.2, 97.4, 62.4, 61.8, 14.2,
14.0.
7.95 (d, 1H, J = 6.97 Hz), 4.26 (q, 2H, J = 7.11 Hz), 1.30 (t, 3H,
13
J= 7.11 Hz); C nmr (dimethyl sulfoxide-d ): δ 172.3, 171.4,
6
164.2, 151.1, 129.2, 126.3, 125.7, 120.2, 105.1, 99.0, 59.8, 13.9.
According to the same procedure, ethyl 6,7-difluoro-4-hydroxy-
quinolin-2(1H)-one-3-carboxylate (5b) was prepared. Compound
5b was obtained in 72% yield from 4b, mp 280° (dec); ir (potassium
Diethyl 4,5-difluoro-2-nitrobenzoylmalonate (4b).
This compound was obtained in 95% yield as a yellow liquid,
-1
1
ir (chloroform); 3390, 1703, 1687, 1460, 1080, cm ; H nmr
(deuteriochloroform): δ 13.26 (br s, 1H), 8.11 (dd, 1H, J = 7.09
Hz, J = 6.93 Hz), 7.33 (dd, 1H, J = 8.69 Hz, J = 7.92 Hz), 4.24
(q, 2H, J = 7.13 Hz), 4.16 (q, 2H, J = 7.12 Hz), 1.26 (t, 3H, J =
-1
1
bromide); 3270-3030, 1649, 1579, 1188 cm ; H nmr (dimethyl
sulfoxide-d ): δ 12.86 (br s, 1H), 8.10 (dd, 1H, J = 9.34 Hz, J = 9.17
6
Hz), 7.71 (dd, 1H, J =7.01 Hz, J = 6.79 Hz), 4.44 (q, 2H, J = 7.13
13
7.13 Hz), 1.18 (t, 3H, J = 7.12 Hz); C nmr (deuterio-
13
Hz), 1.40 (t, 3H, J = 7.13 Hz); C nmr (dimethyl sulfoxide-d ): δ
6
chloroform): δ 169.4, 168.9, 166.2, 158.1, 152.9, 148.2, 120.3,
168.2, 165.6 162.8, 152.0, 148.5, 143.9, 117.2, 112.9, 109.8, 101.9,
+
+
118.6, 113.8, 95.7, 62.0, 61.9, 14.0, 13.8; ms (fab ) 346 (M +1),
274, 186 (base peak), 154, 137; hrms: calcd. for 346.0738, found
+
61.8, 14.3; ms (m/e) 269 (M ), 239 (base peak), 171, 143, 115.
Anal. Calcd. for C H N: C, 53.54; H, 3.37; N, 5.20. Found C,
12
9
+
346.0734 (M +1).
55.36; H, 3.51; N, 5.39.
Ethyl 2-nitrobenzoylacetoacetate (4c).
Ethyl 1-hydroxy-2-methyl-4-oxoquinoline-3-carboxylate (6a).
This compound was obtained in 98% yield as a yellow liquid
(ref [18]), ir (chloroform); 3368, 2951, 1726, 1706, 1454, 1088
cm ; H nmr (deuteriochloroform): δ 13.84 (br s, 1H), 7.69-7.40
A solution of the diketo ester 4c (2.8 g, 10.2 mmoles) in 80 ml
of ethanol was hydrogenated over 10% palladium-on-charcoal
(0.5 g) under atmospheric pressure at room temperature for
2 hours. The reaction mixture was filtered through Celite and
evaporated to give a pale yellow solid, which was recrystallized
from ethanol to give 1.9 g (77%) of 6a, mp 198°; ir (potassium
-1 1
(m, 3H), 7.32 (d, 1H, J = 6.98 Hz), 4.22 (q, 2H, J = 7.13 Hz), 2.43
13
(s, 3H), 1.28 (t, 3H, J = 7.13 Hz); C nmr (deuteriochloroform):
δ 192.5, 174.8, 173.2, 150.6, 133.4, 128.9, 126.8, 125.7, 120.1,
100.6, 61.2, 21.4, 14.1.
-1 1
bromide); 3508, 1713, 1588, 1246, 1096 cm ; H nmr (dimethyl
sulfoxide-d ): δ 13.43 (br s, 1H), 12.25 (br s, 1H), 8.29 (d, 1H,
6
Ethyl 4,5-difluoro-2-nitrobenzoylacetoacetate (4d).
J= 7.94 Hz), 7.64-7.40 (m, 3H), 4.23 (q, 2H, J = 7.12 Hz), 2.32
This compound was obtained in 97% yield as a yellow liquid,
ir (chloroform); 3405, 1712, 1639, 1437, 1014 cm ; H nmr
13
(s, 3H), 1.30 (t, 3H, J = 7.12 Hz); C nmr (dimethyl
-1
1
sulfoxide d ): δ 171.2, 166.5, 154.1, 150.8, 135.4, 128.1, 126.4,
6
(dimethyl sulfoxide-d ): δ 13.55 (br s, 1H), 8.47 (dd, 1H, J = 6.99
120.9, 110.3, 101.7, 57.8, 14.1, 12.7.
6
Hz, J = 6.95 Hz), 7.83 (dd, 1H, J = 7.77 Hz, J = 7.75 Hz), 3.90
(q, 2H, J = 7.09 Hz), 2.45 (s, 3H), 0.86 (t, 3H, J = 7.09 Hz);
Ethyl 6,7-difluoro-1-hydroxy-2-methyl-4-oxoquinoline-3-
carboxylate (6b).
13
C
nmr (dimethyl sulfoxide-d ): δ 192.3, 173.6, 165.8, 157.2, 155.0,
6
+
149.8, 119.6, 118.5, 113.4, 100.3, 58.9, 24.2, 13.4; ms (fab ) 316
A solution of the diketo ester 4d (3.2 g, 10.2 mmoles) in 80 ml
of ethanol was hydrogenated over 10% palladium-on-charcoal
(0.6 g) under atmospheric pressure at room temperature for
6 hours. The reaction mixture was filtered through Celite and
evaporated to give a pale yellow solid, which was recrystallized
from ethanol to give 2.2 g (78%) of 6b, mp 202°; ir (potassium
+
(M +1, base peak), 270, 186, 137; hrms: calcd. for 316.0633,
+
found 316.0632 (M +1).
Ethyl 2-benzoyl-3-(4,5-difluoro-2-nitrophenyl)-3-oxopro-
panonate (4e).
-1
1
This compound was obtained in 98% yield as a beige liquid, ir
(chloroform); 3378, 1711, 1604, 1541, 1411, 1148 cm ; H nmr
bromide); 3450, 1717, 1605, 1475, 1110 cm ; H nmr (dimethyl
-1
1
sulfoxide-d ): δ 12.33 (br s, 1H), 8.04 (dd, 1H, J = 10.07 Hz, J =
6
(dimethyl sulfoxide-d ): δ 13.60 (br s, 1H), 8.62 (dd, 1H, J = 7.16
Hz, J = 7.13 Hz), 8.15-8.05 (m, 3H), 7.95 (dd, 1H, J = 7.93 Hz,
8.44 Hz), 7.91 (dd, 1H, J = 7.09 Hz, J = 6.77 Hz), 4.26 (q, 2H, J =
7.10 Hz), 2.42 (s, 3H), 1.30 (t, 3H, J = 7.10 Hz); C nmr
6
13
J= 7.92 Hz), 7.67-7.60 (m, 2H), 3.94 (q, 2H, J = 7.15 Hz), 0.89
(dimethyl sulfoxide-d ): δ 168.0, 164.8, 152.5, 149.1, 147.3,
6
13
(t, 3H, J = 7.15 Hz); C nmr (dimethyl sulfoxide-d ): δ 193.6,
143.6, 135.2, 119.8, 110.9, 102.3, 58.9, 13.6, 12.1; ms (m/e) 283
6
+
+
173.1, 170.7, 158.0, 152.5, 150.2, 136.4, 133.8, 133.3, 129.8,
(M ), hrms: calcd. for 283.0707, found 283.0727 (M ).
+
129.1, 127.6, 120.2, 118.7, 112.9, 95.8, 60.0, 13.9; ms (fab ) 378
According to the same procedure, ethyl 6,7-difluoro-1-
hydroxy-2-phenyl-4-oxoquinoline-3-carboxylate (6c) was
prepared. Compound 6c was obtained in 71% yield from 4e, mp
+
(M +1, base peak), 332, 274, 193, 105, 77; hrms: calcd. for
+
378.0789, found 378.0789 (M +1).

Jan-Feb 2001
Synthesis of 4-Hydroxyquinolin-2(1H)-one Analogues
65
194-195°; ir (potassium bromide); 3414, 1720, 1608, 1477, 1102
Anal. Calcd. for C H N : C, 44.64; H, 1.66; N, 11.57. Found
9 4 2
C, 44.73; H, 1.71; N, 11.80.
-1
1
cm ; H nmr (dimethyl sulfoxide-d ): δ 12.26 (br s, 1H), 8.17
6
(dd, 1H, J = 8.61 Hz, J = 8.59 Hz), 7.63-7.53 (m, 5H), 3.96
(q, 2H, J = 7.11 Hz), 0.90 (t, 3H, J = 7.11 Hz); C nmr (dimethyl
6,7-Difluoro-2,3,4-trichloroquinolin (10).
13
sulfoxide-d ): δ 169.8, 164.4, 154.5, 150.8, 150.4, 148.6, 145.3,
A solution of 9 (2.5 g, 10.3 mmoles), phosphoryl chloride
(14 ml) and triethylamine (2 ml) was heated at 100° for
2 hours. The excess solvent was evaporated in vacuo and the
residue was poured on 33 ml of ice water. The solution was
brought to pH 6 with 2N sodium hydroxide and then the
precipitated solid was filtered, washed with water, and dried to
afford 2.4 g (86%) of 10 as a white solid, mp 96°; ir (potassium
6
136.8, 130.1, 129.4, 128.5, 127.6, 121.7, 115.1, 112.5, 104.4,
+
59.9, 13.0; ms (m/e) 345 (M ), hrms: calcd. for 329.0863, found
+
329.0847 (M ).
Ethyl 3,4-difluoro-2-nitrobenzoylacetate (7).
A solution of diethyl 4,5-difluoro-2-nitrobenzoylmalonate 4b
(7.0 g, 20.3 mmoles) and p-toluenesulfonic acid (0.2 g) in 80 ml
of water was refluxed for 12 hours. The reaction mixture was
cooled at room temperature and extracted with 120 ml of ethyl
acetate. The organic layer was washed with 2% sodium
bicarbonate and brine, dried over anhydrous magnesium sulfate,
filtered and concentrated to give a yellow oil 5.0 g (91%) of 7, ir
-1 1
bromide); 3390, 1509, 1252, 1196, 660 cm ; H nmr (dimethyl
sulfoxide-d ): δ 8.03 (dd, 1H, J = 8.00 Hz, J = 7.98 Hz), 7.00
6
13
(dd, 1H, J = 7.44 Hz, J = 7.33 Hz); C nmr (dimethyl
sulfoxide-d ): δ 156.2, 153.9, 152.9, 150.5,134.1, 130.6, 122.2,
6
+
116.5, 111.8; ms (m/e) 268 (M ), 232, 220, 197 (base peak),
171, 136, 112.
-1
1
(chloroform); 3280-3045, 1738, 1605, 1070 cm ; H nmr
(deuteriochloroform ): δ 8.07 (dd, 1H, J = 6.71 Hz, J = 6.69 Hz),
7.45 (dd, 1H, J = 7.39 Hz, J = 7.37 Hz), 4.18 (q, 2H, J = 7.14 Hz),
Anal. Calcd. for C H N: C, 40.27; H, 0.75; N, 5.22. Found
9 2
C, 41.23; H, 0.75; N, 5.41.
6,7-Difluoro-4-hydroxyquinolin-2(1H)-3-carboxamide (11).
13
3.88 (s, 1H), 2.54 (s, 1H), 1.28 (t, 3H, J = 7.14 Hz); C nmr
(dimethyl sulfoxide-d ): δ 182.9, 168.2, 159.1, 158.7, 153.5,
A solution of 5b (1.6 g, 5.9 mmoles) in 14 ml of ammomium
hydroxide (28%) was heated at 90° for 6 hours. The reaction
mixture was poured into 16 ml of water and then acidified (pH =
4.0-4.5) with 10% hydrochloric acid. The precipitated solid was
filtered, which was recrystallized from ethanol to give 1.1 g
(75%) of 11 as a beige solid, mp 268° (dec); ir (potassium
6
+
+
133.2, 117.4, 115.6, 61.4, 44.8, 14.1; ms (fab ) 274 (M +1, base
peak), 186, 137, 89; hrms: calcd. for 274.0527, found 274.0528
+
(M +1).
6,7-Difluoro-4-hydroxyquinolin-2(1H)-one (8).
-1 1
Method A The keto ester 7 (5.5 g, 20.1 mmoles) in ethanol
(120 ml) was hydrogenated over 10% palladium-on-charcoal
(1.0 g) at 36 psi for 1 hour. The mixture was filtered through
Celite and evaporated. A dark yellow solid was obtained, which
was recrystallized from ethanol to give 3.8 g (96%) of 8, mp 310°
(dec); ir (potassium bromide); 3200-2230, 1685, 1486, 1173
bromide); 3367, 3154, 1647, 1579, 1211 cm ; H nmr (dimethyl
sulfoxide-d ): δ 11.69 (br s, 1H), 9.52 (br s, 1H), 8.83 (br s, 1H),
6
8.08 (dd, 1H, J = 7.46 Hz, J = 7.44 Hz), 7.96 (dd, 1H, J = 6.83 Hz,
13
J = 6.81 Hz), 7.78 (br s, 1H); C nmr (dimethyl sulfoxide-d ): δ
6
172.8, 168.4, 164.1, 158.4, 155.6, 147.2, 144.0, 136.8, 112.6,
+
+
102.2; ms (fab ) 241 (M +1, base peak), 195, 83; hrms: calcd. for
-1
1
+
cm ; H nmr (dimethyl sulfoxide-d ): δ 11.65 (br s, 1H), 11.34
241.0425, found 241.0420 (M +1).
6
(br s, 1H), 7.69 (dd, 1H, J = 8.69 Hz, J = 8.69 Hz), 7.21 (dd, 1H,
J = 6.99 Hz, J = 6.99 Hz), 5.76 (s, 1H); C nmr (dimethyl
Ethyl 6,7-difluoro-2-methyl-4-oxoquinoline-3-carboxyl-ate (12a).
13
sulfoxide-d ): δ 163.4, 152.8, 149.5, 146.3, 143.1, 136.3, 110.5,
The mixture of 6b (1.4 g, 5.0 mmoles) was dissolved in 16 ml
of 80% v/v aqueous ethanol and the solution treated with sodium
hydrosulfite (1.0 g, 6.0 mmoles). The reaction mixture was
heated at 60° for 3 hours, then cooled to room temperature and
then the mixture was neutralized with 10% hydrochloric acid.
The pale yellow solid was collected by filtration, washed with
water and recrystallized from ethanol to give 1.2 g (90%) of 12a,
mp 212-213°; ir (potassium bromide); 3387, 1692, 1584, 1178
6
+
103.3, 98.4; ms (m/e) 197 (M ); hrms: calcd. for 197.0288, found
+
197.0291 (M ).
Anal. Calcd. for C H N : C, 54.83; H, 2.55; N, 7.10. Found C,
9
5 1
54.89; H, 2.51; N, 7.23.
Method B A mixture of ethyl 6,7-difluoro-4-hydroxyquinolin-
2(1H)-one-3-carboxylate 5b (2.6 g, 7.5 mmoles), 3N hydro-
chloric acid (30 ml) and ethanol (12 ml) was refluxed for 6 hours.
The reaction mixture was cooled to 10° and filtered. The product
was washed with water, dried in the air to afford 1.7 g (92%) of 8
as a white solid. Analyses same as Method A.
-1
1
cm ; H nmr (dimethyl sulfoxide-d ): δ 8.13 (d, 1H, J = 7.91
6
Hz), 7.92 (d, 1H, J = 7.65 Hz), 4.26 (q, 2H, J = 7.14 Hz), 2.31
13
(s, 3H), 1.28 (t, 3H, J = 7.14 Hz); C nmr (dimethyl
sulfoxide-d ): δ 176.3, 168.0, 152.5, 149.1, 147.3, 143.8, 135.3,
119.8, 110.9, 102.3, 58.9, 16.6, 12.3; ms (m/e) 267 (M ), 221
6
6,7-Difluoro-3-nitro-4-hydroxyquinolin-2(1H)-one (9).
+
A solution of 8 (1.1 g, 5.6 mmoles), nitric acid (70%, 12 ml,
8 mmoles) and glacial acetic acid (8 ml) was heated at 90 for
(base peak), 165; hrms: calcd. for 267.0707, found 267.0728
(M ).
o
+
1 hour. The reaction mixture was cooled to room temperature and
then diluted with 12 ml of ice water. The product was filtered and
washed with water, and dried to give 1.0 g (77%) of 9 as a yellow
crystal, mp 193-194°; ir (potassium bromide); 3280-2160, 1658,
According to the same procedure, ethyl 6,7-difluoro-2-phenyl-
4-oxoquinoline-3-carboxylate (12c) was prepared. Compound
12c was obtained in 81% yield from 6c, mp 202-204°; ir (potas-
-1
1
sium bromide); 3362, 1702, 1681, 1565, 1106 cm ; H nmr
-1
1
1420, 1188 cm ; H nmr (dimethyl sulfoxide-d ): δ 11.93
(dimethyl sulfoxide-d ): δ 8.41 (d, 1H, J = 8.02 Hz), 8.03 (d, 1H,
6
6
(br s, 1H), 7.80 (dd, 1H, J = 8.44 Hz, J = 8.42 Hz), 7.11 (dd, 1H,
J = 8.02 Hz), 7.91-7.69 (m, 5H), 4.20 (q, 2H, J = 7.13 Hz), 1.13
13
13
J = 6.89 Hz, J = 6.88 Hz); C nmr (dimethyl sulfoxide-d ): δ
(t, 3H, J = 7.13 Hz); C nmr (dimethyl sulfoxide-d ): δ 179.8,
6
6
156.4, 154.7, 151.4, 147.6, 144.3, 135.9, 127.1, 112.8, 104.5; ms
164.4, 154.5, 150.8, 150.4, 148.6, 145.3, 136.8, 130.8, 129.4,
128.5, 127.6, 121.7, 115.1, 112.5, 104.4, 59.9, 13.9; ms (m/e) 329
(M ); hrms: calcd. for 329.0864, found 329.0848 (M ).
+
(m/e) 242 (M ); hrms: calcd. for 242.0139, found 242.0142
+
+
+
(M ).

66
J.-C. Jung, Y.-J. Jung and O.-S. Park
Vol. 38
Anal. Calcd. for C
H
N: C, 65.65; H, 3.98; N, 4.25. Found
6-Fluoro-2-methyl-1,4-dihydro-7-(1-methylpiperazinyl)-4-
18 13
C, 65.33; H, 3.89; N, 4.23.
oxoquinoline-3-carboxylic Acid (14b).
6,7-Difluoro-2-methyl-4-oxoquinoline-3-carboxylic Acid (13a).
This compound was obtained in 71% yield as a colorless
o
crystal, mp 246 (dec); ir (potassium bromide); 1710, 1650, 1411,
A suspension of 12a (1.2 g, 4.5 mmoles) in 50 ml of 2N
aqueous sodium hydroxide was refluxed for 3 hours. The
reaction mixture was cooled and acidified with 10%
hydrochloric acid. The white solid was collected by filtration,
washed with water and dried to give 1.0 g (94%) of 13a, mp
310∞ (dec); ir (potassium bromide); 3447, 1636, 1465, 1227,
-1
1
1105 cm ; H nmr (dimethyl sulfoxide-d ): δ 13.81 (br s, 1H),
6
8.28 (dd, 1H, J = 7.90 Hz, J = 7.88 Hz), 8.17 (dd, 1H, J = 7.67 Hz,
J = 7.67 Hz) , 3.81-3.55 (m, 4H), 3.30-2.86 (m, 4H), 2.44 (s, 3H),
13
2.29 (s, 3H); C nmr (dimethyl sulfoxide-d ): δ 173.1, 166.1,
6
161.2, 156.7, 148.7, 144.2, 122.1, 116.3, 113.9, 108.1, 55.2, 54.9,
50.2, 49.8, 41.7, 16.7.
-1
1
697 cm ; H nmr (dimethyl sulfoxide-d ): δ 12.48 (br s, 1H),
Anal. Calcd. for C
H N : C, 60.18; H, 5.68; N, 13.16. Found
6
16 18 3
8.25 (dd, 1H, J = 7.76 Hz, J = 7.76 Hz), 8.03 (dd, 1H, J = 7.31
C, 62.35; H, 5.59; N, 12.98.
13
Hz, J = 7.30 Hz) , 2.45 (s, 3H);
C nmr (dimethyl
6-Fluoro-2-phenyl-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-
3-carboxylic Acid (14c).
sulfoxide-d ): δ 173.1, 167.4, 158.2, 149.6, 146.1, 144.8,
6
+
127.1, 115.6, 113.7, 110.2, 16.7; ms (m/e) 239 (M ); hrms:
calcd. for 239.0394, found 239.0403 (M ).
+
This compound was obtained in 80% yield as a pale yellow
solid, mp 204∞; ir (potassium bromide); 1698, 1636, 1460,
Anal. Calcd. for C H N : C, 55.24; H, 2.95; N, 5.86. Found
11
7 1
-1
1
C, 56.63; H, 3.02; N, 5.68.
1121 cm ; H nmr (dimethyl sulfoxide-d ): δ 13.66 (br s, 1H),
6
9.66 (s, 1H), 8.12 (dd, 1H, J = 8.09 Hz, J = 8.05 Hz), 8.09
(dd, 1H, J = 7.92 Hz, J = 7.92 Hz) , 7.73-7.48(m, 5H),
3.68-3.45 (m, 4H), 3.21-2.98 (m, 4H); C nmr (dimethyl
6,7-Difluoro-2-phenyl-4-oxoquinoline-3-carboxylic Acid (13c).
13
To a solution of 12c (0.6 g, 1.8 mmoles) in tetrahydrofuran/-
water (v/v, 3:1, 30 ml) was added lithium hydroxide (0.2 g , 9.0
mmoles) in tetrahydrofuran (8 ml). The mixture was stirred at
room temperature for 18 hours. The reaction mixture was
acidified with 10% hydrochloric acid. The white solid was
collected by filtration, washed with water and dried to give 0.5 g
(92%) of 13c, mp 310∞ (dec); ir (potassium bromide); 3447,
sulfoxide-d ): δ 172.5, 165.9, 165.1, 155.0, 149.3, 143.2,
6
141.9, 130.1, 129.6, 127.9, 127.0, 123.8, 122.7, 116.0, 111.5,
107.3, 52.4, 51.9, 46.5, 45.8;
Anal. calcd. for C
H N : C, 65.39; H, 4.94; N, 11.44. found
20 18 3
C, 63.90; H, 5.03; N, 11.27.
6-Fluoro-2-phenyl-1,4-dihydro-7-(1-methylpiperazinyl)-4-
oxoquinoline-3-carboxylic Acid (14d).
-1
1
1636, 1465, 1227, 697 cm ; H nmr (dimethyl sulfoxide-d ): δ
6
13.02 (br s, 1H), 8.12 (dd, 1H, J = 7.91 Hz, J = 7.86 Hz), 8.96
13
(dd, 1H, J = 7.55 Hz, J = 7.49 Hz), 7.51-7.40 (m, 5H); C nmr
This compound was obtained in 76% yield as a colorless crystal,
-
(dimethyl sulfoxide-d ): δ 172.8, 167.3, 166.1, 158.4, 149.8,
mp 209-210∞; ir (potassium bromide); 1714, 1644, 1420, 1105 cm
6
147.2, 131.6, 130.8, 129.1, 128.5, 127.6, 126.9, 124.0, 116.7,
112.8, 105.9.
1 1
; H nmr (dimethyl sulfoxide-d ): δ 13.93 (br s, 1H), 8.06 (dd, 1H,
6
J = 7.78 Hz, J = 7.78 Hz), 7.90 (dd, 1H, J = 7.65 Hz, J = 7.62 Hz) ,
Anal. Calcd. for C H N: C, 63.79; H, 3.01; N, 4.65. Found C,
16
9
7.68-7.42 (m, 5H), 3.72-3.49 (m, 4H), 3.28-3.04 (m, 4H), 2.29
63.99; H, 3.12; N, 4.51.
13
(s, 3H); C nmr (dimethyl sulfoxide-d ): δ 172.9, 166.6, 165.1,
6
154.6, 143.7, 142.5, 132.9, 130.1, 129.8, 128.3, 127.9, 127.1, 122.7,
116.4, 111.9, 107.3, 55.6, 54.1, 49.0, 48.6, 41.1;
General Procedure for the Preparation of 6-Fluoro-2-(methyl or
phenyl)-1,4-dihydro-7-(1-piperazinyl or 1-methylpiperazinyl)-4-
oxoquinoline-3-carboxylic Acids (14a-d).
Anal. Calcd. for C
H N : C, 66.13; H, 5.29; N, 11.02. Found
21 20 3
C, 65.28; H, 5.42; N, 11.34.
A mixture of 13a,c (3.3 mmoles) and piperazine or
N-methylpiperazine (10.0 mmoles) in 20 ml of pyridine was
heated at 90° for 6-36 hours under nitrogen atmosphere. The
reaction mixture was evaporated under reduced pressure. The
residue was treated with water, and then the resulting precipitate
was collected by filtration, washed with water and recrystallized
from ethanol or N,N-dimethylformamide to afford 14a-d,
respectively.
Acknowledgments.
This work has been supported by the Basic Science Research
Institute Program (BSRI-99-3433), Ministry of Education,
Republic of Korea. The structure analyses of the compounds
were partially supported by Korea Basic Science Institute.
REFERENCES AND NOTES
6-Fluoro-2-methyl-1,4-dihydro-7-(1-piperazinyl)-4-oxo-quino-
line-3-carboxylic Acid (14a).
[1a] R. Gill, R. Hargreaves and J. A. Kemp, J. Cereb. Blood Flow
Metab., 11, 304 (1991); [b] P. D. Leeson, B. J. Williams, M. Rowley, K.
W. Moore, R. Baker and J. A. Kemp, Bioorg. Med. Chem. Lett., 3, 71
(1993); [c] C. F. Neviile, M. F. Grundon, V. N. Ramchandran, G. Reisch
and J. Reisch, J. Chem. Soc. Perkin Trans I, 2261 (1991).
[2a] E. Ziegler and Th. Kappe, Angew. Chem., 76, 921 (1964);
Angew. Chem., Int. Ed. Engl., 3, 754 (1964); [b] E. Ziegler, Th. Kappe
and R. Salvador, Monatsh. Chem., 94, 453 (1963).
[3a] Bayer A. G., British Patent 721,171 (1954); Chem. Abstr., 50,
2685e (1956); Bayer A. G. (U. Horlein inv.), British Patent 733,123
(1955); Chem. Abstr., 50, 10799f (1956); [b] U. Horlein, Chem. Ber., 87,
463 (1954).
This compound was obtained in 78% yield as a beige
crystal, mp 216-217°; ir (potassium bromide); 1702, 1656,
-1
1
1432, 1091 cm ; H nmr (dimethyl sulfoxide-d ): δ 13.62
6
(br s, 1H), 8.25 (dd, 1H, J = 7.22 Hz, J = 7.20 Hz), 8.03 (dd,
1H, J = 7.01 Hz, J = 7.04 Hz), 3.64-3.33 (m, 4H), 2.91-3.24
13
(m, 4H), 2.38 (s, 3H); C nmr (dimethyl sulfoxide-d ): δ
6
174.0, 167.2, 161.9, 156.3, 149.7, 143.7, 123.1, 115.6, 113.8,
107.1, 51.3, 50.9, 45.8, 44.9, 16.5.
Anal. Calcd. for C
H N : C, 59.01; H, 5.28; N, 13.76. Found
15 16 3
C, 60.30; H, 5.13; N, 13.89.

Jan-Feb 2001
Synthesis of 4-Hydroxyquinolin-2(1H)-one Analogues
67
[4a] A. M. Mcleod, S. Grimwood, C. Barton, L. Bristow, K.
[12a] I. V. Ukrainets, S. V. Solobodzyan, V. I. Krivobok, P. A.
Bezuglyi, V. I. Triskach, A. V. Turov, S. V.Gladchenko and G. V.
Oblentseva (Khar'k. Gos.Farm. Inst., Khaekov, USSR). Farm. Zh. (Kiev),
2, 78 (1991); Chem. Abstr., 115, 49362b (1991); [b] S. Fumio, H. Hiroaki,
M. Yoshikazu, I. Akio, I. Shunji and M. Ichiro, Eur. Pat. Appl. EP
458,636 (1991); Chem. Abstr., 116, 235457g (1992).
Saywell, G. R. Marshall and R. G. Ball, J. Med. Chem., 38, 2239 (1995);
[b] R. W. Carling, P. D. Leeson, K. W. Moore, J. D. Smith, C. R. Moyes,
I. M. Mower, S. Thomas, T. Chan, R. Baker, A. C. Foster, S. Grimwood,
J. A. Kemp, G. R. Marshall, M. T. Tricklebank and K.L. Saywell, J. Med
Chem., 36, 3386 (1993).
[13a] M. Ohgoshi, Chemotherapy, 22, 1126 (1974); [b] Methods for
dilution antimicrobial susceptibility tests for bacteria grown aerobically;
approved standard. National Committee for Clinical Laboratory
Standards. (1985); National Committee for Clinical Laboratory
Standards: Villanova, PA, (1985).
[14] H. Koga, A. Itoh, S. Murayama, S. Suzue and T. Irikura, J.
Med. Chem., 23, 1358 (1980)
[15] T. Okada, T. Tsuji and T. Tsushima, J. Heterocyclic Chem., 28,
1061 (1991).
[5] P. Baumgarten and W. Kargel, Ber., 60, 832 (1927); improved
method: W. Stadlbauer, O. Schmut and Th. Kappe, Monatsh. Chem., 111,
1005 (1980).
[6a] D. R. Buckle, B. C. C. Cantello, H. Smith and B. A. Spicer, J.
Med Chem., 18, 726 (1975); [b] Farbenfabrik Hoechst, D. R. P. 102,894;
Chem. Zblt., I, 462 (1899).
[7a] J. R. Price in “Fortschritte der Chemic Organischer
Naturstoffe”, L. Zechmeister, ed, 13, 302 (1956); [b] E. Ziegler and K.
Gelfert, Monatsh. Chem., 90, 822 (1959); [c] E. Ziegler and H. Junek,
Monatsh. Chem., 90, 762 (1959).
[8] Badische Anilin und Sodafabrik, D. R. P. 117,167; Chem.
Zblt., I, 236 (1901).
[16] D. D. Perrin, L. F. Armarego and D. R. Perrin, Purifiation of
nd
Laboratory Chemicals. 2 ed. Pergamon Press, New York, (1980).
[17a] B. Fertel, Lawrence, C. Lin Henry, U.S. Patent 4,994,606, US
Appl. 439,228 (1991); Chem. Abstr., 115, 71130w (1991); [b] Degraw, J.
Chem. Eng. Data, 13, 587 (1968).
[18] D. Sicker, Pharmazie, 48, 604 (1991); Chem. Abstr., 116,
127949k (1992).
[9] E. Ziegler and H. Junek, Monatsh. Chem., 87, 503 (1956).
[10] C. M. Mehta and G. H. Patel, J. Ind. Res. (India), 18b, 391
(1959).
[11] J. C. Jung, J. C. Kim and O. S. Park, Synth. Commun. 29 (20),
3587 (1999).
[19] R. Johannes, S. A. Reza, B. Andreas, M. Michael, Monatsh.
Chem., 119, 781 (1988).