Synthesis and characterization of some new heterocycles incorporating the 1-Phenyl-5-(2-thienyl)pyrazole moiety

Article abstract of DOI:10.1080/10426500902758956

1-Phenyl-3-(2-thienyl)-1H-pyrazole-5-carbohydrazide 4 was prepared from 2-acetylthio- phene by reaction with diethyl oxalate and phenylhydrazine followed by hydrazine hydrate. The reaction of the hydrazide 4 with phthalic anhydride, aromatic aldehydes, and alkene derivatives gave imide 5, hydrazones 6a-d, and bis-pyrazoles 7 and 8, respectively, while its reaction with phenyl isothiocyanate led to thiosemicarbazide 9. The reaction of the latter with ethyl bromoacetate and phenacylbromide afforded 4-thiazolidinone 10 and 1,3-thiazole 11 derivatives, respectively. Reaction of 4 with carbon disulfide in the presence of potassium hydroxide gave potassium hydrazinecarbodithioate derivative 12, which was used as a starting material in the preparation of 2-thioxothiazol-3(2H)-yl)-5-(2-thienyl)-1H-pyrazole-3-carboxamide 14; 1,3,4-thiadiazol-2(3H)-ylidene)-1-phenyl-5-(2-thienyl)-1H-pyrazole-3- carbohydrazides 16a-c; 4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) pyrazole derivative 13; Schiff bases 17a,b; and 1,2,4-triazolo[3,4-b][1,3,4] thiadiazine derivatives 18 and 19a-e.

Full text of DOI:10.1080/10426500902758956

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Synthesis and Characterization of Some
New Heterocycles Incorporating the 1-
Phenyl-5-(2-thienyl)pyrazole Moiety
Bakr F. Abdel-Wahab a & Abdel-Aziz Sayed El-Ahl b
a Applied Organic Chemistry Department , National Research
Center , Dokki, Giza, Egypt
b Chemistry Department, Faculty for Teachers , Umm Al-Qura
University , Kingdom of Saudi Arabia
Published online: 03 Feb 2010.
To cite this article: Bakr F. Abdel-Wahab & Abdel-Aziz Sayed El-Ahl (2010) Synthesis and
Characterization of Some New Heterocycles Incorporating the 1-Phenyl-5-(2-thienyl)pyrazole Moiety,
Phosphorus, Sulfur, and Silicon and the Related Elements, 185:2, 249-260
To link to this article: http://dx.doi.org/10.1080/10426500902758956
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Phosphorus, Sulfur, and Silicon, 185:249–260, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902758956
SYNTHESIS AND CHARACTERIZATION OF SOME NEW
HETEROCYCLES INCORPORATING THE
1-PHENYL-5-(2-THIENYL)PYRAZOLE MOIETY
Bakr F. Abdel-Wahab1 and Abdel-Aziz Sayed El-Ahl2
1Applied Organic Chemistry Department, National Research Center, Dokki, Giza,
Egypt
2Chemistry Department, Faculty for Teachers, Umm Al-Qura University, Kingdom
of Saudi Arabia
1-Phenyl-3-(2-thienyl)-1H-pyrazole-5-carbohydrazide 4 was prepared from 2-acetylthio-
phene by reaction with diethyl oxalate and phenylhydrazine followed by hydrazine hydrate.
The reaction of the hydrazide 4 with phthalic anhydride, aromatic aldehydes, and alkene
derivatives gave imide 5, hydrazones 6a–d, and bis-pyrazoles 7 and 8, respectively, while its
reaction with phenyl isothiocyanate led to thiosemicarbazide 9. The reaction of the latter
with ethyl bromoacetate and phenacylbromide afforded 4-thiazolidinone 10 and 1,3-thiazole
11 derivatives, respectively. Reaction of 4 with carbon disulfide in the presence of potassium
hydroxide gave potassium hydrazinecarbodithioate derivative 12, which was used as a
starting material in the preparation of 2-thioxothiazol-3(2H)-yl)-5-(2-thienyl)-1H-pyrazole-
3-carboxamide 14; 1,3,4-thiadiazol-2(3H)-ylidene)-1-phenyl-5-(2-thienyl)-1H-pyrazole-
3-carbohydrazides 16a–c; 4-amino-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrazole
derivative 13; Schiff bases 17a,b; and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives 18
and 19a–e.
Keywords 2-Acetylthiophene; acid hydrazides; bis-pyrazoles; 3-(2-thienyl)-1H-pyrazoles;
1,2,4-triazolo[3,4-b][1,3,4]thiadiazines
INTRODUCTION
A literature survey revealed that several nitrogen-, oxygen-, and sulfur-containing
heterocyclic compounds incorporating thiophene residues have been found to possess in-
teresting biological properties.1–5 Hydrazides and their functional derivatives have been
used to prepare a series of antitubercular and antibacterial preparations.6,7 Many hete-
rocyclic compounds directly prepared from hydrazides possess valuable biological and
physicochemical properties.8 In the same sense, compounds including a pyrazole nucleus
are known to possess analgesic, anti-inflammatory, antipyretic, antiarrhythmic, tranquil-
izing, muscle relaxant, psychoanaleptic, anticonvulsant, hypotensive, monoamine oxi-
dase inhibitor, antidiabetic, and antibacterial activities.9–16 Also, some thiazole derivatives
have been reported to possess tuberculostatic, antibacterial, and antifungal activities.17–21
Received 1 December 2008; accepted 19 January 2009.
Address correspondence to Bakr F. Abdel-Wahab, Applied Organic Chemistry Department, National Re-
search Center, Dokki, Giza, Egypt. E-mail: Bakrfatehy@yahoo.com
249

250
B. F. ABDEL-WAHAB AND A.-A. S. EL-AHL
Moreover various sulfur compounds have been found to have other biological proper-
ties.22–25 In view of these reports and in continuation with our previous work in the synthesis
of biologically active heterocycles,26–30 in this article we detail our synthesis of some new
heterocycles with 1-phenyl-5-(thiophen-2-yl)-pyrazole moiety.
RESULTS AND DISCUSSION
Ethyl 2-thienoylpyruvate 2 was prepared by the reaction of 2-acetylthiophene with
diethyl oxalate in sodium methoxide.31 The reaction of 2 with phenylhydrazine in boiling
acetic acid led to ethyl pyrazole-3-carboxylate derivative 3, and the action of hydrazine
hydrate on the ester 3 gave the target hydrazide 4 (Scheme 1).
O
O
NH2
NH
O
O
N
O
N
O
O
S
S
O
O
AcOH
NaOMe / MeOH
S
O
O
3
1
2
H
N
O
H2N
N
N
NH2NH2.H2O
EtOH
S
4
Scheme 1
The structure of compounds 3 and 4 was confirmed by their spectral data. For example,
the IR spectrum of ester 3 showed a characteristic absorption band at 1727 cm−1 due to
the presence of the ester-carbonyl group, while the IR spectrum of the hydrazide 4 showed
sharp absorption bands at 3311, 3253 and 3215 cm−1 attributed to the NH2 and NH groups.
Treatment of the acid hydrazide 4 with tetrachlorophthalic anhydride in refluxing
glacial acetic acid afforded the imide 5. The IR spectrum of compound 5 showed three ab-
sorption bands in the region 1685–1778 cm−1 characteristic for three carbonyl groups. Also
its mass spectrum displayed a molecular ion peak at m/z 414, which was in agreement with
the calculated mass and molecular formula. The reaction of 4 with different aromatic alde-
hydes, namely, 4-chlorobenzaldehyde, 4-cyanobenzaldehyde, 2,4-dichlorobenzaldehyde,
1
and 2-chloro-4-nitrobenzaldehyde, afforded the corresponding hydrazones 6a–d. The H
NMR spectrum of 6d showed a singlet proton at δ 9.84 ppm attributed to CH N
(Scheme 2).
In the same sense, the reaction of hydrazide 4 with alkenes derivatives, namely
2-(methoxymethylene)malononitrile or ethyl 2-cyano-3,3-bis(methylthio)acrylate, in re-
fluxing ethanol afforded the bi-pyrazole derivatives 7 and 8, respectively. The IR spectrum
of compound 7 showed characteristic absorption band at 2222 cm−1 due to the presence

1-PHENYL-5-(2-THIENYL)PYRAZOLE MOIETY
251
Cl
Cl
Cl
Cl
O
O
Cl
Cl
Cl
O
O
N
O
N
Cl
H
O
S
N
AcOH
N
Ph
5
O
N
Ar
N
H
ArCHO
S
N
N
Ph
EtOH/AcOH
O
NH2
6a: Ar = 4-Cl-C6H4
6b: Ar = 4-CN-C6H4
6c
N
H
N
: Ar = 2,4-Cl2-C6H3
S
N
6d: Ar = 2-Cl-4-NO2-C6H3
Ph
O
4
CN
N
N
MeO
CN
EtOH
N
S
N
Ph
H2N
CN
7
MeS
MeS
MeS
COOEt
CN
COOEt
NH2
N
N
S
EtOH
N
O
N
Ph
8
Scheme 2
of carbonitrile group, while the IR spectrum of compound 8 revealed absorption bands at
3317 and 3361 cm−1 indicating the presence of an amino group (Scheme 2).
On the other hand, acid hydrazides have long been known to react with isothiocyanates
and α-haloketones to afford a variety of heterocyclic derivatives.32–37 Thus, thiosemicar-
bazide 9 was achieved by the reaction of hydrazide 4 with phenylisothiocyanate, which
upon treatment with ethyl bromoacetate or phenacyl bromide in boiling ethanol containing
anhydrous sodium acetate, afforded 4-thiazolidinone 10 and 1,3-thiazole 11, respectively
(Scheme 3).
The IR spectrum of 10 revealed an absorption band at 1645 and 1680 cm−1 due
1
to the two carbonyl groups, while its H NMR showed a singlet signal at δ 4.12 ppm
corresponding to the methylene protons of the thiazolidene ring. 1H NMR of compound 11
displayed one singlet at δ 5.45 ppm corresponding to the thiazole ring proton.
Acid hydrazides can be considered as useful intermediates leading to the formation of
several heterocycles such as 1,2,4-triazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines.38,39
Treatment of 4 with carbon disulfide in ethanol, in the presence of potassium hydroxide,
resulted in the formation of potassium salt of hydrazinecarbodithioate 12. Treatment of the
salt 12 with hydrazine hydrate in aqueous ethanol afforded the corresponding 4-amino-
1,2,4-triazole-5-thione 13. Reaction of 12 with phenacyl bromide in refluxing ethanol

252
B. F. ABDEL-WAHAB AND A.-A. S. EL-AHL
O
O
H
N
H
N
NH2
N
H
Ph
N
H
PhNCS
EtOH
S
N
N
S
S
N
N
Ph
Ph
9
O
4
Br
EtOH / AcONa
R = Ph
R
R = OEt
O
O
N
N
S
N
S
N
H
H
N
S
N
N
S
N
O
N
Ph
N
Ph
Ph
Ph
Ph
11
10
Scheme 3
afforded thiazolidene derivative 14, while its reaction with some hydrazonoyl chlorides
15a–c in refluxing ethanol gave 16a–c (Scheme 4).
The structures of compounds 13, 14, and 16a–c were in agreement with spectral and
analytical data. For example, the IR spectrum of compound 13 revealed absorption bands
1
at 3315, 3108, 3094 cm−1 corresponding to NH and NH2 groups, while the H NMR of
compound 14 displayed a singlet at 8.09 ppm attributed to CH of 2-thioxothiazole ring,
and the mass spectra of 13, 14, and 16a displayed molecular ion peaks at m/z 340, 460, and
486, respectively, which was in agreement with their calculated masses.
It worth mentioning that the Schiff bases 17a,b were produced by the reaction of
4-amino-1,2,4-triazole-5-thione derivative 13 with substituted benzaldehydes in refluxing
ethanol containing a few drops of glacial acetic acid as a catalyst. The reaction of 13
with phenacyl bromide or hydrazonoyl chlorides 15a–e in ethanol containing a catalytic
amount of triethylamine furnished [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives 18
and 19a–e, respectively (Scheme 5).
The structures of compounds 17a,b, 18, and 19a–e were established based on both
microanalytical and spectral data. For example, the 1H NMR spectrum of compound 17b
1
showed one singlet signal at δ 9.03 ppm attributed to N CH , while H NMR of
compound 18 showed a singlet signal at δ 5.21 ppm corresponding to the two protons of
S CH2 in thiadiazine ring. The mass spectrum of compound 19a showed the molecular
ion peak at m/z 561; this fitted exactly with the calculated mass.
EXPERIMENTAL
All melting points were taken on Electrothermal IA 9000 series digital melting point
apparatus. Elemental analytical data were obtained from the Microanalytical Unit, Cairo
University, Giza, Egypt. The IR spectra (KBr) were recorded on a Shimadzu CVT-04
spectrophotometer. The 1H NMR spectra were recorded at 270 MHz on a Varian EM-360
spectrometer using TMS as an internal standard. The mass spectra were performed using a
Varian MAT CH-5 spectrometer (70 eV). All reactions were monitored by TLC (0.25 mm

1-PHENYL-5-(2-THIENYL)PYRAZOLE MOIETY
253
O
NH2
N
H
S
N
N
Ph
4
CS2/KOH
O
N
NH
H
N
NH2NH2.H2O
SK
S
N
H
S
N
N
N
S
N
S
NH2
N
Ph
Ph
O
12
13
Br
Ph
O
N
Ar
S
Me
N
H
S
O
Cl
N
N
H
15a-c
Ph
S
N
N
Ph
O
Ar
N
N
N
N
H
14
S
N
N
S
Ph
15,16
Me
Ar
Ph
4-BrC6H4
4-FC6H4
O
a
b
c
16a-c
Scheme 4
silica gel, aluminum sheets 60 F254, Merck). Ethyl 2,4-dioxo-4-(thiophen-2-yl)butanoate
was prepared according to the procedure in the literature.31
Ethyl 1-Phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-carboxylate (3)
A mixture of ethyl 2,4-dioxo-4-(thiophen-2-yl)butanoate 2 (2.26 g, 10 mmol) of
glacial acetic acid (30 mL) and phenylhydrazine (1.08 g, 10 mmol) was refluxed for 30
min, and then cooled and poured into water (200 mL). The precipitate was filtered off and
recrystallized from dilute ethanol, giving 86% of 3 with mp 109–110◦C (colorless). IR
1
(KBr) νmax/cm−1 1631 (C N); 1727 (C O); H NMR (DMSO-d6): δ1.51 (t, 3H, CH3),
4.22 (q, 2H, CH2), 7.07 (s, 1H, pyrazole-H); 7.15–7.62 (m, 8H, Ar H); Ms m/z (%): 298
(M+, 100). Anal. Calcd. for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39; S, 10.75. Found: C,
64.53; H, 4.90; N, 9.51; S, 10.87.
1-Phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-carbohydrazide (4)
To a solution of 3 (1.49 g, 5 mmol) in absolute ethanol (25 mL), hydrazine hydrate (1.2
mL, 15 mmol) was added, and the mixture was boiled until a chromatographic check showed

254
B. F. ABDEL-WAHAB AND A.-A. S. EL-AHL
H
N
CHO
Cl
S
N
N
NH
N
N
X
N
S
N
S
N
S
Cl
N
N
Ph
NH2
Ph
X
13
O
17 a: X = Cl
Br
b: X = NO2
Ph
O
N
Ar
Me
N
H
Cl
15a-e
N
N
N
S
N
N
S
S
N
N
N
N
S
N
HN
Ph
N
N
Ph
N
Ph
18
Ar
15, 19
Me
Ar
19a-e
Ph
a
b
b
d
e
4-BrC6H4
4-ClC6H4
4-FC6H4
2,4-ClC6H4
Scheme 5
the absence of 3 from the reaction mixture. The ethanol was distilled off, and the residue
was poured into ice water (200 mL). The precipitate was filtered off and recrystallized from
dilute ethanol, giving 82% of 4 with mp 158–159◦C (colorless). IR(KBr) νmax/cm−1 1594
(C N); 1661 (C O); 1H NMR (DMSO-d6): δ 4.48 (s, 2H, NH2, D2O exchangeable), 7.07
(s, 1H, pyrazole-H); 7.10–7.59 (m, 8H, Ar H), 9.61 (s, 1H, NH, D2O exchangeable); Ms
m/z (%): 284 (M+, 100). Anal. Calcd. for C14H12N4OS: C, 59.14; H, 4.25; N, 19.70; S,
11.28. Found: C, 59.31; H, 4.41; N, 19.79; S, 11.53.
N-(4,5,6,7-Tetrachloro-1,3-dioxoisoindolin-2-yl)-1-phenyl-5-(thiophen-2-
yl)-1H-pyrazole-3-carboxamide (5)
A mixture of 4 (0.28 g, 1 mmol) and tetrachlorophthalic anhydride (0.29 g, 1 mmol)
in glacial acetic acid (25 mL) was refluxed for 5 h. The reaction mixture was evaporated
under reduced pressure. The obtained residue was solidified with ether, filtered off, and
crystallized from AcOH-H2O to give 86% of 5 with mp 256–257◦C (colorless). IR(KBr)
νmax/cm−1 1595 (C N); 1685, 1741, 1778 (3C O); 1H NMR (DMSO-d6): δ 7.03 (s, 1H,
pyrazole-H); 7.17–7.62 (m, 8H, Ar H), 9.62 (s, 1H, NH, D2O exchangeable); Ms m/z
(%):552 (M+, 43), 284 (100). Anal. Calcd. for C22H10Cl4N4O3S: C, 47.85; H, 1.83; N,
10.15; S, 5.81. Found: C, 48.02; H, 1.91; N, 10.32; S, 5.94.

1-PHENYL-5-(2-THIENYL)PYRAZOLE MOIETY
255
Synthesis of Hydrazones 6a–d
A mixture of 4 (0.28 g, 1 mmol) and the appropriate aromatic aldehydes, namely
4-chlorobenzaldehyde, 4-cyanobenzaldehyde, 2,4-dichlorobenzaldehyde, or 2-chloro-4-
nitrobenzaldehyde (1 mmol), in absolute ethanol (30 mL) in the presence of few drops
of glacial acetic acid was refluxed for 2 h. The formed solid was filtered off, dried, and
crystallized from EtOH/DMF (3:1) to give 6a–d.
Nꢀ-(4-Chlorobenzylidene)-1-phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-carbo
hydrazide (6a). Yield (83%, colorless); mp 218–220◦C; IR(KBr) νmax/cm−1 1608
1
(C N); 1662 (C O); H NMR (DMSO-d6): δ 7.06 (s, 1H, pyrazole-H); 7.14–7.63
(m, 12H, Ar H), 9.87 (s, 1H, CH); 12.3 (s, 1H, NH, D2O exchangeable); Ms m/z (%): 406
(M+, 100). Anal. Calcd. for C21H15ClN4OS: C, 61.99; H, 3.72; N, 13.77; S, 7.88. Found:
C, 62.31; H, 3.86; N, 13.84; S, 8.12.
Nꢀ-(4-Cyanobenzylidene)-1-phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-carbo
hydrazide (6b). Yield (68%, colorless); mp 200–201◦C; IR(KBr) νmax/cm−1 1612
1
(C N), 1699 (C O), 2222 (CN); H NMR (DMSO-d6): δ 7.03 (s, 1H, pyrazole-H);
7.12–7.66 (m, 12H, Ar H), 9.89 (s, 1H, CH); 12.34 (s, 1H, NH, D2O exchangeable); Ms
m/z (%): 397 (M+, 100). Anal. Calcd. for C22H15N5OS: C, 66.48; H, 3.80; N, 17.62; S,
8.07. Found: C, 66.58; H, 3.94; N, 17.78; S, 8.22.
Nꢀ-(2,4-Dichlorobenzylidene)-1-phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-
carbohydrazide (6c). Yield (76%, colorless); mp 236–237◦C; IR(KBr) νmax/cm−1 1609
1
(C N), 1691 (C O); H NMR (DMSO-d6): δ 7.03 (s, 1H, pyrazole-H); 7.10–7.63 (m,
11H, Ar H), 9.88 (s, 1H, CH); 12.43 (s, 1H, NH, D2O exchangeable); Ms m/z (%):
441(M+, 100). Anal. Calcd. for C21H14Cl2N4OS: C, 57.15; H, 3.20; N, 12.69; S, 7.27.
Found: C, 57.31; H, 3.54; N, 12.78; S, 7.46.
Nꢀ-(2-Chloro-4-nitrobenzylidene)-1-phenyl-5-(thiophen-2-yl)-1H-pyrazole-
3-carbohydrazide (6d). Yield (88%, colorless); mp 241–243◦C; IR(KBr) νmax/cm−1
1621 (C N), 1685 (C O); 1H NMR (DMSO-d6): δ 7.06 (s, 1H, pyrazole-H); 7.12–7.65
(m, 11H, Ar H), 9.84 (s, 1H, CH); 12.51 (s, 1H, NH, D2O exchangeable); Ms m/z (%):
451(M+, 100). Anal. Calcd. for C21H14ClN5O3S: C, 55.82; H, 3.12; N, 15.50; S, 7.10.
Found: C, 55.91; H, 3.34; N, 15.79; S, 7.26.
Synthesis of Bis-pyrazoles 7 and 8
To a solution of 4 (0.28 g, 1 mmol) in anhydrous ethanol (20 mL), 2-(methoxy
methylene)malononitrile (in the case of 7) or ethyl 2-cyano-3,3-bis(methylthio)acrylate (in
the case of 8) (1 mmol) was added, and the reaction mixtures were refluxed for 4–6 h.
The products, which separated upon cooling, were collected by filtration and recrystallized
from ethanol to give compounds 7 and 8, respectively.
5-Amino-1-(5-(thiophene-2-yl)-1-phenyl-1H-pyrazole-3-carbonyl)-1H-pyra
zole-4-carbonitrile (7). Yield (72%, colorless); mp >300◦C; IR(KBr) νmax/cm−1 1635
1
(C N); 1689 (C O), 2222 (CN), 3287, 3223 (NH2); H NMR (DMSO-d6): δ 7.07 (s,
1H, pyrazole-H); 7.14–7.57 (m, 8H, Ar H), 7.91 (s, 1H, CH), 10.32 (s, 2H, NH2, D2O
exchangeable); Ms m/z (%): 360 (M+, 36), 284 (100). Anal. Calcd. for C18H12N6OS: C,
59.99; H, 3.36; N, 23.32; S, 8.90. Found: C, 60.21; H, 3.52; N, 23.49; S, 9.07.
Ethyl 5-Amino-1-(5-(thiophen-2-yl)-1-phenyl-1H-pyrazole-3-carbonyl)-3-
(methylthio)-1H-pyrazole-4-carboxylate (8). Yield (62%, gray); mp 194–195◦C;
IR(KBr) νmax/cm−1 1626 (C N); 1674 (C O), 1697 (C O, ester), 3361, 3317 (NH2);

256
B. F. ABDEL-WAHAB AND A.-A. S. EL-AHL
1H NMR (DMSO-d6): 1.33(t, 3H, CH3), 2.49 (s, 3H, SCH3), 4.36 (q, 2H, CH2), δ 7.06 (s,
1H, pyrazole-H); 7.15–7.62 (m, 8H, Ar H), 9.96 (s, 2H, NH2, D2O exchangeable); Ms
m/z (%): 453 (M+, 31), 284 (100). Anal. Calcd. for C21H19N5O3S2: C, 55.61; H, 4.22; N,
15.44; S, 14.14. Found: C, 55.72; H, 4.51; N, 15.68; S, 14.31.
2-(5-(Thiophen-2-yl)-1-phenyl-1H-pyrazole-3-carbonyl)-N-phenylhydrazineca-
rbothioamide (9)
A mixture of 4 (1.42 g, 5 mmol) and phenylisothiocyante (0.67 g, 5 mmol) in absolute
ethanol (30 mL) was heated under reflux for 3 h. The formed solid was filtered off and
recrystallized from ethanol-dimethyl formamide, giving 78% of 9 with mp 208–210◦C
1
(colorless). νmax/cm−1 1269 (C S), 1601 (C N); 1649 (C O), 3303–3148 (NH); H
NMR (DMSO-d6): δ 7.07 (s, 1H, pyrazole-H); 7.10–7.62 (m, 13H, Ar H), 975, 10.42 (2s,
3H, 3NH, D2O exchangeable); Ms m/z (%): 419 (M+, 12), 284 (100). Anal. Calcd. for
C21H17N5OS2: C, 60.12; H, 4.08; N, 16.69; S, 15.29. Found: C, 60.32; H, 4.21; N, 16.77;
S, 15.41.
5-(Thiophen-2-yl)-Nꢀ-(4-oxo-3-phenylthiazolidin-2-ylidene)-1-phenyl-1H-
pyrazole-3-carbohydrazide (10)
A mixture of 9 (0.42 g, 1 mmol) and ethyl bromoacetate (0.17 g, 1 mmol) in absolute
ethanol (30 mL) containing anhydrous sodium acetate (0.33 g, 4 mmol) was heated under
reflux for 6 h. The reaction mixture was cooled, diluted with water, and allowed to stand
overnight. The precipitated solid was filtered off and recrystallized from ethanol to give 10
in 58% with mp 159–160◦C (colorless). IR(KBr) νmax/cm−1 1612 (C N); 1645 (C O),
1739 (C O), 3423 (NH); 1H NMR (DMSO-d6): δ 4.12 (s, 2H, CH2), 4.17 (s, 1H, NH, D2O
exchangeable), 7.06 (s, 1H, pyrazole-H), 7.12–7.66 (m, 13H, Ar H); Ms m/z (%): 459
(M+, 16), 77 (100). Anal. Calcd. for C23H17N5O2S2: C, 60.11; H, 3.73; N, 15.24; S,13.96.
Found: C, 60.32; H, 3.96; N, 15.42; S, 14.08.
5-(Thiophen-2-yl)-Nꢀ-(3,4-diphenylthiazol-2-(3H)-ylidene)-1-phenyl-1H-
pyrazole-3-carbohydrazide (11)
A mixture of 9 (0.42 g, 1 mmol) and phenacylbromide (0.2 g, 1 mmol) in absolute
ethanol (30 mL) containing anhydrous sodium acetate (0.33 g, 4 mmol) was heated under
reflux for 6 h. The reaction mixture was cooled, and the formed solid was filtered off
and recrystallized from ethanol-DMF to give 11 (58%) with mp 197–198◦C (colorless).
IR(KBr) νmax/cm−1 1608(C N); 1641 (C O), 3402 (NH); 1H NMR (DMSO-d6): δ 5.45
(s, 1H, thiazole-H), 7.03 (s, 1H, pyrazole-H), 7.10–7.64 (m, 18H, Ar H); 10.78 (s, 1H, NH,
D2O exchangeable); Ms m/z (%): 519 (M+, 22), 77 (100). Anal. Calcd. for C29H21N5OS2:
C, 67.03; H, 4.07; N, 13.48; S, 12.34. Found: C, 67.31; H, 4.24; N, 13.71; S, 12.53.
Potassium 2-(1-Phenyl-5-(thiophen-2-yl)-1H-pyrazole-3-carbonyl)
hydrazinecarbodithioate (12)
To a solution of hydrazide 4 (2.84 g, 10 mmol) in ethanol (100 mL), a solution of
potassium hydroxide (0.84 g, 15 mmol) in water (10 mL) and carbon disulfide (5 mL)
was added. The reaction mixture was heated under reflux for 3 h. The solvent was evapo-
rated under reduced pressure until dryness, then the residue was treated with dry benzene
(30 mL). The formed precipitate was collected by filtration, washed with ether, and dried to

1-PHENYL-5-(2-THIENYL)PYRAZOLE MOIETY
257
afford the potassium salt 12 (80% yield, colorless). IR (KBr) νmax/cm−1 3370, 3130 (2NH),
1650 (C O) cm−1
.
4-Amino-3-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl)-1H-1,2,4-
triazole-5(4H)-thione (13)
To a solution of potassium salt 12 (3.97 g, 10 mmol) in ethanol (20 mL) and water
(20 mL), hydrazine hydrate (1 mL) was added. The reaction mixture was heated under reflux
for 3 h, left to cool, and then poured in crushed ice. The resulted solution was acidified
with dilute hydrochloric acid to pH 7. The resulting solid was collected by filtration,
washed with water, and crystallized from ethanol to give 1,2,4-triazole-5-thione derivative
13 in 73% yield with mp 219–220◦C (pale yellow). IR (KBr) νmax/cm−1 1296 (C S), 1625
(C N); 3315, 3108, 3094 (NH2 and NH); 1H NMR (DMSO-d6): δ 7.06 (s, 1H, pyrazole-H);
7.15–7.63 (m, 8H, Ar H), 10.02 (s, 2H, NH2, D2O exchangeable), 12.99 (s, 1H, NH, D2O
exchangeable); MS m/z (%): 340 (M+, 25.78), 326 (100). Anal. Calcd. for C15H12N6S2: C,
52.92; H, 3.55; N, 24.69; S, 18.84. Found: C, 52.97; H, 3.93; N, 25.01; S, 19.10.
1-Phenyl-N-(4-phenyl-2-thioxothiazol-3(2H)-yl)-5-(thiophen-2-yl)-1H-
pyrazole-3-carboxamide (14)
A mixture of potassium salt 12 (0.79 g, 2 mmol) and phenacyl bromide (0.4 g,
2 mmol) in ethanol (20 mL) was heated under reflux for 3 h. The formed solid was collected
by filtration, washed with ethanol, dried, and recrystallized from ethanol/DMF to afford
thiazole derivative 14 in 58% yield with mp 213–215◦C (colorless); IR (KBr) νmax/cm−1
1592 (C N), 1676 (C O), 3116 (NH); 1H NMR (DMSO-d6): δ 7.08 (s, 1H, pyrazole-H),
7.21–8.02 (m, 13H, Ar H), 8.09 (s, 1H, CH), 9.31 (s, 1H, NH, D2O exchangeable); MS
m/z (%): 460 (M+, 0.11), 105 (100). Anal. Calcd. for C23H16N4OS3: C, 59.98; H, 3.50; N,
12.16; S, 20.88. Found: C, 60.21; H, 3.93; N, 12.32; S, 21.09.
Nꢀ-(5-Acetyl-3-aryl1,3,4-thiadiazol-2(3H)-ylidene)-1-phenyl-5-(thiophen-
2-yl)-1H-pyrazole-3-carbohydrazides (16a–c)
To a solution of potassium salt 12 (0.79 g, 2 mmol) in ethanol (20 mL), the appropriate
hydrazonoyl chloride 15a–c (2 mmol) was added. The reaction mixture was heated under
reflux for 3 h. The formed solid was collected by filtration, washed with ethanol, dried, and
recrystallized from ethanol/DMF to afford 16a–c.
Nꢀ-(5-Acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-1-phenyl-5-(thio
phen-2-yl)-1H-pyrazole-3-carbohydrazide (16a). Yield (84%, dark yellow), mp
280–82◦C; IR (KBr) νmax/cm−1 1614 (C N); 1673 (C O), 3110 (NH); 1H NMR
(DMSO-d6): δ 2.57 (s, 3H, CH3), 7.05 (s, 1H, pyrazole-H); 7.13–8.02 (m, 13H, Ar H),
11.28 (s, 1H, NH, D2O exchangeable); MS m/z (%): 486 (M+, 67.89), 253 (100). Anal.
Calcd. for C24H18N6O2S2: C, 59.24; H, 3.73; N, 17.27; S, 13.18. Found: C, 59.51; H, 3.97;
N, 17.42; S, 13.39.
Nꢀ-(5-Acetyl-3-(4-bromophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1-phenyl-
5-(thiophen-2-yl)-1H-pyrazole-3-carbohydrazide (16b). Yield (86%, orange) mp
1
217–218◦C; IR (KBr) νmax/cm−1 1608 (C N); 1680 (C O), 3182 (NH); H NMR
(DMSO-d6): δ 2.54 (s, 3H, CH3), 7.03 (s, 1H, pyrazole-H); 7.17–8.02 (m, 12H, Ar H),
11.15 (s, 1H, NH, D2O exchangeable); MS m/z (%): 565 (M+, 67.20), 253 (100). Anal.

258
B. F. ABDEL-WAHAB AND A.-A. S. EL-AHL
Calcd. for C24H17BrN6O2S2: C, 50.98; H, 3.03; N, 14.86; S, 11.34. Found: C, 51.23; H,
3.98; N, 15.02; S, 11.63.
Nꢀ-(5-Acetyl-3-(4-fluorophenyl)-1,3,4-thiadiazol-2(3H)-ylidene)-1-phenyl-
5-(thiophen-2-yl)-1H-pyrazole-3-carbohydrazide (16c). Yield (79%, orange),
1
mp 193–195◦C; IR (KBr) νmax/cm−1 1613 (C N); 1681 (C O), 3188 (NH); H NMR
(DMSO-d6): δ 2.52 (s, 3H, CH3), 7.04 (s, 1H, pyrazole-H); 7.15–7.98 (m, 12H, Ar H),
11.22 (s, 1H, NH, D2O exchangeable); MS m/z (%): 504 (M+, 55.02), 253 (100). Anal.
Calcd. for C24H17FN6O2S2: C, 57.13; H, 3.40; N, 16.66; S, 12.71. Found: C, 57.43; H,
3.67; N, 16.93; S, 12.91.
4-(Arylideneamino)-3-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl)-1H-
1,2,4-triazole-5(4H)-thione (17a,b)
A mixture of appropriate aromatic aldehyde (2 mmol) and 4-amino-1,2,4-triazole-
5(4H)-thione derivative 13 (0.68 g, 2 mmol) in ethanol (20 mL) in the presence of glacial
acetic acid (0.2 mL) was refluxed for 4 h. The solid product was collected by filtration,
washed with ethanol, and crystallized from EtOH/DMF to afford 17a,b.
4-(2,4-Dichlorobenzylideneamino)-3-(1-phenyl-5-(thiophen-2-yl)-1H-pyra
zol-3-yl)-1H-1,2,4-triazole-5(4H)-thione (17a). Yield (87%, yellow), mp 203–205◦C;
1
IR (KBr) νmax/cm−1 1621 (C N); 3100 (NH); H NMR (DMSO-d6): δ 7.08 (s, 1H,
pyrazole-H); 7.22–7.86 (m, 11H, Ar H), 9.01 (s, 1H, CH), 12.41 (s, H, NH, D2O
exchangeable); MS m/z (%): 497 (M+, 58.02), 89(100). Anal. Calcd. for C22H14Cl2N6S2:
C, 53.12; H, 2.84; N, 16.90; S, 12.89. Found: C, 53.42; H, 3.11; N, 17.09; S, 13.12.
4-(2-Chloro-4-nitrobenzylideneamino)-3-(1-phenyl-5-(thiophen-2-yl)-1H-
pyrazol-3-yl)-1H-1,2,4-triazole-5(4H)-thione (17b). Yield (83%, yellow), mp
224–225◦C; IR (KBr) νmax/cm−1 1618 (C N); 3187 (NH); 1H NMR (DMSO-d6): δ 7.07
(s, 1H, pyrazole-H); 7.20–7.89 (m, 11H, Ar H), 9.03 (s, 1H, CH), 12.38 (s, H, NH, D2O
exchangeable); MS m/z (%): 507 (M+, 58.02), 89(100). Anal. Calcd. for C22H14ClN7O2S2:
C, 52.02; H, 2.78; N, 19.30; S, 12.62. Found: C, 52.31; H, 3.04; N, 19.54; S, 12.91.
6-Phenyl-3-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl)-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (18)
A mixture of 13 (0.68 g, 2 mmol) and phenacyl bromide (0.4 g, 2 mmol) in absolute
ethanol (30 mL) containing a catalytic amount of triethyl amine was heated under reflux for
3 h. The formed precipitate was filtered off, washed with ethanol, dried, and recrystallized
from EtOH/DMF to give 75% of 18 with mp 210–212◦C (colorless). IR (KBr) νmax/cm−1
1602(C N); 1H NMR (DMSO-d6): δ 5.21 (s, 2H, CH2), 7.08 (s, 1H, pyrazole-H); 7.21–8.09
(m, 13H, Ar H); MS m/z (%): 440 (M+, 3.99), 105 (100). Anal. Calcd. for C23H16N6S2:
C, 62.71; H, 3.66; N, 19.08; S, 14.56. Found: C, 62.97; H, 3.89; N, 19.43; S, 14.76.
6-Methyl-3-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl)-7-(2-
arylhydrazono)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (19a–e)
A mixture of 1,2,4-triazole-5-thione 13 (0.68 g, 2 mmol) and the appropriate hydra-
zonyl chloride (2 mmol) in absolute ethanol (30 mL) containing 2 mmol of triethyl amine
was heated under reflux for 3 h. The precipitated solid was collected by filtration, washed
with ethanol, dried, and then crystallized from EtOH/DMF to afford 19a–e.

1-PHENYL-5-(2-THIENYL)PYRAZOLE MOIETY
259
6-Methyl-3-(1-phenyl-5-(thiophen-2-yl)-1H-pyrazol-3-yl)-7-(2-phenylhydra
zono)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (19a). Yield (68%, orange), mp
1
280–281◦C; IR (KBr) νmax/cm−1 1612 (C N); H NMR (DMSO-d6): δ 2.61 (s, 3H,
CH3), 7.03 (s, 1H, pyrazole-H); 7.10–7.64 (m, 13H, Ar H), 10.31 (s, 1H, NH, D2O
exchangeable); MS m/z (%): 482 (M+, 6.03), 105 (100). Anal. Calcd. for C24H18N8S2: C,
59.73; H, 3.76; N, 23.22; S, 13.29. Found: C, 59.97; H, 3.81; N, 23.52; S, 13.73.
7-(2-(4-Bromophenyl)hydrazono)-6-methyl-3-(1-phenyl-5-(thiophen-2-yl)-
1H-pyrazol-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (19b). Yield (71%,
red), mp 225–226◦C; IR (KBr) νmax/cm−1 1610 (C N); 1H NMR (DMSO-d6): δ 2.56 (s,
3H, CH3), 7.01 (s, 1H, pyrazole-H); 7.16–8.01 (m, 12H, Ar H), 10.33 (s, 1H, NH, D2O
exchangeable); MS m/z (%): 561(M+, 10.01), 105(100). Anal. Calcd. for C24H17BrN8S2:
C, 51.34; H, 3.05; N, 19.96; S, 11.42. Found: C, 51.63; H, 3.32; N, 20.27; S, 11.62.
7-(2-(4-Chlorophenyl)hydrazono)-6-methyl-3-(1-phenyl-5-(thiophen-2-yl)-
1H-pyrazol-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (19c). Yield (71%,
yellow), mp 216–218◦C; IR (KBr) νmax/cm−1 1608 (C N); 1H NMR (DMSO-d6): δ 2.53
(s, 3H, CH3), 7.00 (s, 1H, pyrazole-H); 7.12–8.00 (m, 12H, Ar H), 10.28 (s, 1H, NH, D2O
exchangeable); MS m/z (%): 517(M+, 6.31), 105(100). Anal. Calcd. for C24H17ClN8S2: C,
55.75; H, 3.31; N, 21.67; S, 12.40. Found: C, 55.89; H, 3.78; N, 21.97; S, 12.84.
7-(2-(4-Flurophenyl)hydrazono)-6-methyl-3-(1-phenyl-5-(thiophen-2-yl)-
1H-pyrazol-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (19d). Yield (76%,
1
red) mp 208–210◦C; IR (KBr) νmax/cm−1 1611 (C N); H NMR (DMSO-d6): δ 2.55 (s,
3H, CH3), 7.01 (s, 1H, pyrazole-H); 7.14–8.06 (m, 12H, Ar H), 10.23 (s, 1H, NH, D2O
exchangeable); MS m/z (%): 500(M+, 11.36), 105(100). Anal. Calcd. for C24H17FN8S2:
C, 57.59; H, 3.42; N, 22.39; S, 12.81. Found: C, 57.73; H, 3.81; N, 22.63; S, 12.96.
7-(2-(2,4-Dichlorophenyl)hydrazono)-6-methyl-3-(1-phenyl-5-(thiophen-
2-yl)-1H-pyrazol-3-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine (19e). Yield
(70%, dark yellow) mp 170–172◦C; IR (KBr) νmax/cm−1 1618 (C N); 1H NMR
(DMSO-d6): δ 2.58 (s, 3H, CH3), 7.01 (s, 1H, pyrazole-H); 7.10–7.94 (m, 11H, Ar H),
10.49 (s, 1H, NH, D2O exchangeable); MS m/z (%): 551(M+, 15.36), 105(100). Anal.
Calcd. for C24H16Cl2N8S2: C, 52.27; H, 2.92; N, 20.32; S, 11.63. Found: C, 52.56; H,
2.30; N, 20.64; S, 11.94.
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