Synthesis of new quinolinones from 3-nitropyranoquinolinones

Article abstract of DOI:10.3184/174751916X14579598972166

Alkaline hydrolysis of 3-nitropyranoquinolinones (6-alkyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]quinoline-2,5(6H)-diones) for different reaction times gave five products which were formed by the progressive degradation of the nitropyrano ring. Varying amounts of 3-nitroacetylquinolinones, quinolinones with side-chains of β- And β-ketoacids, quinolinone-3-carboxylic acids and 4-hydroxyquinolinones were isolated. With the aim of preparing new biologically active quinolone derivatives, the products of reaction of the 3-nitropyranoquinolinones with side-chains of α- And β-ketoacids with some nitrogen and carbon nucleophiles were also studied, some giving rise to annulated products.

Full text of DOI:10.3184/174751916X14579598972166

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 APRIL, 239–246
RESEARCH PAPER 239
Synthesis of new quinolinones from 3-nitropyranoquinolinones
Jehan M. Morsy*, Hany M. Hassanin, Mostafa M. Ismail and Marwa M.A. Abd-Alrazk
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy 11711, Cairo, Egypt
Alkaline hydrolysis of 3-nitropyranoquinolinones (6-alkyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]quinoline-2,5(6H)-diones) for
different reaction times gave five products which were formed by the progressive degradation of the nitropyrano ring. Varying
amounts of 3-nitroacetylquinolinones, quinolinones with side-chains of β- and α-ketoacids, quinolinone-3-carboxylic acids and
4-hydroxyquinolinones were isolated. With the aim of preparing new biologically active quinolone derivatives, the products of reaction
of the 3-nitropyranoquinolinones with side-chains of β- and α-ketoacids with some nitrogen and carbon nucleophiles were also studied,
some giving rise to annulated products.
Keywords: β-ketoacids, α-ketoacids, pyranoquinolinone, nucleophilic reagents, cyclic condensation
3-Substituted-γ-pyrones are valuable synthetic intermediates
in the preparation of new heterocyclic systems and many
biologically important substituted quinolinones.1–6 Recently,
quinolinone derivatives have become of increasing interest
since many of these compounds show useful applications as
chemotherapeutic agents. For example, some quinolinones were
recently reported to have potential as inhibitors for hepatitis
C polymerase,7,8 microsomal prostaglandin E2 synthase-1 and
selective ions.9,10 It has been reported that introduction of a nitro
group into position-3 of a γ-pyrone ring enhances the reactivity
of the γ-pyrone system towards nucleophilic reagents.11 Here we
report the alkaline hydrolysis of 3-nitropyranoquinolinones at
different reaction times and a study of the chemical behaviour
of the products towards different nucleophiles to obtain a new
series of quinolinone derivatives of expected biological activity.
It was reported that a nitroalkyl group is easily converted
to a carboxylic group.14,15 That prompted us to increase the
time of the alkaline hydrolysis reaction in order to obtain
carboxylic acid derivatives. Thus, the alkaline hydrolysis of
nitropyrone derivatives 1a,b for 6 h under reflux conditions
gave a mixture of two products, which could be separated by
fractional crystallisation. So, the mixture was crystallised using
ethanol and the minor products that dissolved in hot ethanol
were characterised as the α-ketoacids 2-(1-alkyl-4-hydroxy-
2-oxo-1,2-dihydroquinolin-3-yl)-2-oxoacetic
acids
4a,b
(R = CH3, CH2CH3).16 The major products that were insoluble
in hot ethanol were identified as 3-nitroacetyl derivatives 3a,b
(Scheme 2).
The transformation of nitroacetyl derivatives 3a,b into
α-ketoacid derivatives 4a,b can be explained according to the
suggested mechanism shown in Scheme 3.
When the reaction time of alkaline hydrolysis was increased
to 8 h, three products were obtained; two of the products were
separated by fractional crystallisation using hot ethanol. The
two ethanol-soluble products were separated from each other
by using silica gel column chromatography. The less adsorbed
product that was eluted first was characterised as 3-carboxylic
acid 5a or 5b. The more adsorbed product was characterised as
α-keto acid 4a or 4b.16 The product that was insoluble in ethanol
was identified as 3-nitroacetyl derivative 3a or 3b (Scheme 2).
It was observed that by increasing the time of hydrolysis of the
nitropyrone 1, the β-ketoacid 2 which was formed first was
converted to nitroacetyl 3 and then converted to α-ketoacid
4,14,15 which was further converted to 3-carboxylic acid 5. When
Results and discussion
Alkaline hydrolysis of nitropyrones 1a,b
When nitropyrones 1a,b were subjected to alkaline hydrolysis
using 1 M aqueous sodium hydroxide solution at 80 °C for 30
min, thenovel3-(1-alkyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-
3-yl)-2-nitro-3-oxopropanoic acids 2a,b were obtained in ~98%
yield (Scheme 1). Increasing the time of alkaline hydrolysis
to 4 h resulted in the formation of the corresponding 1-alkyl-
4-hydroxy-3-nitroacetylquinolin-2(1H)-ones 3a,b.12,13 The 1H
NMR spectrum of compound 2a showed a characteristic singlet
at δ 12.40 attributed to the active methine proton, in addition to
a D2O-exchangeable signal at δ 12.65 assigned to O–H.
OH
O
O
O
80 °C, 30 min
OH
NO2
(~98%)
N
O
R
2a,b
NO2
OH
O
aq.NaOH
N
R
O
OH
O
O
Reflux
4h
R=CH3 , C2H5
NO2
1a,b
(~95%)
N
R
3a,b
Scheme 1 Alkaline hydrolysis of 3-ntitropyranoquinolinones 1 for time periods of 0.5 and 4 h.
* Correspondent. E-mail: morsy_jehan@yahoo.com

240 JOURNAL OF CHEMICAL RESEARCH 2016
OH
N
O
O
OH
N
O
O
NO2
Reflux
6 h
OH
+
O
R
R
3a,b
4a,b
(80 %)
(~20%)
OH
O
OH
O
OH
N
R
3a,b
O
O
OH
NO2
OH
Reflux
8 h
+
+
O
N
R
O
N
O
R
5a,b
(~20 %)
O
4a,b
(~70 %)
(~10 %)
NO2
O
OH
O
O
aq.NaOH
OH
Reflux, 12-14 h
OH
N
O
N
R
1a,b
R=CH3 ,C2H5
R
5a,b
(~96 % )
reflux DMF, 4 h
OH
Reflux, one day
N
O
R
6a,b
(~94% )
Scheme 2 Alkaline hydrolysis of 3-nitropyranoquinolinones 1 for time periods of 6, 8, 12 and 24 h.
O-
..
H+
O-
N+
H
OH
N+
O
H
H
O
Prototropy
Prototropy
chain-ring
tautomerism
OH
O
N
O
Nitromethyl-hydroxyoxime
tautomerism
H
OH
OH
O
O
O
O
N
R
O
N
R
N
R
OH
N
OH
..
H
3a,b
OH
N OH
OH
OH
+
N
O
O
± H+
O
+
±
..
O
H
O
H O
:
2
N
R
O
N
R
O
N
R
O
N-hydroxy
acetimidic acid
OH
NH
O
OH
O
O
OH
OH
acetimide-acetamide
prototrpy tautomerism
H2O
hydrolysis
O
+
NH2OH
O
N
R
4a,b
O
N
R
N-hydroxyacetamide
Scheme 3 Transformation of compounds 3a,b into α-ketoacids 4a,b.
the alkaline hydrolysis time was increased to 12 h, the 1-alkyl-
4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (5a or
5b) was produced (~96%). Finally, when the hydrolysis ran for
one day or more, the known parent 1-alkyl-4-hydroxy-2-oxo-1,
2-dihydroquinoline (6a or 6b) was formed.17
Confirmatory synthesis of carboxylic acids 4a,b and 5a,b
Complex formation of acetyl derivatives with boron compounds
substantially increases the reactivity of the methyl or methylene
group.18,19 Therefore, additional support for the structures
assigned to acids 4a,b and 5a,b was achieved through the

JOURNAL OF CHEMICAL RESEARCH 2016 241
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Scheme 4 Synthetic route of 2-oxo-1,2-dihydroquinoline 6 from the corresponding 3-nitroacetyl derivative 3.
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9
4a
ꢓꢝꢔꢞꢖꢗ
Scheme 5 Reaction of 2-oxoacetic acid derivatives 4 with p-toluidine and carbothiodihydrazide as nitrogen nucleophiles.
conversion of 3-nitroacetyl derivatives 3a,b to nitroacetyl boron
chelate complexes 7a,b which are capable of undergoing facile
oxidation with selenium dioxide (Scheme 4).
The IR spectrum of compound 8 exhibited a characteristic
broad absorption band extending from 3500–2500 cm–1 due to
hydrogen bonding of carboxylic and enolic OH groups. Also,
two strong stretching bands of C=O functions, belonging to
carboxylic and quinoline, were observed at 1766 and 1632 cm–1
The 1H NMR spectrum of 7a exhibited a characteristic singlet
at δ 5.86. The mass spectrum of 7b showed that the molecular
ion peak appeared at m/z 323 (40.57%). The oxidation of the
boron complexes 7a,b using selenium dioxide in dioxan for
4 h gave α-keto acids 4a,b. Refluxing the α-keto acids 4a,b
in DMF or dichloroacetic acid,20 gave 1-alkyl-4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids 5a,b.
1
respectively. The H NMR spectrum of compound 8 showed
the presence of two D2O-exchangeable signals at δ 10.00 and
14.87 due to the enolic and carboxylic OH groups. Similarly,
condensation of α-ketoacid 4a with carbothiodihydrazide at
the ratio 1:2 in ethanol in the presence of triethylamine (TEA),
afforded the simple condensation product bis[2-(4-hydroxy-
Reaction of α-ketoacids 4a,b with nucleophiles
1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2-oxoacetic
acid]
The reactivity of 2-(1-ethyl-4-hydroxy-2-oxo-1,2-dihydro-
quinolin-3-yl)-2-oxoacetic acid (4b) towards some nucleophilic
reagents was studied. Thus, treatment of the α-ketoacid
4b with p-toluidine in boiling ethanol containing a few
drops of piperidine afforded (1-ethyl-4-hydroxy -2-oxo-1,2-
dihydroquinolin-3-yl)-p-tolyliminoacetic acid (8) (Scheme 5).
thiocarbodihydrazone (9).
Treatment of α-ketoacid 4b with p-phenylenediamine in DMF
gave N,N’-bis[(1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-
yl) methylidene]-1,4-phenylenediamine (10) (Scheme 6). The
IR spectrum of 10 indicated that the product does not possess

242 JOURNAL OF CHEMICAL RESEARCH 2016
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Scheme 6 Reaction of 2-oxoacetic acid derivative 4b with p-phenylenediamine as a nitrogen nucleophile.
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12
13
Scheme 7 Reaction of 2-oxoacetic acid derivative 4a with chloroacetonitrile and diethyl malonate as a carbon nucleophile.
a carboxylic acid function and displayed absorption bands
at 3418, 2925, and 2863 cm–1 due to enolic OH and aliphatic
C–H vibrations. A relatively high downfield signal due to a
carboxylic proton was absent in the 1H NMR spectrum of 10.
The reaction of the α-ketoacid 4 with some carbon
nucleophiles was also investigated. Thus the reaction of 4a
with chloroacetonitrile, as an active methylene compound,
was performed using TEA in boiling ethanol to give
(3-chloro-2-hydroxy-6-methyl-5-oxo-5,6-dihydro-benzo[h]
[1,6]-naphthyridin-4-yl)carboxylic acid (12) (Scheme 7).
The IR spectrum of the product reveals the disappearance
of the cyano group. Also, the appearance of a peak at δ 12.5
weight of 302 which was consistent with the molecular formula
C13H10N4O5. The IR spectrum showed broad absorption bands
at 3420, 3190 and 2700 cm–1 due to N–H and O–H revealing
a high extent of hydrogen bonding and displayed bands at
1635 and 1596 cm–1 which were attributed to C=O and C=N
respectively. The H NMR spectrum showed signals at δ 6.5
and δ 8.9 due to C–H and N–H protons of the pyrazole ring, in
addition to a band at δ 11.44 due to an enolic OH.
1
The reaction of β-ketoacid 2a with triethyl orthoformate under
fusion conditions for 4 h, followed by refluxing in DMF for
another 4 h, gave 6-methyl-3-nitro-6H-pyrano[3,2-c]quinolin-
4,5(6H)-dione (16) via the intermediate 15 (Scheme 9).12
A
1
suggested mechanism of formation of 3-nitropyranoquinoline
in the H NMR spectrum of compound 12 gave us clear cut
derivative 16 is depicted in Scheme 10.
information that the product 12 was formed via a non-isolable
intermediate 11. The conversion of the intermediate 11 to a
benzo[h][1,6]-naphthyridine 12 took place through a Dimroth
rearrangement.12 Finally, when the α-ketoacid 4a was subjected
to reaction with diethyl malonate under fusion conditions,
6-methyl-2,5-dioxo-5,6-dihydro-2H-pyrano[3,2-c]quinoline3-
carboxylic acid ethyl ester (13) was obtained. The IR spectrum
of the product 13 exhibited characteristic absorption bands at
2958–2858 cm–1 due to stretching vibrations of aliphatic C–H
and two bands at 1728 and 1642 cm–1 due to C=O functions
The IR spectrum of compound 16 showed absorption bands
at 1681 and 1633 cm–1 due to C=O of γ-pyrone and quinolinone
1
and the OH group was absent. The H NMR spectrum of 16
revealed the presence of the C–H proton of a γ-pyrone moiety
at δ 8.9 ppm and there was no evidence of an OH proton.
In addition to the analytical and spectral data which gave
important information about the structure of compound 16,
the preparation of the latter compound by another route gave
further evidence about the correctness of the assigned structure.
Thus, when the 3-nitroacetyl derivative 3a was allowed to
react with triethyl orthoformate under fusion conditions it
gave compound 16 (m.p., mixed m.p., TLC and spectra). Also,
treatment of 3-nitroacetyl derivative 3a with DMF/DMA in
dry toluene gave 3-(3-dimethylamino-2-nitroacryloyl)-4-
hydroxy-1-methylquinolin-2(1H)-one (17). An intramolecular
cyclocondensation occurred on heating compound 17 in glacial
acetic acid to afford 16. The IR spectrum of compound 17
showed a broad absorption band at 3421–2500 cm–1 due to
hydrogen bonded OH and absorption at 1673 and 1637 cm–1
1
belonging to a carboxylic group and a quinolinone. The H
NMR spectrum showed that both OH protons of the hydroxyl
and the carboxylic acid functionalities were absent and there
was a singlet at δ 6.5 due to the proton at position-4.
Reaction of β-ketoacids 2a with nucleophiles
Hydrazinolysis of compound 2a with hydrazine hydrate in
boiling DMF yielded 4-hydroxy-1-methyl-3-(4-nitro-5-oxo-4,5-
dihydropyrazol-3-yl)quinolin-2(1H)-one (14) (Scheme 8). The
analytical data of the product revealed that it had a molecular

JOURNAL OF CHEMICAL RESEARCH 2016 243
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Scheme 8 Hydrazinolysis of 2-nitro-3-oxopropanoic acid derivative 2a.
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ꢋꢌꢍꢎꢏꢐ
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ꢈꢤꢒꢣꢊ
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Scheme 9 Synthetic route to 3-nitropyrano[3,2-c]quinoline-4,5(6H)-dione derivative 16.
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15
Scheme 10 Suggested mechanism for the formation of compound 16.

244 JOURNAL OF CHEMICAL RESEARCH 2016
acidified by dilute HCl. The solid mixture that formed was filtered
off, washed several times with water, air dried and crystallised from
ethanol. The products that crystallised from ethanol were identified
as the α-keto acids 4a,b (20%) and the nitroacetyl compounds 3a,b
formed the pale yellow residue (80%). Similarly after 8 h treatment
with 1 M NaOH the solid mixture that separated after acidification
was crystallised from ethanol. The ethanol-soluble compounds were
found to be mixtures which were separated using silica gel column
chromatography and were identified as the α-keto acids 4a,b and the
quinoline-3-carboxylic acids 5a,b.
due to C=O of propanone and quinolinone moieties. The mass
spectrum of the product exhibited a peak at m/z 216 specific to
1
[M – 1]+. The H NMR spectrum of 17 showed two singlets at
δ 3.10 and δ 3.20 ppm due to protons of two methyl groups of
a dimethylamino functionality and integrations of the aromatic
and olefinic protons indicated the presence of 5 protons at δ
7.12–8.1.
Experimental
Melting points were determined on
a digital Stuart SMP3
apparatus. Infrared spectra were measured on a PerkinElmer 293
spectrophotometer using KBr disks. NMR spectra were obtained on
a Gemini-200 spectrometer (200 MHz), a Mercury 300B (300 MHz)
or a JEOL Eca-500 MHz Varian Gemini 300 spectrometer (1H NMR
at 300 Hz, 13C NMR at 75 Hz) in DMSO-d6 using TMS as an internal
standard. Chemical shifts () are given in ppm and coupling constants
(J) in Hz. Mass spectra were obtained using a GC-2010 Shimadzu gas
chromatography instrument mass spectrometer (70 eV). Elemental
microanalyses were performed on a PerkinElmer CHN-2400 analyser.
The 6-alkyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]quinolin-2,5(6H)-
diones were prepared in our laboratory according to the methodology
described by Hassanin.6
Procedure B
A mixture of boron complex 7a (1.5 g, 5 mmol) or 7b (1.6 g, 5 mmol)
and selenium dioxide (1.11 g, 10 mmol) in dioxane (50 mL) was heated
under reflux for 4 h. The black selenium precipitate that formed during
the course of the reaction was filtered off. The dioxane filtrate was
evaporated to give a solid material which was completely dissolved in
aqueous sodium carbonate solution (100 mL, 2 M) and filtered to give
a clear alkaline solution. The clear solution was acidified by dilute HCl
(100 mL, 2 M) to give a quantitative precipitate. The precipitate was
filtered, dried and crystallised from ethanol to give the α-ketoacid; 4a:
Yield 1.3 g (90%); m.p, 188–190 °C (lit.16 191 °C); or 4b: Yield 82%;
m.p. 200–202 °C (lit.16 203–205 °C).
3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2-nitro-3-
oxopropanoic acid (2a)
1-Alkyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 5a,b
A
solution of the 6-alkyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]
A
suspension of 4-hydroxy-6-methyl-3-nitro-2H-pyrano[3,2-c]
quinolin-2,5(6H)-dione 1a,b (1.4 g, 5 mmol) in 1 M sodium hydroxide
solution (100 mL) was refluxed for 12–14 h. The solution was filtered
from any insoluble materials and the clear solution was acidified by
dilute HCl. The precipitate that formed was filtered off, washed several
times with water, air dried and crystallised from ethanol to give the
acid; 5a: Yield 0.97 g (96%); m.p. 265–266 °C (lit.20 268–269 °C); or
5b: Yield 1.07 g (96%) m.p. 263–264 °C. (lit.20 266–267 °C).
quinoline-2,5(6H)-dione (1a) (1.4 g, 5 mmol) in 1 M sodium hydroxide
solution (100 mL) was refluxed for 1 h. The solution so formed was
filtered from any insoluble materials and the clear solution was
acidified by dilute HCl. The precipitate that formed was filtered off,
washed several times with water, air dried and crystallised from acetic
acid to give 2a as: Yellow crystals; yield 98%; m.p. 164–165 °C; IR
(KBr, cm–1): 3427–2500 (OH), 3083 (CHarom.), 2983, 2828 (CHaliphatic),
1-Alkyl-4-hydroxyquinolin-2(1H)-ones 6a,b
1730 (C=Oacid), 1686 (C=Oketone), 1636 (C=Oquinolinone), 1596, 1383
A
solution of the 6-alkyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]
1
(NO2); H NMR: δ 3.5 (s, 3H, N–CH3), 6.4 (s, 1H, CHNO2), 7.41 (t,
quinolin-2,5(6H)-dione 1a,b (1.4 g, 5 mmol) in 1 M sodium hydroxide
solution (100 mL) was refluxed for 24 h. The solution so formed
was filtered from any insoluble materials and the clear solution was
acidified by dilute HCl. The precipitate that formed was filtered off,
washed several times with water, air dried and crystallised from
methanol to give known compounds; 6a: Yield 92%; m.p. 260–262 °C
(lit.17 268 °C); and 6b: Yield 94%; m.p. 257–259 °C (lit.17 264 °C).
1H, J = 7.2 Hz, H-6), 7.66 (d, 1H, J = 8.7 Hz, H-8), 7.9 (t, 1H, J = 6.0
Hz, H-7), 8.01 (d, 1H, J = 6.6 Hz, H-5); 13C NMR: δ 30 (CH3), 62.0
(CHNO2), 101.2, 103.8, 112.7, 122.2, 135.2, 139.9, 137.3, 160.7,
165.3, 169.8, 179.3; MS m/z (Ir %): 306 (17.53) (M+), 261 (15.46), 200
(6.96), 184 (15.98), 158 (100), 100 (43.81). Anal. calcd for C13H10N2O7
(306.05): C, 50.99; H, 3.29; N, 9.15; found: C, 51.26; H, 3.10; N, 8.82%.
3-(1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-2-nitro-3-
oxopropanoic acid (2b)
4-(Difluoroboryloxy)-1-ethyl/methyl-3-(2-nitroacetyl)quinolin-
2(1H)-ones 7a,7b
A suspension of 1-ethyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]quinoline-
2,5(6H)-dione (1b) (1.51 g, 5 mmol) in 1 M sodium hydroxide solution
(100 mL) was refluxed for 1 h. The solution so formed was filtered from
any insoluble materials and the clear solution was acidified by dilute
HCl. The precipitate that formed was filtered off, washed several times
with water, air dried and crystallised from ethanol to give 2b as: Yellow
In a two-necked flask fitted with a stirrer and a dropping funnel, a
solution of the nitroacetylquinolinone 3a,b (5 mmol), in dry benzene
(50 mL), was heated under reflux. Then a solution of boron triflouride
etherate (0.78 g, 5.5 mmol) in dry benzene (5 mL) was added and
the reaction mixture was refluxed for 4 h. The excess benzene was
evaporated and the precipitate was collected, dried and crystallised
from anisole.
crystals; yield 83%; m.p. 144–145 °C; IR (KBr, cm–1): 3446 (OH),
3079 (CHarom.), 2973, 2935 (CHaliph.), 1716 (C=Oacid), 1690 (C=Oketone),
4-(Difluoroboryloxy)-1-methyl-3-(2-nitroacetyl)quinolin-2(1H)-
1
(C=Oquinolone) and 1616 (C=C); H NMR: δ 1.21 (t, 3H, J = 6.6 Hz,
one (7a): Yield 85%; m.p. 221–222 °C; IR (KBr, cm–1): 3082 (CHarom.),
2956, 2926 (CHaliphatic), 1621 (C=Oquinolinone), 1593, 1372 (NO2);
1H NMR: δ 3.7 (s, 3H, N–CH3), 5.8 (s, 1H, CHNO2), 7.4–8.05 (m, 4H,
Harom); 13C NMR: δ 30.7 (N–CH3), 80.6, 97.8, 115.5, 121.3, 124.1, 126.5,
127.9, 135.5, 163.9, 187.1, 189.8; MS m/z (Ir %): 311 (15) (M + 1), 310
(100) (M+), 309 (80) (M–1), 262 (20), 246 (21), 202 (18), 187 (8), 172
(4), 160 (2), 145 (2), 132 (7), 119 (4), 117 (2), 104 (5), 95 (9), 91 (100),
77 (17) and 65 (22). Anal. calcd for C12H9BF2N2O5 (310.06): C, 46.49;
H, 2.93; N, 9.04; found: C, 46.50; H, 2.90; N, 9.04%.
CH2CH3), 4.34 (q, 2H, J = 6.6 Hz, CH2CH3), 6.38 (s, 1H, CHNO2),
7.15–7.81 (m, 3H, ArH), 8.09 (d, 1H, H-10), 8.53 (s, 1H, H-2) and 12.29
(bs, 1H, OH exchangeable with D2O); 13C NMR: δ 12.3 (CH3), 43.1
(CH2), 62.2 (CHNO2), 101.4, 103.5, 112.5, 122.1, 135.2, 139.7, 137.2,
160.5, 165.1, 169.5, 179.2. Anal. calcd for C14H12N2O7 (320.26): C, 52.51;
H, 3.78; N, 8.75; found: C, 52.23; H, 3.68; N, 8.72%.
2-(1-Alkyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-2-oxoacetic
acid 4a,b
4-(Difluoroboryloxy)-1-ethyl-3-(2-nitroacetyl)quinolin-2(1H)-
Procedure A
one (7b): Yield 81%; m.p. 212–213 °C; IR (KBr, cm–1): 3082 (CHarom.),
2966, 2918 (CHaliphatic), 1720 (C=Ocarboxylic), 1686 (C=OB-keto), 1636
(C=Oquinolinone), 1596, 1383 (NO2); 1H NMR: δ 1.17 (t, 3H, J = 6.0 Hz,
N–CH2CH3), 4.15 (q, 2H, J = 6.3 Hz, N–CH2CH3), 5.8 (s, 1H, CHNO2),
A
solution of the 6-alkyl-4-hydroxy-3-nitro-2H-pyrano[3,2-c]
quinoline-2,5(6H)-dione 1a,b (1.4 g, 5 mmol) in 1 M sodium
hydroxide solution (100 mL) was refluxed for 6 h. The solution was
filtered from any insoluble materials and the clear solution was

JOURNAL OF CHEMICAL RESEARCH 2016 245
7.24 (t, 1H, J = 6.0 Hz, H-6), 7.5 (d, 1H, J = 9.0 Hz, 8-CH), 7.6 (t, 1H,
J = 6.6 Hz, 7-CH), 7.89 (d, 1H, J = 9.0 Hz, 5-CH); 13C NMR: δ 12.8
(CH3), 37.5 (NCH2), 101.5, 113.9, 114.7, 123.6, 123.8, 131.9, 136.1,
146.2, 149.9, 159.3, 162.6; MS m/z (Ir %): 325 (15) (M + 1), 324 (100)
(M+), 323 (80) (M–1), 276 (20), 260 (21), 216 (18), 188 (11), 161 (13),
160 (12), 132 (27), 116 (9), 92 (11), 91 (10), 77 (50) and 76 (31). Anal.
calcd for C13H11BF2N2O5 (324.07): C, 48.18; H, 3.42; N, 8.64; found: C,
48.20; H, 3.40; N, 8.65%.
catalytic amount of TEA was heated under reflux for 4 h. The reaction
mixture was left to cool and poured into water, acidified with HCl and
the precipitate that formed was collected, air dried and crystallised
from ethanol to give compound 12: Yield 67%; m.p. 294–297 °C; IR
(KBr, cm–1): 3430 (OH), 3080 (CHarom.), 2986, 2929 (CHaliphatic), 1730
1
(C=Ocarboxylic,), 1631 (C=Oquinolinone,); H NMR: δ 3.50 (s, 3H, N–CH3),
7.36 (t, 1H, J = 7.8 Hz, H-6), 7.39 (d, 1H, J = 8.4 Hz, H-8), 7.68 (t, 1H,
J = 7.8 Hz, H-7), 8.08 (d, 1H, J = 8.1 Hz, H-5), 12.5 (s, 1H, OHenolic);
13C NMR: δ 29.1 (CH3), 112.5, 115.5, 123.5, 125.3, 136.6, 140.3, 142.2,
149.9, 156.5, 157.5, 161.0, 168.6, 192.5; MS m/z (Ir %): 306 (7) (M+ +
2), 305 (16) (M+ + 1), 304 (78) (M+), 303 (48) (M+ – 1), 260 (100) (M+
– CO2), 226 (100) (M+ – CO2 – Cl), 159 (10), 119 (26), 116 (14), 95 (31),
91 (16), 77 (50) and 64 (31). Anal. calcd for C14H9ClN2O4 (304.03): C,
(1-Ethyl- 4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl) -p-
tolyliminoacetic acid (8)
A mixture of compound 4b (1.30 g, 5 mmol) and p-toluidine (0.53 g, 5
mmol) at molar ratio (Mr 1:1) in ethanol containing a catalytic amount
of piperidine was heated under reflux for 4 h. The reaction mixture
was left to cool and poured into water, acidified with HCl and the
precipitate that formed was collected, air dried and crystallised from
acetic acid to give compound 8: Yield 75%; m.p. 151–154 °C; IR
55.19; H, 2.98; N, 9.19; found: C, 55.16; H, 2.98; N, 9.17%.
6-Methyl-2,5-dioxo-5,6-dihydro-2H-pyrano[3,2-c]quinoline-3-
carboxylic acid ethyl ester (13)
(KBr, cm–1): 3500–2500 (OH), 3081 (CHarom.), 2950 (CHaliphatic), 1766
Diethyl malonate (7.6 mL, 50 mmol) was added to compound 4a
(1.25 g, 5 mmol) and the reaction mixture was refluxed for 8 h, left
to cool and the solid product that formed was isolated by filtration,
washed several times with hot ethanol and crystallised from DMF to
give compound 13: Yield 70%; m.p. 286–288 °C. IR (KBr, cm–1): 3080
(CHarom.), 2985, 2858 (CHaliphatic), 1738 (C=Oester), 1642 (C=Oquinolinone);
(C=Ocarboxylic,), 1632 (C=Oquinolinone,); 1H NMR: δ 1.17 (t, 3H, J = 7.8 Hz,
N–CH2CH3), 4.2 (q, 2H, J = 6.9 Hz, N–CH2CH3), 7.04 (t, 1H, J = 7.4
Hz, H-6), 7.44 (d, 1H, J = 8.4 Hz, H-8), 8.00 (t, 1H, J = 6.9 Hz, H-7),
8.22 (d, 1H, J = 6.6 Hz, H-5), 10.00 (s, 1H, OHenol), 14.8(s, 1H, acid);
13C NMR: δ 30.1, 37.5. (2 CH3), 112.3, 112.5, 115.4, 124.2, 125.3, 130.3,
131.5, 136.3, 140.3, 142.9, 149.2, 156.6, 158.5, 159.8, 160.0, 162.6,
189.3; MS m/z (Ir %): 350 (93) (M+), 306 (100) (M – CO2), 292 (67),
216 (18), 188 (16), 178 (55), 160 (12), 145 (11), 132 (27), 119 (26), 116
(14), 95 (31), 91 (16), 77 (50) and 64 (31). Anal. calcd for C20H18N2O4
(350.13): C, 68.56; H, 5.18; N, 8.00; found: C, 68.53; H, 5.16; N, 8.01%.
1H NMR: δ 1.24 (t, 3H, J = 6.3 Hz, NCH2CH3), 3.40 (s, 3H, N–CH3),
4.34 (t, 3H, J = 6.3 Hz, NCH2CH3), 6.50 (s, 1H, 4-CH), 7.34 (t, 1H,
J = 7.8 Hz, H-6), 7.58 (d, 1H, J = 8.4 Hz, H-8), 7.90 (t, 1H, J = 7.8
Hz, H-7), 8.08 (d, 1H, J = 8.1 Hz, H-5); 13C NMR: δ 14.1 (CH3), 30.2
(CH3N), 38.7 (CH2), 99.6, 102.6, 113.5, 116.8, 123.8, 124.8, 134.3,
134.8, 139.2, 160.1, 163.5, 166.1, 185.2; MS m/z (Ir %): 300 (9) (M+ +
1), 299 (80) (M+), 255 (59) (M+– OEt), 227 (100) (M+ – COOEt), 199
(12), 188 (23), 172 (28), 160 (16), 132 (68), 119 (22), 117 (31), 95 (65),
91 (35), 77 (19) and 64 (39). Anal. calcd for C16H13NO5 (299.08): C,
Bis[2-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-2-
oxoacetic acid] thiocarbo-dihydrazone (9)
A mixture of compound 4a (1.25 g, 5 mmol) and thiocarbodihydrazide
(0.43 g, 4 mmol) at molar ratio (Mr 2:1) in ethanol containing a
catalytic amount of TEA was heated under reflux for 4 h. The reaction
mixture was left to cool and poured into water, acidified with HCl and
the precipitate that formed was collected and washed several times
with hot ethanol to give compound 9: Yield 78%; m.p. 228–230 °C;
IR (KBr, cm–1): 3442 (OH), 3131, 3103 (NH), 3073 (CHarom.), 2937
(CHaliphatic), 1765 (C=Ocarboxylic,), 1637 (C=Oquinolinone,); 1H NMR: δ 3.6 (s,
3H, N–CH3), 7.19 (t, 1H, J = 7.8 Hz, H-6), 7.55 (d, 1H, J = 8.4 Hz, H-8),
7.6 (t, 1H, J = 7.8 Hz, H-7), 8.1 (d, 1H, J = 8.1 Hz, H-5), 11.5, 12.6 (s,
1H, OHenolic), 16.5 (s, 1H, acid); 13C NMR: δ 30.3, 90.7, 115.5, 121.3,
124.1, 126.5, 128.1, 135.1, 155.2, 161.9, 163.2, 164.3, 185.8; MS m/z (Ir
%): 564 (100) (M+), 565 (27) (M + 1), 566 (4) (M + 2). Anal. calcd for
C25H20N6O8S (564.11): C, 53.19; H, 3.57; N, 14.89; found: C, 53.20; H,
3.55; N, 14.84%.
64.21; H, 4.38; N, 4.68; found: C, 64.20; H, 4.36; N, 4.67%.
4-Hydroxy-1-methyl-3-(4-nitro-5-oxo-4,5-dihydropyrazol-3-yl)
quinolin-2(1H)-one (14)
A mixture of nitro-β-keto acid 2a (1.5 g, 5 mmol) and hydrazine
hydrate (0.26 g, 5 mmol) at molar ratio (Mr 1:1) in DMF was heated
under reflux for 4 h. The reaction mixture was left to cool and poured
into water. The precipitate that formed was collected, air dried
and crystallised from DMF to give compound 14: Yield 83%; m.p.
304 °C; IR (KBr, cm–1): 3190 (NH), 3420 (OH), 3085 (CHarom.), 2941
1
(CHaliphatic), 1635(C=Oquinolinone,), 1596, 1383 (NO2); H NMR: δ 3.7 (s,
3H, N–CH3), 6.5 (s, 1H, CH–NO2), 7.45 (t, 1H, J = 7.7 Hz, H-6), 7.7 (d,
1H, J = 8.1 Hz, H-8), 7.95 (t, 1H, J = 7.8 Hz, H-7), 8.14 (d, 1H, J = 8.0
Hz, H-5), 8.9 (s, 1H, NH), 11.4 (s, 1H, OH); 13C NMR: δ 29.2 (CH3),
99.2, 116.1, 123.4, 124.5, 128.8, 133.3, 138.4, 145.9, 158.6, 160.2, 162.2,
168.3; MS m/z (Ir %): 302 (35) (M + 1), 288 (34.00), 229 (42.00), 203
(45.00), 186 (27.50), 174 (42.00), 103 (35.50), 77 (25.58), 64(100).
Anal. calcd for C13H10N4O5 (302.07): C, 51.66; H, 3.33; N, 18.54;
N,N’-Bis[(1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)
methylidene]-1,4-phenylenediamine (10)
A mixture of compound 4b (1.3 g, 5 mmol) and p-phenylenediamine
(0.27 g, 2.5 mmol) at molar ratio (Mr 2:1) in DMF was heated under
reflux for 4 h. The reaction mixture was left to cool and poured into
water and the precipitate that formed was collected, air dried and
crystallised from DMF to give compound 10: Yield 70%; m.p.
found: C, 51.65; H, 3.33; N, 18.51%.
6-Methyl-3-nitro-4H-pyrano[3,2-c]quinolin-4,5(6H)-dione (16)
251–254 °C; IR (KBr, cm–1): 3418–2863 (OH), 3069 (CHarom.), 2925
(CHaliphatic), 1640 (C=Oquinolinone,); 1H NMR: δ 1.26 (t, 3H, J = 7.5 Hz, N–
Procedure A
Triethyl orthoformate (12 mL, 75 mmol) was added to compound 2a
(1.5 g, 5 mmol) and the reaction mixture was refluxed for 4 h, followed
by addition of DMF for another 4 h, left to cool and poured into ice
cold water. The solid product that formed was isolated by filtration and
crystallised from DMF to give compound 16: Yield 80%.
CH2CH3), 4.34 (q, 2H, J = 7.5 Hz, N-CH2CH3), 7.24 (t, 1H, J = 7.5 Hz,
H-6), 7.34 (d, 1H, J = 8.4 Hz, H-8), 7.65 (t, 1H, J = 6.9 Hz, H-7), 7.79
(d, 1H, J = 6.6 Hz, H-5), 13.6 (s, 1H, OHenol); 13C NMR: δ 12.7, 43.1,
84.8, 115.5, 121.4, 123.3, 124.1, 126.4, 128.0, 135.2, 147.2, 153.3, 161.1,
163.5; MS m/z (Ir %): 506 (100) (M+), 507 (32) (M + 1), 508 (6) (M
+ 2). Anal. calcd for C30H26N4O4 (506.2): C, 71.13; H, 5.17; N, 11.06;
found: C, 71.15; H, 5.15; N, 11.00%.
Procedure B
Triethyl orthoformate (12 mL, 75 mmol) was added to compound 3a
(1.31 g, 5 mmol) and the reaction mixture was refluxed for 8 h, left to
cool and poured into ice cold water. The solid product that formed was
isolated by filtration and crystallised from DMF to give compound 16:
Yield 85%.
(3-Chloro-2-hydroxy-6-methyl-5-oxo-5,6-dihydrobenzo[h]
[1,6]-naphthyridin-4-yl)carboxylic acid (12)
A mixture of compound 4a (1.25 g, 5 mmol) and chloroacetonitrile
(0.37 g, 5 mmol) at molar ratio (Mr 1:1) in ethanol containing a

246 JOURNAL OF CHEMICAL RESEARCH 2016
Procedure C
References
1
2
3
4
V. Ya Sosnovskikh, V.S. Moshkin and M.I. Kodess, Tetrahedron Lett.,
2009, 50, 6515.
V. Ya Sosnovskikh, V.S. Moshkin and M.I. Kodess, J. Heterocycl. Chem.,
2010, 47, 629.
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2010, 59, 615.
S. Mkrtchyan, V.O. Iaroshenko, S. Dudkin, A. Gevorgyan, M. Vilches-
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Z. Ghasemi, V. Nazari-Belvirdi, M. Allahvirdinasab and A. Shahrisa,
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Compound 17 (1.58 g, 5 mmol), in glacial acetic acid (15 mL), was
refluxed for 3 h. The reaction mixture was left to cool and poured into
water. The solid product that formed was filtered off and crystallised
from DMF to give compound 16: Yield 77%; m.p. > 300 °C; IR
(KBr, cm–1): 3444 (OH), 3080 (CHarom.), 2924 (CHaliphatic), 1681 (C=O,
C-4), 1633 (C=Oquinolinone,); 1H NMR: δ 3.5 (s, 3H, N–CH3),7.49 (t, 1H,
J = 7.8 Hz, H-6), 7.75 (d, 1H, J = 8.7 Hz, H-8), 7.9 (t, 1H, J = 6.9 Hz,
H-7), 8.1 (d, 1H, J = 8.1 Hz, H-5), 8.9 (s, 1H, CH-2); 13C NMR: δ 29.9
(CH3), 116.3, 123.8, 124.8, 131.2, 134.5, 139.3, 140.3, 142.9, 158.5,
161.1, 162.0, 172.6; MS m/z (Ir %): 273 (16) (M+ + 1), 272 (100) (M+),
271 (48) (M+ – 1), 244 (47), 211 (12), 200 (10), 170 (29), 155 (17), 142
(67), 140 (13), 132 (80), 114 (22), 99 (60), 77 (55), 76 (32). Anal. calcd
for C13H8N2O5 (272.04): C, 57.36; H, 2.96; N, 10.29; found: C, 57.30;
5
6
7
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H, 2.98; N, 10.26%.
8
9
3-(3-Dimethylamino-2-nitroacryloyl)-4-hydroxy-1-methylquinolin-
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DMF/DMA (5 mmol) was added to compound 3a (1.31 g, 5 mmol) in
dry toluene and the mixture was refluxed for 6 h. The reaction mixture
was left to cool. The solid product that settled out was filtered off,
washed and crystallised from methanol to give compound 17: Yield
74%; m.p. >300 °C; IR (KBr, cm–1): 3444 (OH), 3080 (CHarom.), 2924
10 S.G. Durón, A. Lindstrom, C. Bonnefous, H. Zhang, X. Chen, K.T. Symons,
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14 R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017.
15 H. Chikashita, Y. Morita and K. Itoh, Synth. Commun., 1987, 17, 677.
16 M. Abass, H.A. Allimony and H. Hassan. Phosphorus, Sulfur Silicon
Relat. Elem., 2013, 188, 1799.
1
(CHaliphatic), 1673 (C=Oketone), 1638 (C=Oquinolinone,); H NMR (δ): 3.1
(s, 3H, N(CH3)2), 3.30 (s, 3H, N–CH3), 3.70 (s, 3H, N–CH3), 7.14 (s,
1H, CH), 7.18–8.28 (aromatic protons); 13C NMR: δ 30.1, 35.5, 38.5.
(3CH3), 102.9, 125.4, 126.5, 133.1, 139.3, 140.3, 140.9, 158.5, 159.8,
160.0, 162.6, 170.5; MS m/z (Ir %): 317 (M+, 50), 273 (55) (M –
NH(Me)2), 260 (100), 218 (80), 201 (48), 163 (61), 153 (72), 124 (53),
218 (80), 81 (60) and 55 (11). Anal. calcd for C15H15N3O5 (317.1): C,
56.78; H, 4.76; N, 13.24; found: C, 56.76; H, 4.77; N, 13.22%.
17 E.A. Mohamed, J. Chem. Soc. Pak., 1991, 13, 166.
18 A.V. Manaev, I.N. Okhrimenko, K.A. Lyssenko and V.F. Traven, Russian
Chem. Bull., Inter. Ed., 57, 1734.
19 V.F. Traven, I.V. Voevodina, A.V. Manaev and N. Ya. Podkhalyuzina,
Chem. Heterocycl. Comp., 2007, 43, 416.
20 I.V. Ukrainets, P.A. Bezuglyi, V.I. Treskaeh, A.V. Turov and S.V.
Slobodzyan, Chem. Heterocycl. Comp., 1992, 28, 534.
Received 13 February 2016; accepted 20 February 2016
Paper 1603917 doi: 10.3184/174751916X14579598972166
Published online: 24 March 2016