Uses of 1-cyanoacetyl-4-phenyl-3-thiosemicarbazide in heterocyclic synthesis: Synthesis of thiazole, coumarin, and pyridine derivatives with antimicrobial and antifungal activities

Article abstract of DOI:10.1080/10426500701289914

The reaction of cyanoacetyl hydrazine with phenylisothiocyanate gave the thiosemicarbazide 3. The latter underwent a series of heterocyclization reactions when it reacts with either aromatic aldehydes or -haloketones, follwed by further reaction of the pr

Full text of DOI:10.1080/10426500701289914

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Uses of 1-Cyanoacetyl-4-
phenyl-3-thiosemicarbazide
in Heterocyclic Synthesis:
Synthesis of Thiazole,
Coumarin, and Pyridine
Derivatives with Antimicrobial
and Antifungal Activities
Rafat M. Mohareb a , Jonathan Z. Ho b & Abeer A.
Mohamed c
a Department of Chemistry, Faculty of Science, Cairo
University, Giza, A.R., Egypt
b Merck & Co., Inc., Raway, NJ, USA
c National Organization for Drug Control & Research,
Cairo, A.R., Egypt
Published online: 15 Jun 2007.
To cite this article: Rafat M. Mohareb , Jonathan Z. Ho & Abeer A. Mohamed (2007):
Uses of 1-Cyanoacetyl-4-phenyl-3-thiosemicarbazide in Heterocyclic Synthesis:
Synthesis of Thiazole, Coumarin, and Pyridine Derivatives with Antimicrobial and
Antifungal Activities, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:8,
1661-1681
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Phosphorus, Sulfur, and Silicon, 182:1661–1681, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701289914
Uses of 1-Cyanoacetyl-4-phenyl-3-thiosemicarbazide in
Heterocyclic Synthesis: Synthesis of Thiazole, Coumarin,
and Pyridine Derivatives with Antimicrobial
and Antifungal Activities
Rafat M. Mohareb
Department of Chemistry, Faculty of Science, Cairo University, Giza,
A.R. Egypt
Jonathan Z. Ho
Merck & Co., Inc., Raway, NJ, USA
Abeer A. Mohamed
National Organization for Drug Control & Research, Cairo, A.R. Egypt
The reaction of cyanoacetyl hydrazine with phenylisothiocyanate gave the thiosemi-
carbazide 3. The latter underwent a series of heterocyclization reactions when it
reacts with either aromatic aldehydes or α-haloketones, follwed by further reaction
of the products with cyanomethylene reagents or hydrazines to give either thiazole,
coumarin, or pyridine derivatives. The newly synthesized product showed antimi-
crobial and antifungal activities.
Keywords Coumarins; pyrazoles; pyridines; thiazoles
INTRODUCTION
The cyclization of suitable linear compounds is one of the most com-
mon and popular methods for preparing heterocyclic compounds. Un-
symmetrical ureas have been cyclized to produce several heterocy-
cles such as 1,3,4-thiadiazoles, 1,2,4-triazoles, and 1,3,5-triazines.1
2,4-Disubstituted semicarbazones have been proposed as dipeptide
Received Novemeber 18, 2006; accepted January 24, 2007.
R. M. Mohareb exhibits his deepest thanks to Alxander von Humboldt Stiftung in
Germany for affording him a fellowship in Stuttgart during summer, 2006 and for finan-
cial support to complete this work. The authors are thankful to Prof. Dr. S. A. Ouf, Botany
Department, Faculty of Science, Cairo University, for recording the biological activities
of the synthesized compounds reported herein.
Address correspondence to Rafat M. Mohareb, Department of Chemistry, Faculty of
Science, Cairo University, Giza, A.R. Egypt. E-mail: raafat mohareb@yahoo.com
1661

1662
R. M. Mohareb et al.
isosteres2 and could be a new class of urea peptide mimetics. The
possible biological properties of semi- and thiosemicarbazone deriva-
tives make it attractive to study the reactivity of these compounds.
α-Halocarbonyl compounds were allowed to react with alkyl- and
arylidenephenylthiosemicarbazones to give 1,2,4-triazoline and 1,2,4-
dithiazolidines.3 2,4-Disubstituted thiosemicarbazides were cyclized to
1,2,4-triazoline-3-thiones and 1,3,4-thiadiazolines when treated with
acyl isothiocyanates.4 Oxidative cyclization of substituted aldehyde-
thiosemicarbazones, induced by different metallic salts, led to 1,2,4-
triazoline derivatives.5−9 On the other hand, the interaction of thiosemi-
carbazide and dithiocarbazate derivatives with some π-acceptors such
as propanedinitrile, and benzoquinone as well as naphthoquinone
affords thiazines, thiadiazines, thiadiazoles, indazoles, pyridazines,
oxathiadiazoles, and various fused heterocyclic compounds possible via
a single electron transfer before the ring closure step.10−14
RESULTS AND DISCUSSION
Chemistry
We report here the results of our investigations on the reaction of
cyanoacetylhydrazine 1 with phenylisothiocyanate (2) to give the 1-
cyanoacetyl-4-phenylthiosemicarbazide derivative 3. The reaction has
been reported in literature.15 We report here the uses of compound 3
in heterocyclic synthesis via exploring the scope and limitations of the
functional groups present. Thus, the reaction of compound 3 with ben-
zaldehyde (4) gave the benzal derivative 5. Structure of the latter prod-
uct was based on analytical and spectral data. Thus, 1H-NMR showed a
singlet at δ 7.12 corresponding to CH group, a multiplet at δ 7.41–8.01
corresponding to two C6H5 groups, and three singlets at δ 9.76, 10.75,
and 10.80 corresponding to three NH groups.
Compound 5 reacts with α-haloketones (6a–d) to give the thia-
zole derivatives 7a–d. The analytical and spectral data are consistent
1
with the proposed structures. As an example, the H-NMR spectrum
of 7a showed two singlets at δ 5.77 and 6.25 corresponding to thia-
zole H-5 and CH=C groups, a multiplet at δ 6.85–7.83 correspond-
ing to two C6H5 groups, two singlets at δ 9.98, 11.07 corresponding
to NH and OH groups, respectively. Moreover, 13C NMR spectrum
showed δ 58 (thiazole C-4), 116.8 (CN), 117.4, 119.5, 122.5, 124.3,
128.9, 129.5, 140.9, 143.2 (aromatic C), 167.5 (C=O), and 180.5 (thi-
azole C-5). On the other hand, the reaction of compound 3 with sal-
icaldehyde (8) gave the coumarin derivative 9. The reactivity of the
latter product towards α-halocarbonyl compounds was studied in the

Thiosemicarbazides in Heterocyclic Synthesis
1663
aim of formation of coumarin bearing thiazolyl group with poten-
tial biological activities.16−20 Thus, the reaction of 9 with either ethyl
chloroacetate (6a), phenacyl bromide (6b) or chloroacetone (6c) gave
the thiazole derivatives 10a–c (Scheme 1). The reaction of compound 3
with 4-methylphenacyl bromide (11) in 1,4-dioxan solution afforded the
SCHEME 1

1664
R. M. Mohareb et al.
thiazole derivative 12. The analytical and spectral data are in agree-
1
ment with the proposed structure. Thus, H-NMR spectrum of the re-
action product showed two singlets at δ 2.50, 3.80 corresponding to CH3
and CH2 groups, respectively, a singlet at δ 6.33 corresponding to thi-
azole H-5, a muliplet at δ 6.95–7.37 corresponding to C6H5 and C6H4,
and a singlet at δ 10.22 Corresponding to NH group. Moreover, the 13C-
NMR showed δ 25.8 (CH3), 33.6 (CH2), 115.8 (CN), 118.4, 119.5, 120.6,
123.7, 126.8, 129.1, 131.5, 138.2, 140.9 (aromatic C, thiazole C-5), 155.8
(C=N), and 170.9 (C=O).
Compound 12 showed high reactivity towards many chemical
reagents. Thus, it reacts with benzenediazonium chloride (13) to
give the phenylhydrazone derivative 14 for which the analytical and
spectral data are in agreement with the proposed structure. On the
other hand, with benzaldehyde (4), compound 12 gives the benzal
derivative 15. Compound 15 reacts with either hydrazine hydrate
(16a) or phenylhydrazine (16b) to give the pyrazole derivatives 17a
1
and 17b, respectively. The H-NMR and 13C-NMR spectra of 17a are
consistent with the proposed structure (see experimental section). The
reaction took place via formation of amidrazone derivatives followed
by Michael addition and auto-oxidation. Structures of compounds
17a,b were confirmed on the basis of analytical and spectral data
(see experimental section). On the other hand, compound 15 reacts
with either malononitrile (18a) or ethyl cyanoacetate (18b) to give the
pyridine derivatives 19a and 19b, respectively (Scheme 2). In case of
the reaction of compound 15 with malononitrile, a Michael addition
took place while in case of the reaction with ethyl cyanoacetate, ethanol
liberation took place. Analytical and spectral data are the basis of
structures elucidation. Moreover, the reaction of compound 12 with
salicaldehyde (8) gave the coumarin derivative 20.
The reaction of compound 12 with 1,3-dicarbonyl compounds was
studied in the aim of formation of pyridine derivatives with poten-
tial biological activities.21,22 Thus, it reacted with either acetylacetone
(21a) or ethyl acetoacetate (21b) to give the pyridine derivatives 22a
and 22b, respectively. Structures of the latter products were based
on analytical and spectral data (see Experimental section). On the
other hand, the reaction of compound 12 with either malononitrile
(18a) or ethyl cyanoacetate (18b) gave the same pyridine derivative
23 (Scheme 3). The reaction took place via Michael-type addition and
hydrolysis of imino group in case of the reaction with malononitrile,
whereas a loss of ethanol took place in case of the reaction with ethyl
cyanoacetate.
The reaction of compound 3 with both elemental sulfur and phenyl-
isothiocyanate (2) gave the thiazole derivative 24. Elemental analysis,

Thiosemicarbazides in Heterocyclic Synthesis
1665
SCHEME 2
IR, and 1H-NMR spectrum are in agreement with the proposed
structure.
Compound 3 underwent ready cyclization when heated in pyri-
dine solution to give the 5-aminopyrazol-3-one derivative 25. The IR
spectrum of the latter product showed the presence of a C=O group

1666
R. M. Mohareb et al.
SCHEME 3
stretching at 1703 cm−1. Moreover, the 1H-NMR showed a singlet at δ
5.18 corresponding to an NH2 group, a singlet at δ 6.60 corresponding
to pyrazole H-4, a multiplet at δ 6.90–7.62 corresponding to C6H5, and
two singlets at δ 10.41 and 10.98 corresponding to two NH groups, re-
spectively. Compound 25 reacts with benzenediazonium chloride (13)
to give phenyl hydrazone derivative 26.
The reaction of compound 3 with cyclohexanone (27) in the pres-
ence of ammonium acetate gave the condensed product 28. The reac-
tion of compound 3 with either α-cyanocinnamonitrile (29a) or ethyl
α-cyanocinnamate (29b) took place via Michael addition and oxidation
to give the pyridine derivatives 30a and 30b, respectively (Scheme 4).
1
The analytical and H-NMR spectra are the basis of confirming the
structures of the latter products (see Experimental section).

Thiosemicarbazides in Heterocyclic Synthesis
1667
S
C
CONHNH
NHPh
S
S
NH2
N
H2C
NHPh +
S
+ PhNCS
CONHNH
C
S
Ph
24 (58%)
CN
2
3
H
O
N
S
Pyridine
N C NHPh
3
NH2
25 (52%)
H
N
O
S
25
+
N C NHPh
PhN NCl
13
PhHN N
NH
26 (51%)
OH
O
N
N
27
3
Ammomium Acetate
H2N
C
S
NHPh
28 (59%)
O
X
S
CN
PhHC C
NC
Ph
C
NH
NHPh
N
X
29a, X = CN
b, X = COOEt
3
NH2
30a, X = CN (50%)
b, X = COOEt (58%)
SCHEME 4
The work in this section shows the uses of thiosemicarbazide deriva-
tives to form thiazole, coumarin, pyrazole, and pyridine derivatives.
Such a group of compounds might be difficult to obtain via other reac-
tion routes.

1668
R. M. Mohareb et al.
Microbiology
In Vitro Evaluation of Antibacterial and Antifungal Activities
Test organisms. The fungi selected for this study were Fusar-
ium oxysporum f.sp. Lycoperici (SACC.) SNYDER et HANSEN and
Helminthosporium oryea (Cochliobolus miyabeanus) (ITO and KURIB-
AYASHI) DPECHSLER ex DASTUR. The former organism, an impor-
tant plant pathologen causing tomato wilt in Egypt, was isolated from
infected tomato plants. The latter organism was isolated from infected
rice plants.
The newly synthesized products were dissolved in aqueous ethanol to
give a logarithmic series of concentrations from 2 to 256 mg/L upon ten-
fold dilution with the growth medium and spore suspension of the test
fungi. The toxicity of compounds was determined by sporeling bioassay
described by Spendley and Ride,23 which is based on the technique of
Skipp and Bailey.24 A suspension of fungal spores was prepared in wa-
ter and pipetted into the wells of multiwell slides, followed with 25 µL
of the culture medium. The inoculated slides were then incubated at
25◦C until short germ tubes appeared; approximately 50 µm in length
(at 0 h) was calculated. Five µL volumes of the prepared compound test
solutions were added to the inoculated wells, one control well on each
slide being treated with solvent only. The slides were then returned to
the incubator until germ tubes 400 50+/− µm long were visible in the
control wells. Further growth was arrested by the addition of lactophe-
nol aniline blue to each of the wells. Based on these assays, the percent
inhibition of germ-tube growth (with respect to the controls) was plot-
ted against the logarithm of concentration of each compound. From
this, the concentrations producing 50% inhibition (ED50) and 100% in-
hibition (MLD) were directly obtained. When the ED50 or MLD values
exceeded the maximum concentrations of compound used, extrapola-
tion was performed when the last point was within 5% of the ED50 or
MLD line, otherwise the result was expressed as >256 mg/L.
Growth. Since some compounds are lethal at relatively high doses
and others at lower doses, comparison of the effect of compound on the
growth, sporulation, and nucleic acid synthesis of the test fungi was
undertaken at a concentration of 64 mg/L.
A series of conical flasks (250 mL capacity) containing 50 mL Czapek-
Dox liquid medium were used for each fungus. Each of three flasks was
supplemented with 64 mg/L of each compound. The flasks were inocu-
lated with a 5-mm diameter agar disc cut from the margin of actively
growing colonies. The flasks were incubated at 28◦C for 7 days after
which the produced mycelial felts were collected, washed several times
with distilled water, and oven-dried at 80◦C to constant mass.

Thiosemicarbazides in Heterocyclic Synthesis
1669
Sporulation. Plates of Czapek-Dox agar supplemented with 64 mg/L
of each compound were inoculated with a 5-mm diameter agar disc of
the used fungus. The plates were then incubated for 7 days at 28◦C. A
1-cm2 section was cut from the margin of the colony and transferred
to a vial containing 10 mL sterile distilled water. The suspension was
spontaneously shaken for 5 min, and the concentration of spores per
mL was counted in a hemocytometer. Three plates were used for each
treatment.
Most of the tested compounds showed significant toxicity which is
dependent on their chemical structure. The toxicity pattern of the com-
pounds toward the two fungi is similar although the levels of compounds
that were required to produce ED50 and MLD for Helminthosporium
oryzae were higher than those required for Fusarium oxyporum f. sp.
Lycopersici.
The effect of all tested compounds on growth, sporulation and nucleic
acid synthesis was tested at a concentration of 64 mg/L. Compound 20
allowed good mycelial growth, sporulation and nucleic acid synthesis by
the two fungi. This indicates that the two fungi can use the N-containing
heterocyclic ring as a nitrogen source. Introducing the benzal moiety to
compound 3 gives compound 5, the latter showed high antimicrobial
activities than the first. Comparing compounds 7a, 7b, 7c, and 7d. One
can notice that all of them are thiazole derivatives with different substi-
tuted groups. Compound 7d (with the CH3-group showed the highest
activities. However, compounds 10a–c with a coumarin and thiazole
moieties showed reverse activities, where 10a showed higher activi-
ties than 10b and 10c. Compound 17b with the N-Ph group showed
higher activities than 17a (with the N-H group). It is of much interest
that 19a (pyridine with the 2-aminopyridine) showed better activities
than 19b (with the 2-hydroxypyridine). Similarly for compound 22b
(with 2-hydroxypyridine) showed higher activities than 22a (with 2-
methylpyridine).
EXPERIMENTAL
Chemistry
All melting points are uncorrected. IR spectra were recorded for (KBr)
discs on a Pye Unicam SP-1000 spectrophotometer. 1H-NMR and
13C-NMR spectra were measured on a Varian EM-390-400 MHz in
CD3SOCD3 as solvent using TMS as internal standard, and chemical
shifts are expressed as δ Analytical data; they were obtained from the
Microanalytical Data Unit at Cairo University, Giza, Egypt.

1670
R. M. Mohareb et al.
TABLE I Measured Concentrations (mg/L) of Each of the Tested
Compounds Producing 50% Inhibition and 100% Inhibition (MLD)
of Fusarium Oxysporum f. sp. Lycopersici and Helminthosporium
Oryzea
F. Oxysporum f. sp. Lycopersici
H. oryzae
Compound no.
ED50
MLD
ED50
MLD
3
5
7a
7b
7c
7d
9
10a
10b
10c
12
18
80
11
31
12
20
84
90
12
31
20
88
80
14
16
77
18
84
28
79
84
10
88
80
120
76
206
72
80
60
12
73
24
36
36
30
70
244
68
36
30
70
73
16
45
68
31
70
78
201
68
118
63
112
118
78
88
166
236
88
85
88
220
206
36
87
226
88
166
110
196
166
70
230
250
230
50
108
112
250
201
44
120
250
102
118
108
203
118
78
14
15
17a
17b
19a
19b
20
22a
22b
23
24
25
26
28
48
80
70
15
190
196
110
210
>256
205
Synthesis of α-Benzalcyanoacetyl-4-phenyl-
3-thiosemicarbazide (5)
To a solution of compound 3 (3.08 g, 0.013 mol) in 1,4-dioxan (100
mL) containing piperidine (1 mL), benzaldehyde (1.39 g, 0.013 mol)
was added. The reaction mixture was heated under reflux for 3 h and
then poured onto a beaker containing an ice/water mixture containing
few drops of hydrochloric acid. The formed solid product was collected
by filtration and dried.
Yellow crystals (from ethanol), 56% yield (2.40 g), m.p. 100◦C. IR
(υ, cm−1): 3416-3217 (3NH), 3083 (CH aromatic), 2860 (CH=C), 2260
(CN), 1692 (C=O), 1199 (C=S). 1H-NMR (δ, ppm): 7.12 (s, 1H, CH=C),
7.41–8.01 (m, 10H, 2C6H5), 9.76, 10.75, 10.80 (3s, 3H, 3NH). Calc. for

Thiosemicarbazides in Heterocyclic Synthesis
1671
TABLE II Effect of 64 mg/L of Each Compound on Mycelial Dry Mass,
Sporulation and Nucleic Acid Synthesis of Fusarium Oxysporum f. sp.
Lycopersici
Compound
no.
Mycelial dry mass
Mg/50 mL
Sporulation spores,
Nucleic acid mg/g
dry mass RNA
×10−5/mL of culture
DNA
3
5
7a
7b
7c
7d
9
10a
10b
10c
12
168
258
144
102
198
226
330
225
106
104
198
256
258
102
214
330
258
330
168
160
220
101
100
136
228
8.4
23.8
18.6
23.2
33.5
36.6
20.8
8.9
20.2
28.5
33.5
24.6
23.8
20.3
23.2
23.8
24.8
20.8
26.4
20.8
20.6
18.2
10.2
30.2
24.0
14.5
10.4
20.8
10.3
18.6
12.5
18.7
6.3
0.18
0.22
0.23
0.16
0.23
0.33
0.33
0.84
0.30
0.23
0.23
0.34
0.22
0.16
0.34
0.26
0.38
0.33
0.10
0.35
0.38
0.33
0.32
0.32
0.44
6.2
10.0
18.6
10.8
10.4
10.7
10.3
10.4
6.3
18.7
8.5
12.7
16.8
9.2
14
15
17a
17b
19a
19b
20
22a
22b
23
24
25
26
28
6.3
16.0
11.6
C17H14N4OS (322.38): C, 63.33; H, 4.37; N, 17.37; S, 9.94. Found: C,
62.83; H, 4.38; N, 16.87; S, 9.54.
Reaction of Compound (5) with α-Haloketones—General
Procedure for the Synthesis of (7a), (7b), (7c), and (7d)
To a solution of compound 5 (1.26 g, 3.90 ×10−3 mol) in ethanol (40 mL),
either ethyl chloroacetate (0.47 g, 3.90 × 10−3 mol), phenacyl bromide
(0.77 g, 3.90 × 10−3 mol), 4-methylphenacyl bromide (0.83 g, 3.90 ×
10−3 mol), or chloroacetone (0.36 g, 3.90 × 10−3 mol) was added. The
reaction mixture, in each case, was heated under reflux for 3 h then
poured onto a beaker containing an ice/water mixture, and the pH was
adjusted to pH 7 using sodium hydroxide solution. The formed solid
product, in each case, was collected by filtration.

1672
R. M. Mohareb et al.
α-Benzalcyanoacetyl-4-(4-hydroxy-3-phenylthiazol-2-
ylidieno)-hydrazone (7a)
Pale green crystals (from ethanol), yield 65 % (0.93 g), m.p.118◦C. IR
(υ, cm−1): 3525–3190 (OH, NH), 3060 (CH aromatic), 2213 (CN), 1695
(C=O), 1670 (C=N), 1640 (C=C). 1H-NMR (δ, ppm): 5.77 (s, 1H, thiazole
H-5), 6.25 (s, 1H, CH=C), 6.85–7.83 (m, 10H, 2C6H5), 9.98 (s, 1H, NH),
11.07 (s, 1H, OH). 13C-NMR (DMSO): 58 (thiazole C-4), 116.8 (CN),
117.4, 119.5, 122.5, 124.3, 128.9, 129.5, 140.9, 143.2 (aromatic C), 167.5
(C=O), 180.5 (thiazole C-5). Calc. for C19H14N4O2S (362.40): C, 62.97;
H, 3.89; N, 15.45; S, 8.84. Found: C, 63.48; H, 4.30; N, 14.94; S, 8.42.
α-Benzalcyanoacetyl-4-(3,4-diphenylthiazol-2-
ylidieno)hydrazone (7b)
Yellow crystals (from ethanol), 73% yield (1.22 g), m.p. 127◦C. IR (υ,
cm−1): 3300–3240 (NH), 3057 (CH aromatic), 2241 (CN), 1683 (C=O).
1H-NMR (δ, ppm): 4.61 (s, 1H, thiazole H-5), 6.47 (s, 1H, CH=C), 6.67–
8.18 (m, 15H, 3C6H5), 9.22 (s, 1H, NH). Calc. for C25H18N4OS (422.50):
C, 71.07; H, 4.29; N, 13.26; S, 7.58. Found: C, 70.56; H, 4.52; N, 13.66;
S, 8.00.
α-Benzalcyanoacetyl-4-(4-methylphenyl-3-phenylthiazol-2-
ylidieno)hydrazone (7c)
Buff crystals (from ethanol), 69% yield (1.19 g), m.p. 82◦C. IR (υ,
cm−1): 3340–3225 (NH), 3060 (CH aromatic), 2923 (CH3), 2240 (CN),
1727 (C=O). 1H-NMR (δ, ppm): 3.37 (s, 3H, CH3), 4.89 (s, 1H, thiazole
H-5), 6.39 (s, 1H, CH=C), 6.64–8.16 (m, 14H, 2C6H5, C6H4), 11.14 (s,
1H, NH). Calc. for C26H20N4OS (436.53): C, 71.53; H, 4.61; N, 12.83; S,
7.34. Found: C, 71.10; H, 5.08; N, 12.35; S, 7.33.
α-Benzalcyanoacetyl-4-(4-methyl-3-phenylthiazol-2-ylidieno)-
hydrazone (7d)
Green crystals (from ethanol), 67% yield (0.95 g), m.p. 136◦C. IR (υ,
cm−1): 3350–3293 (NH), 3062 (CH aromatic), 2928 (CH3), 2220 (CN),
1
1684 (C=O). H-NMR (δ, ppm): 3.39 (s, 3H, CH3), 4.50 (s, 1H, thia-
zole H-5), 6.05 (s, 1H, CH=C), 6.85–8.09 (m, 10H, 2C6H5), 9.97 (s, 1H,
NH). Calc. for C20H16N4OS (360.43): C, 66.64; H, 4.47; N, 15.54; S, 8.89.
Found: C, 66.16; H, 4.96; N, 15.05; S, 9.38.
Synthesis of 1-Coumarin-3-oyl-4-phenyl-3-
thiosemicarbazide (9)
To a solution of compound 3 (3.00 g, 0.012 mol) in 1,4-dioxan (70
mL) containing piperidine (1 mL), salicaldehyde (1.56 g, 0.012 mol)
was added. The reaction mixture was heated under reflux for 4 h and

Thiosemicarbazides in Heterocyclic Synthesis
1673
then poured into a beaker containing an ice/water mixture containing
few drops of hydrochloric acid. The formed solid product was collected
by filtration and dried.
Orange crystals (from 1,4-dioxan), 68% yield (3.00 g), m.p. 240◦C. IR
(υ, cm−1): 3450–3191(3NH), 3049 (CH aromatic), 1701, 1680 (2C=O),
1195 (C=S). 1H-NMR (δ, ppm): 6.96 (s, 1H, coumarin H-4), 7.32–8.99 (m,
9H, C6H5, C6H4), 9.76, 11.18, 11.80 (3s, 3H, 3NH). 13C-NMR (DMSO): δ
114.2, 118.4, 120.9, 121.4, 123.7, 128.5, 133.6, 136.4 (aromatic C), 156.4
(C=O), 172.5 (C=S). Calc. for C17H13N3O3S (339.37): C, 60.16; H, 3.86;
N, 12.38; S, 9.44. Found: C, 59.67; H, 4.21; N, 11.89; S, 8.89.
Reaction of Compound (9) with α-Haloketones—General
Procedure for the Synthesis of (10a), (10b), and (10c)
To a solution of compound 9 (0.54 g, 1.59 × 10−3 mol) in dimethyl-
formamide (30 mL), either ethyl chloroacetate (0.19 g, 1.59 × 10−3 mol),
phenacyl bromide (0.31 g, 1.59 × 10−3 mol), or chloroacetone (0.14 g,
1.59 × 10−3 mol) was added. The reaction mixture, in each case, was
heated under reflux for 3 h and then poured into a beaker containing
an ice/water mixture, and the pH was adjusted to pH 7 using sodium
hydroxide solution. The formed solid product, in each case, was collected
by filtration and dried.
1-Coumarin-3-oyl-3-(4-hydroxy-3-phenyl-2-ylidienothiazolo)-
hydrazide (10a)
Yellow crystals (from dioxan), 77% yield (0.47 g), m.p. 180◦C. IR (υ,
cm−1): 3550–3283 (OH, NH), 3055 (CH aromatic), 1750, 1701 (2C=O).
1H-NMR (δ, ppm): 4.81 (s, 1H, thiazole H-5), 6.93 (s, 1H, coumarin H-4),
7.37–8.03 (m, 9H, C6H5, C6H4), 11.14 (s, 1H, NH), 11.89 (s, 1H, OH).
Calc. for C19H13N3O4S (379.39): C, 60.15; H, 3.45; N, 11.07; S, 8.45.
Found: C, 60.64; H, 3.93; N, 11.56; S, 7.99.
1-Coumarin-3-oyl-3-(3,4-diphenyl-2-ylidienothiazolo)-
hydrazide (10b)
Brown crystals (from 1,4-dioxan), 74% yield (0.52 g), m.p. 136◦C. IR
(υ, cm−1): 3400–3300 (NH), 3056 (CH aromatic), 1740, 1699 (2C=O).
1H-NMR (δ, ppm): 5.60 (s, 1H, thiazole H-5), 6.93 (s, 1H, coumarin
H-4), 7.30–8.91 (m, 14H, 2C6H5, C6H4), 11.13 (s, 1H, NH). Calc. for
C25H17N3O3S (439.49): C, 68.32; H, 3.89; N, 9.56; S, 7.29. Found: C,
68.81; H, 4.29; N, 9.08; S, 6.94.
1-Coumarin-3-oyl-3-(4-methyl-3-phenyl-2-
ylidienothiazolo)hydrazide (10c)
◦
Buff crystals (from 1,4-dioxan), 59% yield (0.36 g), m.p. 152 C. IR
(υ, cm−1): 3480–3420 (NH), 3056 (CH aromatic), 2925 (CH3), 1730,

1674
R. M. Mohareb et al.
1702 (2C=O). 1H-NMR (δ, ppm): 3.56 (s, 3H, CH3), 6.12 (s, 1H,
thiazole H-5), 6.97 (s, 1H, coumarin H-4), 7.36-8.21 (m, 9H, C6H5,
C6H4), 11.11 (s, 1H, NH). Calc. for C20H15N3O3S (377.42): C, 63.64;
H, 4.00; N, 11.13; S, 8.49. Found: C, 63.21; H, 4.49; N, 10.72; S,
7.97.
Synthesis of 1-N-Cyanoacetylhydrazono-4-(4-methylphenyl-3-
phenyl)-thiazole (12)
To a solution of compound 3 (6.09 g, 0.026 mol) in 1,4-dioxan (70 mL),
4-methylphenacyl bromide (5.54 g, 0.026 mol) was added. The reaction
mixture was heated under reflux for 3 h and then poured into a beaker
containing an ice/water mixture, and the pH was adjusted to pH 7 using
sodium hydroxide solution. The formed solid product was collected by
filtration and dried.
Buff crystals (from ethanol), 64% yield (5.88 g), m.p. 160◦C. IR (υ,
cm−1): 3490–3438 (NH), 3113 (CH aromatic), 2918 (CH3), 2255 (CN),
1
1729 (C=O). H-NMR (δ, ppm): 2.50 (s, 3H, CH3), 3.80 (s, 2H, CH2),
6.33 (s, 1H, thiazole H-5), 6.95-7.37 (m, 9H, C6H5, C6H4), 10.22 (s, 1H,
NH). 13C-NMR (DMSO): δ 25.8 (CH3), 33.6 (CH2), 115.8 (CN), 118.4,
119.5, 120.6, 123.7, 126.8, 129.1, 131.5, 138.2, 140.9 (aromatic C, thia-
zole C-5), 155.8 (C=N), 170.9 (C=O). Calc. for C19H16N4OS (348.42): C,
65.49; H, 4.62; N, 16.08; S, 9.20. Found: C, 65.29; H, 4.91; N, 15.59; S,
9.69.
Synthesis of α-Phenylhydrazonocyanoacetyl-
4-(4-methylphenyl-3-phenyl-2-ylidienothiazolo)hydrazone (14)
To a cold (0–5◦C) solution of compound 12 (1.01 g, 2.89 × 10−3 mol)
in ethanol (50 mL) containing sodium hydroxide solution (10 mL,
10%) and a solution of benzenediazonium chloride (13) (2.89 × 10−3
mol) [which was prepared by dissolving sodium nitrite (0.40 g, 4.30
× 10−3 mol) in water, 2 mL was added to a cold solution of aniline
(0.27 g, 2.89 × 10−3 mol) containing the appropriate amount of hy-
drochloric acid and with continuous stirring] was added with contin-
uous stirring. The reaction mixture was stirred at room temperature
for 3 h, and the formed solid product was collected by filtration and
dried.
Reddish brown crystals (from 1,4-dioxan), 53% yield (0.70 g), m.p.
142◦C. IR (υ, cm−1): 3450–3184 (2NH), 3109 (CH aromatic), 2919 (CH3),
1
2214 (CN), 1737 (C=O). H-NMR (δ, ppm): 3.32 (s, 3H, CH3), 6.35 (s,
1H, thiazole H-5), 6.98-8.27 (m, 14H, 2C6H5, C6H4), 10.50, 11.01 (2s,
2H, 2NH). Calc. for C25H20N6OS (452.53): C, 66.35; H, 4.45; N, 18.57;
S, 7.08. Found: C, 66.92; H, 4.95; N, 18.00; S, 7.59.

Thiosemicarbazides in Heterocyclic Synthesis
1675
Synthesis of α-Benzalcyanoacetylhydrazino-
4-(4-methylphenyl-3-phenyl-2-ylidieno)thiazole (15)
To a solution of compound 12 (1.43 g, 4.11 × 10−3 mol) in ethanol
(25 mL) containing piperidine (0.5 mL), benzaldehyde (4) (0.43 g, 4.11
× 10−3 mol) was added. The reaction mixture was heated under reflux
for 3 h and then poured into a beaker containing an ice/water mixture
containing few drops of hydrochloric acid. The formed solid product was
collected by filtration and dried.
Yellow crystals (from ethanol), 83% yield (1.50 g), m.p. 100◦C. IR (υ,
cm−1): 3350–3295 (NH), 3056 (CH aromatic), 2922 (CH3), 2218 (CN),
1748 (C=O). 1H-NMR (δ, ppm): 3.30 (s, 3H, CH3), 6.21 (s, 1H, thiazole
H-5), 6.91–7.96 (m, 15H, CH=C, 2C6H5, C6H4), 10.72 (s, 1H, NH). Calc.
for C26H20N4OS (436.53): C, 71.53; H, 4.61; N, 12.83; S, 7.34. Found: C,
71.32; H, 5.08; N, 12.30; S, 6.85.
Reaction of Compound (15) with Either Hydrazine Hydrate
or Phenyl Hydrazine—General Procedure for the Synthesis
of (17a) and (17b)
To a solution of compound 15 (0.70 g, 1.60 × 10−3 mol) in ethanol (25
mL), either hydrazine hydrate (0.08 g, 1.60 × 10−3 mol) or phenyl hy-
drazine (0.17 g, 1.60 × 10−3 mol) was added. The reaction mixture,
in each case, was heated under reflux for 3 h and then poured onto a
beaker containing an ice/water mixture. The formed solid product, in
each case, was collected by filtration and dried.
3-Phenyl-4-(4-methylphenyl)-2-ylidieno(3-amino-
5-phenylpyrazol-4-carbohydrazino)thiazole (17a)
Pale brown crystals (from ethanol), 64% yield (0.48 g), m.p. 170◦C.
IR (υ/cm−1): 3500–3396 (NH2, 2NH), 3058 (CH aromatic), 2923 (CH3),
1700 (C=O). 1H-NMR (δ, ppm): 3.29 (s, 3H, CH3), 4.10 (s, 2H, NH2), 6.12
(s, 1H, thiazole H-5), 6.23-8.42 (m, 14H, 2C6H5, C6H4), 9.40, 10.19 (2s,
2H, 2NH). 13C-NMR (DMSO): δ 26.6 (CH3), 106.8, 11.7, 118.9, 119.4,
120.7, 121.7, 124.7, 133.6, 136.2, 138.9, 140.4, 141.7, 146.8 (aromatic
C, thiazole C, pyrazole C), 155.9, 156.6 (2 C=N), 169.8 (C=O). Calc. for
C26H22N6OS (466.56): C, 66.69; H, 4.75; N, 18.01; S, 6.87. Found: C,
66.23; H, 5.24; N, 17.73; S, 7.39.
3-Phenyl-4-(4-methylphenyl)-2-ylidieno(3-amino-1,5-
diphenylpyrazol-4-carbohydrazino)thiazole (17b)
Buff crystals (from ethanol), 70% yield (0.61 g), m.p. 126◦C. IR (υ,
cm−1): 3400–3285 (NH2, NH), 3055 (CH aromatic), 2922 (CH3), 1700
1
(C=O). H-NMR (δ, ppm): 3.26 (s, 3H, CH3), 4.13 (s, 2H, NH2), 6.02

1676
R. M. Mohareb et al.
(s, 1H, thiazole H-5), 6.36–8.06 (m, 19H, 3C6H5, C6H4), 10.37 (s, 1H,
NH). Calc. for C32H26N6OS (542.66): C, 70.82; H, 4.82; N, 15.48; S, 5.90.
Found: C, 70.54, H, 4.68; N, 14.99; S, 6.21.
Reaction of Compound (15) with Cyanomethylene
Reagents—Genaral Procedure for the Synthesis of (19a)
and (19b)
To a solution of compound 15 (0.51 g, 1.16 ×10−3 mol) in ethanol (20 mL)
containing triethylamine (0.5 mL), either malononitrile (0.07 g, 1.16 ×
10−3 mol) or ethyl cyanoacetate (0.13 g, 1.16 × 10−3 mol) was added.
The reaction mixture, in each case, was heated under reflux for 3 h and
then poured into a beaker containing an ice/water mixture containing
few drops of hydrochloric acid. The formed solid product, in each case,
was collected by filtration and dried.
1-N-(2-Amino-3,5-dicyano-4[H]-4-phenyl-6-hydroxy)pyrido-
3-phen-yl-4-(4-methylphenyl)-2-ylidienoaminothiazole (19a)
Buff crystals (from ethanol), 61% yield (0.36 g), m.p. 120◦C. IR (υ,
cm−1): 3600–3452 (OH, NH2), 2970 (CH3), 2240, 2210 (2CN). 1H-NMR
(δ, ppm): 3.29 (s, 3H, CH3), 4.42 (s, 2H, NH2), 5.82 (s, 1H, thiazole
H-5), 6.22 (s, 1H, pyridine H-4), 6.56–8.02 (m, 14H, 2C6H5, C6H4),
11.55 (s, 1H, OH). 13C-NMR (DMS): δ25.3 (CH3), 44.8 (pyridine C-4),
118.0, 118.6 (2 CN), 116.7, 119.5, 119.0, 121.5, 124.6, 127.1, 129.7,
136.4, 139.7, 144.5 (aromatic C, thiazole C, pyridine C-3, C-5, C-6),
155.6 (C=N), 185.8 (pyridine C-2). Calc. for C29H22N6OS (502.59): C,
69.30; H, 4.41; N, 16.72; S, 6.37. Found: C, 68.82; H, 3.82; N, 16.23; S,
6.86.
1-N-(2,6-Dihydroxy-3,5-dicyano-4[H]-4-phenyl)pyrido-
3-phenyl-4-(4-methylphenyl)-2-ylidienoaminothiazole (19b)
Buff crystals (from ethanol), 83% yield (0.49 g), m.p. 86◦C. R (υ, cm−1):
3550–3446 (2OH), 3058 (CH, aromatic), 2980 (CH3), 2200, 2210 (2CN).
1H-NMR (δ, ppm): 3.40 (s, 3H, CH3), 5.72 (s, 1H, thiazole H-5), 6.43 (s,
1H, pyridine H-4), 7.04–7.84 (m, 14H, 2C6H5, C6H4), 11.50, 11.53 (2s,
2H, 2OH). Calc. for C29H21N5O2S (503.58): C, 69.16; H, 4.20; N, 13.90;
S, 6.36. Found: C, 69.68; H, 4.69; N, 13.45; S, 6.81.
Synthesis of 1-Coumarin-3-oyl-3-(3-
phenyl-4-(4-methylphenyl)-2-ylidieno)-hydrazinothiazole (20)
To a solution of compound 12 (1.00 g, 2.87 × 10−3 mol) in ethanol (30 mL)
containing piperidine (0.5 mL), salicaldehyde (0.35 g, 2.87 × 10−3 mol)

Thiosemicarbazides in Heterocyclic Synthesis
1677
was added. The reaction mixture was heated under reflux for 3 h then
poured into a beaker containing an ice/water mixture containing few
drops of hydrochloric acid. The formed solid product was collected by
filtration and dried.
Brick red crystals (from 1,4-dioxan), 76% yield (1.00 g), m.p. 120◦C. IR
(υ, cm−1): 3345–3315 (NH), 3057 (CH aromatic), 2925 (CH3), 1696, 1740
(2C=O). 1H-NMR (δ, ppm): 3.30 (s, 3H, CH3), 6.05 (s, 1H, thiazole H-5),
6.65–8.34 (m, 14H, coumarin H-4, C6H5, 2C6H4), 9.40 (s, 1H, NH). Calc.
for C26H19N3O3S (453.51): C, 68.85; H, 4.22; N, 9.26; S, 7.06. Found: C,
68.56; H, 4.64; N, 8.82; S, 6.99.
Reaction of Compound (12) with β-Ketoesters—General
Procedure for the Synthesis of (22a) and (22b)
To a solution of compound 12 (1.22 g, 3.50 × 10−3 mol) in ethanol (30
mL) containing piperidine (1 mL), either acetylacetone (0.35 g, 3.50 ×
10−3 mol) or ethyl acetoacetate (0.45 g, 3.50 × 10−3 mol) was added.
The reaction mixture, in each case, was heated under reflux for 3 h and
then poured into a beaker containing an ice/water mixture containing
few drops of hydrochloric acid. The formed solid product, in each case,
was collected by filtration and dried.
1-N-(5-Cyano-2,4-dimethyl-3[H]-6-oxo)pyrido-
3-phenyl-4-(4-methyl-phenyl-2-ylidienoaminothiazole (22a)
Buff crystals (from ethanol), 76% yield (1.11 g), m.p. 100◦C. IR
(υ, cm−1): 3056 (CH aromatic), 3029, 2922, 2858 (3CH3), 2221 (CN),
1683 (C=O). 1H-NMR (δ, ppm): 2.40, 2.50, 3.30 (3s, 9H, 3CH3),
6.47 (s, 1H, thiazole H-5), 6.58 (s, 1H, pyridine H-3), 6.90–7.83
(m, 9H, C6H5, C6H4). Calc. for C24H20N4OS (412.51): C, 69.88; H,
4.88; N, 13.58; S, 7.77. Found: C, 69.68; H, 5.32; N, 13.10; S,
7.29.
1-N-(5-Cyano-4-methyl-3[H]-2-hydroxy-6-oxo)pyrido-
3-phenyl-4-(4-methylphenyl)-2-ylidienoaminothiazole (22b)
Buff crystals (from ethanol), 83% yield (1.22 g), m.p. 146◦C. IR (υ,
cm−1): 3550–3434 (OH), 3111 (CH aromatic), 3027, 2921 (2CH3), 2256
1
(CN), 1728 (C=O). H-NMR (δ, ppm): 2.50, 3.34 (2s, 6H, 2CH3), 6.34
(s, 1H, thiazole H-5), 6.47 (s, 1H, pyridine H-3), 6.95-7.37 (m, 9H,
C6H5, C6H4), 11.25 (s, 1H, OH). Calc. for C23H18N4O2S (414.48): C,
66.64; H, 4.37; N, 13.51; S, 7.73. Found: C, 67.12; H, 4.89; N, 13.99; S,
7.24.

1678
R. M. Mohareb et al.
Synthesis of 1-N-(4-Amino-5-cyano-3[H]-2-hydroxy-6-oxo)-
pyrido-3-phenyl-4-(4-methylphenyl)-2-ylidienoaminothiazole
(23)
To a solution of compound 12 (1.30 g, 3.73 × 10−3 mol) in ethanol (25 mL)
containing triethylamine (0.5 mL), either malononitrile (0.24 g, 3.73 ×
10−3 mol) or ethyl cyanoacetate (0.42 g, 3.73 × 10−3 mol) was added.
The reaction mixture, in each case, was heated under reflux for 3 h and
then poured onto a beaker containing an ice/water mixture containing
few drops of hydrochloric acid. The formed solid product, in each case,
was collected by filtration and dried.
Pale brown crystals (from ethanol), 66% yield (1.03 g), m.p. 100◦C.
IR (υ, cm−1): 3600–3433 (OH, NH2), 3114 (CH aromatic), 2921 (CH3),
1
2257 (CN), 1729 (C=O). H-NMR (δ, ppm): 2.50 (s, 3H, CH3), 3.64 (s,
2H, NH2), 6.34 (s, 1H, thiazole H-5), 6.47 (s, 1H, pyridine H-3), 6.96–
7.37 (m, 9H, C6H5, C6H4), 11.29 (s, 1H, OH). Calc. for C22H17N5O2S
(415.47): C, 63.60; H, 4.12; N, 16.85; S, 7.71. Found: C, 63.08; H, 4.18;
N, 17.35; S, 7.36.
Synthesis of 3-Amino-4-phenyl-5-thioxo-2-oyl-
(3-phenylthiouryl)-thiazole (24)
To a solution of compound 3 (1.50 g, 6.41 × 10−3mol) in ethanol (100
mL) containing triethylamine (1 mL), elemental sulfur (0.20 g, 6.41
× 10−3mol) and phenylisothiocyanate (0.86 g, 6.41 × 10−3 mol) were
added. The reaction mixture was heated under reflux for 4 h and then
poured into a beaker containing an ice/water mixture containing few
drops of hydrochloric acid. The formed solid product was collected by
filtration and dried.
Pale brown crystals (from 1,4-dioxan), 58% yield (1.50 g), m.p. 122◦C.
IR (υ, cm−1): 3375–3205 (NH2, 3NH), 3033 (CH aromatic), 1699 (C=O),
1210, 1193 (2C=S). 1H-NMR (δ, ppm): 4.47 (s, 2H, NH2), 6.80–7.93 (m,
10H, 2C6H5), 9.79, 11.06, 12.62 (3s, 3H, 3NH). Calc. for C17H15N5OS3
(401.52): C, 50.85; H, 3.76; N, 17.44; S, 23.95. Found: C, 51.35; H, 3.82;
N, 16.95; S, 23.56.
Synthesis of 5-Amino-3-oxo-4[H]-1-(2-phenylthioamido)-
pyrazole (25)
A solution of compound 3 (1.00 g, 4.27 × 10−3 mol) in pyridine (10
mL) was heated under reflux for 3 h and then poured into a beaker
containing ice/water mixture containing few drops of hydrochloric acid.
The formed solid product was collected by filtration and dried.

Thiosemicarbazides in Heterocyclic Synthesis
1679
Buff crystals (from ethanol), 52% yield (0.52 g), m.p. 218◦C. IR (υ,
cm−1): 3574–3189 (NH2, 2NH), 3033 (CH aromatic), 1703 (C=O), 1203
(C=S). 1H-NMR (δ, ppm): 5.18 (s, 2H, NH2), 6.60 (s, 1H, pyrazole
H-4), 6.90–7.62 (m, 5H, C6H5), 10.41, 10.98 (2s, 2H, 2NH). Calc. for
C10H10N4OS (234.27): C, 51.26; H, 4.30; N, 23.91; S, 13.68. Found: C,
51.36; H, 4.53; N, 23.69; S, 13.67.
Synthesis of 5-Imino-4-Phenylhydrazono-3-oxo-2[H]-1-
phenylthio-amidopyrazole (26)
To a cold solution (0–5◦C) of compound 25 (0.38 g, 1.62 × 10−3 mol)
in ethanol (50 mL) containing sodium hydroxide solution (10 mL,
10%) and a solution of benzenediazonium chloride (1.62 ×−3 mol)
[which was prepared by dissolving sodium nitrite (0.16 g, 2.43 ×
10−3 mol) in water, 2 mL was added to a cold solution of aniline
(0.15 g, 1.62 × 10−3 mol) containing the appropriate amount of hy-
drochloric acid and with continuous stirring] was added with continu-
ous stirring. The formed solid product was collected by filtration and
dried.
Brick red crystals (from dimethylformamide), 51% yield (0.28 g),
m.p. 220◦C. IR (υ, cm−1): 3350–3165 (4NH), 3032 (CH aromatic), 1699
(C=O), 1191 (C=S). 1H-NMR (δ, ppm): 6.94–7.82 (m, 10H, 2C6H5), 9.88,
10.71, 11.50, 11.63 (4s, 4H, 4NH). Calc. for C16H14N6OS (338.38): C,
56.79; H, 4.17; N, 24.83; S, 9.47. Found: C, 56.60; H, 4.54; N, 24.38; S,
10.01.
Synthesis of 5-Amino-4-cyclohexen-1-yl-3-hydroxy-1-
(2-phenylthio-amido) pyrazole (28)
To a mixture of compound 3 (1.02 g, 4.35 × 10−3 mol) and cyclohexanone
(0.41 g, 4.35 × 10−3 mol), ammonium acetate (0.33 g, 4.35 × 10−3 mol)
was added. The reaction mixture was heated in oil bath at 140◦C for 1 h
and then left to cool. The semisolid formed was triturated with ethanol
(40 mL), and the formed solid product was collected by filtration and
dried.
Yellowish brown crystals (from ethanol), 59% yield (0.82 g), m.p.
1
62◦C. IR (υ, cm−1): 3563–3196 (OH, NH2, NH), 1670 (C=N). H-NMR
(δ, ppm): 1.54–2.04 (2m, 8H, 4CH2), 3.36 (s, 2H, NH2), 7.30–7.56 (m,
6H, C6H5, cyclohexene H-2), 8.00 (s, 1H, NH), 9.95 (s, 1H, OH). Calc.
for C16H18N4OS (314.40): C, 61.12; H, 5.77; N, 17.81; S, 10.19. Found:
C, 61.64; H, 6.22; N, 17.35; S, 9.70.

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R. M. Mohareb et al.
Reaction of Compound (3) with Either α-Cyanocinnamonitrile
(29a) or Ethyl α-Cyanocinnamate (29b)—General Procedure
for the Synthesis of Compounds (30a) and (30b)
To a solution of compound 3 (1.11 g, 4.73 × 10−3mol) in 1,4-dioxan (50
mL) containing triethylamine (0.5 mL), either α-cyanocinnamonitrile
(0.73 g, 4.73 × 10−3mol) or ethyl α-cyanocinnamate (0.95 g, 4.73 × 10−3
mol) was added. The reaction mixture, in each case, was heated under
reflux for 3 h and then poured into a beaker containing an ice/water
mixture containing few drops of hydrochloric acid. The formed solid
product, in each case, was collected by filtration and dried.
6-Amino-3,5-dicyano-2-oxo-4-phenyl-1-
(2-phenylthiouryl)pyridine (30a)
Yellow crystals (from ethanol), 50% yield (0.92 g), m.p. over 300◦C.
IR (υ, cm−1): 3445–3237 (NH2, 2NH), 3045 (CH aromatic), 2223, 2220
(2CN), 1688 (C=O).1H-NMR (δ, ppm): 3.58 (s, 2H, NH2), 7.19–7.99 (m,
10H, 2C6H5), 9.62, 10.38 (2s, 2H, 2NH). Calc. for C20H14N6OS (386.43):
C, 62.16; H, 3.65; N, 21.74; S, 8.29. Found: C, 62.68; H, 4.12; N, 21.15;
S, 7.89.
Ethyl-6-amino-3-cyano-2-oxo-4-phenyl-1-
(2-phenylthiouryl)pyridine-5-carboxylate (30b)
Orange crystals (from ethanol), 58% yield (1.20 g), m.p. 264◦C. IR (υ,
cm−1): 3550–3177 (NH2, 2NH), 3058 (CH aromatic), 2207 (CN), 1733,
1
1699 (2C=O). H-NMR (δ, ppm): 1.29 (t, 3H, CH3), 3.58 (s, 2H, NH2),
4.42 (q, 2H, CH2), 6.65–7.99 (m, 10H, 2C6H5), 9.62, 10.36 (2s, 2H, 2NH).
Calc. for C22H19N5O3S (433.48): C, 60.95; H, 4.41; N, 16.15; S, 7.39.
Found: C, 60.46; H, 4.92; N, 16.66; S, 7.48.
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