Synthesis, structure elucidation, and biological evaluation of some fused and/or pendant thiophene, pyrazole, imidazole, thiazole, triazole, triazine, and coumarin systems based on cyanoacetic 2-[(benzoylamino)thioxomethyl] hydrazide

Article abstract of DOI:10.1080/10426500600892776

Aiming to produce cyclized systems with potential bioactivity, a variety of fused and/or pendant thiophene, pyrazole, imidazole, thiazole, triazole, triazine, and coumarin systems were synthesized based on a cyanoacetic 2-[(benzoylamino)thi- oxomethyl] hy

Full text of DOI:10.1080/10426500600892776

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Phosphorus, Sulfur, and Silicon
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Synthesis, Structure
Elucidation, and Biological
Evaluation of Some Fused
and/or Pendant Thiophene,
Pyrazole, Imidazole,
Thiazole, Triazole, Triazine,
and Coumarin Systems
Based on Cyanoacetic 2-
[(Benzoylamino)thioxomethyl]
Hydrazide
Hoda Z. Shams a , Rafat M. Mohareb b , Maher H.
Helal a & Amira E. Mahmoud a
a Chemistry Department, Helwan University, Ain
Helwan, Cairo, Egypt
b Chemistry Department, Cairo University, Giza,
Egypt
Published online: 18 Feb 2007.
To cite this article: Hoda Z. Shams , Rafat M. Mohareb , Maher H. Helal & Amira E.
Mahmoud (2007): Synthesis, Structure Elucidation, and Biological Evaluation of Some
Fused and/or Pendant Thiophene, Pyrazole, Imidazole, Thiazole, Triazole, Triazine,
and Coumarin Systems Based on Cyanoacetic 2-[(Benzoylamino)thioxomethyl]
Hydrazide, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:2, 237-263
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Phosphorus, Sulfur, and Silicon, 182:237–263, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600892776
Synthesis, Structure Elucidation, and Biological
Evaluation of Some Fused and/or Pendant Thiophene,
Pyrazole, Imidazole, Thiazole, Triazole, Triazine, and
Coumarin Systems Based on Cyanoacetic
2-[(Benzoylamino)thioxomethyl] Hydrazide
Hoda Z. Shams
Chemistry Department, Helwan University, Ain Helwan, Cairo, Egypt
Rafat M. Mohareb
Chemistry Department, Cairo University, Giza, Egypt
Maher H. Helal
Amira E. Mahmoud
Chemistry Department, Helwan University, Ain Helwan, Cairo, Egypt
Aiming to produce cyclized systems with potential bioactivity, a variety of fused
and/or pendant thiophene, pyrazole, imidazole, thiazole, triazole, triazine, and
coumarin systems were synthesized based on a cyanoacetic 2-[(benzoylamino)thi-
oxomethyl] hydrazide precursor. The structure of the synthesized compounds was
established based on elemental analysis and spectral data. The antibacterial and
antifungal activities of the compounds are discussed and evaluated.
Keywords Antimicrobial; imidazoles; pyrazoles; thiazoles; thiophenes; triazoles
INTRODUCTION
Substituted aminothioxomethyl hydrazides are important building
blocks in synthetic heterocyclic chemistry. The S/N regioselective nu-
cleophilic competition in the synthesis of heterocyclic systems by in-
termolecular and intramolecular cyclization, as well as the change
in reaction conditions, which might favor an N-attack, S-attack, or
even an attack on the substituted terminals, are important factors for
Received May 4, 2006; accepted June 26, 2006.
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 corresponding to Hoda Z. Shams, Helwan University, Chemistry Department,
Faculty of Science, Ain Helwan, Cairo, Egypt. E-mail: shamshodaz@yahoo.com
237

238
H. Z. Shams et al.
the diversity of produced heterocyclic systems from the title reaction
precursor.
On the other hand, the synthetic potential and biological activity of
several heterocyclics related to the named hydrazides have been ex-
plored to their maximum extent. Among the pharmacological profiles
are their antimicrobial,1,2 antitubercular,3,4 anticonvulsant,5,6 anti-
inflammatory,7,8 antidepressant9 and antitumor10 activities.
Continuing our interest in developing new heterocyclic systems
based on phenylthiosemicarbazide11,12 as well as the design and syn-
thesis of heterocyclics with promising biological activities,13−16 we fo-
cused our work on developing novel polyfunctionalized heterocyclic
compounds with potential bioactivity.
RESULTS AND DISCUSSION
Chemistry
The synthetic strategies adopted to obtain the target systems are out-
lined in Schemes 1–6. CHNS elemental analysis, IR, 1H NMR, 13C
NMR, and MS spectral data are recorded in the Experimental section.
The key precursor for the synthesis of the title systems is the hy-
drazide 1. According to previously reported articles,17,18 compound 1
was prepared by the treatment of cyanoacetic hydrazide with benzoyl
isothiocyanate in acetone and heating under reflux for 2–3 h. Erian
et al.19 reported that using acetone as a solvent afforded almost ex-
clusively the corresponding 1,3,4-thiadiazole condensate, and that us-
ing dioxane as a solvent and heating it under reflux for 2 h afforded
the 1,3,4-thiadiazole via dehydrative cyclization of the initially formed
thiosemicarbazide.
In the present work we herein report the formation of 1 in a
high yield by simply shaking equimolar amounts of cyanoacetic hy-
drazide and benzoyl isothiocyanate in dioxane at r.t. Compound 1
revealed analytical and spectral data in accordance to its molecular
structure. Mass spectral data for compound 1 revealed the molec-
ular formula C11H10N4O2S (m/z 262). Two important common frag-
ments were detected at m/z 105 (base peak) and m/z 77 indicating
[phenyl C O]+ and [phenyl]+ fragment ions, respectively. The reactive
moieties in 1 allowed valuable organic functionalizations, which permit-
ted the synthesis of various systems containing different heterocyclic
cores.
Treating
1 with α-haloketons (XCH2C( O)R; X Cl, R OEt;
X Cl, R CH3; X Br, R Ph) afforded the respective imidazolethione

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 239
O
O
O
S
Ph
O
dioxane
NC
NC
NC
Ph
N C S
NHNH2
N
H
N
N
r.t. shaking
H
H
1
O
S
N
NH
O
N
Ph
XCH2 C
1
R
X
O
a, X=Cl, R=OEt
b, X=Cl, R=CH3
c, X=Br, R=Ph
2a−c
S
H2N
O
N
N
N
Ph
2a−c
CH2(CN)2
CN
X
O
NH2
O
3a−c
S
H
N
Y=H
N
NC
N
Ph
Ph
X
O
H
H
4a−c
2a−c
C
O
O
Y
S
H
N
N
Y=OH
N
Ph
O
O
O
X
N
O
5a−c
S
H
N
N
2a−c
Ph N N Cl
NC
Ph
N
X
O
NHPh
6a−c
(2−6) a−c
a, X=OH
b, X=CH3
c, X=Ph
SCHEME 1
derivatives 2a–c. Compounds 2a–c revealed two absorption bands at
–1
1300 and 1256 cm (IR) characteristic of an imidazole thioxo function
as well as δ-1H singlet at 6.24–7.01 ppm (1H NMR) assigned to an imi-
dazole C5 H proton. Other protons were seen at the expected chemical
shifts and integral values.

240
H. Z. Shams et al.
O
S
Ph
O
R
O
NC
N
N
N
C
H
H
H
X
a, X=R=H
c, X=H, R=CH3
b, X=OH, R=H
Ph
O
Ph
S
NH
NH
O
O
R
N
H
..
N
NH
HN
Ph
O
O
O
S
NH
8
-
HN
C
S
Ph
O
R
NH
HN
N
O
Ph
7, 9
7, R= H
9, R= CH3
SCHEME 2

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 241
Ph
Ph
O
H
NH
O
(i) β- attack
X
(ii) Cyclization
X CH2CN
NH
Ph
N
Ph
HN
N
H2N
O
N
a, X=CN
b, X=CO2Et
H
O
10a,b
a, X=CN
b, X=CO2Et
7
Ph
O
O
H
O
R
7
XCH2 C
N
N
HN
X
a, X=Br, R=Ph
b, X=Cl, R=OEt
O
Ph
11a,b
a, X=Ph
b, X=OEt
SCHEME 3
S
Ph
N
O
N
NH
NH2
O
1,3-dipolar attack by 8
X CH2CN
8
X
O
a, X=CN
b, X=CO2Et
12 a,b
a, X=CN
b, X=CO2Et
O
N
Ph
O
1,4-dinucleophilic attack by 8
XCH2 C
8
NH
N
Ph
R
O
O
S
O
X=Br, R=Ph
13
SCHEME 4

242
H. Z. Shams et al.
elemental S
1
O
S
Ph
O
NC
N
N
N
H
H
H
SH
PhN
C
S
X CH2CN
a, X=CN
b, X=CO2Et
X
N
Ph
N
NH
S
O
O
HN
S
Ph
NH
Ph
S
..
..
HN NH
HN NH
O
O
NH
S
S
(i) 1,5-dipolar cyclization
(ii) -
(i) 1,5-dipolar cyclization
(ii)
HN
C S
-
HN
C S
X
NH2
Ph
NH2
N
O
O
H2N
S
S
S
HN NH
HN NH
Ph
Ph
O
14 a,b
O
a, X=CN
b, X=CO2Et
15
SCHEME 5
The reactivity of 2a–c with malononitrile, aromatic aldehydes, and
diazotized aniline was studied. Thus, treating 2a–c with malononitrile
afforded the pyran systems 3a–c via a anucleophilic attack on the car-
bonitrile reagent followed by 1,6-dipolar intramolecular cyclization. As
expected, as a consequence of cyclization, the acetyl C O stretching

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 243
N
N
Ph
O
NC
ACOH
1
NH
Reflux 5h
S
ring fission
N
N
N
N
NC
NC
SH
Ph
..
SH
intramolecular cyclization
O
O HN
N
H3C
O
Ph
O
O
H3C
C
-
O
A
- H
N
NH
NC
S
N
O
Ph
16
elemental S
16
N
NH
NC
S
N
HS
O
Ph
B
PhN
C S
X CH2CN
a, X=CN
b,X=CO2Et
NH2
S
N
NH
NH2
N
NH
X
S
Ph
N
N
S
N
S
H2N
a, X=CN
O
Ph
S
O
Ph
17 a,b
18
b, X=CO2Et
SCHEME 6

244
H. Z. Shams et al.
–1
observed for 2a–c at about 1740 cm (IR) was not observed in the
1
IR spectra of 3a–c. H NMR of 3a–c displayed two NH2 singlets res-
onating at δ 3.31–4.63 ppm. The signal of methylene CH2 protons was
not observed due to removal of these protons through an attack on the
carbonitrile reagent.
The reaction of 2a–c with aromatic aldehydes, namely benzaldehyde
and salicylaldehyde, afforded benzal derivatives 4a–c and coumarin
derivatives 5a–c, respectively. All data were consistent with the pro-
posed structure. The absence of a CN absorption band and the appear-
–1
ance of a high-frequency C O stretching about the 1719–1722 cm
region cited for a coumarin oxo function in the IR spectra of 5a–c and
the observation of a benzylidene CH proton at about δ 4.62 ppm in the
1H NMR spectra of 4a–c have proven the proposed structure.
The liability of a methylene function in 2a–c for coupling was studied
through a reaction with diazotized aniline to produce the respective azo
1
systems 6a–c. H NMR of 6a–c revealed the absence of a CH2 signal
observed for 2a–c at about δ 4.62 ppm and the presence of a down-
field δ-1H at 12.80–12.90 ppm for hydrazone NH, which confirmed the
assigned structure (Scheme 1).
The reactivity of hydrazide 1 toward condensation was studied
through treatment with aromatic carbonyl reagents. Treating 1 with
benzaldehyde was previously reported to afford the respective conden-
sation adduct20 by subjecting an ethanolic solution of the reactants
containing a catalytic amount of piperidine to reflux for 3 h.
We used dimethylformamide as a solvent to which a slight excess
of piperidine was added, and the reaction mixture was heated under
reflux for 5 h. The reaction product, thus produced, was found to be the
pyrazole derivative 7. It seems likely that 7 was formed via 1,5-dipolar
cyclization of the initially formed adduct followed by rearrangement
via elimination of HN C S. The absence of CN absorption at about the
–1
2200–2250 cm region, the disappearance of a C S stretching band
–1
expected at about 1300 cm (IR), and the absence of a SH singlet ex-
pected around δ 13 ppm for a resonating N C SH proton (1H NMR)
confirmed the assignment for pyrazole structure 7. Mass spectrum of 7
exhibited molecular ion m/z 291 corresponding to molecular formula
C17H13N3O2. Main fragmentation was revealed by a base peak m/z
105 and a fragment ion m/z 77 corresponding to [phenyl C O]+ and
[phenyl]+, respectively. Fragmentation of [phenyl C O]+ from [M++1]
was observed as a fragment ion peak at m/z 187.
Treating 1 with salicyldehyde afforded the coumarin derivative
8. Compound 8 revealed the absence of C N absorption at about
–1
2250 cm
(IR) and of methylene CH2 protons observed with 1

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 245
(1H NMR). δ-1H signals of NH, coumarin C4 H, and aromatic pro-
tons were observed at their respective chemical shifts and integral
values.
When 1 was condensed with acetophenone through fusion in ammo-
nium acetate, pyrazole derivative 9 was obtained. The reaction followed
a similar mechanistic pathway adopted for the pyrazole derivative 7.
Microanalysis, IR, and 1H NMR of 9 were fully consistent with the
proposed structure. The mass spectrum of 9 exhibited a molecular ion
m/z 305 corresponding to the molecular formula C18H15N3O2. The base
peak was observed at m/z 51 corresponding to the [HN C C C] frag-
ment. Fragment ions corresponding to [phenyl C O]+ and [phenyl]+
were also indicated at m/z 105 and m/z 77, respectively (Scheme 2).
Aiming to produce cyclized systems with potential biological activity,
compounds 7 and 8 were subjected to a reaction with different carboni-
trile and carbonyl methylene reagents.
Subjecting 7 to a reaction with methylene carbonitrile reagents
(XCH2CN; X CN; X CO2Et) afforded the respective pyranopyrazole
derivatives 10a and 10b via a β-attack on the benzylidene moiety fol-
lowed by cyclization through the pyrazole oxo function.
–1
The IR spectrum of 10a revealed a characteristic band at 2184 cm
1
attributed to C N stretching. H NMR spectra of 10a and 10b exhib-
ited signals due to a pyran C4 H proton at δ 5.17 and 5.14 ppm and
due to NH2 at δ 3.50 and 3.61 ppm, respectively. δ-1H signals inte-
grated for ester CH3 and CH2 protons were observed at 1.15–1.32 and
1
4.04–4.36 ppm, respectively, in the H NMR of 10b. In the mass spec-
trum of 10a the existing [M+] ion (m/z 357) confirmed the molecular
weight of this compound. The peak at m/z 251 represents the fragmen-
tation of [phenyl C O]+(m/z 105) as a base peak from the [M+-1]
of 10a. A peak observed at m/z 203 indicated the fragmentation of [Ph
CH C(CN)2] (m/z 154) from the [M+] ion.
The treatment of 7 with α-haloketones (XCH2C( O)R; X Br, R Ph;
X Cl, R=OEt) afforded the functionalized pyrazole derivatives 11a and
11b. IR spectra of 11a,b revealed three carbonyl stretching modes at
about 1658, 1622 and 1598 cm–1. Compound 11b exhibited δ-1H ester
signals integrated for a triplet at 1.15–1.25 and a quartet at 4.17–4.66
ppm (1H NMR). The disappearance of a ring NH singlet at about δ
1
10 ppm and the presence of a CH2 singlet at δ 5.22 ppm in the H
NMR of 10b confirmed a nucleophilic displacement mechanism. The
mass spectrum of 11a displayed the [M+] ion at m/z 409 correspond-
ing to the molecular formula C25H19N3O3. The base peak observed at
m/z 105 indicated the fragment ion [phenyl C O]+, and the most abun-
dant peak recorded at m/z 77 indicated [phenyl]+. The peak observed at

246
H. Z. Shams et al.
m/z 304 resulted from the fragmentation of [phenyl C O]+ from [M+],
and that observed at m/z 293 indicated the fragmentation of [phenyl–
C( O) CH2]+ from [M++3] (Scheme 3).
When the coumarin derivative 8 was reacted with methylene car-
bonitrile reagents (XCH2CN; X CN; X CO2Et), the respective pyra-
zole derivatives 12a and 12b were produced. The reaction followed a
1,3-dipolar attack by the hydrazinocarbonyl moiety of 8 on the methy-
lene carbonitrile dipole. Compound 12a revealed two C O stretch-
–1
ing modes at 1712 and 1607 cm and a C N absorption band at
–1
2201 cm
(IR), whereas the IR spectrum of 12b exhibited three
C O absorption bands at 1719, 1665, and 1608 cm
–1
.
1H NMR of
12a and 12b revealed signals due to NH2 and NH at about δ 3.58
and δ 9.18 ppm, respectively. Signals integrated for ester protons in
compound 12b were also observed in the respective field. The mass
spectrum of 12b exhibited molecular ion peak [M+] at m/z 462 corre-
sponding to the formula C23H18N4O5S. Main fragmentation of 12b ap-
peared by the fragments [phenyl C O]+ m/z 105 as the base peak,
[phenyl]+m/z 77, and [coumarin]+·m/z 146. A peak observed at m/z
289 revealed the fragmentation of [coumarin CH NH]+·m/z 173 from
[M+].
Treatment of 8 with phenacyl bromide afforded 1,2,4-triazine-
3-thione derivative 13. The reaction is assumed to follow a 1,4-
dinucleophilic attack by the aminothioxomethylhydrazine moiety
on the α-haloketone. 1H NMR of 13 exhibited singlets due to
triazine C6 H and NH at δ 8.14 and 11.74 ppm, respectively
(Scheme 4).
At the other extreme, when 1 was affected with elemental sulfur
and methylene carbonitrile reagents or phenyl isothiocyanate, the mode
of attack was directed toward the cyanomethylene terminal of 1. The
synthetic pathway used in these reactions are outlined in Scheme 5. A
stepwise pathway is suggested to take place via a Gewald reaction of 1
with elemental sulfur followed by a nucleophilic attack by the resulting
thiol intermediate on the named reagents to afford the respective acyclic
intermediates. The latter then suffered 1,5-dipolar cyclization followed
by an elimination-rearrangement step via the loss of HN C S to afford
the respective thiophenes 14a and 14b or thiazole 15. Compounds 14a,
14b, and 15 revealed the absence of δ-1H CH2 and N C SH singlets
observed for compound 1 at 3.89 and 12.54 ppm (1H NMR), respectively,
thus confirming the assigned structure.
The mass spectrum of 14b showed molecular ion peak [M+] 348
corresponding to its molecular formula C15H16N4O4S. Main fragmen-
tation of 14b appeared by the cleavage of [phenyl C O]+ m/z 105 as

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 247
the base peak and [phenyl]+ fragment ion m/z 77. A peak at m/z = 203
resulting from the fragmentation of [H2N–C(S+) =C CO2Et]
–
m/z 145 from the molecular ion peak was also observed
(Scheme 5).
As a continuation of our work aiming to synthesize heterocyclic sys-
tems with expected biological activities, compound 1 was subjected to
cyclization under acidic conditions. Thus, when 1 was heated under
reflux in acetic acid for 5 h, we observed that the reaction product
was almost exclusively 1,2,4-triazole thione 16. A possible mechanism
is that the reaction proceeded via an initial formation of the 1,3,4-
thiadiazole derivative. The latter undergoes ring opening, under the
reaction conditions, to yield the intermediate A, which then cyclizes
to afford the triazole thione 16. It is noteworthy that acid cycliza-
tion of acylthiosemicarbazides in concentrated sulfuric acid produces
1,3,4-thiadiazole derivatives9,21,22. Cyclization in acetic acid was also
reported to afford 1,3,4-thiadiazole.19
The structure of 16 was confirmed based on analytical and spectral
data. Thus, the IR spectrum revealed absorption bands at 1302 and
1257 cm–1corresponding to C S. H NMR showed a downfield singlet
1
at δ 13.19 ppm attributed to the N C SH proton indicating the facile
thione-thiol tautomerism. The mass spectrum of 16 exhibited a molecu-
lar ion peak [M+] at m/z = 244 corresponding to the molecular formula
C11H8N4OS. The base peak was observed at m/z 105, which corresponds
to [phenyl C O]+. The fragment ion detected at m/z 216 indicated a
direct loss of N2 from the molecular ion. The 13C NMR spectrum of 16
showed the thiocarbonyl carbon at δ 164.81. The signal at δ 160.10 was
assigned to the carbonyl carbon.
Treatment of 16 with elemental sulfur and each of malononitrile,
ethyl cyanoacetate, or phenacyl bromide afforded the respective sys-
tems 17a, 17b, and 18 via the intermediacy of the thiol B. IR spectra
of compounds 17a, 17b, and 18 revealed stretching modes in the 1300
–1
and 1244–1254 cm regions assigned to the thione C S. Mass spec-
tra of compounds 17a and 18 revealed molecular ion peaks at m/z 342
and 411, respectively, corresponding to respective molecular formulas
C14H10N6OS2 and C18H13N5OS3. Main fragmentation of 17a appeared
by the fragments [phenyl C O]+ m/z 105 and [phenyl]+ m/z 77. A peak
at m/z 244 indicated the fragmentation of [NH2 C(S+)=C CN] m/z
–
98 from the molecular ion peak. Loss of [N C S]+ from the fragment
ion m/z 244 resulted in the base peak at m/z 186. The mass spectrum
of 18 revealed a fragment ion at m/z 249 as a result of fragmentation
of benzoyl isothiocyanate from [M++1]. A peak observed at m/z 135
revealed a phenyl isothiocyanate fragment (Scheme 6).

248
H. Z. Shams et al.
Microbiology
In vitro Evaluation of Antibacterial and Antifungal Activities
The synthesized compounds were screened in vitro for their antimi-
crobial activity against a variety of bacterial and fungal isolates.23 The
recorded inhibition zones are summarized in Table I.
The results indicated that most of the synthesized systems exhibited
noticeable antimicrobial activity and that the bacterial isolates were
more susceptible to the synthesized compounds than the fungal isolates.
TABLE I Antimicrobial Activity Data of the Synthesized
Compounds in Terms of Inhibition Zones in mm
–1
(Concentration Level = 25 μg mL
)
Compound
E. coli
X. citri
A. fumigatus R. solani F. oxysporum
F
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
7
26
13
26
26
32
12
11
34
11
12
38
26
36
26
26
22
34
16
20
19
18
28
26
12
16
18
21
18
28
16
14
23
26
12
20
26
34
10
9
14
11
12
28
20
32
28
18
20
30
12
18
28
26
36
26
6
12
6
16
16
32
8
6
12
4
10
5
13
18
20
8
6
6
5
5
16
16
12
18
13
12
14
0
2
16
4
18
16
2
12
4
17
19
17
8
0
0
4
4
16
17
12
16
18
11
18
4
0
19
4
17
14
4
6
18
14
16
15
14
14
18
8
8
10a
10b
11a
11b
12a
12b
13
14a
14b
15
4
32
17
29
18
4
4
6
5
16
30
6
8
18
16
10
16
20
29
14
10
19
4
5
3
4
15
8
4
0
0
0
4
18
8
2
16
17a
17b
18
12
18

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 249
As summarized in Table I, antimicrobial activity of the test com-
pounds against each microbial isolate may be arranged in descending
order according to measured inhibition zones (in mm) following the
sequence “Microbial isolate” (inhibition zone in mm) (test compound
number) as follows.
“Escherichia coli” [38] (5a), [36] (5c), [34] (4a, 7), [32] (3a), [28] (11b,
16), [26] (1, 2b, 2c, 5b, 6a, 6b, 12a), [23] (18), [22] (6c), [21] (14b), [20]
(10a), [19] ( 10b), [18] (11a, 14a, 15), [16] (8, 13, 17a), [14] (17b), [13]
(2a), [12] (3b, 4c, 12b), [11] (3c, 4b).
“Xanthomonas citri” [36] (11b), [34] (3a), [32] (5c), [30] (7), [29] (16),
[28] (5a, 6a, 10b), [26] (1, 2c, 11a, 12a), [20] (2b, 5b, 6c, 15), [19] (18),
[18] (6b, 10a), [16] (13, 14b), [14] (4a, 17a), [12] (2a, 4c, 8), [11] (4b),
[10] (3b, 14a, 17b), [9] (3c), [6] (12b).
“Aspergillus fumigatus” [32] (3a, 10b), [30] (16), [29] (11b), [18] (5a,
7, 12a, 18), [17] (11a), [16] (2b, 2c, 5c, 15), [15] (6a), [14] (5b, 6b, 6c),
[12] (1, 4a), [8] (3b, 8, 17b), [6] (2a, 3c, 4c, 14a, 17a), [5] (14b), [4]
(4b, 10a, 12b, 13).
“Rhizoctonia solani” [20] (3a), [18] (2c, 6a, 11b), [16] (5a, 5b, 10b,
12a), [15] (16), [14] (7), [13] (2b, 6b), [12] (18, 5c, 6c), [10] (1), [8]
(3b,17a), [6] (3c, 4a), [5] (2a, 4b, 4c, 14a), [4] (11a, 13, 15, 17b), [3]
(14b), [2] (10a, 12b), [0] (8).
“Fusarium oxysporum” [19] (2c, 10b), [18] (6b, 7, 16, 18), [17] (2b,
3a, 5b, 11b), [16] (5a, 6a), [14] (12a), [12] (1, 5c), [11] (6c), [8] (3b,
17a), [4] (2a, 4b, 4c, 8, 11a, 12b, 15), [2] (17b), [0] (3c, 4a, 10a, 13,
14a, 14b).
Analysis and evaluation of the antimicrobial spectra of the synthe-
sized systems revealed that compounds 5a, 3a, 5c, 16, and 11b demon-
strated the broadest spectrum inhibitory activity against most of the
test microorganisms. Compound 5a exhibited the highest inhibitory
activity against Escherichia coli and compound 11b was highly active
against Xanthomonas citri, while compounds 3a and10b demonstrated
the highest inhibitory activity against Aspergillus fumigatus.
On the other hand, compound 8, while slightly active against most
of the tested bacterial strains, did not exhibit any activity against Rhi-
zoctonia solani. Also, compounds 3c, 4a, 10a, 13, 14a, and 14b ware
inactive against Fusarium oxysporum. It was also observed that while
compound 4a was totally inactive against F. oxysporum, it exhibited a
high anti–E. coli effect.
EXPERIMENTAL
All melting points were determined on an electrothermal digital melt-
ing point apparatus and are uncorrected. IR spectra were recorded (KBr

250
H. Z. Shams et al.
disks) on FTIR plus 460 or Pay Unicam SP-1000 spectrophotometers.
1H and 13C NMR spectra were recorded with Varian Gemini-200 (200
MHz) and Varian EM-300 (300 MHz) instruments with TMS as an in-
ternal standard (chemical shifts in δ ppm). Mass spectra were recorded
with a Hewlett Packard 5988 A GC/MS system and GCMS-QP 1000 Ex
Shimaduz instruments. Analytical data, obtained from the Microana-
lytical Data Centre at Cairo University, were performed on a Vario EL
III Elemental CHNS analyzer.
Synthesis of Cyanoacetic
2-[(Benzoylamino)thioxomethyl]hydrazide (1)
A suspension of equimolar amounts of ammonium thiocyanate (0.76 g,
0.01 mol) and benzoyl chloride (1.16 g, 0.01 mol) in dioxane (20 mL) was
heated under reflux for 20 min and then left to cool. A cold solution of
cyanoacetic hydrazide (0.99 g, 0.01 mol) in dioxane (15 mL) was then
added while shaking, and the reaction mixture was left at r. t. for 10 min.
The solid product formed upon pouring onto an ice-water mixture was
collected by filtration and recrystallized from ethanol.
(1) C11H10N4O2S, m.wt. 262, white crystals, 80% yield, m.p. 189–
190◦C. Elemental analysis (% calcd./found): 50.38/50.31 (C), 3.82/3.67
(H), 21.37/21.35 (N), 12.21/12.32 (S). IR (ν, cm–1): 3270–3215 (3NH);
3051 (CH aromatic); 2970–2925 (CH2); 2650 (SH); 2260 (CN); 1682,
1
1599 (2C O); 1532, 1491 (C C); 1333 (C S). H NMR (δ, ppm): 3.89
(s, 2H, CH2), 7.50–7.99 (m, 5H, C6H5), 11.25 (s, 1H, NH), 11.79 (s, 1H,
NH), 12.54 (s, 1H, NH). MS m/z (%): 262 [M+] (7.9) , 105 [phenyl C O]+
(100), 77 [phenyl]+ (46.5).
Reaction of Cyanoacetic Hydrazide 1 with α-Haloketones
General Procedure for the Synthesis of 3-Benzoyl-1-
(2-cyanoacetamido)-4-substituted-1,3-dihydro-2H-imidazole-
2-thiones (2a–c)
To a solution of 1 (2.62 g, 0.01 mol) in ethanol (25 mL), ethyl chloroac-
etate (1.225 g, 0.01 mol), chloroacetone (0.925 g, 0.01 mol), or phenacyl
bromide (1.99 g, 0.01 mol) was added. The reaction mixture was heated
under reflux for 5 h. The solid products formed upon pouring onto an
ice-water mixture containing few drops of diluted solution of NaOH
were collected by filtration and recrystallized from dioxane.
3-Benzoyl-1-(2-cyanoacetamido)-4-hydroxy-1,3-dihydro-2H-
imidazole-2-thione(2a). C13H10N4O3S, m.wt. 302, white crystals, 75%
yield, m.p. 244◦C. Elemental analysis (% calcd./found): 51.65/51.90 (C),

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 251
3.31/3.50 (H), 18.54/18.91 (N), 10.60/10.93 (S). IR (ν, cm–1): 3300–3155
(OH, NH); 3067–3011 (CH aromatic); 2940–2915 (CH2); 2250 (CN);
1
1743, 1650 (2C O); 1598, 1488(C C); 1300, 1256 (C S). H NMR (δ,
ppm): 4.62 (s, 2H, CH2), 7.54–8.15 (m, 6H, C6H5, imidazole C5 H),
13.14–13.15 (s, 2H, NH, OH).
3-Benzoyl-1-(2-cyanoacetamido)-4-methyl-1,3-dihydro-2H-imidazole-
2-thi-one (2b). C14H12N4O2S, m.wt. 300, white crystals, 88% yield,
m.p. 243◦C. Elemental analysis (% calcd./found): 56.00/55.86 (C),
4.00/3.74 (H). IR (ν, cm–1): 3200–3155 (NH); 3067–3011 (CH aromatic);
2940–2914 (CH2, CH3); 2250 (CN); 1743, 1650 (2 C O); 1598, 1488
(C C); 1300, 1256 (C S). 1H NMR (δ, ppm): 3.36 (s, 3H, CH3), 4.62–4.63
(s, 2H, CH2), 7.54–8.16 (m, 6H, C6H5, imidazole C5 H), 13.17 (s, 1H,
NH).
3-Benzoyl-1-(2-cyanoacetamido)-4-phenyl-1,3-dihydro-2H-imidazole-
2-thi-one (2c). C19H14N4O2S, m.wt. 362, pale brownish-yellow crys-
tals, 70% yield, m.p. 225◦C. Elemental analysis (% calcd./found):
62.98/62.63 (C), 3.87/3.80 (H),15.47/15.75 (N), 8.84/9.05 (S). IR (ν,
cm–1): 3200–3156 (NH); 3067–3011 (CH aromatic); 2940–2915 (CH2);
2250 (CN); 1742, 1651 (2C O); 1598, 1488 (C C); 1300, 1256 (C S).
1H NMR (δ, ppm): 4.61 (s, 2H, CH2), 6.24 (s, 1H, imidazole C5 H),
7.55–8.16 (m, 10H, 2C6H5), 13.20 (s, 1H, NH).
Reaction of Imidazole Thione Derivatives
2a–c with Malononitrile
General Procedure for the Synthesis of 3-Benzoyl-1-(3-cyano-
4,6-diamino-2H-2-pyranylideneamino)-4-substituted-1,3-
dihydro-2H-imidazole-2-thiones (3a–c)
Equimolar amounts of 2a (3.02 g, 0.01 mol), 2b (3.00 g, 0.01 mol),
or 2c (3.62 g, 0.01mol) and malononitrile (0.66 g, 0.01 mol) in dioxane
containing a catalytic amount of triethylamine were heated under re-
flux for 4 h. The solid products formed upon pouring onto an acidified
ice-water mixture were collected by filtration and recrystallized from
dioxane.
3-Benzoyl-1-(3-cyano-4,6-diamino-2H-pyranylideneamino)-4-hydroxy-
1,3-dihydro-2H-imidazole-2-thione (3a). C16H12N6O3S, m.wt. 368,
brown crystals, 82% yield, m.p. 220◦C. Elemental analysis (%
calcd./found): 52.17/52.38 (C), 3.26/3.31 (H), 22.83/22.80 (N), 8.69/8.98
(S). IR (ν, cm–1): 3428 (OH); 3300–3160 (2NH2); 3067–3014 (CH
aromatic); 2941–2918 (CH2); 2209 (CN); 1652 (C O); 1599, 1490
(C C); 1301, 1258 (C S).1H NMR (δ, ppm): 3.58, 4.62 (2s, 2H each,

252
H. Z. Shams et al.
2NH2), 7.54–8.16 (m, 7H, C6H5, imidazole C5 H, pyran C5 H), 13.17 (s,
1H, resonating OH).
3-Benzoyl-1-(3-cyano-4,6-diamino-2H-pyranylideneamino)-4-methyl-
1,3-dihydro-2H-imidazole-2-thione (3b). C17H14N6O2S, m.wt. 366,
dark brown crystals, 82% yield, m.p. 235◦C. Elemental analysis (%
calcd./found): 55.74/55.67 (C), 3.82/3.69 (H), 22.95/22.71 (N), 8.74/9.00
(S). IR (ν, cm–1): 3200–3158 (2 NH2); 3011 (CH aromatic); 2939–2853
(CH, CH3); 2210 (CN); 1652 (C O); 1599, 1489 (C C); 1301, 1256
1
(C S). H NMR (δ, ppm): 2.52 (s, 3H, CH3), 3.58, 4.63 (2s, 2H each,
2NH2), 7.54–8.16 (m, 7H, C6H5, imidazole C4H, pyran C5 H).
3-Benzoyl-1-(3-cyano-4,6-diamino-2H-pyranylideneamino)-4-phenyl-
1,3-dihydro-2H-imidazole-2-thione (3c). C22H16N6O2S, m.wt. 428,
brown crystals, 88% yield, m.p. 110◦C. Elemental analysis (%
calcd./found): 61.68/61.59 (C), 3.74/3.90 (H), 19.63/19.40 (N), 7.48/7.19
(S). IR (ν, cm–1): 3322–3217 (2NH2); 3060 (CH aromatic); 2921–2853
(CH aliphatic); 2198 (CN); 1722 (C O); 1604, 1475 (C C); 1315, 1283
(C S). 1H NMR (δ, ppm): 3.31, 3.56 (2s, 2H each, 2NH2), 7.53–8.13 (m,
12H, 2C6H5, imidazole C4 H, pyran C5 H).
Reaction of Imidazole Thione Derivatives 2a–c with
Aromatic Aldehydes
General Procedure for the Synthesis of 3-Benzoyl-1-(2-
cyano-3-phenylacrylamido)-4-substituted-1,3-dihydro-2H-
imidazole-2-thiones (4a–c) and 3-benzoyl-1-
(coumarincarbonylamino)-4-substituted-1,3-dihydro-2H-
imidazole-2-thiones (5a–c)
To a solution of 2a (3.02 g, 0.01 mol), 2b (3.00 g, 0.01 mol), or 2c
(3.62 g, 0.01 mol) in dioxane (20 mL) containing a catalytic amount of
pipyridine, each of benzaldehyde (1.06 g, 0.01 mol) or salicylaldehyde
(1.22 g, 0.01 mol) was added. The reaction mixture was heated under
reflux for 5 h. The solid products obtained upon pouring onto an acidified
ice-water mixture were recrystallized from dioxane.
3-Benzoyl-1-(2-cyano-3-phenylacrylamido)-4-hydroxy-1,3-dihydro-
2H-imidazole-2-thione (4a). C20H14N4O3S, m.wt. 390, yellow crystals,
90% yield, m.p. 217◦C. Elemental analysis (% calcd./found): 61.54/61.60
(C), 3.59/3.82 (H), 14.36/14.10 (N), 8.20/8.55 (S). IR (ν, cm–1): 3420–
3157 (resonating OH, NH); 3062–3021 (CH aromatic); 2922–2853 (CH
aliphatic); 2223 (CN); 1669, 1600 (2C O); 1525, 1496 (C C); 1302,
1
1252 (C S). H NMR (δ, ppm): 4.62 (s, 1H, CH), 7.54–8.18 (m, 6H,
C6H5, imidazole C5 H), 8.28 (s, 1H, NH) 13.24 (s, 1H, resonating OH).

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 253
3-Benzoyl-1-(2-cyano-3-phenylacrylamido)-4-methyl-1,3-dihydro-2H
-imidzole-2-thione (4b). C21H16N4O2S, m.wt. 388, yellow crystals, 92%
yield, m.p. 225◦C. Elemental analysis (% calcd./found): 64.95/64.71 (C),
4.12/4.40 (H), 14.43/14.55 (N), 8.25/8.49 (S). IR (ν, cm–1): 3401–3158
(NH); 3062–3014 (CH aromatic); 2926–2855 (CH, CH3); 2224 (CN);
1
1669, 1599 (2C O); 1525, 1496 (C C), 1302, 1253 (C S). H NMR (δ,
ppm): 2.52 (s, 3H, CH3), 4.63 (s, 1H, CH), 7.55–8.19 (m, 11H, 2C6H5,
imidazole C5 H), 8.29 (s, 1H, NH).
3-Benzoyl-1-(2-cyano-3-phenylacrylamido)-4-phenyl-1,3-dihydro-2H-
imidazole-2-thione (4c). C26H18N4O2S, m.wt. 450, greenish brown
crystals, 93% yield, m.p. 220◦C. Elemental analysis for
C26H18N4O2S.H2O (% calcd./found): 66.67/66.92 (C), 4.27/4.52 (H),
11.96/11.62 (N), 6.84/6.94 (S). IR (ν, cm–1): 3394 (NH); 3137–3013 (CH
aromatic); 2926–2855 (CH aliphatic); 2225 (CN); 1664, 1598 (2C O);
1
1527, 1450 (C C); 1305, 1254 (C S). H NMR (δ, ppm): 6.21 (s, 1H,
CH), 7.57–8.17 (m, 16H, 3C6H5, imidazole C5 H), 8.25 (s, 1H, NH).
3-Benzoyl-1-(3-coumarincarbonylamino)-4-hydroxy-1,3-dihydro-2H-
imidazole-2-thione (5a). C20H13N3O5S, m.wt. 407, bright yellow crys-
tals, 98% yield, m.p. 275◦C. Elemental analysis (% calcd./found):
58.97/58.69 (C), 3.19/3.43 (H), 10.32/10.55 (N), 7.86/7.98 (S).
IR(ν, cm–1): 3447–3274 (OH, NH); 3158–3065 (CH aromatic);
2977–2849 (CH, CH2); 1721, 1661, 1601 (3C O); 1568, 1491 (C C),
1298, 1264 (C S ).1H NMR (δ, ppm): 7.23–8.64 (m, 11H, C6H5, C6H4,
imidazole C5 H, coumarin, C4 H), 9.08 (s, 1H, NH), 12.91 (s, 1H,
resonating OH).
3-Benzoyl-1-(2H-3-coumarincarbonylamino)-4-methyl-1,3-dihydro-
2H-imidazole-2-thione (5b). C21H15N3O4S, m.wt. 405, bright yellow
crystals, 98% yield, m.p. 273◦C. Elemental analysis (% calcd./found):
62.22/62.38 (C), 3.70/3.84 (H), 10.37/10.69 (N), 7.90/7.69 (S). IR (ν,
cm–1): 3448–3157 (NH); 3060 (CH aromatic); 3001–2850 (CH, CH3);
1
1722, 1661, 1601 (3 C O); 1569, 1490 (C C), 1299, 1265 (C S). H
NMR (δ, ppm): 3.58 (s, 3H, CH3), 7.24–8.66 (m, 11H, C6H5, C6H4,
imidazole C5 H, coumarin, C4 H), 9.11 (s, 1H, NH).
3-Benzoyl-1-(2H-3-coumarincarbonylamino)-4-phenyl-1,3-dihydro-
2H-imidazole-2-thione (5c). C26H17N3O4S, m.wt. 467, pale brown
crystals, 90% yield, m.p. 200◦C. Elemental analysis (% calcd./found):
66.81/66.68 (C), 3.64/3.95 (H), 8.99/9.24 (N), 6.85/6.95 (S). IR (ν, cm–1):
3397–3152 (NH); 3058 (CH aromatic); 2929–2853 (CH aliphatic); 1720,
1669, 1602 (3C O); 1532, 1492 (C C), 1306, 1250 (C S). 1H NMR

254
H. Z. Shams et al.
(δ, ppm): 6.76 (s, 1H, imidazole C5 H), 7.24–8.12 (m, 15H, 2C6H5, C6H4,
coumarin C4H), 9.07 (s, 1H, NH).
Reaction of Imidazole Thione Derivatives 2a–c
with Diazotized Aniline
General Procedure for the Synthesis of 3-benzoyl-1-[2-cyano-2-
(phenylhydrazono) acetamido]-4-substituted-1,3-dihydro-2H-
imidazole-2-thiones (6a–c)
To a cold solution (0–5◦C) of 2a (3.02 g, 0.01 mol), 2b (3.00 g, 0.01 mol),
or 2c (3.62 g, 0.01 mol) in ethanol (20 mL) containing sodium hydroxide
(1.00 g) an equimolar amount of diazotized aniline was gradually added
while stirring. The solid product formed upon cooling in an ice bath
was collected by filtration, washed with water, and recrystallized from
dioxane.
3-Benzoyl-1-[2-cyano-2-(phenylhydrazono)acetamido]-4-hydroxy-
1,3-dihydro-2H-imidazole-2-thione (6a). C19H14N6O3S, m.wt. 406,
yellowish-green crystals, 81% yield, m.p. 225◦C. Elemental analysis (%
calcd./found): 56.16/56.32 (C), 3.45/3.77 (H), 20.69/20.35 (N), 7.88/7.95
(S). IR (ν, cm–1): 3397 (OH); 3210–3151 (2NH); 3060–3009 (CH aro-
matic); 2934 (CH aliphatic); 2212 (CN); 1672, 1601 (2C O); 1530, 1490
(C C); 1302, 1258 (C S). 1H NMR (δ, ppm): 7.42–7.65 (m, 11H, 2C6H5,
imidazole C5H), 8.12–8.16 (2s, 2H, 2NH), 13.50 (s, 1H, resonating OH).
3-Benzoyl-1-[2-cyano-2-(phenylhydrazono)acetamido]-4-methyl-
1,3-di-hydro-2H-imidazole-2-thione (6b). C20H16N6O2S, m.wt. 404,
greenish-yellow crystals, 76% yield, m.p. 155◦C. Elemental analysis (%
calcd./found): 59.40/59.09 (C), 3.96/3.59 (H), 20.79/20.51 (N), 7.92/7.99
(S). IR (ν, cm–1): 3423–3156 (2NH); 3060 (CH aromatic); 2982–2930
(CH, CH3); 2215 (CN); 1670, 1628 (2C O); 1601, 1492 (C C); 1303,
1261 (C S).1H NMR (δ, ppm): 2.58 (s, 3H, CH3), 7.09–7.66 (m, 11H,
2C6H5, imidazole C5H), 8.12, 8.18 (2s, 2H, 2NH).
3-Benzoyl-1-[2-cyano-2-(phenylhydrazono)acetamido]-4-phenyl-
1,3-di-hydro-2H-imidazole-2-thione (6c). C25H18N6O2S, m.wt. 466,
creamy crystals, 76% yield, m.p. 134◦C. Elemental analysis (%
calcd./found): 64.38/64.12 (C), 3.86/3.87 (H), 18.02/18.10 (N), 6.87/7.12
(S). IR (ν, cm–1): 3419–3162 (2NH); 3060 (CH aromatic); 2930 (CH
aliphatic); 2215 (CN); 1673, 1601 (2 C O); 1531, 1492 (C C); 1304,
1261 (C S). 1H NMR (δ, ppm): 6.58 (s, 1H, imidazole C5 H), 7.14–7.58
(m, 15H, 3C6H5), 8.13, 8.16 (2s, 2H, 2NH).

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 255
Reaction of Cyanoacetic Hydrazide Derivative 1 with Aromatic
Carbonyl Reagents
Reaction of 1 with Benzaldehyde
Equimolar amounts of 1 (2.62 g, 0.01 mol), and benzaldehyde (1.06 g,
0.01 mol) were refluxed for 5 h in dimethylformamide containing a slight
excess of piperidine (2 mL). After cooling, the solution was acidified by
hydrochloric acid. The crude product was precipitated, filtered, washed
with water, and recrystallized from dimethylformamide.
1-Benzoyl-4-benzylidine-5-iminopyrazolidin-3-one(7). C17H13N3O2,
m.wt. 291, pale creamy crystals, 75% yield, m.p. 225◦C. Elemen-
tal analysis for C17H13N3O2.H2O (% calcd./found): 66.02/65.96 (C),
4.85/4.66 (H), 13.59/13.95 (N), IR (ν, cm–1): 3375–3245 (2NH); 3061
(CH aromatic); 3030–2928 (CH aliphatic); 1659, 1620 (2C O); 1601,
1
1495 (C C). H NMR (δ, ppm): 6.70 (s, 1H, CH), 7.11–7.96 (m, 10H,
2C6H5), 8.46–8.48 (s, 1H, NH), 10.03 (s, 1H, NH). MS m/z (%): 291
[M+] (17.1), 187 [(M++ 1)-105] (12.6), 105 [phenyl C O]+ (100), 77
[phenyl]+ (63.5).
Reaction of 1 with Salicylaldehyde
Equimolar amounts of 1 (2.62 g, 0.01 mol) and salicylaldehyde (1.22 g,
0.01 mol) were heated under reflux in ethanol and a catalytic amount of
piperidine for 1 h. The precipitate obtained by cooling was recrystallized
from ethanol.
N-[2-(3-Coumarincarbonyl) Hydrazinothioxomethyl]
Benzamide (8)
C18H13N3O4S, m.wt. 367, yellow crystals, 72% yield, m.p. 275◦C.
Elemental analysis (% calcd./found): 58.85/59.01 (C), 3.54/3.57 (H),
11.44/11.69 (N), 8.72/9.01 (S). IR (ν, cm–1): 3307–3161 (3NH); 3100–
3059 (CH aromatic); 3002–2922 (CH); 1719, 1660, 1603 (3C O); 1567,
1
1490 (C C); 1298 (C S). H NMR (δ, ppm): 7.19–8.15 (m, 10H, C6H5,
C6H4, coumarin C4 H), 8.57 (s, 1H, NH), 9.02, 9.07 (2s, 2H, 2NH).
Reaction of 1 with Acetophenone
To a mixture of equimolar amounts of 1 (2.62 g, 0.01 mol) and acetophe-
none (1.20 g, 0.01 mol), 0.5 g of ammonium acetate was added, and
the reaction mixture was heated to fusion for 45 min. The mixture was
then boiled in ethanol for a few minutes and poured onto an ice-water
mixture, and the product was recrystallized from ethanol.

256
H. Z. Shams et al.
1-Benzoyl-5-imino-4-(1-phenylethylidene)-
pyrazolidin-3-one (9)
C18H15N3O2, m.wt. 305, brown crystals, 60% yield, m.p. 120◦C. El-
emental analysis for C18H15N3O2.H2O (% calcd./found): 66.87/66.67
(C), 5.26/4.99 (H), 13.00/12.98 (N), IR (ν, cm–1): 3397–3189 (2NH);
3100–3062 (CH aromatic); 2924–2854 (CH3); 1654, 1603 (2C O); 1570,
1494 (C C). 1H NMR (δ, ppm): 2.29 (s, 3H, CH3), 7.24–8.12 (m,
10H, 2C6H5), 8.13 (s, 1H, NH), 10.12 (s, 1H, NH). MS m/z (%): 308
[M++3] (33.3), 305 [M+] (17.5), 304 [M+-1] (24.6), 303 [M+-2] (57.0),
288 [(M+-1)-16] (56.1), 204 [(M++4)-105] (27.2), 128 [Ph C(CH3)=C C]
(29.8), 105 [phenyl C O]+ (71.9), 77 [phenyl]+ (57.0), 51 [HN C C C]
(100).
Reaction of Pyrazolidine Derivative 7 with Methylene
Carbonitrile Reagents
General Procedure for the Synthesis of 6-Amino-2-benzoyl-5-
substituted-3-imino-4-phenyl-1,2-dihydro-3H-,4H-pyrano
[2,3-c] Pyrazoles (10a, 10b)
To a solution of 7 (3.09 g, 0.01 mol) in ethanol (25 mL) and
dimethylformamide (5 mL) containing a catalytic amount of triethy-
lamine, malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13
g, 0.01 mol) was added. The reaction mixture was heated under re-
flux for 5 h, cooled, and then neutralized by pouring it onto an
acidified ice-water mixture. The solid product formed in each case
was filtered off and recrystallized from an ethanol/dimethylformamide
mixture.
6-Amino-2-benzoyl-5-cyano-3-imino-4-phenyl-1,2-dihydro-3H-,4H-
pyrano [2, 3-c] pyrazole (10a). C20H15N5O2, m.wt. 357, pale grey crys-
tals, 70% yield, m.p. 196◦C. Elemental analysis for C20H15N5O2.H2O
(% calcd./found): 64.00/63.88 (C), 4.53/4.57 (H), 18.67/18.58 (N). IR
(ν, cm–1): 3310–3207 (2NH, NH2); 3061 (CH aromatic); 2922–2852
1
(CH); 2184 (CN); 1670 (C O); 1598, 1493 (C C). H NMR (δ, ppm):
3.35 (s, 2H, NH2), 5.17 (s, 1H, pyran C4 H), 7.09–7.88 (m, 10H,
2C6H5), 7.98 (s, 1H, NH), 10.50 (s, 1H, NH). MS m/z (%): 357 [M+]
(4.5), 291 [M+-66] (8.5), 251 [(M+-1)-105] (11.0), 203 [M+-154] (8.0),
154 [Ph CH C(CN)2]+· (7.5), 105 [phenyl C O]+ (100), 77 [phenyl]+
(57.0).
6-Amino-2-benzoyl-5-ethoxycarbonyl-3-imino-4-phenyl-1,2-dihydro-
3H-,4H-pyrano[2, 3-c] pyrazole (10b). C22H20N4O4, m.wt. 404, pale
creamy crystals, 65% yield, m.p. 200◦C. Elemental analysis for

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 257
C22H20N4O4.H2O (% calcd./found): 62.56/62.90 (C), 5.21/4.89 (H),
13.27/13.10 (N). IR (ν, cm–1): 3218 (2NH, NH2); 3061 (CH aromatic);
2924–2851 (CH2, CH3); 1720, 1661 (2C O); 1598, 1473 (C C). 1H
NMR(δ, ppm): 1.15–1.32 (t, 3H, CH3), 4.04 (s, 2H, NH2), 4.32–4.36 (q,
2H, CH2), 5.14 (s, 1H, pyran C4 H), 7.19–7.87 (m, 10H, 2C6H5), 8.41 (s,
1H, NH), 10.42 (s, 1H, NH).
Reaction of Pyrazolidine Derivative 7 with α-Haloketones
General Procedure for the Synthesis of 1-Benzoyl-4-
benzylidene-2-substituted-5-imino-3-pyrazolidinones
(11a,11b)
To a solution of 7 (3.09 g, 0.01 mol) in ethanol (30 mL) and dimethyl-
formamide (10 mL), phenacyl bromide (1.99 g, 0.01 mol) or ethyl
chloroacetone (1.225 g, 0.01 mol) was added. The reaction mixture was
heated under reflux for 5 h. The solid products formed upon pouring onto
an ice-water mixture containing potassium carbonate were collected
by filtration and recrystallized from an ethanol/dimethylformamide
mixture.
1-Benzoyl-2-(benzoylmethyl)-4-benzylidene-5-imino-3-pyrazolidi-
none (11a). C25H19N3O3, m.wt. 409, reddish brown crystals, 63%
yield, m.p. 240◦C. Elemental analysis for C25H19N3O3.H2O (%
calcd./found): 70.26/69.92 (C), 4.92/4.65 (H), 9.84/9.53 (N). IR (ν,
cm–1): 3285 (NH); 3060 (CH aromatic); 2923–2853 (CH aliphatic);
1720, 1660, 1620 (3C O), 1598, 1495 (C C). MS m/z (%): 411 [M++2]
(1.52), 410 [M++1] (1.59), 409 [M+] (2.42), 304 [M+-105] (2.41),
293 [(M++3)-119] (12.15), 188 [293-(phenyl C+ =O)] (1.60), 119
[phenyl C( O)CH2]+ (6.4), 105 [phenyl C O]+ (100), 77 [phenyl]+
(66.98).
1-Benzoyl-4-benzylidene-2-(ethoxycarbonylmethyl)-5-imino-3-pyra-
zolidinone (11b). C21H19N3O4, m.wt. 377, pale brown crystals, 60%
yield, m.p. >300◦C. Elemental analysis for C21H19N3O4.H2O (%
calcd./found): 63.80/63.49 (C), 5.32/5.34 (H), 10.63/10.34 (N). IR (ν,
cm–1): 3295 (NH); 3060 (CH aromatic); 2923–2853 (CH2, CH3), 1745,
1658, 1622 (3C O), 1562, 1496 (C C). 1H NMR (δ, ppm): 1.16–1.25 ( t,
3H, CH3), 4.17–4.66 (q, 2H, CH2), 5.22 (s, 2H, CH2), 5.84 (s, 1H, CH),
7.25–7.51 (m, 10H, 2C6H5), 7.97 (s, 1H, NH).

258
H. Z. Shams et al.
Reaction of Coumarin Derivative 8 with Methylenecarbonitrile
Reagents
General Procedure for the Synthesis of N-[5-Amino-4-
substituted-3-(3-coumarinyl)pyrazole-1-
thioxomethyl]benzamides (12a, 12b)
To a solution of 8 (3.67 g, 0.01 mol) in ethanol (20 mL) and dimethyl-
formamide (10 mL) containing a catalytic amount of triethylamine,
malononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol)
was added. The reaction mixture was heated under reflux for 5 h.
The solid products formed upon pouring an onto an acidified ice-
water mixture were collected by filtration and recrystallized from an
ethanol/dimethylformamide mixture.
N-[5-Amino-4-cyano-3-(3-coumarinyl)pyrazole-1-thioxomethyl]-
benzamide (12a). C21H13N5O3S, m.wt. 415, greenish brown crystals,
80% yield, m.p. 185◦C. Elemental analysis (% calcd./found): 60.72/59.57
(C), 3.13/2.91 (H), 16.87/16.83 (N), 7.71/7.40 (S). IR (ν, cm–1): 3341–
3207 (NH, NH2); 3050 (CH aromatic); 2925–2854 (CH); 2201 (CN);
1
1721, 1680 (2C O); 1607, 1488 (C C); 1285 (C S). H NMR (δ, ppm):
3.58 (s, 2H, NH2), 7.02–8.20 (m, 10H, C6H5, C6H4, coumarin C4 H),
8.96 (s, 1H, NH).
N-[5-Amino-3-(3-coumarinyl)-4-ethoxycarbonylpyrazole-1-thioxo-
methyl] benzamide (12b). C23H18N4O5S, m.wt. 462, pale brown
crystals, 72% yield, m.p. 180◦C. Elemental analysis (% calcd./found):
59.74/59.89 (C), 3.90/4.01 (H), 12.12/11.88 (N), 6.93/6.63 (S). IR (ν,
cm–1): 3185 (NH, NH2); 3064 (CH aromatic); 2922–2851 (CH, CH2,
CH3); 1750, 1719, 1665 (3C O); 1608, 1496 (C C); 1289 (C S). 1H
NMR (δ, ppm): 1.18–1.22 (t, 3H, CH3), 3.57 (s, 2H, NH2), 4.03–4.19
(q, 2H, CH2), 7.01–8.20 (m, 10H, C6H5, C6H4, coumarin C4 H), 9.18
(s, 1H, NH). MS m/z (%): 462 [M+] ( 2.0), 350 [(M++1)-113] (2.5),
305 [462-(coumarin C+)] (18.0), 289 [M+-173] (13.0), 204 [C+ =N–
–
N
C (S)–NHCOPh]+(17.0), 173 [coumarin CH NH]+·(36.5), 146
[cou-marin]+·(18.0), 113 [N C CH2 CO2Et]+·, 105 [phenyl C O]+
(100), 77 [phenyl]+ (68.0), 58 [N C S]+ (25.2).
Reaction of Coumarin Derivative 8 with Phenacyl Bromide
Equimolar amounts of 8 (3.67 g, 0.01 mol) and phenacyl bromide (1.99 g,
0.01 mol) in ethanol (20 mL) and dimethylformamide (10 mL) were
heated under reflux for 5 h. The solid product formed upon pouring
onto-an ice-water mixture containing a few drops of diluted solution of

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 259
sodium hydroxide was collected by filtration and recrystallized from an
ethanol/dimethylformamide mixture.
3-(4-Benzoyl-5-phenyl-3-thioxo-3H-1,2,4-triazine-1-(carbonyl)-
coumarin (13)
C26H17N3O4S, m.wt. 467, yellowish brown crystals, 70% yield, m.p.
120◦C. Elemental analysis (% calcd./found): 66.81/66.45 (C), 3.64/4.00
(H), 8.99/9.28 (N), 6.85/6.56 (S). IR (ν, cm–1): 3256 (NH); 3061 (CH aro-
matic); 2924–2854 (CH); 1719, 1650, 1608 (3C O); 1567, 1471 (C C);
1285, 1254 (C S). 1H NMR (δ, ppm): 7.17–8.18 (m, 15H, 2C6H5, C6H4,
triazine C6 H, coumarin C4 H), 8.91 (s, 1H, NH).
Reaction of Cyanoacetic Hydrazide Derivative 1 with
Elemental Sulfur and Methylene Carbonitrile Reagents
General Procedure for Synthesis of Benzoic 2-(3,5-Diamino-4-
substituted-2-thiophenecarbonyl) Hydrazides (14a, 14b)
To a solution of 1 (2.62 g, 0.01 mol) in ethanol (25 mL) containing a
catalytic amount of triethylamine, malononitrile (0.66 g, 0.01 mol) or
ethyl cyanoacetate (1.13 g, 0.01 mol) was added followed by the addition
of an equimolar amount of elemental sulfur. The reaction mixture was
heated under reflux for 3 h and then cooled and neutralized by pouring
it onto an acidified ice-water mixture. The solid product formed in each
case was filtered off and recrystallized from dimethylformamide.
Benzoic 2-(3,5-diamino-4-cyano-2-thiophenecarbonyl) hydrazide
(14a). C13H11N5O2S, m.wt. 301, brown crystals, 60% yield, m.p. 210◦C.
Elemental analysis (% calcd./found): 51.83/51.68 (C), 3.65/3.88 (H),
23.25/22.97 (N), 10.63/10.96 (S). IR (ν, cm–1): 3317–3206 (2NH, 2NH2);
3060 (CH aromatic); 2211 (CN); 1650, 1576 (2C O); 1530, 1460 (C C).
1H NMR (δ, ppm): 3.58 (broad s, 4H, 2NH2), 7.43–7.97 (m, 5H, C6H5),
10.40, 10.58 (2s, 2H, 2NH).
Benzoic 2-(3,5-diamino-4-ethoxycarbonyl-2-thiophenecarbonyl)
hydrazide (14b). C15H16N4O4S, m.wt. 348, pale yellow crystals, 60%
yield, m.p. >300◦C. Elemental analysis (% calcd./found): 51.72/51.90
(C), 4.60/4.43 (H), 16.09/16.33 (N), 9.19/8.88 (S). IR (ν, cm–1): 3315–3106
(2NH, 2NH2); 3066–3031 (CH aromatic); 3001–2823 (CH2, CH3); 1750,
1664, 1577 (3C O); 1537, 1451 (C C). 1H NMR (δ, ppm): 1.14–1.32 (t,
3H, CH3), 3.32 (broad s, 4H, 2NH2), 4.15 (q, 2H, CH2), 7.42–7.98 (m,
5H, C6 H5), 10.26, 10.53 (2s, 2H, 2NH). MS m/z (%): 348 [M+] (0.4), 203
–
[M+-145] (16.0), 173 [NH2 C(S+) =C(CO2Et) C –NH2]+ (12.0), 145
[NH2 C(S+)=C (CO2Et)] (4.0), 121 [phenyl C( O)–NH2]+· (23.0),
–

260
H. Z. Shams et al.
105 [phenyl C O]+ (100), 84 [N C CH2 C( O)–NH2]+· (8.0), 77
[phenyl]+ (63.5).
Reaction of Cyanoacetic Hydrazide Derivative 1 with
Elemental Sulfur and Phenyl Isothiocyanate
To equimolar amounts of 1 (2.62 g, 0.01 mol) and phenyl isothiocyanate
(13.51 g, 0.01 mol) in ethanol (20 mL) containing a catalytic amount
of triethylamine, an equimolar amount (0.32 g, 0.01 mol) of elemental
sulfur was added. The reaction mixture was heated under reflux for
4 h. The solid product formed upon pouring onto an acidified ice-water
mixture was collected by filtration and recrystallized from dioxane.
Benzoic 2-(4-Amino-3-phenyl-2-thioxo-2H-5-thiazolecarbonyl)
Hydrazide (15)
C17H14N4O2S2, m.wt. 370, brown crystals, 71% yield, m.p. 110◦C.
Elemental analysis (% calcd./found): 55.13/54.86 (C), 3.78/4.02 (H),
15.13/15.43 (N), 17.30/16.95 (S). IR (ν, cm–1): 3325–3214 (2NH, NH2);
3100–2981 (CH aromatic); 1650, 1595 (2C O); 1544, 1498 (C C); 1331,
1
1280 (C S). H NMR (δ, ppm): 4.50 (s, 2H, NH2), 7.00–7.99 (m, 10H,
2C6H5), 9.80 (s, 1H, NH), 11.06 (s, 1H, NH).
Cyclization Reaction of Cyanoacetic Hydrazide Derivative 1
with Acetic Acid
A solution of 1 (2.62 g, 0.01 mol) in glacial acetic acid (30 mL) was
heated under reflux for 5 h. The solid product formed upon pouring
onto an ice-water mixture was collected by filtration and recrystallized
from dimethylformamide.
4-Benzoyl-3-cyanomethyl-1,4-dihydro-5H-1,2,4-triazole-5-
thione (16)
C11H8N4OS, m.wt. 244, white crystals, 86% yield, m.p. 232◦C.
Elemental analysis (% calcd./found): 54.10/53.91 (C), 3.28/3.59 (H),
22.95/22.81 (N), 13.11/13.42 (S). IR (ν, cm–1): 3425–3158 (NH); 3067–
3012 (CH aromatic); 2941–2916 (CH2); 2252 (CN); 1651 (C O); 1599,
1
1489 (C C); 1302, 1257 (C S). H NMR (δ, ppm): 4.62 (s, 2H, CH2),
7.54–8.15 (m, 5H, C6H5), 13.20 (s, 1H, resonating N C–SH). MS m/z
(%): 244 [M+] (3.0), 216 [M+-N2] (3.7), 105 [phenyl C O]+ (100), 77
[phenyl]+ (59.2), 51 [CN CH C] (28.9).13C NMR (δ, ppm): 17.78 (CH2),
115.94 (C N), 127.87, 128.13, 128.53, 132.55 (phenyl carbons), 153.62
(triazole C5), 160.10 (C O), 164.81 (C S).

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 261
Reaction of Triazole Thione Derivative 16 with Elemental
Sulfur and Methylene Carbonitrile Reagents
General Procedure for the Synthesis of 4-Benzoyl-3-(2,4-
diamino-3-substituted-5-thenyl)-1,4-dihydro-5H-1,2,4-triazole-
5-thiones (17a, 17b)
To a solution of 16 (2.44 g, 0.01 mol) in ethanol (20 mL) and dimethyl-
formamide (10 mL) containing a catalytic amount of triethylamine, mal-
ononitrile (0.66 g, 0.01 mol) or ethyl cyanoacetate (1.13 g, 0.01 mol) was
added followed by the addition of an equimolar amount (0.32 g, 0.01 mol)
of elemental sulfur. The reaction mixture was heated under reflux for
5 h, cooled, and then neutralized by it pouring onto an acidified ice-
water mixture. The solid products formed in each case were filtered off
and recrystallized from dimethylformamide
4-Benzoyl-3-(2,4-diamino-3-cyano-5-thenyl)-1,4-dihydro-5H-1,2,4-
triazole-5-thione (17a). C14H10N6OS2, m.wt. 342, dark brown crys-
tals, 86% yield, m.p. >300◦C. Elemental analysis (% calcd./found):
49.12/49.25 (C), 2.92/3.11 (H), 24.56/24.20 (N), 18.71/18.41 (S), IR
(ν, cm–1): 3380–3300 (NH, 2NH2); 3157–3050 (CH aromatic); 2193
(CN), 1663 (C O); 1602, 1491 (C C); 1299, 1248 (C S). 1H NMR
(δ, ppm): 3.54–3.55 (2s, 4H, 2NH2), 7.59–7.96 (m, 5H, C6H5), 8.10
(s, 1H, NH). MS m/z (%): 342 [M+] (trace), 341 [M+-1] (0.47), 300
–
[M+-(H2N C N)] (1.96), 244 [M+-(NH2–C(S+) =C CN)] (79.15), 212
[244-S](3.43), 186 [244-(N C S)+] (100), 105 [phenyl C O]+ (26.52),
77 [phenyl]+ (21.63), 59 [HN C S]+· (3.31).
4-Benzoyl-3-(2,4-diamino-3-ethoxycarbonyl-5-thenyl)-1,4-dihydro-
5H-1,2,4-triazole 5-thione (17b). C16H15N5O3S2, m.wt. 389, dark brown
crystals, 65% yield, m.p. 185◦C. Elemental analysis (% calcd./found):
49.36 /49.70 (C), 3.86 /4.22 (H), 17.99/18.10 (N), 16.45/16.64 (S), IR (ν,
cm–1): 3420–3163 (NH, 2NH2); 3062 (CH aromatic); 2922–2850 (CH2,
CH3), 1725, 1672 (2C O); 1600, 1494 (C C); 1302, 1257 (C S). 1H
NMR (δ, ppm): 1.19–1.23 (t, 3H, CH3), 4.25–4.31 (q, 2H, CH2), 4.62 (s,
2H, NH2), 7.55–8.15 (m, 5H, C6H5), 13.00 (s, 1H, NH).
Reaction of Triazole Thione Derivative 16 with Elemental
Sulfur and Phenyl Isothiocyanate
To an equimolar amount of 16 (2.44 g, 0.01 mol) and phenyl isothio-
cyanate (1.35 g, 0.01 mol) in ethanol (20 mL) and dimethylformamide
(10 mL) containing a catalytic amount of triethylamine, elemental sul-
fur (0.32 g, 0.01 mol) was added. The reaction mixture was heated under
reflux for 5 h. The solid product formed upon pouring onto an acidified

262
H. Z. Shams et al.
ice-water mixture was collected by filtration and recrystallized from
dimethylformamide.
4-Benzoyl-3-(4-amino-3-phenyl-2H-2-thioxo-5-thiazolyl)-1,4-
dihydro-5H-1,2,4-triazole-5-thione (18)
C18H13N5OS3, m.wt. 411, deep green crystals, 72% yield, m.p.
200◦C. Elemental analysis (% calcd./found): 52.55/52.23 (C), 3.16/3.49
(H), 17.03/16.83 (N), 23.36/22.98 (S). IR (ν, cm–1): 3398–3163 (NH,
NH2); 3058 (CH aromatic); 1671 (C O); 1599, 1470 (C C); 1300,
1
1244 (C S). H NMR (δ, ppm): 3.51 (s, 2H, NH2), 7.16–8.15 (m, 10H,
2C6H5), 13.06 (s, 1H, NH). MS m/z (%): 412 [M++1] (1.91), 411 [M+]
(6.42), 332 [411- (phenyl)+] (1.51), 249 [412- (Ph C( O)–N C S)]+·
(7.26), 204 [C9H6N3OS]+· (2.49), 135 [phenyl–N C S]+· (46.05), 105
[phenyl C O]+ (100), 77 [phenyl]+ (24.99).
Microbiology: Biological Screening of the Synthesized
Compounds for Antimicrobial Activity
Thirty-two compounds were screened in vitro for their antimicro-
bial activity against two bacterial isolates (Saprophytic, E. coli, Par-
asitic, X. citri) and 3 fungal isolates (Saprophytic, A. fumigatus; Phy-
topathogenic, R. solani; F. oxysporum). The culture medium was the
nutrient agar for bacteria and Czapek’s Dox agar medium for fungi.
The sterile medium was inoculated with the test organism so that each
100 mL of the medium received 1 mL of a 24-hour culture of the bac-
terium or a 7-day-old culture of the spore suspension of the fungus. The
solutions of the tested compounds at 25 μg/mL in dimethylformamide
(DMF) were placed separately in the cup (8 mm diameter). The plates
were incubated at 28◦C, and the resulting inhibition zones were mea-
sured. DMF as a blank exhibited no antimicrobial activity against any
of the tested organisms used. The recorded inhibition zones are sum-
marized in Table I.
CONCLUSION
We have reported a convenient synthesis of a variety of fused and pen-
dant hetero-cyclic systems from cyanoacetic 2-[(benzoylamino) thiox-
omethyl]hydrazide. The S/N regioselective nucleophilic competition, as
well as the selectivity for terminal attack at the cyanoacetic moiety,
led to the diversity of the produced heterocyclic systems. Most of the
synthesized systems were found to be promising antibacterial agents
and hence deserve further pharmacological investigation. Currently,
we are investigating the potential antitumor activity of the synthesized

Synthesis Based on Cyanoacetic 2-[(Benzoylamino)Thioxomethyl] Hydrazide 263
systems and related derivatives. The results of these investigation will
be published in due time.
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