Synthesis and reactions of some new thiobarbituric acid derivatives

Article abstract of DOI:10.1080/10426500701415907

A series of novel thiobarbituric acid derivatives 3a-c, 5, and 12 were synthesized via the reaction of 4-benzoyl-1-cyanoacetylthiosemicarbazide (1) or its derivatives 2a-c, 9 with malonic acid and acetyl chloride. Coupling of thiobarbituric acid derivativ

Full text of DOI:10.1080/10426500701415907

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Phosphorus, Sulfur, and Silicon
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Synthesis and Reactions of
Some New Thiobarbituric Acid
Derivatives
Samir Bondock a , Abd El-Gaber Tarhoni a & Ahmed
A. Fadda a
a Department of Chemistry, Faculty of Science ,
Mansoura University , Mansoura, Egypt
Published online: 15 Jun 2007.
To cite this article: Samir Bondock , Abd El-Gaber Tarhoni & Ahmed A. Fadda
(2007) Synthesis and Reactions of Some New Thiobarbituric Acid Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:8, 1915-1936, DOI:
10.1080/10426500701415907
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Phosphorus, Sulfur, and Silicon, 182:1915–1936, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701415907
Synthesis and Reactions of Some New Thiobarbituric
Acid Derivatives
Samir Bondock
Abd El-Gaber Tarhoni
Ahmed A. Fadda
Department of Chemistry, Faculty of Science, Mansoura University,
Mansoura, Egypt
A series of novel thiobarbituric acid derivatives 3a–c, 5, and 12 were synthesized
via the reaction of 4-benzoyl-1-cyanoacetylthiosemicarbazide (1) or its derivatives
2a–c, 9 with malonic acid and acetyl chloride. Coupling of thiobarbituric acid
derivatives 3a-c and 5 with aromatic diazonium chlorides furnished a new series of
the corresponding bisarylhydrazo-thiobarbituric dyes 4a–c. The reaction of 5 with
cyclohexanone and sulfur under Gewald reaction condition afforded thieno[2,3-
d]pyrimidine derivative 21, that condensed with p-anisladehyde to give 5-arylidene
thiobarbituric acid derivative 22. The reaction of 1 with phenyl isothiocyanate af-
forded the non-isolable adduct 23 which was used as a key intermediate for the
synthesis of polyfunctionally substituted thiazolidinone and thiobarbituric ring
systems.
Keywords Azo coupling; pyrimidine; thiazole; thiophene; thiobarbituric; thiosemicar-
bazide
INTRODUCTION
Pyrimidine is the parent heterocycle of a very important group of
compounds that have been extensively studied due to their occur-
rence in living systems. Pyrimidine moieties were reported to have
anti-bacterial, antifungal and anti- HIV activities.1−5 Certain sub-
stituted 2-thiobarbituric acids have long been used as intravenous
anesthetics6 and as intermediates in the preparation of dyes.7 Re-
cently there has been interest in 2-thiobarbituric acids as antifungal,8
anticonvulsants,9 immunotropic and anti-inflammatory compounds,10
antineoplastic agents,11 and as platforms in the synthesis of other
biologically active compounds.12 Thiobarbituric acid derivatives were
Received March 20, 2007; accepted April 9, 2007.
Address correspondence to Samir Bondock, Department of Chemistry, Faculty of Sci-
ence, Mansoura University, ET-35516 Mansoura, Egypt. E-mail: Bondock@mans.edu.eg
1915

1916
S. Bondock et al.
also reported to possess antiparkinsonian13,14 and hypnotic15 activi-
ties. Substituted aminopyrimidines structures are common in marketed
drugs, such as anti-atherosclerotic aronixil, anti-histaminic thonzy-
lamine, anti-anxielytic buspirone, anti-psoriatic enazadrem, and other
medicinally relevant compounds.16,17 Thienyl compounds are also re-
ported for their anti-microbial and pharmaceutical activities.18−21
In the last few years we have been involved in a program aiming to
develop new, simple procedures for the synthesis of functionally sub-
stituted heterocycles of anticipated biological activity, from available
laboratory starting materials.22−26 In the context of this program some
new functionally substituted thiobarbituric acid derivatives were re-
quired. 4-Benzoyl-1-cyanoacetylthiosemicarbazide (1)27 seemed to be a
good candidate to fulfil our objective via intermolecular cyclization by
the reaction with malonic acid in the presence of acetyl chloride to afford
thiobarbituric acid which reacts with suitable reagents.
RESULTS AND DISCUSSION
Thus, compound 1 was allowed to couple with an appropriate aromatic
diazonium chlorides in pyridine at 0–5◦C to afford the colored arylhy-
drazone derivatives 2a–c. Elemental analysis and spectral data were
in favor of these proposed hydrazo structures. The IR spectra of 2a–c
in general showed absorption bands at 3350–3210 cm−1 region due to
NH, 2210–2207 cm−1 due to conjugated C N, 1680 and 1655 cm−1 due
to two amidic C O functions. The 1H-NMR spectrum of 2c as an exam-
ple displayed a singlet signal at δ 3.90 ppm and multiplet signal at δ
7.17–8.23 ppm region owing to the methoxy and aromatic protons, re-
spectively. Also, the 1H-NMR spectrum showed the absence of activated
methylene protons signal which assigned the structure and confirm the
formation of hydrazone structure. The mass spectrum of 2c showed a
molecular ion peak (M+) at m/z = 396, corresponding to a molecular
formula C18H16N6O3S.
The thiosemicarbazide derivatives 2a–c underwent intermolecular
cyclization by the reaction with malonic acid in the presence of acetyl
chloride and furnished the 2-thiobarbituric acid derivatives 3a–c. The
versatility of the novel synthon 3 was proven by the following trans-
formations. Compounds 3a–c underwent electrophilic substitution re-
action upon coupling with aromatic diazonium chlorides to yield the
corresponding bis-arylhydrazonothiobarbituric acid derivatives 4a–c.
The chemical structural of compounds 4a–c were elucidated on the
basis of elemental analysis and spectral data. For example, the IR
spectrum of 4c exhibited absorption bands at 3400 − 3180 cm−1 region

Thiobarbituric Acid Derivatives
1917
characteristic to NH groups, 2205 cm−1 characteristic to conjugated
C N group and 1675, 1665, 1658 and 1650 cm−1 characteristic to four
amidic C O groups. The 1H-NMR spectrum of 4c showed five singlets at
δ 3.88, 3.95, 7.13, 10.59 and 11.17 ppm due to two methoxy protons and
three NH protons, respectively. The mass spectrum showed a molecu-
lar ion peak (M+) at m/z = 598. Compounds 4a–c could also be obtained
and proved chemically by reacting 1 with malonic acid in the presence of
acetyl chloride to afford thiobarbituric acid derivative 5 which was then
coupled with two equimolar amounts of aromatic diazoinum chlorides
in pyridine at 0–5◦C.
On the other hand, the condensation of 3b with p-anislaldehyde in
refluxing ethanol containing a catalytic amount of piperidine yielded
exclusively the corresponding arylidene derivative 6. The structure of
compound 6 was established on the basis of both analytical and spec-
1
tral data. The H-NMR spectrum of 6 exhibited a new two singlets at
δ 3.95 and 8.03 ppm assignable to the methoxy and methine protons,
SCHEME 1

1918
S. Bondock et al.
respectively, in addition to the expected agreeable signals. The mass
spectrum showed a molecular ion peak at m/z = 566 corresponding to
the molecular weight of compound 6. The reaction of 6 with hydrazine
hydrate in ethanol, under reflux, furnished a single product. Two pos-
sible structures 7 and 8 were considered. The possibility of structure
7 was ruled out on the basis of the chemical tests which revealed the
absence of sulfur. Structure 8 was established for the reaction product
on the basis of its mass spectrum that revealed a molecular ion peak at
m/z = 564 corresponding to a molecular formula C29H24N8O5.
To account for the direct formation of the thiobarbituric acid, the
mechanism outlined in chart 1 is proposed. According to this mecha-
nism, the reaction starts with the formation of the mixed acid anhydride
which undergoes the acid catalyzed cleavage of acetic acid to form mal-
onyl chloride. The latter then undergoes intermolecular nucleophilic
cyclization with thiosemicarbazide via elimination of two molecules of
HCl to give the thiobarbituric acid derivative.
It was found that when compound 1 reacted with ethyl 2-cyano-3-
(4-methoxyphenyl) acrylate in boiling ethanol containing a catalytic
amount of piperidine, compound 9 was obtained instead of the expected
pyridine-2-one derivative 11.28 Formation of 9 was assumed to proceed
via the initial Michael addition of the active methylene of 1 to the α, β-
unsaturated nitrile to afford the non-isolable acylic Michael adduct 10
which then loses the ethyl cyanoacetate to give the arylidene thiosemi-
carbazide derivative 9. Furthermore, the arylidene derivative 9 was
identical (TLC, m.p. and mixed m.p.) with an authentic sample synthe-
sized by stirring p-anisaldehyde with the thiosemicarbazide derivative
CHART 1

Thiobarbituric Acid Derivatives
1919
SCHEME 2
1 in refluxing ethanol in the presence of a catalytic amount of piperidine
as described in Scheme 2.
Analogous to compound 2, cyclocondensation of compound 9 with
malonic acid in acetyl chloride at 50–60◦C afforded the thiobarbituric
acid derivative 12. The reactivity of hydrogen atoms at C-5 is the
most outstanding chemical property of thiobarbituric acid derivative

1920
S. Bondock et al.
12 which undergoes the characteristic condensation and electrophilic
substitution reactions. Thus, coupling of compound 12 with different
aromatic diazonium chlorides in pyridine at 0–5◦C afforded the cor-
responding 5-arylhydrazonothiobarbituric acid derivatives 13a–c. The
structures of 13a–c were identified on the basis of their elemental anal-
ysis and spectral data. Thus, the IR spectrum of 13b as a represen-
tive example displayed absorption bands at 3300–3210 cm−1 region
attributed to two NH functions and at 1590 cm−1 attributed to C N
function. Moreover, its 1H-NMR spectrum revealed the presence of two
broad signals at δ 11.18 and 12.44 ppm characteristic to two NH pro-
tons and three singlet signals at δ 8.03, 3.95, 2.66 ppm characteristic
to the methine proton (CH ), OCH3, and CH3 protons, respectively.
The mass spectrum of 13b showed a molecular ion peak at m/z = 566,
corresponding to a molecular formula C29H22N6O5S.
When compound 12 was treated with an excess of hydrazine hydrate
in boiling ethanol aiming to get compound 14, unfortunately, compound
14 was not formed and 2-hydrazinobarbituric acid derivative 15 was
obtained in good yield. Compound 14 was eliminated based on the ele-
ment test which showed the absence of sulfur indicating that the sulfur
was removed via H2S elimination. Furthermore, the IR spectrum of
15 showed the presence of C N stretching band and absence of C S
stretching band. Also, the 1H-NMR spectrum exhibited a broad singlet
signal at δ 10.19 ppm assignable to NH2 protons and a singlet signal
at δ 8.01 ppm assignable to the methine proton together with the other
expected signals. The mass spectrum showed a molecular ion peak at
m/z = 446, corresponding to a molecular formula C22H18N6O5.
The condensation of compound 12 with p-anisaldehyde in boiling
ethanol containing a catalytic amount of piperidine gave bis-arylidene
thiobarbituric derivative 16. The structure 16 has been proved on the
1
basis of its elemental analysis and spectral data. Analysis of the H-
NMR spectrum revealed the appearance of a new two singlet signals
at δ 8.03 and 8.12 ppm assignable to two methine protons and the dis-
appearance of signals assignable to the methylene protons of thiobar-
bituric acid. The mass spectrum of 16 showed a molecular ion peak at
m/z = 566, corresponding to molecular formula C30H22N4O6S. Further
proof for structure 16 was provided by its preparation through another
route via the condensation reaction of compound 5 with two equimolar
amounts of p-anisaldehyde in ethanol containing a catalytic amount of
piperidine.
In a similar manner, the reaction of compound 16 with an excess of
hydrazine hydrate gave the 2-hydrazinobarbituric acid derivative 18,
instead of compound 17. The structure 18 seemed to be logical accord-
ing to elemental analysis and spectral data. Thus, the IR spectrum

Thiobarbituric Acid Derivatives
1921
revealed the presence of NH2 absorption band at 3415–3354 cm−1 and
conjugated C N absorption band at 2205 cm−1 and the absence of C S
absorption band. Moreover, the 1H-NMR spectrum displayed two char-
acteristic singlet signals at δ 8.15 and 8.18 ppm for two methine protons,
in addition to, a broad singlet signal at δ 6.25 characteristic to NH2 pro-
tons. The mass spectrum of 18 showed a molecular ion peak at m/z =
564, corresponding to a molecular formula C30H24N6O6.
Similarly, the reaction of compound 5 with equimolar amounts of
either hydrazine hydrate or phenyl hydrazine in ethanol solution, un-
der reflux, yielded the corresponding 2-hydrazino or 2-phenylhydrazino
barbituric acid derivatives 19a–b, respectively, via H2S elimination.
2-Aminothiophenes and thieno[2,3-d]pyrimidines have recently re-
ceived considerable attention because of their synthetic and pharma-
ceutical importance. In the present work we explore the synthetic poten-
tialities of 5 to obtain some novel thieno[2,3-d]pyrimidine derivatives.
Thus, the Gewald reaction of thiobarbituric acid derivative 5 with el-
emental sulfur, cyclohexanone and morpholine as a basic catalyst in
a mixture of ethanol and dimethylformamide (1:1) gave compound 21
via the acyclic intermediate 20. However, the product isolated was as-
signed the structure 21 on the basis of elemental analysis and spectral
data. Thus, its IR spectrum revealed the absence of absorption band
characteristic to C N function and the presence of absorption bands at
3350 cm−1 assignable to NH and at 1682, 1670 and 1662 cm−1 for three
1
amidic C O functions. Moreover, its H-NMR spectrum exhibited the
disappearance of a signal characteristic to cyanomethylene protons and
the appearance of a broad singlet signal at δ 11.21 ppm characteristic
to NH proton. The mass spectrum of 21 showed a molecular ion peak
at m/z = 522, corresponding to a molecular formula C26H26N4O4S2.
The condensation of compound 21 with p-anisaldehyde in a mix-
ture of ethanol and dimethylformamide (1:1) containing a catalytic
amount of triethylamine under reflux yielded the corresponding aryli-
dene derivative 22. The assignment of structure 22 was based on analyt-
ical and spectral data. The mass spectrum showed a molecular ion peak
at m/z = 640, corresponding to a molecular formula C34H32N4O5S. The
1H-NMR spectrum exhibited a singlet signal at δ 3.96 ppm assignable
to the methoxy protons, a singlet signal at δ 8.06 ppm assignable to the
methine proton beside a broad singlet signal at δ 11.24 ppm distinctive
for the NH proton.
1,3-Thiazole derivatives are considered to be very interesting het-
erocyclic ring systems because of their biological activities such as
antiparasitic, analgesic, antibacterial and CNS depressant.29,30 Thus,
the behaviour of 4-benzoyl-1-cyanoacetylthiosemicarbazide (1) itself to-
wards phenyl isothiocyanate as a convenient route to some new thiazole

1922
S. Bondock et al.
SCHEME 3
derivatives was described. The reaction of 1 with an equimolar amount
of phenyl isothiocyanate in DMF in the presence of potassium hydroxide
gave the non-isolable adduct 23 that reacted with chloroacetyl chloride
to give thiazolidin-5-one derivative 24. The structure 24 was elucidated
on the basis of elemental analysis and spectral data. The IR spectrum
displayed absorption bands at 3300–3206 cm−1 region for NH stretch-
ing, at 2202 cm−1 for C N function, and at 1735 cm−1 for thiazolidin-
1
5-one C O group. The H-NMR spectrum revealed the disappearance
of cyanomethylene signal and the presence of a new singlet signal at
δ 5.25 ppm assignable to the methylene protons of thiazolidin-5-one
ring and a multiplet signal at δ 7.18–8.15 ppm due to two phenyl pro-
tons. The mass spectrum showed a molecular ion peak at m/z = 437,
corresponding to a molecular formula C20H15N5O3S2.
Coupling of compound 24 with different aromatic diazonium chlo-
rides in pyridine afforded the corresponding arylhydrazone of thiazo-
lidinone derivatives 25a–c. The structures 25a–c were supported on
the basis of elemental analysis and spectral data. The IR spectrum of
25c as an example revealed absorption bands at 3420–3160 cm−1 re-
gion for NH stretching, at 1710 cm−1 for thiazolidinone C O stretching.
The 1H-NMR spectrum exhibited the disappearance of a signal belong
to the methylene protons of thiazolidinone ring and the appearance of
the signal belong to methoxy protons at δ 3.97 ppm. The mass spectrum
showed a molecular ion peak at m/z = 571, corresponding to a molecular
formula C27H21N7O4S2.

Thiobarbituric Acid Derivatives
1923
SCHEME 4
As an extension of our investigation, cyclocondensation of compound
25c with malonic acid in acetyl chloride at 50–60◦C yielded thiobarbi-
turic acid derivative 26. The structure 26 was elucidated on the basis of
elemental analysis and spectral data. It’s IR spectrum revealed absorp-
tion bands at 3390–3150 cm−1 for NH stretching, at 1710 cm−1 for thia-
zolidinone C O stretching, and at 1662 cm−1 for pyrimidinone stretch-
1
ing. Furthermore, its H-NMR spectrum exhibited the appearance of
an additional a singlet signal belongs to thiobarbituric CH2 protons at
δ 3.11 ppm. The mass spectrum of 26 showed a molecular ion peak at
m/z = 639, corresponding to a molecular formula C30H21N7O6S2.
In addition, the condensation of compound 26 with p-anisaldehyde
in boiling ethanol containing a catalytic amount of piperidine afforded

1924
S. Bondock et al.
the corresponding arylidene derivative 27. The structure 27 was sup-
ported on the basis of elemental analysis and spectral data. Thus, its IR
spectrum revealed absorption bands at 3380–3150 cm−1 region for NH
stretching, at 1709 cm−1 for thiazolidinone C O stretching, at 1657
cm−1 for pyrimidine diketone stretching, and at 1610 cm−1 for C C
stretching. Moreover, its 1H-NMR spectrum showed the appearance
of two sharp singlet signals at δ 3.97and 3.89 ppm characteristic to
two methoxy protons and the disappearance of a signal characteristic
to methylene protons of thiobarbituric acid. The mass spectrum of 27
showed a molecular ion peak at m/z = 741, corresponding to a molecular
formula C38H27N7O6S2.
In conclusion, we reported herein a simple and convenient route for
the synthesis of some new thiobarbituric acid derivatives with antic-
ipated biological activity starting from readily available 4-benzoyl-1-
cyanoacetylthioemicarbazide.
EXPERIMENTAL
Melting points were determined with a Gallenkamp melting point ap-
paratus (capillary method) and were uncorrected. Elemental analyses
were carried out at the Microanalytical Unit of the Faculty of Science,
Cairo University, and all compounds gave satisfactory elemental anal-
yses. IR spectra (KBr) were recorded with a Mattson 5000 FTIR spec-
trometer (not all frequencies are reported). The 1H NMR spectra were
acquired using a Bruker WP300 spectrometers at 300 MHz. Mass spec-
tra were obtained on a Finnigan MAT 212 instrument by electron im-
pact at 70 eV. 4-Benzoyl-1-cyanoacetylthiosemicarbazide (1) was pre-
pared according to the reported literature procedure.27
General Procedure for Coupling Reactions: Synthesis
of Compounds (2a–c), (4a–c), (13a–c), and (25a–c)
A solution of sodium nitrite (0.70 g in 10 ml water) was gradually added
to a well-cooled (0–5◦C) solution of the aromatic amine (10.0 mmol)
in concentrated HCl (3.0 ml). The diazonium salt solution was added
with continuous stirring to a cold (0–5◦C) solution of compounds 1, 3,
5, 12, and /or 24 (0.01 mol) in pyridine (30 ml). The reaction mixture
was allowed to stir at (0–5◦C) for 2 hrs, and then the solid was col-
lected by filtration. The crude products thus obtained, were dried and
recrystallized from the appropriate solvent to give the corresponding
arylhydrazone derivatives.

Thiobarbituric Acid Derivatives
1925
N-[N ’-[2-Cyano-2-(phenyl-hydrazono)-acetyl]-
hydrazinocarbothioyl]benzamide (2a)
Pale yellow crystal (EtOH-CHCl3); Yield 87%; mp 215–216◦C; IR (KBr):
v˜max. /cm−1 = 3330–3210 (4NH), 2208 (C N), 1670, 1660 (2C O),1590
1
(C N). H-NMR (DMSO–d6): δppm = 6.98 (s, 1H, NH), 7.17–8.23 (m,
10H, Ar-H), 9.85 (s, 1H, NH), 10.51 (s, 1H, NH), 12.44 (s, 1H, NH).
Anal. For C17H14N6O2S (366.40) Calcd.: C 55.73; H 3.85; N 22.94%,
Found: C 55.42; H 3.96; N 22.77%.
N-[N ’-[2-Cyano-2-(p-tolyl-hydrazono)-acetyl]-
hydrazinocarbothioyl]benzamide (2b)
Orange crystal (EtOH-DMF); Yield 83%; mp 223–224◦C; IR (KBr):
v˜max. /cm−1 = 3320–3205 (4NH), 2208 (C N), 1668, 1659 (2C O), 1585
(C N). 1H-NMR (DMSO-d6):δppm ( 2.19 (s, 3H, CH3), 6.96 (s, 1H, 1NH),
7.12, 7.65 (two d, J = 8.0Hz, each 2H, C6H4-CH3), 7.75–8.23 (m, 5H,
Ar-H), 9.78 (s, 1H, NH), 10.50 (s, 1H, NH), 12.47 (s, 1H, NH).MS m/z
(%): 380 (M+, 14.71), 216 (11.76), 186 (36.75), 159 (29.41), 132 (47.06),
105 (100), 77 (63.23), 51 (17.64). Anal. for C18H16N6O2S (380.42) Calcd.:
C 56.83; H 4.24; N 22.09%, Found: C 56.72; H 4.19; N 21.97%.
N-[N’-[2-Cyano-2-[(4-methoxy-phenyl)-hydrazono]-acetyl]-
hydrazinocarbothioyl] benzamide (2c)
Pale red crystal (EtOH-DMF); Yield 82%; m.p. 234–235◦C; IR (KBr):
v˜max./cm−1 = 3300–3190 (4NH), 2206 (C N), 1665, 1655 (2C O), 1582
1
(C N). H-NMR (dMSO - d6): δppm = 3.90 (s, 3H, OCH3), 6.97 (s, 1H,
1NH), 7.17, 7.71 (two d, J = 7.8 Hz, each 2H, C6H4-OCH3), 7.75–8.23 (m,
5H, Ar-H), 9.86 (s, 1H, NH), 10.51 (s, 1H, NH), 12.44 (s, 1H, NH).MS m/z
(%): 396 (M+, 14.41), 319 (3.23), 276 (19.11), 232 (27.94), 202 (39.70),
174 (47.05), 148 (34.55), 105 (100), 77 (67.67), 51 (32.35). Anal. For
C18H16N6O3S (396.42) Calcd.: C 54.54; H 4.07; N 21.20%, Found: C
54.85; H 3.95; N 21.41%.
N-[3-Benzoyl-4,6-dioxo-5-(phenyl-hydrazono)-2-thioxo-
tetrahydro-pyrimidin-1-yl]-2-cyano-2-(phenyl-hydrazono)-
acetamide (4a)
Orange crystal (EtOH-DMF); Yield 84%; mp 275–276◦C; IR (KBr):
v˜max./cm−1 = 3410–3195 (3NH), 2208 (C N), 1675, 1665, 1660, 1652
(4C O), 1582 (C N). 1H-NMR (dMSO-d6): δ ppm = 7.03 (s, br, 1H,
1NH), 7.26–8.26 (m, 15H, Ar-H), 10.54 (s, 1H, NH), 11.07 (s, br, 1H,

1926
S. Bondock et al.
NH). MS m/z (%): 538 (M+, 12.03), 364 (19.14), 319 (27.14), 144 (30.02),
105 (100), 77 (82.86), 51 (17.14). Anal. for C26H18N8O4S (538.54) Calcd.:
C 57.99; H 3.37; N 20.81%, Found: C 57.78; H 3.45; N 20.70%.
N-[3-Benzoyl-4,6-dioxo-2-thioxo-5-(p-tolyl-hydrazono)-
tetrahydro-pyrimidin-1-yl]-2-cyano-2-(p-tolyl-hydrazono)
acetamide (4b)
Red crystal (EtOH-CHCl3); Yield 86%; mp 215–217◦C; IR (KBr):
v˜max./cm−1 = 3398–3192 (3NH), 2208 (C N), 1671, 1665, 1658, 1648
1
(4C O), 1580 (C N). H-NMR (DMSO–d6): δppm = 2.05 (s, 3H, CH3),
2.24 (s, 3H, CH3), 7.12 (s, br, 1H, NH), 7.26, 7.66 (two d, J = 7.8Hz, each
2H, C6H4-CH3), 7.35, 7.85 (two d, J = 7.8 Hz, each 2H, C6H4-CH3),
7.87–8.26 (m, 5H, Ar-H), 10.55 (s, br., 1H, NH), 11.14 (s, br,1H, NH).MS
m/z (%): 566 (M+, 7.43), 461 (14.29), 347 (17.30), 163 (19.71), 105 (100),
77 (61.43), 51 (17.30). Anal. for C28H22N8O4S (566.59) Calcd.: C 59.35;
H 3.91; N 19.78%, Found: C 59.13; H 3.98; N 19.87%.
N-[3-Benzoyl-5-[(4-methoxy-phenyl)-hydrazono]-4,6-dioxo-2-
thioxo-tetrahydro-pyrimidin-1-yl]-2-cyano-2-[(4-methoxy-
phenyl)-hydrazono]-acetamide (4c)
Reddish brown crystal (EtOH-DMF); Yield 82%; m.p. 284–285◦C; IR
(KBr): v˜max./cm−1 = 3380–3174 (3NH), 2204 (C N), 1670, 1660, 1651,
1
1642 (4C O), 1573 (C N). H-NMR (DMSO–d6):δppm = 3.88 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 7.13 (s, br, 1H, NH), 7.24, 7.65 (two d, J = 8
Hz, each 2H, C6H4-OCH3), 7.37, 7.86 (two d, J ( 8 Hz, each 2H, C6H4-
OCH3), 7.87– 8.29 (m, 5H, Ar-H), 10.59 (s, br., 1H, NH), 11.17 (s, br, 1H,
NH).MS m/z (%): 598 (M+, 10.28), 424 (11.43), 202 (21.71), 174 (37.14),
105 (100), 77 (55.71), 51 (20.02). Anal. for C28H22N8O6S (598.59) Calcd.:
C 56.18; H 3.70; N 18.72%, Found: C 56.47; H 3.46; N 18.51%.
N-[3-Benzoyl-4,6-dioxo-5-(phenyl-hydrazono)-2-thioxo-
tetrahydro-pyrimidin-1-yl]-2-cyano-3-(4-methoxy-phenyl)
acrylamide (13a)
Yellow crystal (EtOH-DMF); Yield 84%; m.p. 257–258◦C; IR (KBr):
v˜max./cm−1 = 3300, 3214 (2NH), 2207 (C N), 1683, 1672, 1661, 1653
1
(4C O), 1617 (C C), 1592 (C N). H-NMR (DMSO–d6): δppm = 3.95
(s, 3H, OCH3), 7.15, 7.60 (two d, J = 8.0 Hz, each 2H, C6H4-OCH3),
7.78-8.14 (m, 10H, Ar-H), 8.27 (s,1H, CH ), 11.14 (s, 1H, NH), 12.41
(s, br, 1H, NH). MS m/z (%): 552 (M+, 4.85), 447 (26.28), 333 (23.42),
163 (31.22), 105 (100), 77 (46.57), 51 (19.71). Anal. for C28H20N6O5S

Thiobarbituric Acid Derivatives
1927
(552.56). Calcd.: C 60.86; H 3.65; N 15.21%, Found: C 60.71; H 3.72; N
15.31%.
N-[3-Benzoyl-4,6-dioxo-2-thioxo-5-(p-tolyl-hydrazono)-
tetrahydro-pyrimidin-1-yl]-2-cyano-3-(4-methoxy-phenyl)
acrylamide (13b)
Red crystal (EtOH-CHCl3); Yield 83%; m.p. 266–267◦C; IR (KBr):
v˜max./cm−1 = 3270, 3203 (2NH), 2207 (C N), 1685, 1669, 1658, 1647
(4C O), 1612 (C C), 1584 (C N). 1H-NMR (DMSO-d6): δppm = 2.66 (s,
3H, CH3), 3.90 (s, 3H, OCH3), 7.17, 7.65 (two d, J = 8.0 Hz, each 2H,
C6H4-OCH3), 7.25, 7.78 (two d, J = 8.0 Hz, each 2H, C6H4-CH3), 7.79–
8.14 (m, 5H, Ar-H), 8.24 (s, 1H, CH ), 11.17 (s, 1H, NH), 12.44 (s, br, 1H,
NH). MS m/z (%): 566 (M+, 9.14), 461 (28.57), 380 (8.04), 163 (30.85), 105
(100), 77 (47.14), 51 (15.71). Anal. for C29H22N6O5S (566.59). Calcd.: C
61.48; H 3.91; N 14.83%, Found: C 61.79; H 3.97; N 14.66%.
N-{3-Benzoyl-5-[(4-methoxy-phenyl)-hydrazono]-4,6-dioxo-2-
thioxo-tetrahydro-pyrimidin- 1-yl}-2-cyano-3-(4-methoxy-
phenyl) acrylamide (13c)
Red crystal (EtOH-DMF); Yield 82%; m.p. 272–273◦C; IR (KBr):
v˜max./cm−1 = 3252, 3185 (2NH), 2203 (C N), 1680, 1665, 1652, 1640
(4C O), 1607 (C C), 1574 (C N). 1H-NMR (DMSO-d6): δppm = 3.66 (s,
3H, OCH3), 3.95 (s, 3H, OCH3), 7.21, 7.75 (two d, J = 8.0 Hz, each 2H,
C6H4-OCH3), 7.27, 7.78 (two d, J = 8.0 Hz, each 2H, C6H4-OCH3), 7.79–
8.16 (m, 5H, Ar-H), 8.26 (s, 1H, CH ), 11.19 (s, 1H, NH), 12.43 (s, br, 1H,
NH). MS m/z (%): 582 (M+, 7.42), 449 (11.32), 363 (28.21), 186 (31.71),
163 (52.28), 105 (100), 77 (51.42), 51 (14.28). Anal. for C29H22N6O6S
(582.59). Calcd.: C 59.79; H 3.81; N 14.43%, Found: C 59.92; H 3.84;
N14.54%.
N-(N’-2-Cyano-2-[5-oxo-3-phenyl-4-(phenyl-hydrazono)-
thiazolidin-2-ylidene] acetyl-hydrazinocarbothioyl) benzamide
(25a)
Yellow crystal (EtOH-DMF); Yield 83%; m.p. 265–266◦C; IR (KBr):
v˜max./cm−1 = 3450–3198 (4NH), 2213 (C N), 1725 (ring C O), 1685,
1
1676 (2C O), 1622 (C C), 1235 (C S). H-NMR (DMSO-d6): δppm
=
6.86 (s, br, 1H, NH), 7.14 (s, br., 1H, NH), 7.42–8.26 (m, 10H, Ar-H),
10.68 (s, 1H, NH), 11.99 (s, 1H, NH). Anal. for C26H19N7O3S2 (541.60)
Calcd.: C 57.66; H 3.54; N 18.10%, Found: C 57.98; H 3.38; N 18.19%.

1928
S. Bondock et al.
N-(N’-2-Cyano-2-[5-oxo-3-phenyl-4-(p-tolyl-hydrazono)-
thiazolidin-2-ylidene]-acetyl-hydrazinocarbothioyl)-
benzamide (25b)
Orange crystal (EtOH-CHCl3); Yield 82%; m.p. 272–273◦C; IR (KBr):
v˜max./cm−1 = 3430–3172 (4NH), 2210 (C N), 1715 (ring C O), 1685,
1
1672 (2C O), 1620 (C C), 1230 (C S). H-NMR (DMSO–d6): δppm
=
2.27 (s, 3H, CH3), 6.80 (s, br, 1H, NH), 7.15 (s, br, 1H, NH), 7.29, 7.38
(two d, J = 7.8 Hz, each 2H, C6H4-CH3), 7.52–7.92 (m, 5H, Ar-H), 10.72
(s, 1H, NH), 11.96 (s, 1H, NH). Anal. for C27H21N7O3S2 (555.63) Calcd.:
C 58.36; H 3.81; N 17.65%, Found: C 58.17; H 3.87; N 17.77%.
N-[N’-(2-Cyano-2-[4-[2-(4-methoxy-phenyl)-hydrazono]-5-oxo-
3-phenyl-thiazolidin-2-ylidene]-acetyl)-hydrazinocarbothioyl]
benzamide (25c)
Red crystal (EtOH-DMF); Yield 80%; m.p. 282-283◦C; IR (KBr):
v˜max./cm−1 = 3420–3160 (4NH), 2205 (C N), 1710 (ring C O), 1682,
1
1670 (2C O), 1615 (C C), 1225 (C S). H-NMR (DMSO–d6): δppm
=
3.97 (s, 3H, OCH3), 6.84 (s, br, 2H, 2NH), 7.17, 7.26 (two d, J = 7.5
Hz, each 2H, C6H4-OCH3), 7.56–7.96 (m, 5H, Ar-H), 10.65 (s, 1H, NH),
11.94 (s, 1H, NH). MS m/z (%): 571 (M+, 9.28), 451 (12.86), 349 (24.28),
244 (30.02), 222 (39.57), 164 (42.85), 105 (100), 77 (71.42), 51 (25.71).
Anal. for C27H21N7O4S2 (571.63) Calcd.: C 56.73; H 3.70; N 17.15%,
Found: C 56.39; H 3.61; N 17.31%.
General Procedure for the Synthesis of the Thiobarbituric
Acid Derivatives (3), (5), (12), and (26)
To a stirred solution of compounds 1, 2, 9 and / or 25c (0.015 mol) in
acetyl chloride (10 ml), malonic acid (0.02 mol) was added. The reac-
tion mixture was left for 2 h at ambient temperature and then heated
for 4 hrs at 50◦–55◦C. The contents were then poured onto crushed
ice, cooled to 10◦C, and the separated solid was filtered off, dried and
recrystallized from the appropriate solvent to give the corresponding
thiobarbituric acid derivatives.
N-(3-Benzoyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-1-yl)-2-
cyano-2-(phenyl-hydrazono) acetamide (3a)
Yellow crystal (Acetic acid); Yield 76%; m.p. 248–249◦C; IR (KBr):
v˜max./cm−1 = 3310–3165 (2NH), 2207 (C N), 1685, 1670, 1660 (3C O),

Thiobarbituric Acid Derivatives
1929
1
1240 (C S). H-NMR (DMSO-d6): δppm = 3.22 (s, 2H, ring CH2), 7.35–
7.88 (m, 10H, Ar-H), 11.15 (s, br, 1H, NH), 12.08 (s, br, 1H, NH). Anal.
for C20H14NO4S (434.43) Calcd.: C 55.29; H 3.25; N 19.35%, Found: C
55.57; H 3.40; N 19.23%.
N-(3-Benzoyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-1-yl)-2-
cyano-2-(p-tolyl-hydrazono)acetamide (3b)
Orange crystal (Acetic acid); Yield 78%; m.p. 252–253◦C; IR (KBr):
v˜max./cm−1 = 3307–3152 (2NH), 2205 (C N), 1680, 1667, 1658 (3C O),
1234 (C S). 1H-NMR (DMSO-d6): δppm = 2.26 (s, 3H, CH3), 3.20 (s, 2H,
ring CH2), 7.16, 7.35 (two d, J = 8.0 Hz, each 2H, C6H4-CH3), 7.46–7.98
(m, 5H, Ar-H), 11.05 (s, br, 1H, NH), 12.11 (s, br, 1H, NH). MS m/z (%):
448 (M+, 13.23), 392 (17.94), 229 (11.91), 186 (22.06), 163 (33.82), 159
(44.12), 105 (100), 77 (69.29), 51 (20.59). Anal. for C21H16N6O4S (448.45)
Calcd.: C 56.24; H 3.60; N18.74%, Found: C 56.41; H 3.53; N18.85%.
N-(3-Benzoyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-1-yl)-2-
cyano-2-[(4-methoxy-phenyl)- hydrazono] acetamide (3c)
Red crystal (EtOH-DMF); Yield 72%; m.p. 257–258◦C; IR (KBr):
v˜max./cm−1 = 3290–3154 (2NH), 2205 (C N), 1680, 1662, 1655 (3C O),
1
1235 (C S). H-NMR (DMSO-d6): δppm = 3.19 (s, 2H, ring CH2), 3.96
(s, 3H, OCH3), 7.26, 7.42 (two d, J = 8.0 Hz, each 2H, C6H4-OCH3),
7.52–8.34 (m, 5H, Ar-H), 11.02 (s, br, 1H, NH), 12.02 (s, br, 1H, NH).
MS m/z (%): 464 (M+, 12.05), 408 (16.18), 245 (30.88), 148 (38.24), 105
(100), 77 (57.35), 51 (11.76). Anal. for C21H16N6O5S (464.45) Calcd.: C
54.31; H 3.47; N 18.09%, Found: C 54.07; H 3.38; N 17.96%.
N-(3-Benzoyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-1-yl]-2-
cyano-acetamide (5)
Orange crystal (Acetic acid); Yield 80%; m.p. 242–243◦C; IR (KBr):
1
v˜max./cm−1 = 3250 (NH), 2235 (C N), 1685, 1672, 1662 (4C O). H-
NMR (DMSO-d6): δppm = 3.12 (s, 2H, ring CH2), 4.87 (s, 2H, NCCH2),
7.53–8.14 (m, 5H, Ar-H), 11.14 (s, br, 1H, NH). MS m/z (%): 330 (M+,
13.04), 253 (29.13), 163 (27.39), 105 (100), 77 (58.69), 51 (17.39). Anal.
for C14H10N4O4S (330.32) Calcd.: C 59.91; H 3.05; N 16.96%, Found: C
59.70; H 3.15; N 17.05%.

1930
S. Bondock et al.
N-(3-Benzoyl-4,6-dioxo-2-thioxo -tetrahydro-pyrimidin-1-yl)-2-
cyano-3-(4-methoxy-phenyl) acrylamide (12)
Orange crystal (EtOH-DMF); Yield 71%; m.p. 226–227◦C; IR (KBr):
1
v˜max./cm−1 = 3230 (NH), 2205 (C N), 1680, 1662, 1653 (4C O). H-
NMR (DMSO-d6): δppm = 3.11 (s, 2H, ring CH2), 3.93 (s, 3H, OCH3),
7.17, 7.28 (two d, J = 7.8 Hz, each 2H, C6H4-OCH3), 7.56–8.14 (m, 9H,
Ar-H), 8.38 (s, 1H, CH ), 11.83 (s, br, 1H, NH). MS m/z (%): 448 (M+,
18.38), 343 (20.88), 186 (34.55), 105 (100), 77 (50.73), 51 (18.23). Anal.
for C22H16N4O5S (448.45) Calcd.: C 58.92; H 3.60; N 12.49%, Found: C
58.81; H 3.69; N 12.37%.
N-(3-Benzoyl-4,6-dioxo-2-thioxo-tetrahydro-pyrimidin-1-yl)-2-
cyano-2-{4-[(methoxy-phenyl)-hydrazono]-5-oxo-3-phenyl-
thiazolidin-2-ylidene}acetamide (26)
Reddish brown crystal (EtOH-DMF); Yield 67%; m.p. 295–296◦C; IR
(KBr): v˜max./cm−1 = 3365, 3203 (2NH), 2205 (C N), 1710 (ring C O),
1
1680, 1670, 1662 (4C O), 1220 (C S). H-NMR (DMSO– d6): δppm
=
3.15 (s, 2H, ring CH2), 3.96 (s, 3H, OCH3), 7.25, 7.36 (two d, J = 8.0 Hz,
each 2H, C6H4-OCH3), 7.64–8.12 (m, 5H, Ar-H), 10.25 (s, br, 1H, NH),
11.71 (s, br, 1H, NH). Anal. for C30H21N7O6S2 (639.66) Calcd.: C 56.33;
H 3.31; N 15.33%, Found: C 56.54; H 3.18; N 15.45%.
General Procedure for the synthesis of the arylidene
derivatives (6), (16), (22), and (27)
A mixture of the active methylene compounds 3, 5, 21and / or 26 (0.005
mol) and p-anisaldehyde (0.005 mol) in ethanol (30 ml) containing a cat-
alytic amount of piperidine (3 drops) was boiled under reflux for 3 h. The
reaction mixture was cooled and the solid product which precipitated
was collected by filtration, dried and crystallized from the appropriate
solvent to give the corresponding arylidene derivatives.
N-[3-Benzoyl-5-(4-methoxy-benzylidene)-4,6-dioxo-2-thioxo-
tetrahydro-pyrimidin -1-yl]-2-cyano-2-[(p-tolyl-hydrazono)
acetamide (6)
Brown crystal (EtOH-CHCl3); Yield 69%; m.p. 288–289◦C; IR (KBr):
v˜max./cm−1 = 3280, 3142 (2NH), 2206 (C N), 1673, 1665, 1657, 1645
1
(4C O), 1610 (C C). H-NMR (DMSO-d6): δppm = 2.28 (s, 3H, CH3),
3.96 (s, 3H, OCH3), 7.13, 7.26 (two d, J ( 8.0 Hz, each 2H, C6H4-OCH3),
7.18, 7.36 (two d, J = 7.8 Hz, each 2H, C6H4-OCH3), 7.66–8.24 (m, 5H,

Thiobarbituric Acid Derivatives
1931
Ar-H), 11.15 (s, br, 1H, NH), 11.86 (s, br, 1H, NH). MS m/z (%): 566
(M+, 8.02), 461 (8.57), 380 (20.28), 186 (40.57), 158 (28.57), 105 (100),
77 (55.14), 51 (23.42). Anal. for C29H22N6O5S (566.59) Calcd.: C 61.48;
H 3.91; N 14.83%, Found: C 61.76; H 3.84; N 14.96%.
N-[3-Benzoyl-5-(4-methoxy-benzylidene)-4,6-dioxo-2-thioxo-
tetrahydro-pyrimidin-1-yl]-2-cyano-3-(4-methoxy-phenyl)
acrylamide (16)
Brown crystal (EtOH-DMF); Yield 71%; m.p. 282–283◦C; IR (KBr):
v˜max./cm−1 = 3270 (NH), 2209 (C N), 1682, 1668, 1657 (4C O), 1606
1
(C C). H-NMR (DMSO-d6): δppm = 3.83 (s, 3H, OCH3), 3.93 (s, 3H,
OCH3), 7.18, 7.36 (two d, J = 8.0 Hz, each 2H, C6H4-OCH3), 7.24, 7.42
(two d, J = 8.0 Hz, each 2H, C6H4-OCH3), 7.78–7.98 (m, 5H, Ar-H), 8.02
(s, 1H, CH ), 8.12 (s, 1H, CH ), 10.84 (s, 1H, NH). MS m/z (%): 566 (M+,
11.14), 461 (11.71), 386 (17.14), 186 (26.28), 163 (47.14), 131 (31.10), 105
(100), 77 (65.71), 51 (19.14). Anal. for C30H22N4O6S (566.58) Calcd.: C
63.60; H 3.91; N 9.89%, Found: C 63.37; H 3.98; N 9.76%.
(5E)-1-Benzoyl-5-(4-methoxybenzylidene)-3-(4-oxo-1,4,
5,6,7,8-hexahydro-3H-spiro[1-benzothieno[2,3-d]pyrimidine-
2,1’-cyclohexan]-3-yl)-2-thioxodihydro- pyrimidine-4,6(1H,5H)-
dione (22)
Brown crystal (EtOH-DMF); Yield 60%; m.p. 292–293◦C; IR (KBr):
1
v˜max./cm−1 = 3340 (NH), 1680, 1667, 1658 (4C O), 1610 (C C). H-
NMR (DMSO-d6): δppm = 1.17–1.67 (m, 10H, cyclohexane), 1.77–2.52
(m, 8H, tetrahydrobenzothiophene), 3.96 (s, 3H, OCH3), 7.26, 7.38 (two
d, J = 7.5 Hz, each 2H, C6H4-OCH3), 7.56–7.89 (m, 5H, Ar-H), 8.26
(s, 1H, CH ), 11.24 (s, br, 1H, NH). Anal. for C34H32N4O5S2 (640.77)
Calcd.: C 63.73; H 5.03; N 8.74%, Found: C 63.95; H 5.14; N 8.59%.
N-[3-Benzoyl-5-(4-methoxy-benzylidene)-4,6-dioxo-2-thioxo-
tetrahydro-pyrimidin-1-yl]-2-cyano-2-{4-[(methoxy-phenyl)-
hydrazono]-5-oxo-3-phenyl-thiazolidin-2-ylidene}acetamide
(27)
Brown crystal (EtOH-DMF); Yield 61%; m.p. >300◦C; IR (KBr):
v˜max./cm−1 = 3357, 3184 (2NH), 2203 (C N), 1709 (ring C O), 1680,
1
1668, 1657 (4C O), 1610 (C C). H-NMR (DMSO-d6): δppm = 3.89 (s,
3H, OCH3), 3.97 (s, 3H, OCH3), 7.15, 7.38 (two d, J = 8.0 Hz, each
2H,C6H4-OCH3), 7.26, 7.45 (two d, J = 8.0 Hz, each 2H, C6H4-OCH3),
7.76–7.92 (m, 5H, Ar-H), 8.02 (s, 1H, CH ), 11.57 (s, br, 1H, NH), 12.78

1932
S. Bondock et al.
(s, br, 1H, NH). Anal. for C38H27N7O7S2 (757.79) Calcd.: C 60.23; H 3.59;
N 12.94%, Found: C 60.53; H 3.52; N 12.83%.
Synthesis of N-N‘-[2-Cyano-3-(4-methoxy-phenyl)-
acryloyl]hydrazinocarbothioyl benzamide (9)
Method A
A mixture of 1 (2.62 g, 0.01 mol) and p-anisaldehyde (0.01 mol) in
ethanol (30 ml) containing a catalytic amount of piperidine (3 drops) was
refluxed for 3 hrs. The reaction mixture was allowed to cool, and then
the precipitated product was filtered off, dried well and recrystallized
from DMF to give compound 9.
Method B
A mixture of 1 (2.62 g, 0.01 mol) and ethyl p-methoxybenzylidene
cyanoacetate (2.31 g, 0.01 mol) in ethanol (30 ml) containing a catalytic
amount of piperidine (3 drops) was refluxed for 3 hrs. The precipitated
product was formed upon cooling, filtered off, dried well and recrystal-
lized from dMF to give compound 9.
Yellow crystal; Yield 82%; m.p. 210–211◦C; IR (KBr): v˜max./cm−1
=
3320–3236 (3NH), 2210 (C N), 1672, 1664 (2C O), 1610 (C C), 1238
(C S). 1H-NMR (DMSO-d6): δppm = 3.90 (s, 3H, OCH3), 7.17, 7.65 (two
d, J = 8.0 Hz, each 2H, C6H4-OCH3), 7.82– 8.14 (m, 5H, Ar-H), 8.23 (s,
1H, CH ), 11.14 (s, br, 1H, NH), 11.87 (s, 1H, NH), 12.44 (s, br, 1H, NH).
MS m/z (%): 380 (M+, 17.21), 217 (45.50), 186 (67.40), 158 (26.40), 105
(100), 77 (91.80), 51 (54.80). Anal. for C19H16N4O3S (380.42) Calcd.: C
59.99; H 4.24; N 14.73%, Found: C 61.28; H 4.13; N 14.81%.
General Procedure for the Synthesis of 2-Hydrazonobarbituric
Acid Derivatives (8), (15), and (18)
To a solution of 12 and ( or 16 (0.005 mol) in ethanol (20ml), hydrazine
hydrate (0.375 g, 0.0075 mol) was added. The reaction mixture was
heated under reflux for 4 h (until evolution of hydrogen sulfide ceased),
cooled at room temperature, and was left overnight. The precipitate
was formed, collected and recrystallized from ethanol to give the corre-
sponding 2-hydrazonobarbituric acid derivatives.
2-(3-Benzoyl-2-hydrazono-5-(4-methoxybenzylidene)-4,6-
dioxo-tetrahydro-pyrimidin-1(2H)-ylamino)-2-oxo-Nꢀ-p-
tolyacetohydrazonyl cyanide (8)
Brown crystal (EtOH-DMF); Yield 65%; m.p. 284–285◦C; IR (KBr):
v˜max./cm−1 = 3415–3354 (NH2), 3249 (NH), 2206 (C N), 1672, 1661,

Thiobarbituric Acid Derivatives
1933
1
1650 (4C O), 1586 (C N). H-NMR (DMSO-d6): δppm = 3.79 (s, 3H,
OCH3), 3.88 (s, 3H, OCH3), 5.56 (s, br, 2H, NH2), 7.20, 7.36 (two d, J =
7.5 Hz, each 2H, C6H4-OCH3), 7.28, 7.78 (two d, J = 7.8 Hz, each 2H,
C6H4-OCH3), 7.85–8.05 (m, 5H, Ar-H), 8.16 (s, 1H, CH ), 10.56 (s, br.
1H, NH), 11.12 (s, br, 1H, NH). Anal. for C30H24N8O6 (580.55) Calcd.:
C 60.00; H 4.17; N 19.30%, Found: C 60.02; H 4.15; N 19.27%.
N-(3-Benzoyl-2-hydrazono-4,6-dioxo-tetrahydro-pyrimidin-1-
yl]-2-cyano-3-(4-methoxy-phenyl) acrylamide (15)
Pale brown crystal (EtOH-CHCl3); Yield 61%; m.p. 278–279◦C; IR
(KBr): v˜max./cm−1 ( 3426–3375 (NH2), 3263 (NH), 2210 (C N), 1674,
1
1665, 1652 (4C O), 1595 (C N). H-NMR (DMSO-d6): δppm = 3.10 (s,
2H, ring CH2), 3.94 (s, 3H, OCH3), 7.18, 7.26 (two d, J = 7.8 Hz, each
2H, C6H4-OCH3), 7.66–7.97 (m, 5H, Ar-H), 8.01 (s, 1H, CH ), 10.19 (s,
br, 2H, NH2), 11.37 (s, br, 1H, NH). MS m/z (%): 446 (M+, 8.82), 390
(14.70), 229 (19.86), 186 (21.17), 161 (28.67), 132 (33.82), 105 (100), 77
(56.18), 51 (17.64). Anal. for C22H18N6O5 (446.42) Calcd.: C 59.19; H
4.06; N 18.83%, Found: C 58.92; H 4.17; N 18.90%.
N-(3-Benzoyl-2-hydrazono-5-(4-methoxy-benzyliene)-4,6-
dioxo-tetrahydro-pyrimidin-1-yl]-2-cyano-3-(4-methoxy-
phenyl)acrylamide (18)
Pale brown crystal (EtOH-DMF); Yield 60%; m.p. >300◦C; IR (KBr):
v˜max./cm−1 = 3415–3354 (NH2), 3249 (NH), 2205 (C N), 1670, 1660,
1
1648 (4C O), 1582 (C N). H-NMR (DMSO-d6): δppm = 3.78 (s, 3H,
OCH3), 3.86 (s, 3H, OCH3), 5.54 (s, br, 2H, NH2), 7.23, 7.34 (two d, J =
7.5 Hz, each 2H, C6H4-OCH3), 7. 26, 7.76 (two d, J = 7.8 Hz, each 2H,
C6H4-OCH3), 7.84–8.02 (m, 5H, Ar-H), 8.15 (s, 1H, CH ), 8.18 (s, 1H,
CH ), 11.08 (s, br, 1H, NH). MS m/z (%): 564 (M+, 12.57), 459 (8.57), 201
(17.42), 161(33.14), 132 (27.71), 105 (100), 77 (62.28), 51 (16.85). Anal.
for C30H24N6O6 (564.55) Calcd.: C 63.82; H 4.28; N 14.89%, Found: C
63.69; H 4.15; N 15.02%.
Synthesis of 2-Hydrazono- & 2-Phenylhydrazonobarbituric
Acid Derivatives (19a–b)
To a solution of 5 (3.3 g, 0.01 mol) in ethanol (20 ml), either hydrazine
hydrate (0.75 gm, 0.015 mol) or phenyl hydrazine (1.02 gm, 0.015 mol)
was added. The reaction mixture was heated under reflux for 6hrs (until
evolution of H2S ceased), cooled at room temperature, and poured into

1934
S. Bondock et al.
cold water (20 ml), where upon the solid product thus precipitated was
collected by filtration and recrystallized from ethanol-chloroform (2:1)
to give 19a–b.
N-(3-Benzoyl-2-hydrazono-4,6-dioxo-tetrahydro-pyrimidin-1-
yl)-2-cyanoacetamide (19a)
Buff crystal; Yield 63%; m.p. 250–251◦C; IR (KBr): v˜max./cm−1 = 3440–
3387 (NH2), 3274 (NH), 2242 (C N), 1680, 1669, 1658 (4C O), 1592
(C N). 1H-NMR (DMSO-d6): δppm = 3.18 (s, 2H, ring CH2), 4.75 (s, 2H,
NCCH2), 5.54 (s, br, 2H, NH2), 7.64–7.85 (m, 5H, Ar-H), 11.08 (s, br, 1H,
NH). MS m/z (%): 328 (M+, 13.40), 300 (27.26), 195 (29.13), 161 (42.17),
105 (100), 77 (64.34), 51 (23.91). Anal. for C14H12N6O4 (328.28) Calcd.:
C 51.22; H 3.68; N 25.60%, Found: C 51.54; H 3.60; N 25.72%.
N-[3-Benzoyl-4,6-dioxo-2-(phenyl-hydrazono)-tetrahydro-
pyrimidin-1-yl]-2-cyano-acetamide (19b)
Yellow crystal; Yield 59%; m.p. 262–261◦C; IR (KBr): v˜max./cm−1 = 3386,
3317 (2NH), 3274 (NH), 2238 (C N), 1682, 1670, 1662 (4C O), 1584
(C N). 1H-NMR (DMSO -d6): δppm = 3.16 (s, 2H, ring CH2), 4.73 (s, 2H,
NCCH2), 7.17–8.14 (m, 10H, Ar-H), 11.15 (s, 1H, NH), 12.47 (s, br, 1H,
NH). MS m/z (%): 404 (M+, 11.76), 376 (23.52), 237(29.41), 131 (26.47),
105 (100), 77 (52.79), 51 (23.24). Anal. for C20H16N6O4 (404.38) Calcd.:
C 59.40; H 3.99; N 20.78%, Found: C 59.16; H 4.08; N 20.65%.
Synthesis of 1-Benzoyl-3-(4-oxo-1,4,5,6,7,8-hexahydro-3H-
spiro[1-benzothieno [2,3-d]pyrimidine-2,1‘-cyclohexan]-3-yl)-
2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (21)
To a mixture of compound 5 (3.3 g, 0.01 mol), cyclohexanone (0.01 mol),
finely powdered sulfur (0.013 mol) in ethanol (30 ml) was added drop-
wise morpholine (0.02 mol). The mixture was stirred for 6hrs at 45–50
-C. After the reaction mixture was cooled, the solid product was fil-
tered off, washed with cold ethanol, dried well and recrystallized from
methanol to give 21.
Green crystal; Yield 63%; m.p. 262–263◦C; IR (KBr): v˜max./cm−1
=
1
3350 (NH), 1688, 1682, 1670, 1662 (4C O). H-NMR (DMSO-d6): δppm
= 1.17–1.65 (m, 10H, cyclohexane), 1.77–2.67 (m, 8H, tetrahydroben-
zothiophene), 3.11 (s, 2H, thiobarbituric ring CH2), 7.55–8.14 (m, 5H,
Ar-H), 11.21 (s, br, 1H, NH). MS m/z (%): 522 (M+, 6.28), 445 (10.15), 303
(14.28), 163 (39.04), 131 (51.42), 105 (100), 77 (54.28), 51 (18.28). Anal.

Thiobarbituric Acid Derivatives
1935
for C20H16N6O4 (522.64) Calcd.: C 59.75; H 5.01; N 10.72%, Found: C
59.87; H 4.89; N 10.60%.
Synthesis of N-N‘-[2-Cyano-2-(5-oxo-3-phenyl-thiazolidin-
2-ylidene)-acetyl] -hydrazinocarbothioyl-benzamide (24)
To a cooled suspension of finally divided potassium hydroxide (0.01
mol) in dimethylformamide (30 ml) were added the cyano methylene
compound 1 (2.62 g, 0.01 mol), followed by phenyl isothiocyanate (0.01
mol). The mixture was stirred at room temperature overnight and then
treated with chloro acetyl chloride (0.01 mol) and left at room temper-
ature for additional 12hrs. The reaction mixture was then triturated
with cold water (50 ml), and few drops of dilute HCl (0.1N, 5drops) was
added (till pH = 7). The resultant solid product, so precipitated was
collected by filtration, dried well and crystallized from ethanol-dMF to
give compound 24.
Pale brown crystal; Yield 73%; m.p. 232–233◦C; IR (KBr): v˜max./cm−1
= 3300–3206 (3NH), 2207 (C N), 1735 (ring C O), 1685, 1674 (2C O),
1620 (C C). 1H-NMR (DMSO-d6): δppm = 5.25 (s, 2H, thiazolidin-5-
one CH2), 7.18–8.15 (m, 10H, Ar-H), 11.04 (s, 1H, NH), 11.85 (s, 1H,
NH), 12.44 (s, br, 1H, NH). MS m/z (%): 437 (M+, 17.64), 317 (13.97),
273 (20.28), 243 (27.94), 187 (35.29), 164 (41.17), 105 (100), 77 (54.41),
51 (22.05). Anal. for C20H16N6O4 (437.49) Calcd.: C 54.91; H 3.46; N
16.01%, Found: C 54.62; H 3.55; N 15.87%.
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