Convenient synthesis of some new substituted pyrazolyl-1,3,4-oxadiazoles and pyrazolyl-1,2,4-triazoles

Article abstract of DOI:10.1002/jhet.5570430508

A simple and versatile method for the synthesis of pyrazol-3-yl-1,3,4- oxadiazole, pyrazol-3-yl-1,2,4-triazole, (1,5-diphenylpyrazol-3-yl)-(3,5- dimethyl-1-carbonyl)pyrazole and (1,5-diphenylpyrazol-3-yl)-(5-hydroxy-3- metheyl-1-carbonyl)pyrazole derivati

Full text of DOI:10.1002/jhet.5570430508

Sep-Oct 2006
1183
Convenient Synthesis of Some New Substituted Pyrazolyl-1,3,4-
oxadiazoles and Pyrazolyl-1,2,4-triazoles
Yehya M. Elkholya*, Korany A. Alib and Ahmad M. Faragb
aDepartment of Chemistry, Faculty of Science, Helwan University, Ain- Helwan , Cairo, Egypt
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
Received October 24, 2005
Ph
N
N
CONHNH2
N
N
H
Y
X
N
Ph
O
N
N
Ph
Ph
O
N
Ph
Ph
X=O,NH,NPh
Y=SH,SMe
A simple and versatile method for the synthesis of pyrazol-3-yl-1,3,4-oxadiazole, pyrazol-3-yl-1,2,4-
triazole, (1,5-diphenylpyrazol-3-yl)-(3,5-dimethyl-1-carbonyl)pyrazole and (1,5-diphenylpyrazol-3-yl)-(5-
hydroxy-3-metheyl-1-carbonyl)pyrazole derivatives from 1,5-diphenylpyrazole-3-carboxylic acid
hydrazide has been developed..
J. Heterocyclic Chem., 43, 1183 (2006).
Introduction.
1 by the action of acetic anhydride-sulfuric acid mixture)
with aromatic diazonium salts, afforded colored products
that were identified as 3-arylhydrazono-5-aryl-3H-furan-
2-one derivatives (3a,b). The structures of the latter
products were confirmed by the appearance of hydrazone
NH and carbonyl bands near 3280 and 1750 cm-1,
respectively in their IR spectra and the lack of the
Many substituted 1,3,4-oxadiazoles have a wide variety
of applications as biologically active compounds in
medicine and agriculture. For example, they are used as
antiperipheral vasomotility [1], central nervous system
(CNS) stimulant, anti-inflammatory, hypotensive [2],
hypoglycemic [3,4], analgesic, anticonvulsant, antiemetic,
diuretic [5], muscle relaxant [6,7], bactericidal [8],
pesticidal [9], insecticidal [10], herbicidal [11,12] and
fungicidal agents [13,14]. On the other hand, the
therapeutic effects of 1,2,4-triazoles have been well
documented [15-17]. Several 1,2,4-triazole derivatives
show anti-inflammatory [18], vasodilatory [19] and
psychotropic properties [20]. Recently, our interest in the
synthesis of various substituted heterocyclic systems,
which could be adapted for the preparation of small
libraries, has been the subject of several publications from
our laboratory [21-31]. During our investigation, we have
found that acid hydrazides can be used as useful
intermediates leading to the formation of several
heterocycles of potential biological activity such as 1,2,4-
triazoles, 1,3,4-oxadiazoles and 1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazines [23,32].
1
characteristic signals due to methylene protons in their H
NMR spectra. Compounds (3a,b) were also obtained from
the reaction of intermediate 5-aryl-3H-furan-2-one
derivatives (2a,b) with N-nitrosoacylarylamine [34], in
ethanol at room temperature (Scheme 1).
Scheme 1
O
O
Ar
OH
1
-
Ac2O/H2SO4
Ar' N2+ Cl
Ar'
NO
N
Ar' NCOCH3
EtOH
N
H
Ar
O
O
O
Ar
O
3
2
In this context, we report a convenient rout to some new
pyrazolyl-1,2,4-triazole, pyrazolyl-1,3,4-oxadiazole, (1,5-
diphenyl-1H-pyrazol-3-yl)-(3,5-dimethyl-1-carbonyl)pyrazole
and (1,5-diphenyl-1H-pyrazol-3-yl)-(5-hydroxy-3-metheyl-1-
carbonyl)pyrazole starting from a readily accessible 1,5-
diphenyl-1H-pyrazole-3-carboxylic acid hydrazide.
NH2NH2
CONHNH2
N-NH-Ar'
Ar
N
Ar
N
N
N
H
O
Ar'
4
Results and Discussion.
5
Treatment of 5-aryl-3H-furan-2-ones (2a,b) [33,35]
(formed in situ by cyclization of 4-oxo-4-arylbutyric acid
2, 3, 4, 5
a: Ar = Ar'= Ph
b: Ar = Ar'= 4-CH3C6H4

1184
Y. M. Elkholy, K. A. Ali and A. M. Farag
Vol 43
Scheme 2
When the 3-arylhydrazono-5-aryl-3H-furan-2-one
derivatives (3a,b) were treated with hydrazine hydrate,
they afforded products identified as the 1,5-diaryl-1H-
pyrazole-3-carboxylic acid hydrazide derivatives (4a,b),
respectively (Scheme 1). The structures of the isolated
products were assigned on the basis of their elemental
analysis and spectral data. For example, the IR spectra of
the isolated products showed three bands in each case, in
the region 3286-3210 cm-1 corresponding to NH and NH2
groups and a carbonyl absorption band near 1689 cm-1.
S
-
+
CONHNH-C-SK
CS2 / KOH
Ph
4a
N
N
Ph
6
NH2NH2
KOH or pyridine/
1
The H NMR spectrum of (4a), as an example, showed a
N
N
N
N
singlet signal at ꢀ 6.81 corresponding to 4-CH of the
pyrazole ring and two broad bands (D2O-exchangeable) at
ꢀ 4.34 and 8.73 due to NH2 and NH protons, respectively,
in addition to a multiplet signal in the region ꢀ 7.13-7.53
due to aromatic protons. Moreover, the mass spectrum of
the same product revealed a peak corresponding to its
molecular ion at m/z 278. The other possible 3-aryl-5-
arylhydrazono-1H-pyridazine-6-one structure (5) was
SH
N
NH2NH2
SH
O
N
Ph
N
NH2
N
Ph
N
8
Ph
7
Ph
hydrate, afforded a single product (as tested by TLC)
identified as 4-amino-5-(1,5-diphenyl-1H-pyrazol-3-yl)-
4H-1,2,4-triazole-3-thiol (7) according to its elemental
analysis and spectral data. For example, its IR spectrum
revealed absorption band in the region 3147 cm-1
characteristic for NH2 group. Its mass spectrum revealed a
peak at m/z 334 corresponding to its molecular ion.
When the potassium salt (6) was heated in pyridine, it
gave only one isolable product that was identified as
5-(1,5-diphenyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole-2-thiol
1
ruled out on the basis of the IR and H NMR spectra of
the reaction products (see experimental part).
Treatment of 1,5-diphenyl-1H-pyrazole-3-carboxylic
acid hydrazide (4a) with carbon disulphide in ethanolic
potassium hydroxide solution afforded the corresponding
potassium 2-[(1,5-diphenyl-1H-pyrazole-3-yl)carbonyl]-
hydrazinecarbodithioate intermediate (6) (Scheme 2).
Treatment of the potassium salt (6) with hydrazine
Scheme 3
S
CONHNH-C-NHPh
PhNCS/EtOH
N
4a
Ph
N
Ph
9
NaOH
N
N
N
N
N
NH
NHPh
O
SH
S
N
N
N
Ph
N
N
Ph
N
Ph
Ph
Ph
N
N
Ph
Ph
Ph
10a
11
10b
CH l/CH CH ONa
3
3
2
CH
3
N
N
N
N
S
SMe
N
N
N
N
Ph
Ph
Ph
12
Ph
N
N
Ph
13
Ph

Sep-Oct 2006
Convenient Synthesis of Some New Substituted Pyrazolyl-1,3,4-oxadiazoles
1185
(8) according to its elemental analysis and spectral data.
This conclusion was further supported by the chemical
transformation of the latter product into 4-amino-5-(1,5-
diphenyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (7)
by reaction with hydrazine hydrate (Scheme 2).
When the pyrazole-3-carboxylic acid hydrazide (4a)
was treated with phenyl isothiocyanate, it afforded a
single product identified as 1-(1,5-diphenyl-1H-pyrazole-
3-carbonyl)-4-phenyl-thiosemicarbazide (9). Treatment of
a suspension of the latter product with sodium hydroxide
solution, under reflux, afforded 5-(1,5-diphenyl-1H-
a catalytic amount of piperidine, it afforded a product
identified as (1,5-diphenyl-1H-pyrazol-3-yl)-(5-hydroxy-
3-metheyl-1-carbonyl)pyrazole (17) (Scheme 5). The IR
spectrum of the isolated product revealed a characteristic
carbonyl absorption band at 1650 cm-1, whereas its mass
spectrum revealed a peak corresponding to its molecular
ion at m/z 344.
Similarly, the pyrazole-3-carboxylic acid hydrazide
(4a) reacts with acetylacetone, under the same reaction
condition, to afford the corresponding (1,5-diphenyl-1H-
pyrazol-3-yl)-(3,5-dimethyl-1-carbonyl)pyrazole
(18)
pyrazol-3-yl)-4-phenyl-4H-1,2,4-triazole-3-thiole
(10)
(Scheme 5). The structure of the latter product was
established on the basis of its elemental analysis and
spectral data (see experimental part).
(Scheme 3). The structures of the isolated products were
established on the basis of their elemental analysis and
spectral data (see experimental part).
Scheme 5
Treatment of the 1,2,4-triazole-3-thiol (10) with
ethanolic solution of sodium ethoxide followed by the
addition of an equimolar amount of methyl iodide,
4a
O
O
O
O
afforded
5-(1,5-diphenyl-1H-pyrazol-3-yl)-4-phenyl-3-
CH3
CH3
H3C
EtO
methylthio-4H-1,2,4-triazole (12) (Scheme 3).
EtOH/pip.
H
On the other hand, when the pyrazole-3-carboxylic acid
hydrazide (4a) was treated with a solution of potassium
thiocyanate in the presence of hydrochloric acid, it
CH3
O
O
N
O
N
N
N
afforded
1-(1,5-diphenyl-1H-pyrazole-3-carbonyl)thio-
N
N
Ph
Ph
N
N
CH3
CH3
semicarbazide (14) (Scheme 4). The latter product
underwent an intramolecular cyclization upon treatment
with sodium hydroxide to afford a single product (TLC
analysis), for which the 5-(1,5-diphenyl-1H-pyrazol-3-yl)-
4H-1,2,4-triazole-3-thiole structure (15) was assigned.
The mass spectrum of the reaction product revealed a
peak at m/z 319. This indicates that the thiosemicarbazide
(14) undergoes intramolecular cyclization via the loss of a
water molecule which supports the assigned structure (15)
and ruled out the other possible structure (16) (Scheme 4).
Ph
Ph
17
18
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting
point apparatus and are uncorrected. The infrared spectra were
recorded in potassium bromide disks on a Pye Unicam SP-3-300
and Shimadzu FT IR 8101 PC infrared spectrophotometer. The
NMR spectra were recorded on a Varian Mercury VX-300 NMR
spectrometer. 1H spectra were run at 300 MHz and 13C spectra
were run at 75.46 MHz in deuterated chloroform (CDCl3) or
dimethylsulphoxide (DMSO-d6). Chemical shifts are quoted in ꢀ
and were related to that of the solvents. The mass spectra were
recorded on a Shimadzu GCMS-QP-1000EX mass spectrometer
at 70 eV. Elemental analyses were carried out at the Micro-
analytical Center of Cairo University. 5-Aryl-3H-furan-2-ones
(2a,b) were prepared according to literature procedure [33,35].
Scheme
4
S
CONHNH-C-NH2
KNCS/HCl
N
Ph
4a
N
Ph
14
3-Arylhydrazono-5-aryl-3H-furan-2-ones (3a,b).
Method A.
NaOH/EtOH
General Procedure: The appropriate 4-oxo-4-arylbutyric acid
(1) (40 mmol) was added to acetic anhydride (40 mL) containing
few drops (0.5 mL) of sulfuric acid and the mixture was heated on
a water bath for 70 min. then allowed to cool to room temperature
[33]. This solution was added dropwise with stirring to solution of
the appropriate aromatic diazonium salt (40 mmol) at 0-5ºC over a
period of 30 min. After complete addition, the reaction mixture
was allowed to stand overnight on a refrigerator and the
precipitated solid was collected by filtration, washed with water
and finally crystallized from ethanol/DMF to afford the
corresponding hydrazone derivatives (3a,b).
-H2S
-H2O
N
N
N
N
NH2
SH
O
N
N
N
Ph
Ph
H
N
N
Ph
15
16
Ph
Next, when the pyrazole-3-carboxylic acid hydrazide
(4a) was treated with ethyl acetoacetate, in the presence of

1186
Y. M. Elkholy, K. A. Ali and A. M. Farag
Vol 43
Method B.
A solution of potassium hydroxide (0.78 g, 20 mmol), in
absolute ethanol (20 mL) and the appropriate acid hydrazide (4a)
(2.78 g, 10 mmol) was treated by the addition of carbon disulfide
(1.14 g, 15 mmol) and the mixture was stirred for 16 hours. It was
then diluted with 20 mL of dry ether and the precipitated solid was
collected by filtration, washed with 20 mL of ether and dried
under vacuum at 65°C to afford potassium 2-[(1,5-diphenyl-1H-
pyrazole-3-yl)carbonyl]hydrazinecarbodithioate (6). The latter salt
was obtained in nearly quantitative yield and was used for the next
reactions without further purification. Its characteristic spectral
feature: IR (KBr) ꢀ cm-1 1658 (C=O), 3363 (NH).
General Procedure: To the appropriate 5-aryl-3H-furan-2-one (2)
[33,35] (10 mmol) (prepared in situ according to procedure A
above) was added the appropriate N-nitrosoacylarylamine (10
mmol) [34,35]. The reaction mixture was shaken to effect complete
dissolution of the reactants and then left to stand overnight at room
temperature. The precipitated solid was collected by filtration,
washed with water and finally crystallized from ethanol/DMF to
afford products identical in all respects (mp, mixture mp and IR
spectra) with those obtained from Method A above.
5-Phenyl-3-phenylhydrazono-3H-furan-2-one (3a).
4-Amino-5-(1,5-diphenyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-
thiol (7).
Yield 67%; mp 227-228°C (lit. [35] mp 227).
5-(4-Methylphenyl)-3-(4-methylphenylhydrazono)-3H-furan-2-
one (3b).
Method A.
A suspension of the potassium salt (6) (3.76 g, 10 mmol),
hydrazine hydrate (20 mmol, 95%) and water (2 mL) was
refluxed with stirring for 3 hours. The color of the reaction
mixture changed to green, hydrogen sulfide was evolved (lead
acetate paper and odor) and a homogeneous solution resulted.
Dilution with cold water (100 mL) and acidification with
concentrated hydrochloric acid precipitated a white solid. This
product was collected by filtration, washed with cold water
and recrystallized from ethanol-water to afford 4-amino-5-
(1,5-diphenyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiol (7);
Yield 40%, mp 129°C, IR (KBr) ꢀ cm-1 3147 (NH2), 2677
(SH); MS m/z 334 (M+), 252, 170, 140, 115, 77; 1H NMR
(CDCl3): ꢁ 5.91 (s, br., D2O-exchangable 2H, NH2), 6.63 (s,
1H, pyrazole-4CH), 7.00-7.86 (m, 10H, ArHs), 13.78 (s, br,
D2O-exchangable 1H, SH); 13C NMR (DMSO-d6): ꢁ 148.07,
144.96, 129.94, 129.33, 129.26, 129.11, 128.99, 128.73,
125.60, 118.93, 112.23, 109.36, 107.24.
Yield 89%; mp 230-231°C; IR (KBr) ꢀ cm-1 3263 (NH), 1743
1
(C=O); MS, m/z 292 (M+), 200, 106, 93, 77; H NMR)DMSO-
d6): ꢁ 2.27 (s, 3H, CH3), 2.38 (s, 3H, CH3), 7.17-7.61 (m, 9H,
furan-4CH and ArHs), 11.19 (s, br., D2O-exchangable 1H, NH);
13C NMR (DMSO-d6): ꢁ 164.23, 154.45, 140.84, 140.67,
131.94, 129.89, 129.43,128.88, 125.31, 124.75, 114.39, 94.80,
21.13, 20.43.
Anal. Calcd. For C18H16N2O2 (292.33): C, 73.96 H, 5.52; N,
9.58. Found: C, 73.6; H, 5.5; N, 9.6.
1,5-Diaryl-1H-pyrazole-3-carboxylic acid hydrazides (4a,b).
General Procedure: Hydrazine hydrate (80%, 3 mL) was
added to a suspension of the appropriate 3-arylhydrazono-
furanone derivative (3) (10 mmol) in ethanol (20 mL) and the
reaction mixture was stirred at room temperature for 1 h. The
color of the arylhydrazone derivative disappeared and a white
deposit was formed. It was allowed to stand overnight, poured
into water and the precipitate was collected by filtration, washed
with water and crystallized from ethanol-water.
Anal. Calcd. for C17H14N6S (334.40): C, 61.06; H, 4.22; N,
25.13; S, 9.59. Found: C, 61.1; H, 4.3; N, 25.3; S, 9.6.
Method B.
1,5-Diphenyl-1H-pyrazole-3-carboxylic acid hydrazide (4a).
Yield 72%; m.p. 153°C (lit. [35] mp 149-150°C).; IR (KBr) ꢀ
A mixture of the pyrazolyl-oxadiazole (8) (3.20 g, 10 mmole),
and hydrazine hydrate (5 ml, 95%) in water (20 mL) was refluxed
with stirring for 4 hours then diluted with cold water (200 mL),
acidified by the dropwise addition of concentrated hydrochloric
acid, and the solid that formed was collected by filtration. The
solid that formed was washed with the least amount of cold water
and recrystallization from ethanol-water (1:1). The spectra of
pyrazolyl-triazole obtained by this route are superimposed on
those for the same substance obtained by Method A above.
1
cm-1 3286 (NH), 3210 (NH2), 1689 (C=O); H NMR (CDCl3): ꢁ
4.34 (s, 2H, NH2), 8.73 (s, 1H, NH); 6.81 (s, 1H, pyrazole-
4CH), 7.13-7.53 (m, 10H, ArHs); 13C NMR (DMSO-d6): ꢁ
156.2, 148.17, 147.12, 145.3, 136.56, 129.78, 129.69, 129.45,
126.33, 120.16, 112.96, 98.48; MS m/z 278 (M+), 187, 130, 93,
77.
Anal. Calcd. for C16H14N4O (278.31): C, 69.09; H, 5.07; N,
20.13. Found: C, 69.1; H, 5.2; N, 20.2.
5-(1, 5-Diphenyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole-2-thiole (8).
1,5-Di(4-methylphenyl)-1H-pyrazole-3-carboxylic acid hydrazide
(4b).
Method A.
To a solution of the hydrazide (4a) (2.78 g, 10 mmol) in
ethanol (10 mL), a solution of carbon disulphide (1.14 g, 15
mmol) in water (3 mL) and potassium hydroxide (1 g) was
added and the mixture was refluxed until the evolution of H2S
ceased (7-8 hours). The reaction mixture was allowed to cool
and then acidified with dilute hydrochloric acid. The solid
obtained was collected by filtration, washed with the least
amount of water and recrystallized from ethanol-water (1:1).
Yield 83%; mp 160°C; IR (KBr) ꢀ cm-1 3301 (NH), 3210
(NH2), 1690 (C=O); H NMR (DMSO-d6): ꢁ 2.35 (s, 3H, CH3),
3.12 (s, 3H, CH3), 4.85 (s, br., D2O-exchangable, 2H, NH2), 8.78
(s, 1H, NH), 6.93 (s, 1H, pyrazole-4CH), 7.11-7.28 (m, 8H,
ArHs); 13C NMR (DMSO-d6): 156.20, 148.17, 147.12, 145.31,
137.09, 136.56, 129.88, 129.78, 129.69, 129.45, 126.33, 120.16,
22.20, 21.52.
1
Anal. Calcd. for C18H18N4O (306.36): C, 70.57; H, 5.92; N,
18.29. Found: C, 70.6; H, 6.0; N, 18.3.
Method B.
Reaction of 1,5-Diphenyl-1H-pyrazole-3-carboxylic acid
hydrazide (4a) with Carbon disulfide.
A mixture of the potassium salt (6) (3.76 g, 10 mmol) and a
solution of potassium hydroxide solution (50 mL, 20%) was

Sep-Oct 2006
Convenient Synthesis of Some New Substituted Pyrazolyl-1,3,4-oxadiazoles
1187
refluxed for 2 hours, then allowed to cool and acidified with
concentrated hydrochloric acid. The precipitate that formed was
collected by filtration and washed with cold water and
recrystallization from ethanol-water (1:1). Yield 50%; mp
110°C; IR (KBr) ꢀ cm-1 1600 (C=N); 2650 (SH); 1H NMR
(DMSO-d6): ꢁ 6.66 (s, 1H, pyrazole-4CH), 7.11-7.42 (m, 10H,
ArHs), 12.71 (s, 1H, SH); 13C NMR (DMSO-d6): ꢁ 169.07,
148.02, 145.81, 139.42, 136.95, 129.95, 129.88, 129.80, 129.62,
129.44, 129.36, 129.21, 129.97; MS m/z 320 (M+), 278, 187,
130, 93, 77.
1-(1,5-Diphenyl-1H-pyrazole-3-carbonyl)thiosemicarbazide
(14).
To a solution of the hydrazide (4a) (2.78 g, 10 mmol) in
methanol (50 mL), a solution of potassium thiocyanate (20
mmol) and hydrochloric acid (3 mL) was added with constant
stirring. The mixture was immediately evaporated to dryness on
a steam bath and heated for an additional hour with another 50
mL methanol. The resulting solid was treated with water and
with little ethanol and finally recrystallized from ethanol. Yield
75%, mp. 150°C, IR (KBr) ꢀ cm-1 3250 (NH2), 3310 (NH, NH)
1681 (C=O); 1H NMR (CDCl3): ꢁ 2.81 (s, br, 2H, NH2), 6.71 (s,
1H, pyrazole-4CH), 7.05-7.37 (m, 10H, ArHs), 9.21 (s, br, 1H,
NH), 10.24 (s, 1H, NH); 13C NMR (DMSO-d6): ꢁ 169.81,
161.03, 142.33, 142.29, 139.99, 135.15, 129.07, 128.92, 127.86,
127.44, 126.51, 125.96, 107.87.
Anal. Calcd. for C17H12N4OS (320.37): C, 63.73; H, 3.77; N,
17.48; S, 9.99. Found: C, 63.7; H, 3.8; N, 17.5; S, 10.0.
1-(1,5-Diphenyl-1H-pyrazole-3-carbonyl)-4-phenylthiosemi-
carbazide (9).
A mixture of an equimolar quantity of the pyrazole acid
hydrazide (4a) (2.78 g, 10 mmol) and phenyl isothiocyanate (10
mmol), in absolute ethanol (40 mL) was refluxed for 6 hours. On
cooling to room temperature, fine crystals deposited which were
collected by filtration and recrystallized from ethanol. Yield
75%; mp 198°C; IR (KBr) ꢀ cm-1 3310, 3201 (NH, NH), 1658
(C=O); 1H NMR (DMSO-d6): ꢀ 6.8 (s, 1H, pyrazole-4CH), 7.12-
7.51 (m, 15H, ArHs), 9.6 (s, br., D2O-exchangable, 2H, 2NH),
10.5 (s, br., D2O-exchangable, 1H, NH).
Anal. Calcd. for C17H15N5OS (337.40): C, 60.52; H, 4.48; N,
20.76, S, 9.50. Found: C, 60.6; H, 5.0; N, 20.8; S, 9.6
5-(1,5-Diphenyl-1H-pyrazol-3-yl)-4H-1,2,4-triazole-3-thiole
(15)
A suspension of the thiosemicarbazid derivative (14) (0.34 g,
1 mmol) in sodium hydroxide solution (10 mL, 10%) was heated
under reflux for one hour. The reaction mixture was allowed to
cool then adjusted to pH 6 with 10% hydrochloric acid. The
precipitate that formed was collected by filtration, washed with
water, dried and recrystallized from ethanol. Yield 78%; mp
Anal. Calcd. for C23H19N5OS (413.50): C, 66.81; H, 4.63; N,
16.94; S, 7.75. Found: C, 66.8; H, 4.7; N, 17.0; S, 7.7.
1
173°C; IR (KBr) ꢀ cm-1 1598 (C=N); H NMR (DMSO-d6): ꢁ
5-(1, 5-Diphenyl-1H-pyrazol-3-yl)-4-phenyl-4H-1,2,4-triazole-
3-thiole (10).
6.9 (s, 1H, pyrazole-4CH), 7.05-7.47(m, 10H, ArHs), 13.7 (s,
1H, NH), 13.8 (s, 1H, SH). MS m/z 319 (M+), 264, 246, 116, 77,
51; 13C NMR (DMSO-d6): ꢁ 169.31, 149.75, 146.50, 144.50,
129.22, 129.10, 128.94, 128.73, 126.77, 125.64, 124.68, 109.63,
106.46.
A suspension of the thiosemicarbazide (9) (2.07, 5 mmol) in
sodium hydroxide solution (25 mL, 5%) was heated under reflux
for one hour. The reaction mixture was allowed to cool, and then
adjusted to pH 6 with 10% hydrochloric acid. The precipitate
that formed was collected by filtration, washed with water, dried
and finally recrystallized from ethanol. Yield 83%; mp 210°C;
IR (KBr) ꢀ cm-1 2650 (SH), 1589 (C=N), 1496 (C=C); 1H NMR
(DMSO-d6): ꢀ 6.61 (s, 1H, pyrazole-4CH), 6.99-7.54 (m, 15H,
ArHs), 14.10 (s, br., D2O-exchangable, 1H, SH). MS m/z 395
(M+), 246, 198, 149, 116, 77; 13C NMR (DMSO-d6): ꢁ 168.75,
145.22, 144.65, 143.49, 138.91, 134.93, 129.33, 129.05, 128.99,
128.95, 128.72, 128.56, 128.18, 124.70, 119.00, 113.27, 107.82.
Anal. Calcd. for C23H17N5S (395.49): C, 69.85; H, 4.33; N,
17.71, .S, 8.11. Found: C, 69.9; H, 4.4; N, 17.8; S, 8.2.
Anal. Calcd. for C17H13N5S (319.40): C, 63.93; H, 4.10; N,
21.92; S, 10.04. Found: C, 64.0; H, 4.2; N , 22.0; S, 10.0.
(1,5-Diphenyl-1H-pyrazol-3-yl)-(5-hydroxy-3-metheyl-1-carbonyl)-
pyrazole (17).
To
a mixture of 1,5-diphenylpyrazol-3-carboxylic acid
hydrazide (4a) (2.78 g, 10 mmol) and ethyl acetoacetate (10
mmol) in ethanol (20 mL), piperidine (0.4 mL) was added, and
the mixture was refluxed for 10 hours. The precipitated solid
was collected by filtration and recrystallized from 95% ethanol.
Yield 42%; mp 166°C IR (KBr) ꢀ cm-1 1650 (C=O). MS m/z 344
1
(M+), 303, 264, 247, 105, 77. H NMR (CDCl3): ꢁ 2.45 (s, 3H,
5-(1,5-Diphenyl-1H-pyrazol-3-yl)-4-phenyl-3-methylthio-4H-
1,2,4-triazole (12).
CH3), 6.23 (s, 1H, CH pyrazole), 6.74 (s, 1H, pyrazole-4CH),
7.09-7.59 (m, 10H, ArH's), 10.8 (s, br., D2O-exchangeable 1H,
OH); 13C NMR (DMSO-d6): ꢁ 169.47, 144.41, 143.48, 141.27,
139.79, 139.25, 133.46, 129.21, 128.67, 128.52, 128.32, 127.78,
125.50, 107.99, 95.25, 16.60.
The triazole-thiol (10) (0.4 g, 1 mmol) was dissolved in an
ethanolic solution of sodium ethoxide [prepared from sodium
metal (0.023 g) in ethanol (15 mL)], then methyl iodide (0.3 g, 2
mmol) was added gradually to the resulting solution. The
Anal. Calcd. for C20H16N4O2 (344.37): C, 69.75; H, 4.68; N,
16.27. Found: C, 69.8; H, 4.7; N, 16.3.
reaction mixture was heated under reflux for
2 hours,
concentrated, cooled, diluted with water and left overnight. The
precipitate obtained was collected by filtration, washed with
water and recrystallized from ethanol. Yield 65%; mp 149°C; IR
(KBr) ꢀ cm-1 1600 (C=N), 1498 (C=C).1H NMR (CDCl3): ꢁ 2.61
(s, 3H, CH3), 6.74 (s, 1H, pyrazole-4CH), 6.9-7.56 (m, 15H,
ArH's); 13C NMR (DMSO-d6): ꢁ 168.52, 146.02, 145.92, 144.79,
129.13, 129.07, 128.82, 128.54, 128.35, 126.85, 126.57, 126.28,
126.12, 123.99, 123.64, 123.63.
(1,5-Diphenyl-1H-pyrazol-3-yl)-(3,5-dimethyl-1-carbonyl)-
pyrazole (18).
To a mixture of 1,5-diphenylpyrazol-3-yl-carboxylic acid
hydrazide (4a) (2.78 g, 10 mmol) and acetylacetone (10 mmol)
in ethanol (20 mL), piperidine (0.4 mL) was added, and the
mixture was refluxed for 8 hours. The precipitated solid was
collected by filtration and recrystallized from 95% ethanol.
Yield 43%; mp 130°C; IR (KBr) ꢀ cm-1 1676 (C=O); MS m/z
Anal. Calcd. for C24H19N5S (409.51): C, 70.40; H, 4.68; N,
17.10; S, 7.83. Found: C, 70.9; H, 4.7; N, 17.2; S, 7.6.
1
342 (M+), 266, 247, 219, 171, 116, 77, 51. H NMR (CDCl3): ꢁ

1188
Y. M. Elkholy, K. A. Ali and A. M. Farag
Vol 43
[15] B. Tozkoparan, N. Gökhan, G. Aktay, E. Yeꢀilada, M. Ertan,
Eur. J. Med. Chem., 35, 743 (2000).
[16] N. Demirbas, R. Ugurluoglu, A. Demirbas, Bioorg. Med.
Chem., 10, 3717 (2002).
[17] G. Turan-Zitouni, M. Sıvaci, F. S. Kiliç, K. Erol, Eur. J.
Med. Chem., 36, 685 (2001).
[18] M. Tandon, J. P. Bartwal, T. N. Bahalla, K. P. Bhargava,
Indian J. Chem., 20, 1017 (1981).
2.45 (s, 3H, CH3), 2.79 (s, 3H, CH3), 6.61 (s, 1H, pyrazole-
4CH), 6.68 (s, 1H, CH pyrazole), 7.10-7.83 (m, 10H, ArH's); 13
NMR (DMSO-d6): ꢀ 190.02, 148.06, 145.74, 144.96, 143.30,
139.61, 133.20, 129.27, 128.99, 128.73, 128.50, 127.50.
Anal. Calcd. for C21H18N4O (342.40): C, 73.66; H, 5.30; N,
16.36. Found: C, 73.6; H, 5.3; N, 16.4.
C
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[24] A. M. Farag, K. M. Dawood, H. A. Elmenoufy, Heteroatom
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