Substituted quinolinones. Part 13 a convenient route to heterocyclization reactions with 3-substituted 4-hydroxyquinolin-2(1H)-one

Article abstract of DOI:10.1002/jhet.5570440206

(Chemical Equation Presented) The reactivity of 3-[(dimethylamino)prop-2- enoyl]-4-hydroxyl-1-methylquinolin-2(1H)-one (2) towards different nucleophilic and electrophilic reagents was investigated. The convenient synthesis of several 3-heterocyclyl-quino

Full text of DOI:10.1002/jhet.5570440206

Mar-Apr 2007
315
Substituted Quinolinones. Part 13
A Convenient Route to Heterocyclization Reactions with
3-Substituted 4-Hydroxyquinolin-2(1H)-one
Mohamed Abdel-Megid, Mohamed Abass* and Mohamed Hassan
Department of Chemistry, Faculty of Education, Ain Shams University,
Roxy, Cairo 11757, Egypt. E-mail: m.abass@chemist.com
Received April 15, 2006
OH
Heterocycle
N
O
OH
O
O
Me
1,3-binucleophiles
Me
Heterocyclo
N
Me
N
N
Me
Me
Me
N
O
Me
OH
O
O
Ph
N
O
OHC
OH
Me
Me
N
HN
i.
N
N
Me
N
N
R
N
HO
O
HO
N
O
ii. N2H4.H2O
N
Me
Me
The reactivity of 3-[(dimethylamino)prop-2-enoyl]-4-hydroxyl-1-methylquinolin-2(1H)-one (2) towards
different nucleophilic and electrophilic reagents was investigated. The convenient synthesis of several 3-
heterocyclyl-quinolinones such as 3-pyridazinyl- 10, 11, 3-pyranyl 19a,b and 3-pyrazolylquinolinones
20a,b, 22, 26a,b, 27a,b, 31 and 33 has been described starting from the 3-acetylquinolinone 1 and
enaminone 2. In addition, certain heterocyclo[c]quinolinones such as pyrimido- 12, 14 pyrano- 3, 17a,b
and pyrazolopyranoquinolinone 29 were obtained in good yields.
J. Heterocyclic Chem., 44, 315 (2007).
Quinolin-2-ones represent one of the most active
classes of heterocyclic compounds possessing a wide
variety of significant medicinal, pharmacological, and
industrial applications [1-4]. Due to these important
applications of quinolinone derivatives and in
continuation of our program, devoted for studying the
chemistry of biologically active quinolin-2-ones and
enaminones [2,5-8], prompted our interest to explore
the reactivity of 4-hydroxyquinolin-2-one bearing an
electron push-pull enaminone side chain moiety at
position 3. The chemical behavior of this system was
checked towards different reagents at the purpose of
production of new substituted quinolinones. This
work describes the synthetic utility of the newly
prepared enaminone 2 [2], which is leading to several
hetero-aromatic ring systems as fused or substituents
at the quinolinone moiety of expected biological
activity.
condensation of 3-acetyl-4-hydroxyl-1-methylquin-
olin-2(1H)-one (1) [9] with dimethylformamide
dimethylacetal (DMF-DMA) [2,7]. This enaminone 2
when boiled in glacial acetic acid underwent an
intramolecular cyclo-condensation furnishing
a
crystalline material that was characterized as 6-
methyl-4H-pyrano[3,2-c]quinoline-4,5(6H)-dione (3).
Two primary amines viz. aniline and propylamine
were taken as examples to check the nucleophilic
condensation behavior of the enaminone 2.
Interestingly,
two
structures
are
probable;
enaminoimine 4 and enaminone 5. However, in
glacial acetic acid at room temperature the reaction
afforded only the derivatives 5a,b. Structure 4 was
ruled out on basis of the 1H nmr spectrum which
confirmed the absence of two signals at δ ≈ 3.0–3.5
ppm which characterize the NMe2 grouping. The
ease of removal NMe2 moiety was also achieved by
treatment of enaminone 2 with piperidine giving
The starting compound 3-[(2E)-3-(dimethylamino)-
prop-2-enoyl]-4-hydroxy-1-methyl-quinolin-2(1H)-
one (2) was smoothly obtained via thermal
rise to the 2E-3-(piperidin-1-yl)prop-2-enone
6
(Scheme I).

316
M. Abdel-Megid, M. Abass and M. Hassan
Vol 44
Scheme I
O
OH
O
O
OH
O
O
Me
O
AcOH
Me
N
DMF-DMA
Me
N
O
N
N
Me
3
Me
Me
NH2
R
1
2
NH
R
OH
O
OH
N
OH
O
O
Me
N
N
NH
R
Me
O
N
N
O
N
Me
Me
Me
4
5a, R = Ph
b, R = Pr
6
Combination of pyridazine and/or pyrimidine and
quinolinone, in one molecular framework, is rarely
reported in the literature. For this reason and because of
the well-known biological activities of these ring systems,
the enaminone 2 was employed as promising synthon for
such targets. Thus, compound 2 smoothly coupled with 4-
nitrobenzenediazonium chloride to produce the
inseparable arylazo intermediate 8 [10], which is readily
hydrolyzed in the reaction course to yield the α-
hydrazono-β-oxopropanal 9.
of compound 9 with hippuric acid in acetic anhydride
afforded the 4-benzoylamino-6-[(quinolin-3-yl)carbonyl]-
pyridazin-3(2H)-one 11, in 66% yield (Scheme II).
Moreover reaction of enaminone 2 with thiourea in ethan-
olic potassium hydroxide solution did not give the anticipated
pyrimidinylquinolinone 13 and instead the pyrimido[5,4-
c]quinolin-5(1H)-one 12 was afforded. Compound 12 gave
negative ferric chloride test due to the absence of OH group.
Also, 1H nmr spectrum showed the presence of two singlets
at δ = 3.30 and 3.45 ppm due to NMe2, in addition to the
characteristic signals of the trans-olefinic protons. Moreover,
similar treatment of the enaminone 2 with cyanoguanidine
gave another pyrimido[5,4-c]quinolinone derivative 14 and
herein again the pyrimidinylquinolinone structure 15 was
obviously excluded (Scheme III).
Cyclization of the hydrazone derivative 9 with malono-
nitrile in the presence of piperidine furnished the 3-
iminopyridazine-4-carbonitrile derivative 10. The reaction
Scheme II
When the enaminone 2 was allowed to react with some
active methylene compounds such as ethyl cyanoacetate and
malononitrile in the presence of potassium hydroxide, the
pyranoquinolinone derivatives 17a (X = O) and 17b (X =
NH) were respectively obtained. The reaction of compound 2
with hippuric acid and/or aceturic acid in boiling acetic
anhydride [13], afforded 4-acetoxy-3-[3-(benzoyl or acetyl)-
amino-2-oxo-2H-pyran-6-yl]-1-methyl-quinolin-2(1H)-ones
19a,b (R = Ph, Me). The spectral data revealed disappearance
of dimethylaminovinyl system and the structure 19 indicated
that the cyclization process does not involve the hydroxyl
group at position-4 of quinolinone (Scheme IV).
N2Cl
OH
O
O
OH
O
O
Me
N
NO2
0-5 o
O
N
Me
N
2
N
N
NH
N
Me
C
Me
NO2
9
8
NO2
CN
CN
Both the acetyl 1 and enaminone 2 derivatives of 4-
hydroxyquinolinone are considered as appropriate inter-
mediates for pyrazole heterocyclization reactions. Thus,
treatment of the compound 2 with thiosemicarbazide and
thiocarbodihydrazide furnished the 1H-pyrazole-1-carbothio-
amide 20a and 1H-pyrazole-1-carbothiohydrazide 20b,
respectively. Cyclo-condensation of 7-chloro-4-hydrazino-
quinoline (21) with the enaminone 2, in glacial acetic acid,
afforded 4-hydroxyl-1-methyl-3-[1-(7-chloroquinolin-4-yl)-
1H-pyrazol-3-yl]quinolin-2(1H)-one (22). The structure
CO2H
NHCOPh
OH
O
OH
O
CN
NH
NHCOPh
O
N
N
N
O
N
N
N
O
Me
Me
10
11
NO2
NO2

Mar-Apr 2007
Substituted Quinolinones. Part XIII
317
Scheme III
CN
N
HN
S
N
HN
N
N
O
Me
Me
N
N
Me
Me
N
O
CN
NH2
Me
NH
Me
S
HN
NH2
12
14
NH2
2
CN
KOH
HN
KOH
SH
N
N
N
N
OH
OH
O
O
N
N
Me
Me
13
15
Scheme IV
X
CN
R
CN
O
OH
Me
Me
N
RCH2CN
KOH
N
Me
Me
O
N
N
O
Me
Me
17a, X = O
b, X = NH
16
2
O
NHCOR
O
O
OAc
OH
O
RCONHCH2CO2H
Ac2O
CO2H
NHCOR
N
O
N
Me
Me
19a, R = Ph
b, R = Me
18
Scheme V

318
M. Abdel-Megid, M. Abass and M. Hassan
Vol 44
suggested for the compound 22 was chemically fortified by
its alternative synthesis starting from the acetylquinolinone 1.
Thus, the hydrazone 23 was obtained on treatment of the
compound 1 with the compound 21. In situ, thermal conden-
sation of the hydrazone 23 with DMF-DMA smoothly led to
the compound 22 (Scheme V).
linone, which in turn hydrolyzed to give the separated
tetracyclic system 29. Another possibility is the hydrolysis
of the intermediate 28 into the corresponding carboxylic
acid is responsible for the formation of the pyrone ring via
an intramolecular condensation. Anyhow both routes are
logical and possible.
Scheme VI
NNHR
OHC
OH
CHO
H
N
NHR
OH
OH
N
O
RNHNH2
DMF-POCl3
R
Me
N
N
N
Ph
N
N
O
N
O
Me
Me
Me
OHC
OH
27a, R = H
b, R = CSNH2
24a, R = H
b, R = Ph
25
N
R
Ph
N
N
N
O
N
NC
OH
Me
HO
O
Me
1
N
26a, R = H
b, R = Ph
HONH2.HCl
AcOH
N
Ph
N
O
Piperidine
N
O
N
O
O
32
Me
HO
OH
Me
28
NH
N
AcONa
AcOH
NH2NH2.H2O
N
O
Me
30
Ph
O
O
Me
N
HN
N
Ph
N
HO
N
N
O
OH
N
Ph
N
Me
N
HO
N
O
HO
O
N
N
O
N
Me
O
N
Me
Me
NH
O
33
29
31
Condensation of the acetylquinolinone 1 with hydrazine
hydrate and with phenylhydrazine afforded the respective
hydrazones 24a,b [11] (Scheme VI). The hydrazones 24a,b
were subjected to react with Vilsmeier-Haack reagent
(DMF-POCl3) [12] to give the substituted pyrazole-4-
carbaldehydes 26a (R = H) and 26b (R = Ph) through the
intermediacy of the corresponding 3-(1-hydrazono-2,2-
diformylethyl)quinolinone 25. Traditional condensation
reaction of the aldehyde 26b with hydrazine hydrate and
thiosemicarbazide yielded the hydrazone 27a (R = H) and
thiosemicarbazone 27b (R = CSNH2), respectively in good
yields. Surprisingly, the condensation of 26b with
hydroxylamine hydrochloride, in glacial acetic acid did not
give the expected oxime or even the probable carbonitrile
28. The compound that separated from the latter reaction
was characterized as 6-methyl-16-phenyl-16H-pyrazolo-
[3',4':4,5]pyrano[3,2-c]quinoline-7, 12(6H)-dione (29)
(Scheme VI). It seems that successive steps took place in
which condensation leading to the oxime is followed by
dehydration to the carbonitrile 28. Afterwards the carbo-
nitrile underwent cycloaddition to an iminopyranoquino-
Selectively, we carried out Knoevenagel condensation
reaction of the aldehyde 26b with the pyrazolinone 30
[13] as an active methylene compound possessing both
quinolinone and pyrazole nuclei in the same molecule.
This reaction led to facile synthesis of the newly isolated
tetracyclic system 31. Attractively, another system of this
category was prepared in two steps. Thus, the
condensation of the available acetylquinolinone 1 with the
aldehyde 26b gave the α,β-unsaturated ketone 32, which
was treated with hydrazine hydrate to form the
polynuclear heterocyclic compound 33 having two
quinolinone and two pyrazole moieties in one molecular
frame (Scheme VI).
EXPERIMENTAL
All melting points were measured on a Gallenkamp MFB-595
apparatus and are uncorrected. IR spectra were recorded on
1
Perkin-Elmer FT-IR 1650 spectrophotometer in KBr disks. H
and 13C nmr spectra were recorded on a Varian Gemini 400
MHz (at 100.58 MHz for 13C) instrument, using either CDCl3 or
DMSO-d6 as solvents and TMS as an internal standard. Mass

Mar-Apr 2007
Substituted Quinolinones. Part XIII
319
spectra were obtained on HP MS-5988 and Carlo–Erba QMD-
1000 instrument by direct inlet, at beam energy 70 eV.
Elemental analyses were carried out on Perkin-Elmer 2400
Analyzer or at Cairo University Microanalytical Centre and Ain
Shams University Analytical Unit. Silica gel plates (Merck
F254) and silica gel 60 (Merck 230-400 mesh) were used for
analytical TLC and for flash chromatography, respectively. 3-
Acetyl-4-hydroxy-1-methylquinolin-2(1H)-one (1) [9], 1-(4-
hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-dimethyl-
amino-2-propen-1-one (2) [2,7], and 3-[1-(hydrazono and
phenylhydrazono)-ethyl]-4-hydroxy-1-methylquinolin-2(1H)-
ones 24a,b [11] were prepared according to the literature
methods.
(m, 3H, Harom + Holefin), 7.63 (t, 1H, C7-H), 8.16 (d, J,J = 15
Hz,1H, Holefin), 8.24 (d, J,J = 8 Hz, 1H, C5-H); MS (EI, 70 eV):
m/z (I%) 312 (22.19) (M+), 294 (13.19), 228 (51.07), 202 (4.95),
134 (5.54), 110 (100), 105 (7.56). Anal. Calcd. for C19H16N2O3:
C, 67.21; H, 6.45; N, 8.72 %. Found: C, 67.14; H, 6.19; N, 8.69.
(2E)-3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-
yl)-2-[(4-nitrophenyl)hydrazono]-3-oxopropanal (9). A cold
solution of 4-nitrobenzenediazonium chloride (10 mmol)
(prepared by adding a solution of 1.5 g sodium nitrite in 10 mL
H2O to a cold solution of 4-nitroaniline in 5 mL concentrated
HCl) was added with continuous stirring to a cold solution of
enaminone 2 in ethanol (50 mL, 95%) containing sodium
hydroxide (20 mmol). The mixture was stirred at room
temperature for 1 h and the solid product, so formed, was
collected by filtration, dried, and crystallized from DMF, in 75%
yield, m.p. 237-239 °C; IR (KBr): νmax 3390-2780 (br, NH +
OH), 1700 (C=Oaldeyde), 1650 (C=Oquinolone), 1620 (C=N), 1603,
6-Methyl-4H-pyrano[3,2-c]quinoline-4,5(6H)-dione (3).
The compound 2 (10 mmol) was refluxed in glacial acetic acid
(20 mL) for 2 h, and then left to cool to room temperature. The
precipitated crystalline material was filtered, washed with
ethanol, dried, and recrystallized from DMSO, in 90% yield,
m.p. 225-227 °C; IR (KBr): νmax 1660 (C=Opyrone), 1640
(C=Oquinolone), 1600, 1592 cm-1; MS (EI, 70 eV): m/z (I%) 227
(100) (M+), 201 (66.23) (M+– C2H2), 199 (57.73) (M+– CO), 175
1
1588 cm-1; H nmr (DMSO-d6): δH 3.60 (s, 3H, NMe), 6.40 (s,
1H, NH), 7.30-8.30 (m, 8H, Harom), 8.65 (s, 1H, CH=O); MS (EI,
70 eV): m/z (I%) 394 (5.00) (M+), 385 (2.42), 365 (7.00), 257
(28.80), 202 (100), 175 (17.05), 146 (8.40), 105 (18.13), 104
(19.40), 77 (21.05). Anal. Calcd. for C19H14N4O6: C, 64.46; H,
4.16; N, 11.56 %. Found: C, 64.29; H, 4.01; N, 11.38.
+
(78.05) (M+– C2HO•), 104 (53.00) (CH2=N-C6H4 ), 77 (58.77)
+
(C6H5 ). Anal. Calcd. for C13H9NO3: C, 68.72; H, 3.99; N, 6.16
%. Found: C, 68.54; H, 3.77; N, 5.98.
6-[(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
carbonyl]-3-imino-2-(4-nitrophenyl)-2,3-dihydropyridazine-
4-carbonitrile (10). To a suspension of the propanal 9 (10
mmol), in absolute ethanol (30 mL), malononitrile (10 mmol)
and a few drops of piperidine were added. The mixture was
heated under reflux for 6 h, left to cool to room temperature, and
then poured into water. The solid product that formed was
purified by flash-chromatography using ethyl acetate/ petroleum
ether as eluent (1:1, v/v) and then crystallized from ethanol, in
55% yield, m.p. 280-282 °C; IR (KBr): νmax 3419-3000 (br, OH,
NH), 2211 (C≡N), 1655 (C=Oketone), 1643 (C=Oquinolone), 1620
General Procedure for the Preparation of Enaminones
5a,b. To a solution of the compound 2 (10 mmol), in glacial
acetic acid (20 mL), each of aniline and n-propylamine was
added (10 mmol). The mixture was stirred at room temperature
for 1 h. The precipitate so formed was filtered and purified by
flash-chromatography by ethyl acetate/petroleum as eluent ether
(1:2, v/v) and then crystallized from acetic acid.
3-[(2E)-3-Anilinoprop-2-enoyl]-4-hydroxy-1-methylquinolin-
2(1H)-one (5a). This compound was obtained in 89.8% yield,
m.p. 265-266 °C; IR (KBr): νmax 3210 (NH), 2800-2700 (H-
1
1
(C=N), 1550 cm-1; H nmr (DMSO-d6): δH 3.65 (s, 3H, NMe),
bonded OH), 1645 (C=Oquinolone), 1618, 1600, 1589; H nmr
(DMSO-d6): δH 3.71 (s, 3H, NMe), 7.15-8.30 (m, 11H, Harom
+
5.85 (s, 1H, NH), 7.30-8.30 (m, 9H, Harom); MS (EI, 70 eV): m/z
(I%) 442 (357.41) (M+), 433 (42.35), 277 (32.30), 185 (51.07),
134 (33.29), 105 (53.70) , 91 (100), 77 (53.33). Anal. Calcd. for
C22H14N6O5: C, 59.73; H, 3.16; N, 19.00 %. Found: C, 59.58; H,
3.00; N, 18.87.
Holefin), 11.60 (bs, 1H, NH); 13C nmr (DMSO-d6): δC 30,01,
96.98, 104.44, 114.01, 116.53, 116.78, 121.75, 124.34, 125.72,
129.84, 133.80, 139.90, 140.93, 146.41, 161.74, 173.56, 192.70;
MS (EI, 70 eV): m/z (I%) 320 (7.33) (M+), 228 (100), 202
(10.35), 145 (2.15), 134 (7.48), 118 (10.34), 77 (13.85). Anal.
Calcd. for C19H16N2O3: C, 71.24; H, 5.03; N, 8.75 %. Found: C,
71.10; H, 4.86; N, 8.59.
4-Benzoylamino-6-[(4-hydroxy-1-methyl-2-oxo-1,2-dihydro-
quinolin-3-yl)carbonyl]-2-(4-nitrophenyl)pyridazin-3(2H)-one
(11). A mixture of the propanal 9 (10 mmol), hippuric acid (10
mmol), and acetic anhydride (20 mL) was heated under reflux
for 2 h. The excess solvent was evaporated under reduced
pressure in vacuum. The pasty residue obtained was triturated
with ethanol (25 mL), and the solidified material was collected
by filtration, washed thoroughly with diethyl ether (25 mL) and
crystallized from acetic acid, in 66% yield, m.p. >300 °C; IR
(KBr): νmax 3300, 3150-3077 (br, NH, OH), 1655 (C=Oketone),
1647 (C=Oamide), 1619 (C=N), 1562 cm-1; MS (EI, 70 eV): m/z
(I%) 537 (4.10) (M+), 432 (4.47) (M+– C6H5CHO), 335 (22.23)
(M+– C11H8NO3), 312 (2.15), 277 (9.80), 105 (100) (C6H5C≡O+).
Anal. Calcd. for C28H19N5O7: C, 62.57; H, 3.56; N, 13.03 %.
Found: C, 62.33; H, 3.28; N, 12.76.
General Procedure for the Preparation of Pyrimido-
quinolinones 12, 14 and Pyranoquinolinones 17a,b.
Equimolar amounts (10 mmol) of the compound 2 and each of
thiourea, cyanoguanidine, malononitrile, and ethyl cyanoacetate,
in absolute ethanol (20 mL), were treated with potassium
hydroxide (20 mmol) and then heated under reflux for 3 h.
Afterwards, neutralization of the reaction mixture with dilute
4-Hydroxy-1-methyl-3-[(2E)-3-(propylamino)prop-2-enoyl]-
quinolin-2(1H)-one (5b). This compound was obtained in 75%
yield, m.p. 243-244 °C; IR (KBr): νmax 3137 (NH), 2980
(CHaliph), 2873-2850 (H-bonded OH), 1651 (C=Oquinolone), 1620,
1
1590 cm-1; H nmr (CDCl3): δH 1.01 (t, 3H, CH3), 1.59 (m, 2H,
CH2), 3.20 (q, 2H, CH2), 3.60 (s, 3H, NMequinolone), 6.90-8.11 (m,
6H, Harom + Holefin), 9.76 (bs, 1H, NH); MS (EI, 70 eV): m/z (I%)
286 (34.06) (M+), 228 (38.60), 202 (51.26), 175 (11.71), 134
(28.13), 77 (100). Anal. Calcd. for C16H18N2O3: C, 67.12; H,
6.34; N, 9.79 %. Found: C, 67.01; H, 6.09; N, 9.52.
4-Hydroxy-1-methyl-3-[(2E)-3-(piperidin-1-yl)prop-2-enoyl]-
quinolin-2(1H)-one (6). A suspension of the compound 2 (10
mmol) was treated with piperidine (10 mmol), and then heated
under reflux for 3h. The crystalline precipitate so formed during
the course of the reaction was collected by filtration and
recrystallized from acetic acid, in 68% yield, m.p. 222-224 °C;
IR (KBr): νmax 2916 (CHaliph), 2860 (OH), 1654 (C=O), 1646
(C=O), 1626, 1595 cm-1; 1H nmr (CDCl3): δH 1.50 (m, 6H,
(CH2)3), 3.58 (m, 4H, CH2-N-CH2), 3.64 (s, 3H, NMe), 7.21-736

320
M. Abdel-Megid, M. Abass and M. Hassan
Vol 44
acetic acid gave a precipitate which was filtered off, washed
with water and purified by flash-chromatography using ethyl
acetate/petroleum ether as eluent (1:2, v/v) and then crystallized
from the proper solvent.
4-[(E)-2-(Dimethylamino)vinyl]-6-methyl-2-thioxo-2,6-dihy-
dropyrimido[5,4-c]quinolin-5(1H)-one (12). This compound
was obtained in 65% yield, m.p. 190-192 °C (ethanol); IR
(KBr): νmax 3150 (NH), 2925 (CHaliph), 1650 (C=Oquinolone), 1618
(C=N), 1607, 1590, 1212, 1140 cm-1 (C=S); 1H nmr (CDCl3): δH
3.30, 3.45 (two s, 6H, NMe2), 3.69 (s, 3H, NMequinolone), 6.29 (s,
1H, NH), 7.16- 8.3 (m, 6H, Harom + Holefin). Anal. Calcd. for
C16H16N4OS: C, 61.52; H, 5.16; N, 17.93 %. Found: C, 61.28; H,
5.01; N, 17.77.
4-[(E)-2-(Dimethylamino)vinyl]-6-methyl-5-oxo-5,6-dihydro-
pyrimido[5,4-c]quinolin-2-ylcyanamide (14). This compound
was obtained in 60% yield, m.p. 202-204 °C (acetone); IR
(KBr): νmax 3212(NH), 2950-2900 (CHaliph), 2200 (C≡N), 1651
(C=Oquinolone), 1620, 1590 cm-1; 1H nmr (DMSO-d6): δH 3.20,
3.40 (two s, 6H, NMe2), 3.46 (s, 3H, NMequinolone), 6.30 (b, 1H,
NH), 7.21-8.4 (m, 6H, Harom + Holefin); MS (EI, 70 eV): m/z (I%)
320 (2.14) (M+), 280 (2.41), 149 (3.58), 97 (4.97), 77 (2.39), 58
(100). Anal. Calcd. for C17H16N6O: C, 63.74; H, 5.03; N, 26.23
%. Found: C, 63.55; H, 4.79; N, 25.98.
4-[(E)-2-(Dimethylamino)vinyl]-6-methyl-2,5-dioxo-5,6-
dihydro-2H-pyrano[3,2-c]quinoline-3-carbonitrile (17a). This
compound was obtained in 70% yield, m.p. 260-263 °C
(dioxane); IR (KBr): νmax 2919 (CHaliph), 2223 (C≡N), 1689
(C=Opyrone), 1645 (C=Oquinolone), 1600, 1590 cm-1; 1H nmr
(DMSO-d6): δH 3.10 (s, 3H, NMe), 3.30 (s, 3H, NMe), 3.65 (s,
3H, NMequinolone), 7.10-8.20 (m, 6H, Harom + Holefin). Anal. Calcd.
for C18H15N3O3: C, 67.28; H, 4.71; N, 13.08 %. Found: C, 67.01;
H, 4.38; N, 12.82.
nmr (DMSO-d6): δH 2.22 (s, 3H, NCOMe), 2.50 (s, 3H,
OCOMe), 3.68 (s, 3H, NMe), 7.20-7.62 (m, 4H, Harom), 7.71 (d,
1H, γ-CHpyrone), 8.03 (s, 1H, NH), 8.30 (d, 1H, β-CHpyrone); MS
(EI, 70 eV): m/z (I%) 368 (17.25) (M+), 326 (100), 284 (47.30),
256 (50.99), 227 (59.48), 202 (36.88), 175 (58.19), 149 (32.65),
104 (36.41), 77 (46.89). Anal. Calcd. for C19H16N2O6: C, 61.96;
H, 4.38; N, 7.61 %. Found: C, 61.67; H, 4.08; N, 7.44.
General Procedure for the Preparation of Pyrazolylquino-
linones 20a,b and 22. To a solution of the compound 2 (10
mmol), in glacial acetic acid (20 mL), was added 10 mmol of
each of thiosemicarbazide, thiocarbodihydrazide, and 7-chloro-
4-hydrazinoquinoline (21). The reaction mixture was heated
under reflux for 4 h, cooled, and poured into crushed ice. The
solid precipitate was collected by filtration, dried, purified by
flash-chromatography using ethyl acetate/petroleum ether as
eluent (1:2, v/v) and then crystallized from the proper solvent.
3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
1H-pyrazole-1-carbothioamide (20a). This compound was
obtained in 75% yield, m.p. 245-247 °C (acetic acid); IR (KBr):
νmax 3240-2800 (br, NH2, OH), 1645 (C=Oquinolone), 1620, 1570,
1330, 1225 (N-C=S) cm-1; MS (EI, 70 eV): m/z (I%) 300 (3.16)
(M+), 282 (2.47) (M+–H2O), 240 (5.27) (M+–CHSNH2), 149
+
+
(12.04), 104 (2.36) (CH2=NC6H4 ), 83 (100) (C3H5N3 ), 77
+
(3.97) (C6H5 ). Anal. Calcd. for C14H12N4O2S: C, 55.99; H, 4.03;
N, 18.65 %. Found: C, 55.75; H, 3.86; N, 18.42.
3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
1H-pyrazole-1-carbothiohydrazide (20b). This compound was
obtained in 75% yield, m.p. 170-172 °C (DMF); IR (KBr): νmax
3216-3450 (br, NH2, NH, OH), 1650 (C=Oquinolone), 1627, 1577,
1326, 1160 (N-C=S) cm-1; MS (EI, 70 eV): m/z (I%) 315 (75.00)
(M+), 240 (1.58), 212 (6.33), 175 (1.40), 146 (6.42), 104 (12.50),
77 (82.67), 76 (100). Anal. Calcd. for C14H13N5O2S: C, 53.32; H,
4.11; N, 22.22 %. Found: C, 52.99; H, 4.01; N, 22.11.
4-Hydroxyl-1-methyl-3-[1-(7-chloroquinolin-4-yl)-1H-pyra-
zol-3-yl]quinolin-2(1H)-one (22). Method a. This compound
was obtained according to the above general procedure, in 80%
yield, m.p. 212-214 °C (DMF).
4-[(E)-2-(Dimethylamino)vinyl]-2-imino-6-methyl-5-oxo-
5,6-dihydro-2H-pyrano[3,2-c]quinoline-3-carbonitrile (17b).
This compound was obtained in 66% yield, m.p. 282-283 °C
(methanol); IR (KBr): νmax 3435 (NH), 2923 (CHaliph), 2203
1
(C≡N), 1655 (C=Oquinolone), 1600, 1585 cm-1; H nmr (DMSO-
d6): δH 3.42 (two s, 6H, NMe2), 3.46 (s, 3H, NMequinolone), 7.20-
8.20 (m, 5H, Harom+ Holefin), 8.61 (d, J,J = 15.5 Hz, 1H, Holefin);
MS (EI, 70 eV): m/z (I%) 320 (9.00) (M+), 291 (4.57), 250
(1.13), 105 (1.40), 77 (1.36), 85 (8.95), 58 (100). Anal. Calcd.
for C18H16N4O2: C, 67.49; H, 5.03; N, 17.49 %. Found: C, 67.35;
H, 4.80; N, 17.22.
General Procedure for the Preparation of Pyranylquino-
linones 19a,b. A solution of the enaminone 2 (10 mmol) and
each of hippuric acid or aceturic acid (10 mmol), in acetic
anhydride (10 mL), was heated under reflux for 2 h. The
reaction mixture was concentrated and the crystalline product
that obtained upon cooling was isolated by filtration and
recrystallized from acetic acid.
4-Acetoxy-3-(3-benzoylamino-2-oxo-2H-pyran-6-yl)-1-methyl-
quinolin-2(1H)-ones (19a). This compound was obtained in
85% yield, m.p. 226-228 °C; IR (KBr): νmax 1694 (C=Oacetoxy),
1684 (C=Opyrone), 1648 (C=Oamide), 1600, 1590 cm-1; 1H nmr
(CDCl3): δH 2.50 (s, 3H, COMe), 3.65 (s, 3H, NMe), 7.20-7.80
(m, 9H, Harom), 7.90 (d, 1H, γ-CHpyrone), 8.60 (d, 1H, β-CHpyrone),
8.75 (s, 1H, NH). Anal. Calcd. for C24H18N2O6: C, 66.97; H,
4.22; N, 6.51 %. Found: C, 66.74; H, 3.98; N, 6.32.
Method b. To a solution of the acetylquinolinone 1 (10
mmol), in DMF (20 mL), 7-chloro-4-hydrazinoquinoline (21)
(10 mmol) was added. The reaction mixture was heated under
reflux for 1 h. A canary yellow crystalline precipitate of the
hydrazone 23 was obtained which was not separated. DMF-
DMA (6 mmol) was added and the reaction mixture was heated
under reflux for 4 h. The solvent was remove by evaporation
under reduced pressure and the solid residue was triturated with
methanol (5 mL), filtered, dried and crystallized from DMF to
give the compound 22, in 74% yield, m.p. 212-213 °C (no
depression in mixed m.p.); IR (KBr): νmax 3320-2750 (br, H-
bonded OH), 1643 (C=Oquinolone), 1625, 1551, 760 (C-Cl) cm-1;
MS (EI, 70 eV): m/z (I%) 402.5 (2.60) (M+), 312 (32.08), 302
(42.41), 288 (52.72), 241 (63.85) (M+– [7-chloroquinoline]•), 68
(100) (1H-pyrazolium ion). Anal. Calcd. for C22H15N4O2Cl: C,
65.59; H, 3.73; N, 13.91 %. Found: C, 65.38; H, 3.57; N, 13.77.
General Procedure for the Preparation of the Aldehydes
26a,b. Phosphoryl chloride (30 mmol) was dropwisely added to
a stirred, ice-bath cooled, DMF (30 mmol) for 10 min. The
mixture was kept at 0 °C for 30 min and then a solution of each
of the hydrazones 24a and 24b (10 mmol), in DMF (10 mL) was
added dropwise. The reaction mixture was then stirred at room
temperature for 1 h and then heated at 70-80 °C for 4 h. After
cooling to room temperature, the mixture was poured onto
crushed ice and neutralized with a cold potassium carbonate
4-Acetoxy-3-(3-acetylamino-2-oxo-2H-pyran-6-yl)-1-methyl-
quinolin-2(1H)-ones (19b). This compound was obtained in
80% yield, m.p. 212-214 °C; IR (KBr): νmax 1770 (C=Oacetoxy),
1
1703 (C=Opyrone), 1680-1645 (C=Oamide), 1605, 1589 cm-1; H

Mar-Apr 2007
Substituted Quinolinones. Part XIII
321
solution. The product so deposited was filtered, washed with
water, purified by flash-chromatography using ethyl
acetate/petroleum ether as eluent (1:1, v/v) and then crystallized
from the proper solvent.
eV): m/z (I%) 343 (100) (M+), 315 (5.55), 314 (13.05), 299
(1.52), 157 (22.89), 104 (21.04), 77 (99.89). Anal. Calcd. for
C20H13N3O3: C, 69.97; H, 3.82; N, 12.24 %. Found: C, 69.77; H,
3.52; N, 12.03.
3-(4-Hydroxy-1-methyl-1,2-dihydro-2-oxoquinolin-3-yl)-1H-
pyrazole-4-carbaldehyde (26a). This compound was obtained
in 30% yield, m.p. 240-243 °C (DMF); IR (KBr): νmax 3226,
3162 (NH, OH), 1650 (CH=O) , 1640 (C=Oquinolone), 1618
4-Hydroxy-3-{[(3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydro-
quinolin-3-yl)-1-phenyl-1H-pyrazol-4-yl)methylene]-5-oxo-
4,5-dihydro-1H-pyrazol-3-yl}-1-methylquinolin-2(1H)-one
(31).
A mixture of the aldehyde 26b (10 mmol), the
1
(C=N), 1594 cm-1; H nmr (DMSO-d6): δH 3.75 (s, 3H, NMe),
pyrazolinone 30 [13] (10 mmol), and anhydrous sodium acetate
(15 mmol), in glacial acetic acid (20 mL), was refluxed for 4 h
and then poured into ice-cold water. The resulting solid
precipitate was collected by filtration and crystallized from
acetic acid, in 75% yield, m.p. >300 °C; IR (KBr): νmax 3400-
2800 (H-bonded OH, NH), 1648(C=Oquinolone), 1620 (C=N),
1580-1550 (C=C) cm-1; MS (EI, 70 eV): m/z (I%) 584 (100)
(M+), 343 (33.40), 317 (64.89), 175 (8.40), 143 (10.56), 77 (100)
7.33 (t, 1H, C6-H), 7.41 (d, 1H, C8-H), 7.66 (t, 1H, C7-H), 8.04
(d, 1H, C5-H), 8.07 (s, 1H, C5'-Hpyrazole), 9.76 (s, 1H, CH=O);
MS (EI, 70 eV): m/z (I%) 269 (40.52) (M+), 252 (13.88), 202
(6.69), 105 (13.25), 73 (100). Anal. Calcd. for C14H11N3O3: C,
62.45; H, 4.12; N, 15.61 %. Found: C, 62.23; H, 3.85; N, 15.51.
3-(4-Hydroxy-1-methyl-1,2-dihydro-2-oxoquinolin-3-yl)-1-
phenyl-1H-pyrazole-4-carbaldehyde (26b). This compound
was obtained in 40% yield, m.p. 228-230 °C (ethanol); IR
(KBr): νmax 3.80 (s, 3H, NMequinolone), 7.35-7.76 (m, 8H Harom),
8.24 (dd, 1H, C5-Hquinolone), 8.60 (s, 1H, C5-Hpyrazole), 10.40 (s,
+
(C6H5 ). Anal. Calcd. for C33H24N6O5: C, 67.80; H, 4.14; N,
14.38 %. Found: C, 67.55; H, 3.80; N, 14.05.
4-Hydroxy-1-methyl-3-[(2E)-3-[3-(4-hydroxy-1-methyl-2-
oxo-1,2-dihydroquinolin-3-yl)1-phenyl-1H-pyrazol-4-yl]prop-
2-enoyl]quinolin-2(1H)-one (32). To a mixture of the acetyl-
quinolinone 1 (10 mmol) and the aldehyde 26b (10 mmol) a few
drops of piperidine was added and the mixture was heated at 100
°C for 3 h. The pasty product obtained was then triturated with
methanol (20 mL) and the formed solid material was collected
by filtration, washed with diethyl ether, purified by flash-
chromatography using ethyl acetate/petroleum ether as eluent
(1:2, v/v), and then crystallized from DMF, in 70% yield, m.p.
288-290 °C; IR (KBr): νmax 3315-3200 (broad H-bonded OH),
1650 (C=O), 1633 (C=O), 1620 (C=N), 1557, 1505, 1456, 1425
cm-1; MS (EI, 70 eV): m/z (I%) 544 (31.10) (M+), 175 (73.64)
1
1H, CH=O), 12.06 (s, 1H, OH) cm-1; H nmr (DMSO-d6): δH
3124-2904 (NH, OH), 1678 (CH=O), 1643 (C=Oquinolone), 1620,
1591; 13C nmr (DMSO-d6): δC 187.9, 160.9, 161.7, 149.1, 138.5
132.3, 130.4, 129.9, 128.2, 124.8, 124.5, 122.1, 119.5, 115.9,
114.1, 101.2, 29.7; MS (EI, 70 eV): m/z (I%) 345 (76.92) (M+),
317 (73.48), 300 (3.15), 286 (6.00), 226 (2.29), 77 (100). Anal.
Calcd. for C20H15N3O3: C, 69.56; H, 4.38; N, 12.17 %. Found: C,
69.22; H, 4.12; N, 12.00.
General Procedure for the Preparation of the Hydrazones
27a,b. To a stirred solution of the aldehyde 26b (10 mmol), in
ethanol (20 mL), was added 10 mmol of each of hydrazine
hydrate (98%) and/or thiosemicarbazide, at room temperature.
The mixture was stirred for 3 h and the precipitate so formed
was filtered off and crystallized from the proper solvent.
3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-
phenyl-1H-pyrazole-4-carbaldehyde Hydrazone (27a). This
compound was obtained in 80% yield, m.p. 216-218 °C
(ethanol-water, 5:1); IR (KBr): νmax 3430-3215 (OH, NH2), 1636
+
(C10H9NO2 ), 146 (28.05), 134 (54.70), 104 (52.24)
+
+
(CH2=NC6H4 ), 77 (100) (C6H5 ). Anal. Calcd. for C32H24N4O5:
C, 70.58; H, 4.44; N, 10.29 %. Found: C, 70.32; H, 4.11; N,
10.00.
4-Hydroxy-3-{5-[3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydro-
quinolin-3-yl)-1-phenyl-1H-pyrazol-4-yl]-4,5-dihydro-1H-
pyrazol-3-yl}-1-methylquinolin-2(1H)-one (33). A mixture of
the compound 32 (10 mmol) and hydrazine hydrate (12 mmol),
in absolute ethanol (20 mL) was heated under reflux for 2 h. The
reaction mixture was then cooled and poured into cold-water.
The solid obtained was collected by filtration, dried and
crystallized from ethanol, in 58% yield, m.p. >300 °C; IR (KBr):
νmax 3340-3120 (br, NH), 2800-2650 (br, H-bonded OH), 1645
(C=O), 1631 (C=O), 1612 (C=N), 1585, 1550, 1501, 1442, 1426
cm-1; MS (EI, 70 eV): m/z (I%) 558 (6.81) (M+), 202 (3.16)
1
(C=Oquinolone), 1618, 1570, 1558 cm-1; H nmr (DMSO-d6): δH
3.58 (s, 3H, NMequinolone), 7.11-7.60 (m, 11H, Harom), 6.78 (b, 2H,
NH2), 7.87 (d, 2H, Harom), 8.04 (d, 1H, C5-Hquinolone), 8.59 (s, 1H,
C5'-Hpyrazole), 8.97 (s, 1H, CH=N), 11.92 (b, 1H, OH). Anal.
Calcd. for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68 %. Found: C,
72.18; H, 5.01; N, 12.45.
3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-1-
phenyl-1H-pyrazole-4-carbaldehyde Phenylhydrazone (27b).
This compound was obtained in 70% yield, m.p. 260-262 °C
(pyridine); IR (KBr): νmax 3430-3157 (NH2, NH, OH), 1645
(C=Oquinolone), 1610, 1591, 1358,1232 (N-C=S) cm-1; MS (EI, 70
eV): m/z (I%) 418 (7.46) (M+), 342(12.20), 325 (9.32), 326
(43.92), 77 (100). Anal. Calcd. for C21H18N6O2S: C, 60.27; H,
4.34; N, 20.08 %. Found: C, 60.01; H, 4.08; N, 19.76.
+
+
(C11H10N2O2 ), 175 (100) (C10H9NO2 ), 146 (40.74), 134 (21.43),
105 (42.15) (C6H5C≡O+). Anal. Calcd. for C32H26N6O4: C, 68.81;
H, 4.69; N, 15.04 %. Found: C, 68.49; H, 4.50; N, 14.85.
Acknowledgements. The authors wish to thank Prof. Dr. E.
A. Mohamed and Ass. Prof. Dr. M. M. Ismail, for their valuable
helps. Hassan thanks department of organic chemistry at
Florence University, Firenze, Italy, for literature support and for
some complimentary analyses during the present work.
6-Methyl-16-phenyl-16H-pyrazolo[3',4':4,5]pyrano[3,2-c]-
quinoline-7,12(6H)-dione (29). To a mixture of the aldehyde
26b (10 mmol) and hydroxylamine hydrochloride (10 mol) in
glacial acetic acid (25 mL). The reaction mixture was heated
under reflux for 6 h, and then the solution was left to cool at
room temperature and poured onto crushed ice. The solid so
obtained was filtered, dried, and crystallized from acetic acid, in
75% yield, m.p. 183-184 °C; IR (KBr): νmax 1764 (C=Oα-pyrone),
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M. Abdel-Megid, M. Abass and M. Hassan
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