Synthesis of bioactive 4-oxo-4H-chromenes bearing heterocyclic systems from hydrazonecarbodithioic acid and thiocarbohydrazone

Article abstract of DOI:10.1080/10426500701851291

Condensation 4-oxo-4H-chromene-3-carboxaldehydes (1a,b) with acid hydrazine-carbodithioic acid and/or thiocarbohydrazide afforded hydrazonecarbodithioic acid 2, monothiocarbohydrazone 3a,b and bisthiocarbohydrazone 4, respectively. Heterocyclization of 2-

Full text of DOI:10.1080/10426500701851291

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Synthesis of Bioactive 4-
Oxo-4H-Chromenes Bearing
Heterocyclic Systems from
Hydrazonecarbodithioic Acid
and Thiocarbohydrazone
T. E. Ali a , S. A. Abdel-Aziz a , H. M. El-Shaaer a , F.
I. Hanafy a & A. Z. El-Fauomy a
a Department of Chemistry, Faculty of Education,
Ain Shams University, Cairo, Egypt
Published online: 12 Aug 2008.
To cite this article: T. E. Ali , S. A. Abdel-Aziz , H. M. El-Shaaer , F. I. Hanafy & A. Z.
El-Fauomy (2008): Synthesis of Bioactive 4-Oxo-4H-Chromenes Bearing Heterocyclic
Systems from Hydrazonecarbodithioic Acid and Thiocarbohydrazone, Phosphorus,
Sulfur, and Silicon and the Related Elements, 183:9, 2139-2160
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Phosphorus, Sulfur, and Silicon, 183:2139–2160, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701851291
Synthesis of Bioactive 4-Oxo-4H-Chromenes Bearing
Heterocyclic Systems from Hydrazonecarbodithioic Acid
and Thiocarbohydrazone
T. E. Ali, S. A. Abdel-Aziz, H. M. El-Shaaer, F. I. Hanafy,
and A. Z. El-Fauomy
Department of Chemistry, Faculty of Education, Ain Shams University,
Cairo, Egypt
Condensation 4-oxo-4H-chromene-3-carboxaldehydes (1a,b) with acid hydrazine-
carbodithioic acid and/or thiocarbohydrazide afforded hydrazonecarbodithioic
acid 2, monothiocarbohydrazone 3a,b and bisthiocarbohydrazone 4, respectively.
Heterocyclization of 2–4 via reaction with oxygen, sulfur and/or halogen reagents
in different media yielded pyridazinethione 5; 1,3-thiazoles 7; pyrazoles 9–12; 1,2,4-
thiadiazoles 8,13,14, and 23; 1,2,4-triazolethiones 15–17; 1,2,4-triazinethiones 18–
22; imidazolethione 24 and pyrimidinethione 25 derivatives. Antifungal activity
was screened for some the new synthesized compounds. Formulations of all prod-
1
ucts have been deduced by elemental analysis and spectral data (IR, H NMR and
Mass spectroscopy).
Keywords Antifungal activity; chromone; heterocycles; hydrazonecarbodithioic acid;
synthesis; thiocarbohydrazone
INTRODUCTION
A literature survey revealed that 4-oxo-4H-chromenes possess a broad
spectrum of biological activity. They proved to be antimicrobial,1,2
antifungal,3,4 antiparasitic immunosuppresent agent,5 and plant
growth inhibitors.6 On the other hand, some pyrazoles, pyrimidines,
1,2,4-triazoles, and 1,2,4-triazines are considered very interesting ni-
trogen heterocyclic rings systems because of their bioactivities in-
cluding, antibacterial,7,8 antifungal,9,10 anti-inflammatory agents,11
and antitumor.12 It was also found that some 1,3-thiazoles and
1,2,4-thiadiazoles derivatives showed diverse biological activities as
antifungal,13 HIV14 and herbicidal.15,16 From all the forgoing facts and
Received 29 September 2007; accepted 14 November 2007.
Address correspondence to T. E. Ali, Department of Chemistry, Faculty of Education,
Ain Shams University, Roxy, 11711, Cairo, Egypt. E-mail: tarik elsayed1975@yahoo.com
2139

2140
T. E. Ali et al.
SCHEME 1
as a continuation of our interest in the synthesis of isolated heterocy-
cles containing 4-oxo-4H-chromenes,17,18 we report herein the synthe-
sis of some new isolated chromone moiety bearing some nitrogen and/or
sulfur heterocyclic systems which may have expected pharmacological
activities via treatment of hydrazonecarbodithioic acid 2, monothiocar-
bohydrazone 3a,b, and bisthio-carbohydrazone 4 with oxygen, sulfur
and/or halogen reagents.
RESULTS AND DISCUSSION
4-Oxo-4H-chromene-3-carboxaldehydes (1a,b) condensed with equimo-
lar amount of hydrazinecarbodithioic acid and/or thiocarbohydrazide
in ethanol to give the corresponding hydrazone derivatives 2 and 3a,b,
respectively (Scheme 1). Also, when compound 2 was allowed to re-
act with hydrazine hydrate in ethanol produced 3b. Condensation of
3b with equimolar amount of 1b in ethanol gave bisthiocarbohydra-
zone 4 (Scheme 1). The Structures of compounds 2–4 were confirmed by

Bioactive 4-oxo-4H-chromenes
2141
SCHEME 2
elemental analysis and spectral data (Tables I and II). The IR spectra
showed absorption bands for NH/NH2, C O pyrone and C N groups
1
at 3164–3265, 1636–1651 and 1584–1620 cm−1, respectively. Also, H
NMR spectrum of 2 showed singlet signals at δ 11.97 and 12.19 ppm
due to NH and SH protons beside signals at δ 7.60 and 8.85 ppm for
H–9 and H–2 protons, while compound 3b showed broad signals at δ
10.66 and 10.15 ppm due to NH and NH2 protons and multiplet signal
at δ 8.19 ppm for H–2 and H–9 protons. Also, their mass spectral data
gave good accordance with the proposed formulas.
Fusion of hydrazonecarbodithioic acid 2, above its melting point
gave 8-chloro-4-thioxo-3,4-dihydro-10H-chromeno[2,3-d]pyridazin-10-
one (5) (Scheme 2). IR spectrum of compound 5 showed broad absorption
band at 3254 cm−1 for NH group, strong band at 1640 cm−1 for the car-
bonyl group of pyrone ring and strong band at 1605 cm−1 for C N group.
Also, 1H NMR spectrum of compound 5 showed doublet signal for H–8
at δ 7.0 ppm, multiplet signals for aromatic protons at δ 7.31–7.94 ppm

2142

2143

2144

2145

2146

Bioactive 4-oxo-4H-chromenes
2147
and singlet signal for NH proton at δ 10.43 ppm (Table II). Moreover, its
mass spectrum recorded a molecular ion peak at m/e = 265 (M+, 100%).
Treatment of hydrazonecarbodithioic acid 2 with aniline in ethanol
yielded N-(6-chloro-4-oxo-4H-chromene-3-carbaldehyde)phenylthiose
micarbazone (6), which also was obtained in high yield from conden-
sation of 6-chloro-4-oxo-4H-chromene-3-carboxaldehyde (1b) with 4-
phenylthiosemicarbazide in ethanol (melting point and mixed melting
point gave no depression) (Scheme 2). IR spectrum of 6 showed strong
bands at 3273, 3227 cm−1 for NH groups, strong band at 1636 cm−1 for
C O pyrone group and strong band at 1596 cm−1 for C N group. Also,
1H NMR spectrum of 6 recorded two singlet signals at δ 8.28 and 9.38
ppm for H–9 and H–2 protons, respectively and the other two singlet sig-
nals at δ 10.16 and 12.01 ppm for NH protons, while its mass spectrum
recorded a molecular ion peak at m/e = 358 (M+, 1.94%) (Tables I and II).
The addition–condensation reaction of thioglycolic acid to thiosemi-
carbazone 6 in boiling DMSO furnished, 1-[2-(6-chloro-4-oxo-4H-
chromen-3-yl)-4-oxo-1,3-thiazolidin-3-yl]-3-phenylthiourea (7), which
on cyclization with concentrated sulfuric acid afforded 3-(2-anilino-1,
3-thiazolo[4,3-b][1,3,4]thiadiazol-5-yl)-6-chloro-4H-chromen-4-one (8)
(Scheme 2). The reaction pathway is assumed to proceed via intramolec-
ular nucleophilic attack by the thionic S of the thiourea moiety to cyclic
electrophilic C O of thiazolidinone moiety followed by elimination of
water molecule.15 IR spectrum of compound 7 revealed broad bands at
3258, 3148 cm−1 for NH groups, strong bands at 1689, 1626, and 1602
cm−1 for C O thiazolidinone, C O pyrone, and C N groups, respec-
tively, while that of compound 8 showed absence of carbonyl group of
thiazolidinone and the presence of strong band at 1659 cm−1 for car-
bonyl group of pyrone is agreement with the postulated structure. Also,
1H NMR spectrum of compound 7 recorded singlet signal at δ 3.91 ppm
for CH2 of thiazolidinone, signal at δ 6.50 ppm due to H–2 of thiazo-
lidinone proton, multiplet signals at δ 6.89–7.45 ppm due to aromatic
protons and two singlet signals at δ 10.70, 11.60 ppm for NH protons
(Table II). Mass spectral data of compounds 7 and 8 gave a good accor-
dance with the formed structures (Table I).
On treating monothiocarbohydrazone 3b with malononitrile, diethyl
malonate and/or cinnamaldehyde in DMF and few drops of piperidine
afforded the pyrazoles derivatives 9–11, respectively (Scheme 3). As-
signment of the products 9 and 10 was based on their elemental analy-
sis, IR, 1H NMR, and MS spectral data (Tables I and II). Their IR spectra
revealed absorption bands for NH2 and NH groups and strong bands
1
for carbonyl groups of pyrone. The H NMR spectrum of compound 9
showed two singlet signals at δ 3.91, 4.48 ppm for NH2 protons, multi-
plet signals at δ 8.52–8.69 ppm for H–2, H–9 protons and singlet signal

2148
T. E. Ali et al.
SCHEME 3
at δ 10.45 ppm for NH proton. Mass spectra of compounds 9 and 10
exhibited a molecular ion peaks at m/e = 335 (M–HCN, 17.06%) and
m/e = 370 (M+5, 33.3%), respectively. On the other hand, IR spectrum
of 11 revealed the presence of NH group at 3424 cm−1, C O pyrone
group at 1625 cm−1 and strong band at 1597 cm−1 due to C N group.
The1H NMR spectrum of compound 11 exhibited signals due to CH2
and CH–N of pyrazole moiety at δ 1.90 and 2.89 ppm respectively, sin-
glet signal at δ 8.93 ppm for H–2 proton and singlet signal at δ 10.45
ppm for NH proton (Table II).
Also, treatment of 3b with ethyl 2-chloro-acetoacetate in DMF19,20
yielded unexpected product ethyl 5-[2-(6-chloro-4-oxo-4H-chromen-
3-ylmethylene)hydrazino]-3-methyl-1H-pyrazole-4-carboxylate
(12)
(Scheme 3). Formation of compound 12 may be occurred by carbanion
attack of ethyl 2-chloroacetoacetate at C S group of compound 3b

Bioactive 4-oxo-4H-chromenes
2149
SCHEME 4
to form intermediate A which accept proton to form intermediate
B followed by elimination of HSCl molecule to give intermediate
C. Cyclocondensation reaction of intermediate C gave compound 12
(Scheme 4). Sulfur test and spectral data of compound 12 emphasized
that sulfur atom was removed through the reaction. IR spectrum of
compound 12 showed broad band at 3198 cm−1 for NH groups and
strong bands at 1709, 1627, and 1596 cm−1 for C O ester, C O pyrone
and C N group, respectively, while its 1H NMR spectrum recorded
signals at δ 1.09, 4.10 ppm due to ethoxy protons, singlet signals at
δ 8.08, 8.62, 10.68, and 13.56 ppm for H–9, H–2, and NH protons,
respectively (Table II).
On the other hand, refluxing of compound 3b with excess formic acid
at 95◦C yielded 6-chloro-3-(1,3,4-thiadiazol-2-yl-hydrazonomethyl)-4H-
chromen-4-one (13) (Scheme 5). Structure of compound 13 was deduced
from IR spectrum which showed broad band at 3274, 3126 cm−1 for NH

2150
T. E. Ali et al.
SCHEME 5
group and broad bands at 1628 and 1581 cm−1 for C O pyrone and C N
1
groups, respectively, while its H NMR spectrum recorded multiplet
signals at δ 7.01–8.36 ppm for aromatic protons and singlet signals at
δ 9.01, 9.52 ppm for NH proton (Table II). Moreover, its mass spectrum
recorded a molecular ion peak at m/e = 307 (M+, 5.7%) (Table I).
Also, refluxing of compound 3a with acetic anhydride gave N-acetyl-
Nꢀ-[4-acetyl-5-(6-methyl-4-oxo-4H-chromen-3-yl)-4,5-dihydro-1,
3,4-
thiadiazol-2-yl]acetohydrazide (14), (Scheme 5). IR spectrum of com-
pound 14 showed broad bands at 3262, 1715 and 1646 cm−1 for NH, C O
acetyl groups and C O pyrone, respectively. Also, its 1H NMR spectrum
showed singlet signals at δ 2.05, 2.45, and 2.51 ppm for four groups of
methyl protons, singlet signal at δ 8.92 ppm for H–2 proton and singlet
signal at δ 11.02 ppm for NH proton (Table II). Formation of compound
13 took place by formylation of amino group of compound 3b with formic
acid instead of reduction of C N and then cyclization of the formyl
derivative (Scheme 6), while Formation compound 14 may be occurred

Bioactive 4-oxo-4H-chromenes
2151
SCHEME 6
via acetylation of amino group followed by cycloaddition reaction of
thiol form of monothiocarbohydrazone 3a in acidic medium to form an
intermediate which on acetylation gave compound 14 (Scheme 6).21
A facile route to synthesize 6-methyl-3-[3-thioxo-1,5-dihydro-1,2,4-
triazol-4-yliminomethyl]-4H-chromen-4-one (15) and 6-methyl-3-[5-
methyl-3-thioxo-1,5-dihydro-1,2,4-triazol-4-yliminomethyl]-4H-chro-
men-4-one (16) have been achieved by refluxing of monothiocarbo-
hydrazone 3a with triethylorthoformate and/or acetyl chloride in
pyridine, respectively (Scheme 5). In addition, refluxing 3b with
carbon disulfide in pyridine gave 1,2,4-triazole-3,5-dithione derivative
17 (Scheme 5). Formation of compound 17 may be occurred via addition
reaction of NH2 group to carbon disulfide followed by cyclocondensation
reaction with elimination of one molecule of H2S. The spectral data of
15–17 were consistent with their structures (Tables I and II). IR spectra
showed broad bands at 3219–3109 cm−1 for NH groups and also strong
bands at 1625–1639 and 1598–1619 cm−1 for C O pyrone and C N
1
groups, respectively. The H NMR spectrum of compounds 15 and 16
showed characteristic signals for NH triazole at δ 10.65 and 11.03 ppm,
respectively, while 1H NMR spectrum of compound 17 recorded multi-
plet signals at δ 6.98–9.35 ppm for aromatic protons, two singlet signals
at δ 10.51, 10.64 ppm for NH protons and the other two singlet signals at

2152
T. E. Ali et al.
SCHEME 7
δ 12.01, 12.37 ppm for SH protons which support that compound 17
exists in tautomeric forms. Mass spectra of compounds 15–17 recorded
molecular ion peaks at m/e = 286 (M+, 32.9%), and 300 (M+, 0.44%)
and 339 (M+, 2.35%), respectively.
Cyclocondensation reaction of monothiocarbohydrazone 3a,b with
chloroacetyl chloride, dichloroacetic acid, and/or oxalyl chloride in DMF
and few drops of piperidine as catalyst led direct to the formation of
1,2,4-triazine-3-thione derivatives 18–20, respectively (Scheme 7). As-
signment of the products 18–20 was based on their elemental analy-
1
sis, IR, H NMR and MS spectral data (Tables I and II). The IR spec-
tra revealed characteristic absorption broad bands at 3112–3425 cm−1
for NH groups, strong bands at 1647–1702 cm−1 for C O triazinone
groups and strong bands at 1619–1650 cm−1 for C O pyrone groups.
The 1H NMR spectrum of compound 18 recorded singlet signal at δ 3.77
(CH2), 10.60 (NH triazine) and 11.49 ppm (NH triazine). Also, 1H NMR
spectrum of 19 showed singlet signal at δ 9.48 ppm (C6 H triazinone)
and broad signal at δ 10.50 ppm for NH triazinone. Mass spectral data
of compounds 18–20 showed gave a good accordance with the formed
structures.

Bioactive 4-oxo-4H-chromenes
2153
The interaction between compound 3b and phenacyl bromide in
DMF containing few drops of piperidine gave 4-([6-chloro-4-oxo-4H-
chromen-3-ylmethylene)amino]-5-phenyl-3-thioxo-2,3-dihydro-1,2,4-
triazine (21) and while cyclocondensation reaction of monothiocarbo-
hydrazone 3a with ethyl pyruvate in ethanol and presence of potas-
sium carbonate yielded 6-methyl-4-[(6-methyl-4-oxo-4H-chromen-3-
ylmethylene)amino]-3-thioxo-3,4-dihydro-1,2,4 -triazin-5(2H)-one (22)
(Scheme 7). IR spectra of compounds 21 and 22 showed characteristic
absorption broad band at 3111, 3173 cm−1 for NH groups and strong
bands at 1624 and 1641 cm−1 for C O pyrone groups, respectively.
1
Also, the H NMR spectra of compounds 21 and 22 recorded singlet
signals at δ 10.70 and 13.66 ppm for NH protons, respectively (Table
II); while their mass spectra recorded a molecular ion peaks at m/e 367
(M-N2H2, 8.93%) and 328 (M+, 8.30%), respectively (Table I).
Cycloaddition of bisthiocarbohydrazone 4 with acetyl chloride
in glacial acetic acid21,22 afforded 6-chloro-4-oxo-4H-chromene-3-
carbaldehyde[4-acetyl-5-(6-chloro-4-oxo-4H-chromen-3-yl)-4,5-dihydro
-1,3,4-thiadiazol-2-yl]hydrazone (23) (Scheme 8). IR spectrum of
compound 23 showed a broad band at 3066 cm−1 for NH group and
strong bands at 1724, 1651 and 1605 cm−1 for C O acetyl, C O
pyrone and C N groups respectively. The 1H NMR spectrum of
compound 23 recorded singlet signal at δ 2.89 ppm for acetyl protons,
doublet signal at δ 6.38 ppm for H–8 proton, multiplet signals at δ
7.00–7.51 ppm for aromatic protons and three singlet signals at δ
8.42, 8.49, and 11.23 ppm for H–2, H–2ꢀ and NH protons, respectively
(Table II).
Finally, 2-thioxoimidazolidin-4-one 24 and 2-thioxodihydro-
pyrimidine-4,6(1H, 5H)-dione 25 derivatives were obtained from
treatment bisthiocarbohydrazone 4 with chloroacetic acid and/or di-
ethyl malonate, respectively in DMF containing few drops of piperidine
(Scheme 8).23 IR spectra of 24 and 25 showed the disappearance of NH
groups and appearance of a new strong bands at 1695 cm−1 for C O
imidazolinone and 1710 cm−1 for C O pyrimidinedione, respectively.
The 1H NMR spectrum of 24 confirmed appearance new multiplet
signal at δ 3.59–3.63 ppm for CH2 of imidazolinone and broad singlet
signal at δ 12.20 ppm for enolic OH group of imidazole (Table II).
Mass spectral data of 24 and 25 gave accordance with the suggested
formulas (Table I).
Antifungal Activity
Some new synthesized compounds were screened for their antifun-
gal activities against three species of fungi, Alternaria alternata,

2154
T. E. Ali et al.
SCHEME 8
Aspergillus niger, and Aspergillus flavipes using disc diffusion
method.24,25 The tested compounds were dissolved in DMF, which was
used as a control to get 1 mg/ml solution. The inhibition zones of mi-
crobial growth surrounding the filter paper disc (2.5 mm) were mea-
sured in millimeters at the end of an incubation period at 30◦C for
3 days. Activity of each compound was compared with that of flucana-
zole as the standard. The investigation of fungicidal screening data
(Table III) revealed compound 4 and 8 showed high activity against
the three species of fungi. Also, Compound 6 showed high activities
against Aspergillus flavipes and moderate activities against Alternaria
alternata and Aspergillus niger, while compound 10 showed moder-
ate activities against Alternaria alternata and Aspergillus flavipes
and lower activity against Aspergillus niger. Moreover, compounds
19 and 12 showed moderate activities against the three species
of fungi, while compounds 17 and 25 showed moderate activities
against Aspergillus niger and Aspergillus flavipes, while Compound 13
showed lower activities against Alternaria alternata and Aspergillus
niger.

Bioactive 4-oxo-4H-chromenes
2155
TABLE III Antifungal Activities Data of Some the Prepared
Compounds
Diameter of inhibition zone (mm)
Compd. no. Alternaria alternata Aspergillus niger Aspergillus flavipes
4
6
8
10
12
13
17
19
+++
++
+++
++
++
+
+++
++
++++
+++
+++
++
+++
+
++
++
+
++
+
++
++
++
+
++
++
25
++
++
flucanazole
++++
++++
++++
+ (Inhibition zone 1–10 mm) = lower active; ++ (inhibition zone
11–20 mm) = moderately active; +++ (inhibition zone 21–30 mm) = high
active. and ++++ (inhibition zone >30 mm) = very high active.
EXPERIMENTAL
Melting points were determined on a digital Stuart SMP3 and are
uncorrected. Infrared spectra were measured on Perkin-Elmer 293
spectrophotometer (γ in cm−1), using KBr disks. 1H NMR spectra were
measured on Gemini-200 spectrometer (200 MHz), using DMSO-d6 as
a solvent and TMS (δ, 0.0 ppm) as internal standard. The mass spectra
were measured on gas chromatographic GCMSqp 1000-ex Shimadzu
instrument or HP MS 5988 mass spectrometer by direct inlet oper-
ating at 70 eV. Elemental microanalyses were performed on Perkin
Elmer CHN–2400 analyzer or C, H, N manual in microanalysis center
at Cairo University. 4-Oxo-4H-chromene-3-carboxaldehydes (1a,b),26
hydrazinecarbodithioic acid,27 and thiocarbohydrazide27 were prepared
by published methods.
2-[(6-Chloro-4-oxo-4H-chromen-3-yl)
methylene]hydrazinecarbodithioic acid (2)
A mixture of 1b (2.08 g, 10 mmol) and hydrazinecarbodithioic acid (1.08
g, 10 mmol) in absolute ethanol (50 ml) was refluxed for 2 h. The ob-
tained solid was filtered off and crystallized from the proper solvent to
give 2 (Table I).

2156
T. E. Ali et al.
N‘-[(6-Substituted-4-oxo-4H-chromen-3-yl)
methylene]thiocarbohydrazide (3a,b)
Method A
Equimolar amounts of 1a,b (10 mmol) and thiocarbohydrazide (1.06
g, 10 mmol) in absolute ethanol (50 ml) was refluxed for 2 h. The ob-
tained solid was filtered off and crystallized from the proper solvent to
give 3a,b (Table I).
Method B
A mixture of 2 (2.98 g, 10 mmol) and hydrazine hydrate (0.5 g,
10 mmol) in ethanol (50 ml) was refluxed for 3 h. The obtained solid
was filtered off and crystallized from the proper solvent to give 3b
(Table I).
1,5-Bis[(6-chloro-4-oxo-4H-chromen-3-yl)
methylene]thiocarbohydrazide(4)
A mixture of 3b (2.96 g, 10 mmol) and 6-chloro-3-formylchromone (1b)
(2.08 g, 10 mmol) in absolute ethanol (50 ml) was refluxed for 5 h. The
obtained solid was filtered off and crystallized from the proper solvent
to give 4 (Table I).
8-Chloro-4-thioxo-3,4-dihydro-10H-chromeno[2,3-d]
pyridazin-10-one (5)
Nꢀ-(6-chloro-4-oxo-4H-chromen-3-ylmethylene)hydrazinecarbothioic
acid (2b) (1 g) was fused above its melting point for 15 min. The product
was treated with methanol then filtered off and crystallized from the
proper solvent to give 5 (Table I).
N-(6-Chloro-4-oxo-4H-chromene-3-carbaldehyde)
phenylthiosemicarbazone (6)
Method A
A mixture of 2 (2.98 g, 10 mmol) and aniline (0.93 g, 10 mmol) in
ethanol (50 ml) was refluxed for 5 h. The obtained solid was filtered off
and crystallized from the proper solvent to give 6 (Table I).
Method B
A mixture of 1b (2.08 g, 10 mmol) and 4-phenylthiosemicarbazide
(1.67 g, 10 mmol) in ethanol (50 ml) was refluxed for 1 h. The obtained

Bioactive 4-oxo-4H-chromenes
2157
solid was filtered off and crystallized from the proper solvent to give 6
(Table I).
1-[2-(6-Chloro-4-oxo-4H-chromen-3-yl)-4-oxo-1,3-thiazolidin-3-
yl]-3-phenyl-thiourea (7)
A mixture of 6 (3.57 g, 10 mmol) and thioglycolic acid (0.92 g, 10 mmol) in
DMSO (50 ml) was refluxed for 6 h. The solution was cooled and poured
onto ice–water. The solid obtained was filtered off and crystallized from
the proper solvent to give 7 (Table I).
3-(2-Anilino[1,3]thiazolo[4,3-b][1,3,4]thiadiazol-5-yl)-6-chloro-
4H-chromen-4-one (8)
A mixture of 7 (4.31 g, 10 mmol) and concentrated sulfuric acid (20 ml)
was stirred for 1 h at 0–5◦C and poured onto ice. The obtained solid was
filtered off and crystallized from the proper solvent to give 8 (Table I).
The 1H-pyrazole-1-thiocarbohydrazide Derivatives
(9–11)—General Method
A mixture of 3b (2.96 g, 10 mmol) and malononitrile, diethyl malonate
or cinnamaldehyde (10 mmol) in DMF (50 ml) containing few drops of
piperidine was refluxed for 10 h. The mixture was cooled and poured
onto ice–water. The solid obtained was filtered off and crystallized from
the proper solvent to give 9–11, respectively (Table I).
Ethyl 5-{[2-(6-chloro-4-oxo-4H-chromen-3-ylmethylene)
hydrazino]}-3-methyl-1H-pyrazole-4-carboxylate (12)
A mixture of 3b (2.96 g, 10 mmol) and ethyl 2-chloroacetoacetate (1.64
g, 10 mmol) in DMF (50 ml) was refluxed for 6 h. The mixture was
cooled and poured onto ice–water. The solid obtained was filtered off
and crystallized from the proper solvent to give 12 (Table I).
6-Chloro-3-(1,3,4-thiadiazol-2-ylhydrazonomethyl)-4H-
chromen-4-one (13) and N-Acetyl-Nꢀ-[4-acetyl-5-
(6-methyl-4-oxo-4H-chromen-3-yl)-4,5-dihydro-1,3,4-
thiadiazol-2-yl]acetohydrazide (14)
A mixture of 3a or 3b (10 mmol) and formic acid or acetic anhydride (40
ml) was refluxed for 6 h. The mixture was cooled and neutralized with
sodium carbonate solution (10%). The solid obtained was filtered off

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T. E. Ali et al.
and crystallized from the proper solvent to give 13 and 14, respectively
(Table I).
6-Methyl-3-[(3-thioxo-1,5-dihydro-1,2,4-triazol-4-ylimino)
methyl]-4H-chromen-4-one (15)
A mixture of 3a (2.76 g, 10 mmol) and triethylorthoformate (30 ml) was
refluxed for 4 h. The obtained mixture was concentrated to half volume
then cold water (20 ml) was added. The obtained solid was filtered off
and crystallized from the proper solvent to give 15 (Table I).
6-Methyl-3-[(5-methyl-3-thioxo-1,5-dihydro-1,2,4-triazol-4-
ylimino)methyl]-4H-chromen-4-one (16) and
6-chloro-3-{[(3,5-dithioxo-1,2,4-triazolidin-4-ylimino)
methyl]}–4H-chromen-4-one (17)
A mixture of 3a or 3b (10 mmol) and acetyl chloride or carbon disulfide
(10 mmol) in pyridine (50 ml) was refluxed for 6 h. The mixture was
cooled and poured onto ice–HCl. The solid obtained was filtered off and
crystallized from the proper solvent to give 16 and 17, respectively
(Table I).
The 3-thioxo–1,2,4-triazine derivatives (18–21)—General
Method
A mixture of 3a or 3b (10 mmol) and chloroacetyl chloride, dichloroacetic
acid, oxalyl chloride or phenacyl bromide (10 mmol) in DMF (50 ml)
containing few drops of piperidine was refluxed for 4 h. The mixture was
cooled and poured onto ice–water. The solid obtained was filtered off and
crystallized from the proper solvent to give 18–21 respectively (Table I).
6-Methyl-4-[(6-methyl-4-oxo-4H-chromen-3-
ylmethylene)amino]-3-thioxo-1,2,4-triazin-5(2H)-one (22)
A mixture of 3a (2.76 g, 10 mmol) and ethyl pyruvate (1.10 g, 10 mmol)
in ethanol (50 ml) and potassium carbonate solution (10%, 20 ml) was
refluxed for 8 h. The mixture was cooled and poured onto ice–water. The
solid obtained was filtered off and crystallized from the proper solvent
to give 22 (Table I).

Bioactive 4-oxo-4H-chromenes
2159
6-Chloro-4-oxo-4H-chromen-3-carbaldehyde[4-acetyl-5-
(6-chloro-4-oxo-4H-chromen-3-yl)-4,5-dihydro-1,3,4-thiadiazol-
2-yl]hydrazone (23)
A mixture of 4 (2.43 g, 5 mmol) and acetyl chloride (0.39 g, 5 mmol) in
glacial acetic acid (50 ml) was refluxed for 6 h. The mixture was cooled
and neutralized with sodium carbonate (10%). The solid obtained was
filtered off and crystallized from the proper solvent to give 23 (Table I).
1,3-Bis[(6-chloro-4-oxo-4H-chromen-3-ylmethylene)amino]-2-
thioxoimidazolidin-4-one (24) and 1,3-Bis[(6-chloro-4-oxo-4H-
chromen-3-ylmethylene)amino]-2-thioxodihydro-pyrimidine-
4,6(1H,5H)-dione (25)
A mixture of 4 (2.43 g, 5 mmol) and chloroacetic acid or diethyl malonate
(5 mmol) in DMF (50 ml) containing few drops of piperidine was refluxed
for 10 h. The mixture was cooled and poured onto ice–water. The solid
obtained was filtered off and crystallized from the proper solvent to give
24 and 25, respectively (Table I).
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