Substituted quinolinones, Part 12: Heterocyclization reactions of 3-(3-chromonyl)acryloylquinolinone with some bifunctional nucleophiles

Article abstract of DOI:10.1080/00397910601033930

4-Hydroxy-1-methyl-3-[E-3-(4-oxo-4H-chromen-3-yl)acryloyl]quinolin-2(1H) -one (3) was smoothly obtained via a one-pot aldol dehydration reaction of 3-acetyl-4-hydroxyquinolin-2(1H)-one with 3-formylchromone and was utilized to prepare miscellaneous triheterocyclic systems containing the quinolinone moiety. Both the α,β-unsaturated ketone side chain and the γ-pyrone ring in compound 3 were subjected to nucleophilic cyclization with certain 1,2- and 1,3-bifunctional N,N-, N,O-, N,C-, and O,C-nucleophiles under different reaction conditions. Many pyrazolinyl-, isoxazolinyl-, pyrimidinyl-, and pyridinylquinolinones bearing other six- or five-membered heterocyclic systems have been conveniently synthesized using more than one synthetic route. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601033930

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Substituted Quinolinones, Part 12:
Heterocyclization Reactions of
3‐(3‐Chromonyl)acryloylquinolinone with
Some Bifunctional Nucleophiles
Mohamed Abass a , Mohamed Abdel‐Megid a & Mohamed Hassan a
a Department of Chemistry, Faculty of Education, Ain Shams University,
Roxy, Heliopolis, Cairo, Egypt
Version of record first published: 25 Jul 2007.
To cite this article: Mohamed Abass , Mohamed Abdel‐Megid & Mohamed Hassan (2007): Substituted
Quinolinones, Part 12: Heterocyclization Reactions of 3‐(3‐Chromonyl)acryloylquinolinone with Some
Bifunctional Nucleophiles, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:2, 329-352
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Synthetic Communicationsw, 37: 329–352, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601033930
Substituted Quinolinones, Part 12:
Heterocyclization Reactions of
3-(3-Chromonyl)acryloylquinolinone with
Some Bifunctional Nucleophiles
Mohamed Abass, Mohamed Abdel-Megid,
and Mohamed Hassan
Department of Chemistry, Faculty of Education, Ain Shams University,
Roxy, Heliopolis, Cairo, Egypt
Abstract: 4-Hydroxy-1-methyl-3-[E-3-(4-oxo-4H-chromen-3-yl)acryloyl]quinolin-
2(1H)-one (3) was smoothly obtained via a one-pot aldol dehydration reaction of
3-acetyl-4-hydroxyquinolin-2(1H)-one with 3-formylchromone and was utilized to
prepare miscellaneous triheterocyclic systems containing the quinolinone moiety.
Both the a,b-unsaturated ketone side chain and the g-pyrone ring in compound 3
were subjected to nucleophilic cyclization with certain 1,2- and 1,3-bifunctional
N,N-, N,O-, N,C-, and O,C-nucleophiles under different reaction conditions. Many pyr-
azolinyl-, isoxazolinyl-, pyrimidinyl-, and pyridinylquinolinones bearing other six- or
five-membered heterocyclic systems have been conveniently synthesized using more
than one synthetic route.
Keywords: chromone, nucleophilic cycloaddition, quinolinone, a,b-unsaturated
ketone
INTRODUCTION
Quinolinones are the effective moiety in a large number of natural and
synthetic heterocyclic compounds that exhibit significant antibiotic activity
Received in the U.K. April 27, 2006
Dedicated to the memory of the late Professor Sayed Ibrahim El-Nagdi.
Address correspondence to Mohamed Abass, Department of Chemistry, Faculty of
Education, Ain Shams University, Roxy, Heliopolis 11757, Cairo, Egypt. E-mail:
m.abass@chemist.com
329

330
M. Abass, M. Abdel-Megid, and M. Hassan
with very wide applications.[1–7] Our current program on chemistry of
quinolinone is devoted to the synthesis of novel five- or six-membered substi-
tuted 3- or 4-hetarylquinolinone derivatives.[8–12] A special interest in this
program is directed to the production of derivatives including pyrazoles and
isoxazoles, which are known to exhibit significant antibiotic properties.
Thus, pyrazoles showed important antimicrobial and antifungal activity,[13]
cholesterol acyl-transferase inhibitory activity,[14] antidiabetic activity,[15] anti-
depressant activity,[16] and antianxiety activity.[17] Recently pyrazolines have
received renewed attention with the registration of Indoxacarb, which has
neuronal target action on insects.[18] On the other hand, isoxazoles and
isoxazolines possess analgesic activity,[19] antiprotozoal activity,[20] anti-
influenza virus activity,[21] antifungal activity,[22] antibacterial activity,[23] anti-
depressant,[24] anti-ischemic effects,[25] and anti-inflammatory activity.[26]
Because of these interesting biological activities of quinolinones, pyrazoles,
and isoxazoles, considerable attention has been directed at the synthesis of
some new derivatives containing these moieties in one molecular frame.
Among the methods employed in the synthesis of 2-pyrazolines and
isoxazolines, the condensation of a,b-unsaturated carbonyl compounds with
hydrazines and hydroxylamine is commonly used.[27] Chromones are
usually readily ring-opened via nucleophilic attack at the 2-position and
when treated with a suitable binucleophile, ring opening can be effected,
followed by ring closure leading to new ring systems (e.g., hydrazine and
hydroxylamine give pyrazole and isoxazoles, respectively.[28–30] Recently
we have disclosed that when both a g-pyrone and an a,b-unsaturated
carbonyl side chain are present in the same molecule, the reactivity of both
moieties toward 1,2- and 1,3-binucleophiles is competitive, and the reaction
mostly proceeds regioselectively, depending on the ambient reaction con-
ditions and the used binucleophile reagent.[9] Building on this, our strategy
to synthesize the target isolated triheterocyclic systems, which contain a qui-
nolinone moiety, was obtain an easily accessible synthetic precursor that on
modification can furnish the desired heterocycles. The key synthetic
precursor should include an a,b-unsaturated carbonyl side chain connecting
quinolinone and chromone moieties. These structural features are well
assembled in the newly synthesized starting compound 3-[3-(chromon-3-yl)
acryloyl]-quinolinone 3.
RESULTS AND DISCUSSION
The desired precursor 4-hydroxy-1-methyl-3-[E-3-(4-oxo-4H-chromen-3-yl)-
acryloyl]quinolin-2(1H)-one (3) was smoothly obtained via a one-pot aldol
dehydration reaction of 3-acetyl-4-hydroxyl-1-methylquinolin-2(1H)-one
1
(1)[31] with 3-formylchromone (2),[32] in 80% yield (Scheme 1). The H
NMR spectrum revealed that the olefinic a-proton is shifted downfield to
the extent that it appears in the aromatic region (d ¼ 7.58), and the

Substituted Quinolinones, Part 12
331
Scheme 1.
b-proton is considerably shifted to d ¼ 9.24 as doublet (J ¼ 16 Hz). The
structure is assuming E-form, which suffers anisotropic effect due to the
neighboring C55O of chromone system.
The reaction of compound 3 with an equimolar amount of hydrazine
hydrate, in boiling ethanol, led to the opening of the pyrone ring. This was
1
confirmed by the presence of an additional phenolic OH proton in its H
NMR spectrum. The data also revealed the enone side chain remains unaf-
fected, and the product was characterized as 4-hydroxy-3-fE-3-[3-(2-hydroxy-
phenyl)-2H-pyrazol-4-yl]acryloylg-1-methylquinoline-2(1H)-one (4), in 80%
yield. Thus, under these conditions, the expected isomeric 3-quinolyl-5-
chromonyl-2-pyrazoline (QCP) is completely ruled out. Fortunately, usage
of glacial acetic acid as the solvent oriented the reaction away from the
g-pyrone nucleus and gave 3-[1-acetyl-5-(4-oxo-4H-chromen-3-yl)-4,5-
dihydro-1H-pyrazol-3-yl]-4-hydroxy-1-methylquinolin-2(1H)-one (5), an
N-acetylated derivative of the anticipated pyrazoline (QCP) (Scheme 2).
1
Unfortunately, the H NMR of the product cannot be measured because of
its dimethyl sulphoxide (DMSO)-insolubility problem, but the integrated
available data ensured enough routes to determine this structure. Thus,
compound 5 does not give violet coloration with the phenolic OH ferric
chloride test, indicating that g-pyrone ring was not attacked, and also its IR
spectrum shows characteristic bands due to chromone, quinolinone, and N-
acetyl C55O groups at 1646, 1652, and 1666 cm21, respectively. The
molecular ion peak obtained by mass spectrum of compound 5 (m/z 429) is
the base peak (I%, 100). The fragmentation pattern showed a (M–COCH3)
peak at m/z 386. Furthermore, C, H, and N elemental analyses gave satisfac-
tory results within +0.15%. In addition, this result is in accordance with the
reported cyclization of a,b-unsaturated carbonyl compounds with hydrazine
in glacial acetic acid.[9,29]
When compound 3 was reacted with 2 equivalent of hydrazine hydrate
in boiling dimethyl formamide (DMF), nucleophilic attack occurs at both the
chromone ring and the a,b-unsaturated ketone side chain, leading to the
formation of 4-hydroxy-3-[30-(2-hydroxyphenyl)-3,4-dihydro-10H,2H-3,40-
bipyrazol-5-yl]-1-methylquinolin-2(1H)-one (6) in 73% yield. The 1H
NMR spectrum revealed typical peaks for the 2-pyrazoline nucleus as
follows: two peaks appeared as multiplets at d ¼ 3.21–3.38 due to 4-CH2
and a peak at d ¼ 3.84 due to 5-CH of pyrazoline. Further evidence for

332
M. Abass, M. Abdel-Megid, and M. Hassan
Scheme 2.
the structure of compound 6 was obtained when the same product was
obtained by treating the pyrazolylacryloylquinolinone 4 with an excess
amount of hydrazine hydrate in boiling DMF in 60% yield. Interestingly the
reaction of compound 3 with 2 equivalent of hydrazine in acetic acid did
not lead to either compound 5 or compound 6. The spectral data of the
product showed the presence of an acetyl group as indicated by a singlet
peak at d ¼ 2.21 beside clear evidence for pyrone ring-opening. Accordingly,
it is believed that the product is an N-acetyl derivative of compound 6
and is formulated as 3-[2-acetyl-30-(2-hydroxyphenyl)-3,4-dihydro-1H0,2H-
3,4-bipyrazol-5-yl)-4-hydroxy-1-methylquinolin-2(1H)-one (7). Elucidative
synthesis of compound 7 was achieved by treatment of compound 4 with
hydrazine hydrate in glacial acetic acid and/or by treatment of compound 5
with hydrazine hydrate in boiling DMF (Scheme 2).

Substituted Quinolinones, Part 12
333
When the starting compound 3 was reacted with equimolar amount of
hydroxylamine hydrochloride in a mixed solvent of ethanol–DMF (v/v
80:20),
4-hydroxy-3-fE-3-[5-(2-hydroxyphenyl)isoxazol-4-yl]acryloylg-1-
methylquinolin-2(1H)-one (8) was obtained in 65% yield. The refluxing of
compound 3 with hydroxylamine hydrochloride at the same molar ratio
(1:1) in glacial acetic acid proceeds in a completely different manner, and
accordingly 4-hydroxy-1-methy1-3-[5-(4-oxo-4H-chromen-3-y1)-4,5-dihy-
droisoxazol-3-yl)quinolin-2(1H)-one (9) was characterized resulting from
attack of the g-pyrone nucleus. The reaction of both compounds 8 and 9
with hydroxylamine hydrochloride in boiling pyridine or DMF led smoothly
to the formation of 4-hydroxy-3-[5-(2-hydroxypheny1)-40,50-dihydro-4,50-
biisoxazol-30-y1]-1-methy1quinolin-2(1H)-one (10), which is obtainable
directly from compound 3, by using an excess of hydroxy1amine hydrochlo-
ride (1:2) in boiling pyridine (Scheme 3).
Interestingly, the chromeny1isoxazoliny1quinolinone 9 was treated with
hydrazine hydrate in boiling DMF to give 4-hydroxy-3-f5-[3-(2-hydroxy-
phenyl)-1H-pyrazol-4-yl]-4,5-dihydroisoxazol-3-y1g-1-methylquinoline-2(1H)-
one (11), in 75% yield, whereas its isomer 4-hydroxy-3-f5-[5-(2-hydroxyphenyl)
isoxazol-4-y1]-4,5-dihydro-1H-pyrazol-3-ylg-1-methy1quinolin-2(1H)-one
(12) was afforded upon treating isoxazolylacryloy1quinolinone 8 with
hydrazine hydrate in boiling DMF. Boiling compound 12 in glacial acetic
acid led to acetylation, affording 3-f1-acetyl-5-[5-(2-hydroxypheny1)
isoxazol-4-y1]-4,5-dihydro-1H-pyrazol-3-y1g-4-hydoxy-1-methyl-quinolin-
2(1H)-one (13), a compound that was also obtained during heterocyclization
of the acryloy1 derivative 8 by means of hydrazine hydrate in glacial acetic
acid. In turn, treatment of N-acetylpyrazoline 5 with hydroxylamine hydro-
chloride furnished the same compound 13 (Scheme 3). However, the N-acet-
ylpyrazolines are desirable since Chimenti et al. reported that the presence of
the acetyl group on the N-1 of the pyrazoline nucleus is an important requisite
and necessary for its antibacterial activity.[13]
The reaction of compound 3 with thiourea, as a 1,3-binucleophile, was
carried out under different reaction conditions. Thus, the reaction at molar
ratio (1:1) in the presence of sodium ethoxide afforded 4-hydroxy-3-fE-3-
[4-(2-hydroxypheny1)-2-thioxo-3H-pyrimidin-5-y1]acryloylg-1-methylqui-
nolin-2-(1H)-one (14), in 68% yield. It is known that the condensation of
thiourea with 1,3-diketones can be either acid or base catalyzed. In the
present case, the base is required to effect ring opening of the g-pyrone
(Scheme 4). In boiling ethanol containing a catalytic amount of hydrochloric
acid or in boiling glacial acetic acid, the same reaction led to the formation of
4-hydroxy-1-methyl-3-[6-(4-oxo-4H-chromen-3-y1)-2-thioxo-1,2,5,6-tetra-
hydropyrimidin-4-y1]quinolin-2(1H)-one (15), in 78% yield. The mass
spectrum of product 15 exhibited a base peak at m/z ¼ 171 corresponding
to the 3-vinylchromone radical cation. The 1H NMR spectrum revealed
characteristic chemical shifts of skeletal 5,6-dihydro-pyimidine-2(1H)-
thione with two multiplets at d ¼ 3.42–3.54 (5-CH2) and 4.23 (6-CH), in

334
M. Abass, M. Abdel-Megid, and M. Hassan
Scheme 3.
addition to an acidic proton at d ¼ 9.18 (N-H) as a broad peak, revealing the
existence of this ring system as the thione tautomer rather than the thiol tautomer.
The reaction of compound 15 with both hydrazine hydrate and hydroxyl-
amine hydrochloride proceeded smoothly using ethanolic potassium

Substituted Quinolinones, Part 12
335
Scheme 4.
hydroxide to yield 4-hydroxy-3-f6-[5(2-hydroxyphenyl)-1H-pyrazol-4-yl]-2-
thioxo-1,2,5,6-tetrahydro-pyrimidin-4-ylg-1-methylquinolin-2(1H)-ones (16)
and its isoxazolyl analogue 17, respectively (Scheme 4). The 1H NMR
spectrum of compound 16 showed the characteristic chemical shifts corre-
sponding to the pyrimidinyl 5-CH2 (HAHB), 4-CHX system at d ¼ 3.47,
3.53, and 5.51. Independent alternative synthesis of both compounds 16 and

336
M. Abass, M. Abdel-Megid, and M. Hassan
17 was employed to confirm both structures. Thus, the reaction of compound 4
with thiourea in glacial acid led to compound 16, whereas treatment of
compound 8 with thiourea in acetic acid gave compound 17 (Scheme 4).
2-Thioxopyridine-3-carbonitriles are of increasing interest because of
their use as intermediates for the synthesis of certain medicines. Thus, 5-[E-
3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-oxoprop-1-enyl]-
6-(2-hydroxyphenyl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (18) was
prepared in the course of the reaction of an equimolar amount of cyano-
thioacetamide with compound 3, using sodium ethoxide as a catalyst
(Scheme 5). The 1H NMR spectrum showed that the cyclization took
place on the chromone and not on the enone side chain, where the chemical
shifts at d ¼ 6.53 and 8.16 (J ¼ 15.6 Hz) (due to CO-CH55CH) confirmed
the propensity for chromone ring opening in basic media. Evidence was
provided by approaching another possible product accessible by a Michael
route starting from compound 3 and cyanothioacetamide, at the same
molar ratio (1:1), conducted in a relatively moderate basic medium
using piperidinium acetate. Under these conditions, the g-pyrone ring
system is preserved, and the opportunity for Michael addition at the
enone gives 6-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-4-(4-
oxo-4H-chromen-3-yl)-2-thioxo-1,2,3,4-tetahydropyridine-3-carbonitrile (19).
1H NMR spectrum supported the structure 19 because the specific chemical
shift due to the chromone C2-proton typically appeared at d ¼ 8.46. In
addition, the disappearance of the olefinic system, which was replaced
with the characteristic chemical shifts of tetrahydropyridine nucleus, was
evidently noticed.
The heterocyclization reaction of both compounds 18 and 19 with hydro-
xylamine hydrochloride, in boiling DMF and/or pyridine, gave two interest-
ing triheterocyclic systems: 5-[3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydro-
quinolin-3-yl)-4,5-dihydro-isoxzol-5-yl]-6-(2-hydroxyphenyl)-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (20) and 6-(4-hydroxy-1-methyl-2-oxo-1,2-
dihydroquinolin-3-yl)-4-[5-(2-hydroxyphenyl)-isoxazol-4-yl]-2-thioxo-1,2,3,
4-tetrahydro-pyridine-3-carbonitnile (21). However, the alternative prep-
aration of the same two products, 20 and 21, via treatment of compounds 9
and 8 with cyanothioacetamide in the presence of sodium ethoxide and/or
piperidinium acetate, respectively, strongly supports their proposed structures
(Scheme 5).
2-Thiobarbituric acid can be considered as a reactive cyclic methylene
compound of the 1,3-dione type, which has been widely used to obtain pyra-
nopyrimidines when cyclized with either enone systems or 1,3-dicarbonyl
compound and recently with 3-substituted chromones.[9] Treatment of
compound 3 with 2-thiobarbitunic acid at the molar ratio (1:1), in the
presence of sodium ethoxide, afforded 6-[E-3-(4-hydroxy-1-methyl-2-oxo-
1,2-dihydroquinolin-3-yl)-3-oxopropenyl]-7-(2-hydroxyphenyl)-2-thioxo-
2,3-dihydropyrano[2,3-d]pyrimidin-4-one (22). When the same reaction
was carried out in the presence of piperidinium acetate, a completely

Substituted Quinolinones, Part 12
337
Scheme 5.
different product was isolated and identified as 7-(4-hydroxy-1-methyl-2-
oxo-1,2-dihydroquinolin-3-yl)-5-(4-oxo-4H-chromen-2-yl)-2-thioxo-1,2,3,
5-tetrahydro pyrano[2,3-d]pyrimidin-4-one (23). Furthermore, both products
22 and 23 were reacted with hydroxylamine hydrochloride in boiling DMF
to furnish the 6-[3-(4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
4,5-dihydroisoxazol-5-yl]-7-(2-hydroxyphenyl)-2-thioxo-2,3-dihydropyrano
[2,3-d]-pyrimidin-4-one (24) and 7-(4-hydroxy-1-methyl-2-oxo-1,2-dihydro-
quinolin-3-yl)-5-[5-(2-hydroxyphenyl)isoxazol-4-yl]-2-thioxo-1,2,3,5-tetra-
hydro-pyrano[2,3-d]pyrimidin-4-one (25). Here again compounds 9 and 8
were utilized to synthesize the same products 24 and 25 by an alternate

338
M. Abass, M. Abdel-Megid, and M. Hassan
Scheme 6.
route involving treatment with 2-thiobarbitunic acid in the presence of the
proper catalyst (Scheme 6).
In summary, an efficient flexible route to obtain a wide range of poly-
heterocyclic scaffolds, which have expected useful biological properties, has
been developed. The presence of both enone and chromone in the precursor
that bears a quinolinone moiety seems to be satisfying to large-scale

Substituted Quinolinones, Part 12
339
heterocyclizations depending on the nature of the used bifunctional
nucleophiles, the molar ratios, and the ambient reaction conditions.
EXPERIMENTAL
Melting points were determined in open capillary tubes on Gallenkamp MFB-
595 or Buchi digital melting-point apparatuses and are uncorrected. IR spectra
were recorded on Perkin-Elmer FT-IR 1650 spectrophotometer in KBr disks.
1H NMR spectra were recorded on a Varian Gemini (200-MHz) instrument
using DMSO-d6 as solvent and TMS as an internal standard reference. Mass
spectra were obtained on HP MS-5988 spectrometer by direct inlet (beam
energy 70 eV). Elemental analyses were performed at Cairo University Micro-
analytical Centre and Ain Shams University Analytical Unit. Silica-gel plates
(Merck F254) were used to check purity. The compounds 1[31] and 2[32] were
obtained according to the literature methods. Analytical and spectral data are
listed in Tables 1 and 2, respectively.
4-Hydroxy-1-methyl-3-[E-3-(4-oxo-4H-chromen-3-yl)
acryloyl]quinolin-2(1H)-one (3)
A mixture of acetylquinolinone 1 (2.17 g, 10 mmol), 3-formylchromone 2
(1.74 g, 10 mmol), and piperidine (0.2 mL) in ethanol (50 mL) was heated
on a boiling water bath for 3 h. The reaction mixture was triturated with
ethanol. The solid so obtained was filtered off, washed with diethyl ether,
and crystallized to give compound 3.
4-Hydroxy-3-fE-3-[3-(2-hydroxyphenyl)-2H-pyrazol-4-yl]acryloylg-
1-methyl-quinolin-2(1H)-one (4)
A mixture of 3 (1.87 g, 5 mmol) and hydrazine hydrate (0.25 mL, 5 mmol) in
absolute ethanol (10 mL) was heated under reflux for 2 h and then poured into
ice-cold water. The resulting solid was filtered and crystallized to give
compound 4.
3-[1-Acetyl-5-(4-oxo-4H-chromen-3-yl)-4,5-dihydro-1H-pyrazol-3-yl]-
4-hydroxy-1-methylquinolin-2(1H)-one (5)
A solution of start 3 (1.87 g, 5 mmol) and hydrazine hydrate (0.25 mL,
5 mmol) in glacial acetic acid (10 mL) was heated at reflux for 6 h. The
reaction mixture was left to cool to room temperature. The crystalline
product so obtained was filtered off and recrystallized to give compound 5.

Table 1. Analytical data of the new compound
Microanalysis calcd. (found) (%)
H
Compd.
no.
Yield
(%)ꢀ
Mp
Crystn.
solvent
M.
M.
wt
(8C)
formula
C
N
3
4
80
80
60
226–228
228–230
270–272
245–246
232–234
210–212
.300
AcOH
EtOH/H2O
AcOH
C
22H15NO5
373.73
387.40
429.25
401.43
443.33
388.38
388.38
403.40
402.41
402.41
444.00
431.47
431.47
445.50
446.49
455.50
455.50
470.51
470.51
499.51
499.51
514.52
514.52
70.77 (70.64)
68.21 (68.15)
67.13 (67.08)
65.83 (65.70)
65.01 (64.88)
68.04 (67.85)
68.04 (68.00)
65.50 (65.32)
65.67 (65.44)
65.67 (65.54)
64.86 (64.77)
64.03 (63.85)
64.03 (63.80)
62.01 (61.85)
61.87 (61.58)
65.92 (65.78)
65.92 (65.80)
63.82 (63.69)
63.82 (63.66)
62.52 (62.30)
62.52 (62.29)
60.70 (60.59)
60.70 (60.55)
4.05 (3.85)
4.42 (4.22)
4.45 (4.30)
4.77 (4.65)
4.75 (4.60)
4.15 (4.03)
4.15 (3.89)
4.25 (4.01)
4.51 (4.31)
4.51 (4.25)
4.54 (4.21)
3.97 (3.69)
3.97 (3.65)
4.30 (4.08)
4.06 (3.89)
3.76 (3.60)
3.76 (3.59)
3.86 (3.75)
3.86 (3.74)
3.43 (3.22)
3.43 (3.18)
3.53 (3.38)
3.53 (3.21)
3.75 (3.60)
10.85 (10.69)
9.79 (9.65)
C22H17N3O4
C24H19N3O5
5
6
73,a 60b
DMF/H2O
AcOH
EtOH
C22H19N5O3
C24H21N5O4
17.45 (17.25)
15.80 (15.68)
7.21 (7.10)
7
66,a 68,b 52,c 98d
65
8
C
C
22H16N2O5
22H16N2O5
9
60
AcOH
7.21 (7.05)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
70,a 68,e 79f
75
55
264–266
240–242
204–206
.300
Dioxane
DMF
DMF
C22H17N3O5
10.42 (10.22)
13.92 (13.75)
13.92 (13.88)
12.61 (12.39)
9.74 (9.66)
C
C
22H18N4O4
22H18N4O4
66,c 78e
Dioxane
DMF
C24H20N4O5
23H17N3O4S
68
.300
C
78
185–187
238–240
277–278
.300
DMF/H2O
Acetone
EtOH
C23H17N3O4S
C23H19N5O3S
C23H18N4O4S
9.74 (9.68)
70,b 65g
70,e 63g
67
15.72 (15.68)
12.55 (12.41)
9.23 (9.11)
DMF
C
C
25H17N3O4S
25H17N3O4S
80
234–236
202–204
230–232
.300
Pyridine
Acetone
Pyridine
DMF
9.23 (9.08)
77,f 68h
75,e 78i
63
C25H18N4O4S
C25H18N4O4S
11.91 (11.80)
11.91 (11.59)
8.41 (8.15)
C
C
26H17N3O6S
26H17N3O6S
66
68,f 70j
68,e 64k
190–192
260–263
240–243
DMF
DMF
8.41 (8.28)
10.89 (10.66)
10.89 (10.58)
C26H18N4O6S
C26H18N4O6S
DMF
a
b
c
d
e
f
g
h
i
j
k
ꢀYield starting from compounds: 3, 4, 5, 6, 8, 9, 15, 18, 19, 22, and 23

Table 2. Spectral data of the new compounds
Cpd. no.
IR (KBr), n (cm21
)
1H NMR (DMSO-d6), d
Mass, m/z (I %)
˜
3
2923 (C–Haliph), 2700 (br,
H-bonded OH), 1654–1642
(C55O), 1600, 1590
3.65 (s, 3H, NCH3), 7.37 (t, 1H, C6-H), 7.58–7.92 (m, 7H,
Haromþ CHa55CH), 8.17 (d, J ¼ 6.4 Hz, 1H, C8-H), 8.21
(d, 1H, C80-H), 9.02 (s, 1H, C20-H), 9.24 (d, J ¼16 Hz, 1H,
CH55CHb)
373 (38.65) (Mþ.), 228 (8.90),
202 (11.29), 171 (100), 145
(1.46), 104 (12.34), 77 (25.02)
4
5
3323–2680 (H-bonded OH and
NH), 2900 (CHaliph), 1640
(C55O), 1620, 1612
3.58 (s, 3H, NCH3), 6.84–6.92 (m, 3H, Haromþ Hpyrazole),
7.22–7.75 (m, 6H, Haromþ Holefin), 8.02 (d, J ¼ 7 Hz, 1H,
387 (23.13) (Mþ.), 371 (9.24),
228 (6.17), 202 (9.09), 171
(39.43), 104 (14.25), 73 (100)
C5-H), 8.15 (d, 1H, J ¼ 13 Hz, Holefin
)
2955 (C–Haliph), 1666 (C55O),
1652 (C55O), 1646 (C55O),
1622, 1610, 1585
429 (100) (Mþ.), 386 (57.48),
277 (20.96), 202 (20.23), 170
(22.47), 105 (14.91), 73
(88.27)
6
7
3322–2715(br, H-bondedNH and
OH), 1644 (C55O), 1620, 1600
3.21–3.38 (m, 2H, 4-CHpyrazoline), 3.57 (s, 3H, NCH3),
3.84 (m, 1H, 5-CHpyrazoline), 4.97 (br, 1H, NHpyrazoline),
6.82–6.98 (m, 3H, Harom), 7.18–7.31 (m, 3H, Harom),
7.40 (br, 1H, N-Hpyrazole), 7.47 (d, J ¼ 7 Hz, 1H, Harom),
7.64 (t, 1H, Harom), 8.02 (d, J ¼ 6.6 Hz, 1H, 5-CHquinolone
401 (11.96) (Mþ.), 241 (26.46),
202 (30.98), 175 (37.94), 104
(20.92), 73 (100)
)
3350–2800 (br, H-bonded OH
and NH), 1656 (C55O), 1644
(C55O), 1620, 1605
2.21 (s, 3H, NCOCH3), 3.24 (d, 1H, 4-CHpyrazoline), 3.43
(d, 1H, 4-CHpyrazoline), 3.58 (s, 3H, NCH3), 3.97
443 (21.06) (Mþ.), 242 (81.93),
171 (41.55), 104 (17.16), 77
(100)
(m, 1H, C3-Hpyrazoline), 6.81 (m, 3H, Harom), 7.22–7.78
(m, 6H, Harom þ N-Hpyrazole), 8.10 (d, J ¼ 6.8 Hz, 1H,
C5-Hquinolone
)
(continued)

Table 2. Continued
Cpd. no.
IR (KBr), n (cm21
)
1H NMR (DMSO-d6), d
Mass, m/z (I %)
˜
8
2900 (C–Haliph), 2679 (br,
H-bonded OH), 1644 (C55O),
1620, 1607
3.64 (s, 3H, NCH3), 6.87–7.44 (m. 5H, Harom), 7.59–7.88
(m, 2H, Haromþ CHb55CH), 7.97 (s, 1H, 3-CHisoxazole),
8.05 (dd, J ¼ 7.8 & 1.2 Hz, 1H, 5-CHquinolone), 8.20
(d, J ¼ 16 Hz, 1H, CHa55CH), 11.20 (br, 1H, OH), 11.67
(br, 1H, OH)
388 (9.90) (Mþ.), 341 (74.17),
228 (10.79), 201 (9.99), 171
(100), 104 (52.91), 77 (89.45)
9
2678 (br, H-bonded OH), 2950
(C–Haliph), 1650–1643
(C55O), 1600, 1584
388 (42.08) (Mþ.), 341 (100),
228 (2.47), 202 (3.22), 171
(18.21), 104 (49.83), 77
(79.48)
10
2850 (br, H-bonded OH), 2900
(C–Haliph), 1650 (C55O),
1600, 1574
3.30–3.45 (m, 2H, 4-CHisoxazoline), 3.56 (s, 3H, NCH3),
4.25 (m, 1H, 5-CHisoxazoline), 6.93–7.70 (m, 7H, Harom),
8.02 (d, J ¼ 6.7 Hz, 1H, 5-CHquinolone), 8.19 (s, 1H,
3-CHisoxazole), 10.67 (br, 1H, OH), 12.32
(br, 1H, OH)
403 (18.81) (Mþ.), 228 (19.40),
175 (7.17), 104 (39.19), 57
(100)
11
12
3409–2689 (br, H-bonded NH
and OH), 1635 (C55O), 1618
(C55N), 1583
3.32–3.57 (m, 2H, 4-CHisoxazoline), 3.68 (s, 3H, NCH3),
4.26 (m, 1H, 3-CH isoxazoline), 6.86–7.65 (m, 7H, Harom),
8.02 (d, J ¼ 6.7 Hz, 1H, 5-CHquinolone), 8.19 (s, 1H,
3-CH isoxazole), 11.89 (br, 1H, OH) 12.54 (br, 1H, OH)
402 (2.59) (Mþ.), 216 (32.53),
201 (25.66), 184 (100), 171
(43.80), 104 (35.80), 77
(63.20)
3220–2770 (br, H-bonded OH
and NH), 1647 (C55O), 1622
(C55N), 1585
3.25–347 (m, 2H, 4-CH2pyrazoline), 3.58 (s, 3H, NCH3), 4.05
(m, 1H, 5-Hpyrazoline), 5.22 (br, 1H, NHpyrazoline), 6.85–
7.78 (m, 7H, Harom), 7.98 (d, J ¼ 6.8 Hz, 1H, 5-Hquinolone),
402 (13.68) (Mþ.), 216 (55.08),
201 (23.29), 171 (51.88), 104
(39.23), 77 (55.08), 60 (100)
8.10 (s, 1H, 3-Hpyrazole
)

13
2943 (C–Haliph), 2677 (br,
H-bonded OH), 1650 (C55O),
1660 (C55Oacetyl), 1620 (C55N),
1587
2.41 (s, 3H, COCH3), 3.01, 3.14 (dd, 2H, 4-CH2pyrazolin), 3.67
(s, 3H, NCH3) 5.59 (m, 1H, 5-Hpyrazoline), 6.79–7.46
(m, 7H, Harom), 8.06 (d, J ¼ 6.6 Hz, 1H, 5-Hquinolone),
8.15 (s, 1H, 3-Hisoxazole), 10.74 (br, 1H, OH),
12.55 (br, 1H, OH)
14
15
3350–2700 (br H-bonded OH,
NH), 1655–1640 (C55O),
1622, 1605, 1220 (C55S)
3.64 (s, 3H, NCH3), 6.80–7.92 (m, 10H, Haromþ Holefin þ
6-Hpyrimidine), 8.02 (d, J ¼ 6.7 Hz, 1H, 5-Hquinolone), 10.08
(br, 1H, NHpyrimidins), 12.54 (br, 1H, OH)
3355–2740 (br, H-bondedNH and
OH), 1654–1644 (C55O),
1618-1590, 1337–1223
(NH-C55S)
3.42–3.54 (m, 2H, 5-CH2 pyrimidine), 3.67 (s, 3H, N-CH3),
4.23 (m, 1H, 6-H pyrimidine), 6.96–7.82 (m, 7H, Harom),
8.18 (dd, J ¼ 6.9 & 1.1 Hz, 1H, 5-Hquinolone), 8.42
(s, 1H, C2-Hchromone), 9.18 (br, 1H, NHpyrimidine),
12.52 (br, 1H, OH)
431 (4.88) (Mþ.), 228 (3.25), 202
(10.09), 171 (100), 104
(12.00), 73 (9.38)
16
17
3300–2660 (br, H-bonded NH
and OH), 1644 (C55O), 1621,
1585, 1215 (NH-C55S)
3.47–3.53 (m, 2H, 5-CHpyrimidine), 3.67 (s, 3H, NCH3),
5.51–5.57 (br, 1H, 4-CHpyrimidine), 6.76 (br, 1H,
N-Hpyrimidine), 6.80–7.63 (m, 7H, Harom), 8.08
(dd, J ¼ 7 & 1.3 Hz, 1H, 5-Hquinolone), 8.21 (s, 1H,
3-Hpyrazole), 8.42 (br, 1H, NHpyrazole), 12.44
(br, 1H, OH), 12.68 (br, 1H, OH)
445 (24.84) (Mþ.), 227 (33.60),
171 (21.38), 105 (18.15)
3340–2730 (br, H-bonded NH
and OH), 1648 (C55O),
1624–1590, 1240 (NH-C55S).
3.46–3.56 (m, 2H, 5-CH2 pyrimidine), 3.72 (s, 3H, NCH3),
5.63–5.68 (m, 1H, 4-Hpyrimidine), 7.01 (br, 1H,
N-Hpyrimidine), 7.12–7.62 (m, 7H, Harom), 7.98
(d, J ¼ 6.5 Hz, 1H 5-H quinolone), 8.66 (s, 1H, 3-Hisoxazole),
11.88 (br, 1H, OH), 12.76 (br, 1H, OH)
446 (20.01) (Mþ.), 73 (100)
(continued)

Table 2. Continued
Cpd. no.
IR (KBr), n (cm21
)
1H NMR (DMSO-d6), d
Mass, m/z (I %)
˜
18
3322–2647 (br, H-bonded NH
;;
and OH), 2222 (C N),
1660–1646 (C55O), 1622,
3.66 (s, 3H, N-CH3), 6.53 (d, J ¼ 15.6 Hz, 1H, COCH55CH),
7.22–7.85 (m, 7H, Harom), 8.05 (dd, J ¼ 7.1 & 1.3 Hz,
1H, C5-H), 8.16 (d, J ¼ 15.6 Hz, 1H, COCH55CH),
8.70 (s, 1H, 4-Hpyridine), 11.40 (br, 1H, N-Hpyridine),
12.43–12.52 (br, 2H, 2 ꢁ OH)
1608, 1321, 1274 (NH-C55S)
19
20
21
3430–2650 (br, H-bonded NH
;;
1655–1643 (C55O), 1621
(C55N), 1595, 1338, 1208
(NH-C55S)
3.65 (s, 3H, N-CH3), 3.80 (m, 1H, 4-Hpyridine), 4.17
(d, J ¼ 2.3 Hz, 1H, 3-Hpyridime), 6.12 (d, J ¼ 5.3 Hz, 1H,
5-Hpyriidine), 7.20–7.66 (m, 7H, Harom), 8.07 (dd, J ¼ 6.8
& 1.2 Hz, 1H, 5-Hquinolone), 8.46 (s, 1H, 2-Hchromone),
9.91 (br, 1H, NH)
and OH), 2226 (C N),
3244–2779 (br, H-bonded NH
;;
and OH), 2212 (C N), 1645
(C55O), 1221 (C55S)
3.16–3.33 (m, 2H, 4-H2isoxazoline), 3.67 (s, 3H, N-CH3),
5.56 (m, 1H, 5-H isoxazoline), 7.22–7.73 (m, 7H, Harom),
7.99 (dd, J ¼ 6.9 & 1.2 Hz, 1H, 5-Hquinolone), 8.92
(s, 1H, 4-Hpyridine), 11.47 (br, 1H, NHpyridine), 12.43–12.39
(br, 2H, 2 ꢁ OH)
470 (3.49) (Mþ.), 401 (3.08), 256
(1.76), 105 (1.40), 73 (100)
3430–2650 (br, H-bonded NH
;;
and OH), 2215 (C N), 1643
(C55O), 1619 (C55N), 1210
3.65 (s, 3H, N-CH3) 4.43–4.74 (m, 2H, 3-H and 4-Hpyridine),
6.32 (d, J ¼ 13.2, 1H, 5-Hpyridine,), 7.20–7.82 (m, 7H,
H
1H, 5-Hquinolone), 9.62 (br, 1H, NHpyridine), 12.45–12.39
arom), 7.96 (s, 1H, 3-Hisoxazole), 8.09 (d, J ¼ 6.8 Hz,
(NH-C55S)
(br, 2H, 2 ꢁ OH)

22
23
3300–2650 (br, H-bonded NH
and OH), 1648–1658 (C55O),
1618–1610, 1240 (NH-C55S)
3.64 (s, 3H, NCH3), 6.85 (d, 1H, J ¼ 15.8 Hz, COCH55CH),
7.18–7.71 (m, 7H, Harom), 8.00 (d, 1H, J ¼ 15.7 Hz,
COCH55CH), 8.13 (dd, J ¼ 6.5, 1.1 Hz, 1H, 5-Hquinolone),
8.24 (s, 1H, 4-Hpyran), 9.54 (br, 1H, NH), 12.49–12.72
(br, 1H, 2 ꢁ OH)
3.63 (s, 3H, NCH3), 4.44 (d, J ¼ 5.2 Hz, 1H, 4-Hpyran), 5.26
(d, J ¼ 5.1 Hz, 1H, 3-Hpyran), 6.83–7.54 (m, 7H, Harom),
8.08 (d, J ¼ 6.2 Hz, 1H, 5-Hquinolone), 8.42 (s, 1H,
2-Hchromone), 10.44 (br, 1H, NH), 11.32 (br, 1H, NH),
12.58 (br, 1H, OH)
3330–3150 (br, H-bonded NH
and OH), 1650–1643 (C55O),
1618 (C55N), 1590, 1210
(NH-C55S)
499 (4.12) (Mþ.), 439 (3.31), 330
(2.69), 210 (1.99), 73 (100)
24
25
3240–3090 (br, H-bonded NH
and OH), 1644 (C55O), 1595,
1200 (NH-C55S)
3.24 (m, 2H, 4-H2 isozazoline), 3.67–3.51 (s, 3H, NCH3), 6.20,
(t, 1H, 5-Hisoxazaline), 7.22–7.80 (m, 7H, Harom), 8.11
(d, J ¼ 5.8 Hz, 1H, 5-Hquinolone), 8.20 (s, 1H, 4-Hpyran),
9.54 (br, 1H, NHpyrimidine), 12.49–12.53 (br, 2H, 2 ꢁ OH)
3.64 (s, 3H, NCH3), 4.07 (d, J ¼ 2.6 Hz, 1H, 4-Hpyran), 5.63
(d, J ¼ 6.6 Hz, 1H, 3-Hpyran), 7.18–7.78 (m, 7H, Harom),
8.06 (d, J ¼ 6.8 Hz,1H, 5-H), 8.15 (s, 1H, 3-H), 10.46
(br, 1H, NHpyrimidine), 11.87 (br, 1H, NHpyrimidine), 12.54
(br, 1H, OH)
514 (3.27) (Mþ.), 202 (1.70), 189
(2.04), 175 (1.13), 105 (3.14),
73 (100)
3210–3000 (br, H-bonded NH
and OH), 1643 (C55O), 1590,
1210 (NH-C55S)

346
M. Abass, M. Abdel-Megid, and M. Hassan
4-Hydroxy-3-[30-(2-hydroxyphenyl)-3,4-dihydro-10H,2H-3,40-
bipyrazol-5-yl]-1-methylquinolin-2(1H)-one (6)
A mixture of either 3 (1.87 g, 5 mmol) or compound 4 (1.94 g, 5 mmol) and
hydrazine hydrate (0.5 mL, 10 mmol) in DMF (20 mL) was heated under
reflux for 4 h and then poured into ice-cold water. The resulting solid was
filtered and crystallized to give bipyrazole 6.
3-[2-Acetyl-30-(2-hydroxyphenyl)-3,4-dihydro-10H,2H-3,4-
bipyrazol-5-yl)-4-hydroxy-1-methylquinolin-2(1H)-one (7)
Procedure A
Compound 5 (2.15 g, 5 mmol) and hydrazine hydrate (0.25 mL, 5 mmol) in
DMF (10 mL) were heated under reflux for 4 h. After cooling, the precipitate
was filtered and crystallized to give compound 7.
Procedure B
A mixture of either 3 (1.87 g, 5 mmol) or compound 4 (1.94 g, 5 mmol) and
hydrazine hydrate (0.5 mL, 10 mmol) in glacial acetic acid (20 mL) was
heated under reflux for 3 h and then poured into ice-cold water. The
resulting solid was filtered and crystallized to give compound 7.
Procedure C
A solution of compound 6 (1.2 g, 3 mmol) in glacial acetic acid (10 mL) was
boiled for 3 h. The reaction solution was left overnight to give a crystalline
product, which was filtered off and recrystallized to give compound 7.
4-Hydroxy-3-fE-3-[5-(2-hydroxyphenyl)isoxazol-4-yl]acryloylg-
1-methylquinolin-2(1H)-one (8)
A mixture of 3 (1.87 g, 5 mmol) and hydroxylamine hydrochloride (0.35 g,
5 mmol) in ethanol (20 mL) and DMF (5 mL) was refluxed for 5 h. The
reaction mixture was cooled to room temperature and diluted with water
(25 mL). The solid was collected by filtration and crystallized to give
compound 8.

Substituted Quinolinones, Part 12
347
4-Hydroxy-1-methy1-3-[5-(4-oxo-4H-chromen-3-y1)-4,
5-dihydroisoxazol-3-yl)-quinolin-2(1H)-one (9)
A mixture of 3 (1.87 g, 5 mmol) and hydroxylamine hydrochloride (0.35 g,
5 mmol) in glacial acetic acid (10 mL) was refluxed for 6 h. On cooling the
reaction mixture to room temperature, a solid crystalline product was
afforded, which was filtered off and recrystallized to give isoxazole 9.
4-Hydroxy-3-[5-(2-hydroxypheny1)-40,50-dihydro-4,
50-biisoxazol-30-y1]-1-methy1-quinolin-2(1H)-one (10)
A solution of 3 (1.87 g, 5 mmol) or compound 8 (1.94 g, 5 mmol) in pyridine
(10 mL) or 9 (1.94 g, 5 mmol) in DMF (15 mL) was treated with hydroxyla-
mine hydrochloride (0.35 g, 5 mmol) and heated under reflux for 4 h. The
reaction mixture was left to cool and acidified with dilute HCl (25 mL, 6 M).
The solid was collected by filtration and crystallized to give bisoxazole 10.
4-Hydroxy-3-f5-[3-(2-hydroxyphenyl)-1H-pyrazol-4-yl]-4,
5-dihydroisoxazol-3-y1g-1-methylquinoline-2(1H)-one (11)
To a suspension of compound 9 (1.94 g, 5 mmol) in DMF (10 mL), hydrazine
hydrate (0.4 mL, 8 mmol) was added, and the reaction mixture was refluxed
for 4 h. The precipitate so formed after cooling was filtered and crystallized
to give compound 11.
4-Hydroxy-3-f5-[5-(2-hydroxyphenyl)isoxazol-4-y1]-4,5-dihydro-
1H-pyrazol-3-ylg-1-methy1quinolin-2(1H)-one (12)
A mixture of compound 8 (1.94 g, 5 mmol) and hydrazine hydrate (0.4 mL,
8 mmol) in DMF (10 mL) was refluxed for 2 h. The solid that deposited on
cooling to room temperature was filtered off and crystallized to give
compound 12.
3-f1-Acetyl-5-[5-(2-hydroxypheny1)isoxazol-4-y1]-4,5-dihydro-1H-
pyrazol-3-y1g-4-hydoxy-1-methylquinolin-2(1H)-one (13)
Procedure A
A solution of compound 5 (2.15 g, 5 mmol) and hydrazine hydrate (0.4 mL,
8 mmol) in pyridine (10 mL) was refluxed for 4 h. Then the reaction

348
M. Abass, M. Abdel-Megid, and M. Hassan
mixture was poured onto acidified ice-cold dilute HCl (25 mL, 6 M), and the
resulting deposits were filtered and crystallized to give compound 13.
Procedure B
A mixture of compound 8 (1.94 g, 5 mmol) and hydrazine hydrate (0.5 mL,
10 mmol) in glacial acetic acid (20 mL) was heated under reflux for 3 h and
then poured into ice-cold water. The resulting solid was filtered and crystal-
lized to give compound 13.
Procedure C
A solution of compound 12 (1.2 g, 3 mmol) in glacial acetic acid (10 mL) was
heated under reflux for 3 h. The reaction solution was left overnight to give
crystalline product 13.
4-Hydroxy-3-fE-3-[4-(2-hydroxypheny1)-2-thioxo-3H-pyrimidin-5-y1]
acryloylg-1-methylquinolin-2(1H)-one (14)
A mixture of 3 (3.73 g, 10 mmol), thiourea (0.77 g, 10 mmol), and sodium
ethoxide (0.23 g of sodium in 5 mL of ethanol; 10 mmol) in ethanol
(20 mL) was refluxed for 6 h. The reaction mixture was then cooled,
poured onto water (50 mL), and acidified with dilute HCl (50 mL, 6 M)
to give a solid precipitate, which was filtered off and crystallized to give
pyrimidine 14.
4-Hydroxy-1-methyl-3-[6-(4-oxo-4H-chromen-3-y1)-2-thioxo-
1,2,5,6-tetrahydro-pyrimidin-4-y1]quinolin-2(1H)-one (15)
A mixture of 3 (1.87 g, 5 mmol) and thiourea (0.39 g, 5 mmol) in ethanol
(10 mL) containing hydrochloric acid (0.5 mL, 36%) was heated under
reflux for 3 h. Then the reaction mixture was poured into ice-cold
water. The resulting precipitate was filtered and crystallized to give
compound 15.

Substituted Quinolinones, Part 12
349
4-Hydroxy-3-f6-[5(2-hydroxyphenyl)-1H-pyrazol-4-yl]-2-thioxo-
1,2,5,6-tetrahydro-pyrimidin-4-ylg-1-methylquinolin-2(1H)-ones (16)
and 4-Hydroxy-3-f6-[5-(2-hydroxyphenyl)-1H-isoxazol-4-yl]-2-thioxo-
1,2,5,6-tetrahydropyrimidin-4-ylg-1-methylquinolin-2(1H)-ones (17)
Procedure A
A mixture of compound 15 (2.16 g, 5 mmol) and the appropriate reagent
[hydrazine hydrate (0.25 mL, 5 mmol) and hydroxylamine hydrochloride
(0.35 g, 5 mmol)] in ethanol (25 mL, 95%) was treated with finely
powdered potassium hydroxide (0.56 g, 10 mmol) and then refluxed for
3 h. Afterward it was left to cool and acidified with dilute HCl
(6 M) until complete precipitation. The obtained yellow precipitate was
filtered, dried, and crystallized to give pyrazole 16 and isoxazole 17,
respectively.
Procedure B
A mixture of either compound 4 or 8 (1.94 g, 5 mmol) and thiourea (0.39 g) in
glacial acetic acid (20 mL) was heated at reflux for 4 h and then poured into
ice-cold water. The resulting solid was filtered and crystallized to afford
pyrazole 16 and isoxazole 17, respectively.
5-[E-3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-3-
oxoprop-1-enyl]-6-(2-hydroxyphenyl)-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (18)
Sodium ethoxide (0.23 g of sodium in 5 mL of ethanol; 10 mmol) was added
to a mixture of 3 (1.87 g, 5 mmol) and cyanothioacetamide (0.5 g, 5 mmol)
in ethanol (20 mL). The mixture was heated under reflux on a boiling water
bath for 4 h. Then the reaction mixture was left to cool and acidified with
dilute HCl (50 mL, 6 M). The solid was filtered and crystallized to afford
pyridine 18.
6-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-4-(4-oxo-
4H-chromen-3-yl)-2-thioxo-1,2,3,4-tetahydropyridine-3-
carbonitrile (19)
Piperidinium acetate (0.44 g, 3 mmol) was added to a mixture of 3 (1.87 g,
5 mmol) and cyanothioacetamide (0.5 g, 5 mmol) in ethanol (20 mL). The
mixture was heated under reflux on a boiling water bath for 4 h. The solid
was filtered, washed with water, and crystallized to afford pyridine 19.

350
M. Abass, M. Abdel-Megid, and M. Hassan
5-[(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-4,5-
dihydroisoxazol-5-yl]-6-(2-hydroxyphenyl)-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (20) and 6-(4-Hydroxy-1-methyl-2-
oxo-1,2-dihydroquinolin-3-yl)-4-[5-(2-hydroxyphenyl)-isoxazol-4-yl]-
2-thioxo-1,2,3,4-tetrahydropyridine-3-carbonitnile (21)
Procedure A
A mixture of compound 18 or 19 (2.28 g, 5 mmol) and hydroxylamine
hydrochloride (0.35 g, 5 mmol), in pyridine (5 mL) and/or DMF (20 mL),
was heated under reflux for 4 h. The reaction mixture was cooled to
room temperature and acidified with dilute HCl (20 mL, 6 M). The solid
was collected by filtration and crystallized to give compounds 20 and 21,
respectively.
Procedure B
Cyanothioacetamide (0.5 g, 5 mmol) was added to either a mixture of
compound 9 and piperidinium acetate (0.44 g, 3 mmol) or compound 8
(1.94 g, 5 mmol) and sodium ethoxide (0.23 g sodium in 5 mL ethanol;
10 mmol), in absolute ethanol (30 mL). The mixture was refluxed for 4 h,
on a boiling water bath, then cooled and acidified with dilute HCl (20 mL,
6 M). The solid that obtained was filtered off and crystallized to give
compounds 20 and 21, respectively.
6-[E-3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-
3-oxopropenyl]-7-(2-hydroxyphenyl)-2-thioxo-2,3-
dihydropyrano[2,3-d]pyrimidin-4-one (22)
Sodium ethoxide (0.23 g of sodium in 5 mL of ethanol; 10 mmol) was added
to a mixture of 3 (1.87 g, 5 mmol) and 2-thiobarbituric acid (0.72 g, 5 mmol),
in ethanol (20 mL). The reaction mixture was heated under reflux on a boiling
water bath for 4 h, left to cool, and acidified with dilute HCl (25 mL, 6 M).
The solid so obtained was filtered and crystallized to give pyrimidine 22.
7-(4-Hyroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-5-(4-oxo-
4H-chromen-2-yl)-2-thioxo-1,2,3,5-tetrahydropynano[2,3-d]
pyrimidin-4-one (23)
Piperidinium acetate (0.44 g, 3 mmol) was added to a mixture of 3 (1.87 g,
5 mmol) and 2-thiobarbituric acid (0.72 g, 5 mmol), in ethanol (20 mL).
The mixture was heated under reflux on a boiling water bath for 4 h.

Substituted Quinolinones, Part 12
351
The solid was filtered, washed with water, and crystallized to afford
pyrimidine 23.
6-[3-(4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)-4,5-
dihydroisoxazol-5-yl]-7-(2-hydroxyphenyl)-2-thioxo-2,3-
dihydropyrano[2,3-d]pyrimidin-4-one (24) and 7-(4-Hydroxy-1-
methyl-2-oxo-1,2-dihydro-quinolin-3-yl)-5-[5-(2-hydroxy-phenyl)
isoxazol-4-yl]-2-thioxo-1,2,3,5-tetrahydropyrano[2,3-d]pyrimidin-
4-one (25)
Procedure A
A mixture of compound 22 or 23 (2.5 g, 5 mmol) and hydroxylamine hydro-
chloride (0.35 g, 5 mmol), in pyridine (5 mL) and/or DMF (20 mL), was
heated under reflux for 4 h. The reaction mixture was cooled to room tempera-
ture and diluted with acidified cold water (20 mL). The solid was collected by
filtration and crystallized to give isoxazoline 24 and isoxazole 25,
respectively.
Procedure B
A mixture of either compound 9 (1.94 g, 5 mmol) and sodium ethoxide
(0.23 g of sodium in 5 mL of ethanol; 10 mmol) or compound 8 (1.94 g,
5 mmol) and piperidinium acetate (0.44 g, 3 mmol), in absolute ethanol
(30 mL), was treated with 2-thiobarbituric acid (0.72 g, 5 mmol). The
mixture was then refluxed for 4 h on a boiling water bath. After that, it
was cooled and acidified with dilute HCl (50 mL, 6 M). The solid was
filtered off and crystallized to give the isoxazoline 24 and isoxazole 25,
respectively.
ACKNOWLEDGMENTS
The authors thank E. A. Mohamed and M. M. Ismail of the Chemistry Depart-
ment, Faculty of Education, Ain Shams University, and Akram Hassan, of the
Ministry of Education, for their valuable services and facilities.
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