An efficient synthesis of some new isolated and fused triazole derivatives

Article abstract of DOI:10.1002/jhet.1110

A facile and efficient route to 5-hydrazinyl-3-phenyl-3H-[1,2,4]triazole from the reaction of triazol-3-one and hydrazine hydrate is described. In addition, the formation of isolated and fused triazole derivatives was prepared via reaction of with some selected electrophilic reagents in basic medium.

Full text of DOI:10.1002/jhet.1110

Month 2013
An Efficient Synthesis of Some New Isolated and Fused Triazole
Derivatives
Eman A. El Rady
Chemistry Department, Faculty of Science, South Valley University, Aswan 81528, Egypt
*
E-mail: emanelradi@hotmail.com
Received August 2, 2011
DOI 10.1002/jhet.1110
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
N
N
N
N
N
R1
R2
H
H
N
N
N
N
N
N
Ph
N
N
N
O
N
N
R
H
Ph
Ph
N
N
N
NH2
N
O
Ph
2
H
N
H
N
N
N
N
N
N
N
Cl
N
N
N
S
N
NH
Ph
N
N
Ph
Ph
O
Ph
Ph
A facile and efficient route to 5-hydrazinyl-3-phenyl-3H-[1,2,4]triazole 2 from the reaction of triazol-3-one 1
and hydrazine hydrate is described. In addition, the formation of isolated and fused triazole derivatives was
prepared via reaction of 2 with some selected electrophilic reagents in basic medium.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
1,2,4-Triazoles are an important class of heterocyclic
compounds; they are well-known for their biological
properties [1], such as antifungal [2–4], antimicrobial
[5–9], antitumor, antiviral [10–13], anti-asthmatic [14],
hypotonic [15], anticonvulsant [16,17], and anti-arthritic
activities [18]. Also, 1,2,4-triazole derivatives were found
as potential antitubercular agents [19,20], anticancer [21],
as receptor antagonists [22–24], and exhibits efficacy
against a broad range of viruses in vitro [25,26]. On the
other hand, cytotoxicity and effects of some 1,2,4-triazoles
on immunocompetent cells were investigated. Since,
triazoles were ascertained to exhibit high cytotoxicity in
test in vitro against thymocytes and lymphocytes [27,28].
In view of the aforementioned versatile benefits of 1,2,4-
triazoles and as a continuation of our efforts to the synthesis
of isolated and fused heterocyclic compounds [29–35],
we report herein a facile and convenient route to 5-hydrazi-
nyl-3-phenyl-3H-[1,2,4]triazole 2, which is considered as
a key intermediate for the synthesis of new triazolylpyra-
zole, triazolo[3,4-c][1,2,4]triazole, triazolo[4,3-d]tetrazole,
triazolo[3,4-c][1,2,4]triazine, triazolyl-thiazolidinone, and
triazolyl-azetidinone.
The 5-hydrazinyl-3-phenyl-3H-[1,2,4]triazole 2 was
synthesized by the reaction of triazol-3-one 1 [35] with
hydrazine hydrate in pyridine at refluxing temperature.
The formation of compound 2 may proceed via an elimina-
tion of water (Scheme 1). The structure of compound 2 was
established on the basis of analytical and spectral analyses.
The IR spectrum of compound 2 confirmed the presence of
intense absorption bands at n 3450, 3455, and 3120 cmÀ1
due to amino and imino groups, respectively. The 1H
NMR spectrum of compound 2 showed one singlet signal
at d 2.56 ppm due to amino, in addition to multiplets at d
7.40–7.84 ppm attributed to aromatic protons, H-3 triazole,
and imino group, respectively. The MS of compound 2
showed m/z at 175 (M+, 70%). Compound 2 considered a
good and available starting material for the synthesis of new
functionalized heterocyclic compounds, since; it contains a
nucleophillic hydrazinyl group. Thus, triazolylpyrazole 3–7
have been synthesized by the reaction of 5-hydrazinyl triazole
2 with active methylene reagents and/or 1,3 diketones in the
presence of catalytic amount of piperidine in ethanol at reflux
temperature (Scheme 1). The progress of the reaction has
been monitored using TLC, and the final yields for these
© 2013 HeteroCorporation

E. A. El Rady
Vol 000
Scheme 1. Synthesis of 1,2,4-triazolyl pyrazoles (3–7).
N
N
CH2(CN)2
Ph
N
N
N
NH2
H2N
N
3
N
N
CN-CH2CO2Et
Ph
Ph
N
N
4
NH-NH2
NH2
O
N
O
N
N
N2H4
N
N
N
N
CH2(CO-CH3)2
N
NH
Ph
N
N
Ph
1
2
5
CH3
H3C
N
N
N
CH2(CO2Et)2
Ph
H
N
N
6
O
O
N
N
CH3CO-CH2CO2Et
Ph
N
N
N
7
CH3
O
reactions ranges from 40 to 60%. IR spectroscopy data of
compounds 3–7 have variable intensity, sometimes broad
absorption bands as well as stretching vibrations typical for
the functional groups in their structure. Compound 3 has
strong absorption bands at n 3450 and 3500 cmÀ1 for the
two amino groups, and compound 4 has medium absorption
bands at n 3400 and 1690 cmÀ1 for one amino group and one
carbonyl group, respectively. Also, compound 6 gave strong
absorption bands at n 1700 and 1710 cmÀ1 for two carbonyl
Also, the 5-hydrazinyl-3-phenyl-3H-[1,2,4]triazole
2
underwent other several cyclization reactions (Scheme 2).
Thus, treatment of compound 2 with acetic anhydride in
pyridine solution gave the corresponding 3-methyl-5-phenyl-
1H-[1,2,4]triazolo[3,4-c][1,2,4]triazole 9. The IR spectrum
of compound 9 showed the lack of absorption band due to
amino function and exhibited characteristic absorption band
at n 3140 cmÀ1 due to imino group. The 1H NMR spectrum
of compound 9 displayed one singlet signal at d 1.32 ppm
due to methyl, in addition to multiplet at d 7.22–7.94 ppm
for aromatic and NH-triazole protons. The MS of compound
9 showed an intense ion peak at m/z at 199 (M+, 60%).
The reactivity of the hydrazinyl group in compound 2 is
also explored through its reaction with carbon disulfide. Thus,
refluxing of compound 2 with carbon disulfide in pyridine
at refluxing temperature gave 5-phenyl-1H-[1,2,4]triazolo
[3,4-c][1,2,4]triazole-3-thiol 11. The IR spectrum of com-
pound 11 showed the absence of absorption band assignable
to amino group and displayed absorption band at n
3170 cmÀ1 due to imino group. The formation of 11 may pro-
ceed through the addition of the amino protons to CS2 via the
formation of intermediate 10, which is followed by cyclization
through elimination of hydrogen sulfide (Scheme 2).
1
groups. However, in their H NMR spectra, the multiplet
signals appears between d 7.23–7.77 ppm due to aromatic
and H-3 triazole protons. The single proton of the pyrazole
ring (3 and 5) has a signal in the area of 7.12–722 ppm, and
the two protons of the pyrazole ring (4, 6, and 7) have a signal
in the area of 5.22–5.75 ppm. The two amino groups of the
pyrazole ring in compound 3 have two singlet signals at
3.21 and 3.32 ppm, whereas a singlet signal is recorded at
d 2.51 ppm due to the amino protons of compound 4. The
two methyl groups of the pyrazole ring in compound 5 have
two singlet signals at 2.89 and 2.98 ppm, and the methyl
group of compound 7 appears as one singlet signal at
d 1.33 ppm. The mass spectroscopic molecular ion observed
in the spectra of all compounds confirms their structures.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
An Efficient Synthesis of Some New Isolated and Fused Triazole Derivatives
Scheme 2. Synthesis of [1,2,4]triazolo[3,4-c][1,2,4]triazoles and [1,2,4]triazolo[4,3-d]tetrazole.
H
N
H
H
N
(CH3CO)2O
N
NH
N
N
N
N
N
N
N
N
N
NH
-H2O
N
CH3
CH3
O
HO
CH3
Ph
Ph
Ph
9
8
H
N
H
N
H
N
N
N
N
N
N
N
N
N
CS2
N
NH
HS
-H2S
N
N
NH-NH2
SH
HS
SH
SH
N
N
Ph
Ph
Ph
N
11
10
Ph
H
H
N
H
N
2
N
HCOOH
-H2O
N
N
N
N
N
N
N
N
-H2O
N
N
NH
N
HO
HO
Ph
Ph
Ph
13
12
H
N
H
N
H
N
N
N
N
N
N
N
N
N
N
N
N
N
HONO
-H2O
N
NH
HO
-H2O
N
HO
Ph
Ph
Ph
15
14
Similarly, 5-phenyl-1H-[1,2,4]triazolo[3,4-c][1,2,4]triazole
13 was obtained via treatment of compound 2 with formic
acid. The IR spectrum revealed the absence of absorption
band attributed to amino group. The MS of compound 13
showed m/z at 185 (M+, 55%).
On the other hand, compound 2 reacted with nitrous acid
to afford 6-phenyl-3H-[1,2,4] triazolo [4,3-d] tetrazole 15,
which may be formed via elimination of water through
intermediate 14. The IR spectrum of compound 15
revealed the absence of absorption band attributed to
amino group and showed absorption band at n 3135 cmÀ1
due to imino function. The MS of compound 15 showed
an intense ion peak at 186 (M+, 56%) (Scheme 2).
compound 17 showed an intense ion peak at 215
(M+, 45%) (Scheme 3).
Also, compound 2 is condensed with benzaldehyde
in ethanolic piperidine solution at refluxing temperature
affording the corresponding Schiff base 18. The IR
spectrum of compound 18 showed the absence of the
absorption band of the amino group and exhibited the
presence of absorption bands at n 3134 cmÀ1 due to NH
1
function. The H NMR spectrum of compound 18 showed
singlet signal at d 6.12 ppm for N═CH group. The MS of
compound 18 showed an intense ion peak at m/z at 263
(M+, 50%). The reactivity of Schiff base 18 could be
shown by the reaction of thioglycolic acid; the isolated
thiazolidinone 20 may be formed by a nucleophilic addition
of thiol function to the imino carbon of compound 18
through intermediate 19 that underwent a cyclization to 20
via loss of water. The MS of compound 20 showed a peak
at m/z 337 (M+, 50%) (Scheme 3).
However, the addition of chloroacetyl chloride to Schiff
base 18 gave intermediate 21, which in turn undergoes
cyclization via elimination of hydrogen chloride to afford
the new b-lactam compound 22. The IR spectrum of
compound 22 showed the presence of absorption bands at n
3132 and 1697 cmÀ1 due to (NH) and (CO) functions,
respectively. The 1H NMR spectrum of compound 22
showed two doublet signals at d 5.12 and 5.29 ppm for the
protons at C3 and C4 of the azetidinone. The MS of
3-Phenyl-3,7-dihydro[1,2,4]triazolo[3,4-c][1,2,4]triazin-6
(5H)-one 17 could be obtained through the reaction
of compound 2 with chloroacetyl chloride in ethanolic
piperidine solution at refluxing temperature. The formation
of compound 17 may proceed via an elimination of
hydrogen chloride through intermediate 16, then cyclized
via an elimination of other molecule of hydrogen chloride.
The IR spectrum of compound 17 revealed the absence of
absorption band attributed to amino group and appearance
of absorption bands at n 3150 and 1690 cmÀ1 due to NH
1
and CO groups. The H NMR spectrum of compound 17
showed singlet signal at d 3.44 ppm for triazine-CH2
protons and multiplet between d 7.23 and 7.88ppm for
H-3 triazole, imino, and aromatic protons. The MS of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. A. El Rady
Vol 000
Scheme 3. Synthesis of [1,2,4]triazolo[3,4-c]triazine, [1,2,4]triazolyl thiazolidine, and [1,2,4]triazolyl azetidine.
H
N
H
H
N
N
N
N
N
N
NH
ClCH2COCl
-HCl
N
N
N
N
O
O
N
N
NH
-HCl
Cl
Cl
O
NH
NH2
N
N
Ph
Ph
Ph
16
17
N
NH
N
PhCHO
-H2O
N
N
Ph
2
CHPh
N
Ph
18
O
Cl
O
HO
H
H
N
H
H
SHCH2COOH
N
ClCH2COCl
N
N
N
N
N
S
Cl
N
N
Ph
N
Ph
Ph
Ph
21
19
O
-HCl
-H2O
O
H
H
N
N
N
N
Cl
N
N
S
N
N
N
N
Ph
Ph
20
22
Ph
Ph
acidified cold water. The solid product formed was filtered off,
washed with cold water, dried, and recrystallized with ethanol to
give 2 as buff powder. Yield 73%, 0.13g, mp 180–182ꢀC; IR
(nmax, cmÀ1): 3450 and 3455 (NH2), 3120 (NH). 1H NMR
(300 MHz, CDCl3): d ppm 2.56 (s, 2H, NH2), 7.40–7.84 (m, 7H,
Ar-H+ H-3 triazole+ NH). 13C NMR (75 MHz, CDCl3): d ppm
73.55, 125.82, 128.77, 129.55, 137.23, 163.55. MS, m/z
(%) = 175 ([M]+, 70), 144 ([M]+–NHNH2, 60), 98 ([M]+–Ph, 40).
Anal. Calcd for C8H9N5 (175.19): C, 54.85; H, 5.18; N, 39.98%.
Found: C, 54.91; H, 5.27; N, 39.99%.
1-(3-Phenyl-3H-1,2,4-triazol-5-yl)-1H-pyrazole-3,5-diamine
(3). A mixture of 2 (1.75 g, 10 mmol) and malononitrile (0.6 g,
10 mmol) in 30 mL of ethanol containing 0.2 mL of piperidine
was refluxed for 5 h. The solvent was evaporated under
vacuum, and the residue was triturated with methanol. The
solid product was filtered and recrystallized from methanol
as colorless crystals. Yield 40%, 0.11 g, mp 225–227ꢀC; IR
(nmax, cmÀ1): 3450 and 3500 (NH2). 1H NMR (300 MHz,
CDCl3): d ppm 3.21 (s, 2H, NH2), 3.32 (s, 2H, NH2), 7.22
(s, 1H, H-pyrazole), 7.28–7.67 (m, 6H, Ar-H + H-3 triazole).
13C NMR (75 MHz, CDCl3): d ppm 71.85, 78.77, 125.83,
128.75, 129.54, 137.23, 148.12, 149.88, 163.55. MS, m/z
(%) = 241 ([M]+, 50), 225 ([M]+–NH2, 60), 209 ([M]+–2NH2, 20),
132 (C11H5–Ph, 54). Anal. Calcd for C11H11N7 (241.25): C,
54.76; H, 4.60; N, 40.64%. Found: C, 54.81; H, 4.76; N, 40.74%.
3-Amino-1-(3-phenyl-3H-1,2,4-triazol-5-yl)-1H-pyrazole-5
(4H)-one (4). A mixture of 2 (1.75 g, 10 mmol) and ethylcyanoacetate
(1.13 g, 10 mmol) in 30 mL of ethanol containing 0.2 mL of
piperidine was refluxed for 5 h. The solvent was evaporated
under vacuum, and the residue was triturated with methanol.
compound 22 displayed an intense ion peak at m/z 339
(M+, 52%) (Scheme 3).
CONCLUSION
Despite the several existing methods for the synthesis of
triazole derivatives, there still is demand for general
strategies, which can efficiently provide variously substituted
triazole systems. Thus, this work opened a simple avenue for
the synthesis of a variety of isolated and fused triazole
derivatives with the use of 5-hydrazinyl-3-phenyl-3H-
[1,2,4] triazole.
EXPERIMENTAL
Melting points were determined on a Gallenkamp electrothermal
melting point apparatus and are uncorrected. IR spectra were
recorded as potassium bromide pellets with the use of an FTIR unit
Bruker-vector 22 spectrophotometer. 1H NMR and 13C NMR
spectra were obtained in DMSO-d6 as solvent at 300 and
75MHz, respectively on a Varian Gemini NMR spectrometer
using TMS as internal standard. Chemical shifts are reported in
d units (ppm). Mass spectra were recorded on a Hewlett Packard
MS-5988 spectrometer at 70eV. Elemental analysis was carried
out at the Micro analytical Center of Cairo University, Egypt.
Synthesis of 5-hydrazinyl-3-phenyl-3H-[1,2,4]triazole (2).
A solution of 5-phenyl-4,5-dihydro-3H-1,2,4-triazol-3-one 1
(10 mmol) and hydrazine hydrate (10 mmol) in 20mL of pyridine
was refluxed for 4 h, then allowed to cool, and poured into
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
An Efficient Synthesis of Some New Isolated and Fused Triazole Derivatives
The solid product was filtered and recrystallized from methanol as
130.21, 148.96, 149.56, 152.87. MS, m/z (%) = 199 (M+, 60).
Anal. Calcd for C10H9N5 (199.21): C, 60.29; H, 4.55; N,
35.16%. Found: C, 60.37; H, 4.64; N, 35.24%.
5-Phenyl-1H-[1,2,4]triazolo[3,4-c][1,2,4]triazole-3-thiol (11).
A mixture of 2 (1.75 g, 10 mmol) and carbon disulfide
(10 mmol) was heated at reflux for 4 h and then allowed to cool.
The solid product was collected by filtration and recrystallized
white crystals. Yield 50%, 0.12 g, mp 230–232ꢀC; IR (nmax
,
1
cmÀ1): 3400 (NH2), 1690 (CO). H NMR (300 MHz, CDCl3):
d ppm 2.51 (s, 2H, NH2), 5.75 (s, 2H, CH2-pyrazole), 7.25–7.69
(m, 6H, Ar-H + H-3 triazole). 13C NMR (75 MHz, CDCl3):
d ppm 70.85, 72.76, 125.82, 128.75, 129.53, 137.23, 159.88,
163.55, 164.78. MS, m/z (%)= 242 ([M]+, 55), 216 ([M]+–NH2,
20), 165 ([M]+–Ph, 30). Anal. Calcd for C11H10N6O (242.24):
C, 54.54; H, 4.16; N, 34.69%. Found: C, 54.63; H, 4.23; N,
34.74%.
from methanol. Yield 50%, 0.11 g, mp 200–202ꢀC; IR (nmax
,
cmÀ1): 3170 (NH); 1H NMR (300MHz, CDCl3): d ppm
7.23–7.90 (m, 6H, Ar-H + NH), 10.55 (s, 1H, SH). 13C NMR
(75 MHz, CDCl3): d ppm 126.82, 128.77, 129.53, 130.45, 148.88,
152.55, 168.76. MS, m/z (%)= 217 ([M]+, 60), 219 (M + 2, 4%).
Anal. Calcd for C9H7N5S (217.25): C, 49.76; H, 3.25; N, 32.24%.
Found: C, 49.85; H, 3.32; N, 32.35%.
3,5-Dimethyl-1-(3-phenyl-3H-1,2,4-triazol-5-yl)pyrazole (5).
A
mixture of 2 (1.75 g, 10 mmol) and acetylacetone
(1.3 g, 10 mmol) in 30 mL of ethanol containing 0.2 mL of
piperidine was refluxed for 5 h. The solvent was evaporated under
vacuum, and the residue was triturated with methanol. The solid
product was filtered and recrystallized from methanol as colorless
crystals. Yield 60%, 0.14g, mp 235–237ꢀC; 1H NMR (300 MHz,
CDCl3): d ppm 2.89 (s, 3H, CH3), 2.98 (s, 3H, CH3), 7.12 (s, 1H,
H-pyrazole), 7.23–7.70 (m, 6H, Ar-H + H-3 triazole). 13C NMR
(75 MHz, CDCl3): d ppm 11.47, 17.88, 71.76, 105.76, 125.82,
128.77, 129.59, 137.34, 143.89, 149.88, 163.55. MS, m/z
(%) = 239 ([M]+, 65), 209 ([M]+–2CH3, 43), 132 ([M]+–Ph,
–2CH3, 32). Anal. Calcd for C13H13N5 (239.28): C, 65.25; H,
5.48; N, 29.27%. Found: C, 65.36; H, 5.58; N, 29.39%.
5-Phenyl-1H-[1,2,4]triazolo[3,4-c][1,2,4]triazole (13). A mixture
of 2 (1.75 g, 10 mmol) and formic acid (15 mL) was heated under
reflux for 4 h and then allowed to cool. The solid product was
collected by filtration and recrystallized from methanol. Yield
60%, 0.11 g, mp 233–235ꢀC; IR (nmax, cmÀ1): 3190 (NH);
1H NMR (300 MHz, CDCl3): d ppm 7.23–7.97 (m, 7H,
Ar-H + CH-triazole + NH). 13C NMR (75 MHz, CDCl3): d ppm
126.82, 128.75, 129.53, 130.43, 139.99, 148.44, 152.54. MS,
m/z (%) = 185 ([M]+, 55). Anal. Calcd for C9H7N5 (185.19): C,
58.37; H, 3.81; N, 37.82%. Found: C, 58.45; H, 3.92; N, 37.90%.
1-(3-Phenyl-3H-1,2,4-triazol-5-yl)-pyrazolidine-3,5-dione (6).
A mixture of 2 (1.75 g, 10 mmol) and diethymalonate (1.3 g,
10 mmol) in 30 mL of ethanol containing 0.2 mL of
piperidine was refluxed for 5 h. The solvent was evaporated
under vacuum, and the residue was triturated with methanol.
The solid product was filtered and recrystallized from methanol
as colorless crystals. Yield 60%, 0.15 g, mp 227–229ꢀC; IR
(nmax, cmÀ1): 3140 (NH), 1700 and 1710 (CO). 1H NMR
(300 MHz, CDCl3): d ppm 5.22 (s, 2H, CH2-pyrazolidine),
7.28–7.77 (m, 7H, Ar-H + H-3 triazole + NH). 13C NMR
(75 MHz, CDCl3): d ppm 47.89, 70.95, 125.82, 128.75, 129.53,
137.21, 163.85, 170.78, 170.99. MS, m/z (%) = 243 ([M]+, 63),
225 ([M]+ À 18, 20), 166 ([M]+-Ph, 35). Anal. Calcd for
C11H9N5O2 (243.22): C, 54.32; H, 3.73; N, 28.79%. Found: C,
54.41; H, 3.82; N, 28.88%.
6-Phenyl-3H-[1,2,4]triazolo[4,3-d]tetrazole (15). To an ice-
cooled solution of 2 (1.75 g, 10 mmol) in hydrochloric acid/
acetic acid (20:10 v/v), a solution of sodium nitrite (10 mmol) in
water (10 mL) was added dropwise. The solution was stirred at
room temperature for an additional 2 h; the crude product
obtained was filtered off and recrystallized from ethanol as buff
powder. Yield 60%, 0.11 g, mp 190–192ꢀC; IR (υ cmÀ1): 3160
(NH). 1H NMR (300 MHz, CDCl3): d ppm 7.22–7.94 (m, 6H,
Ar-H + NH). 13C NMR (75 MHz, CDCl3): d ppm 126.82,
128.77, 129.58, 130.47, 148.15, 148.99. MS, m/z (%) = 186
([M]+, 56). Anal. Calcd for C8H6N6 (186.17): C, 51.61; H, 3.25;
N, 45.14%. Found: C, 51.72; H, 3.36; N, 45.26%.
3-Phenyl-3,7-dihydro[1,2,4]triazolo[3,4-c][1,2,4]triazin-6
(5H)-one (17). An equimolar mixture of 2 (1.75 g, 10mmol) and
chloroacetylchloride (1.0g, 10 mmol) in 30 mL of ethanol
containing 0.2 mL of piperidine was refluxed for 6 h. The
reaction mixture was concentrated and poured into acidified cold
water. The solid product formed was filtered off, washed with
cold water, dried, and recrystallized with ethanol/H2O (3:1) to
yield brown powder. Yield 45%, 0.11 g, mp 222–224ꢀC; IR
(nmax, cmÀ1): 3150 (NH), 1690 (CO). 1H NMR (300MHz,
CDCl3): d ppm 3.44 (s, 2H, CH2-triazine), 7.23–7.88 (m, 7H,
Ar-H+ H-3 triazole+ NH). 13C NMR (75 MHz, CDCl3): d ppm
40.87, 76.87, 125.81, 128.79, 129.53, 140.23, 159.37, 160.81.
MS, m/z (%) = 215 ([M]+, 50), 187 (M–CO, 45), 138 ([M]+–Ph,
30). Anal. Calcd for C10H9N5O (215.21): C, 55.81; H, 4.22; N,
32.54%. Found: C, 55.92; H, 4.34; N, 32.66%.
3-Methyl-1-(3-phenyl-3H-1,2,4-triazol-5-yl)-1H-pyrazol-5
(4H)-one (7). A mixture of 2 (1.75 g, 10 mmol) and ethylacetoacetate
(1.1 g, 10 mmol) in 30 mL of ethanol containing 0.2 mL of
piperidine was refluxed for 5 h. The solvent was evaporated
under vacuum, and the residue was triturated with methanol.
The solid product was filtered and recrystallized from methanol
as colorless crystals. Yield 59%, 0.14 g, mp 237–239ꢀC; IR
1
(nmax, cmÀ1): 1705 (CO). H NMR (300 MHz, CDCl3): d ppm
1.33 (s, 3H, CH3), 5.35 (s, 2H, CH2-pyrazole), 7.25–7.72 (m, 6H,
Ar-H + H-3 triazole). 13C NMR (75 MHz, CDCl3): d ppm 22.90,
33.89, 40.89, 70.80, 125.82, 128.75, 129.53, 137.24, 159.23,
163.55, 172.78. MS, m/z (%)= 241 ([M]+, 60), 223 ([M]+–H2O,
30), 226 ([M]+–CH3, 20), 131 (C11H4N5–Ph, 33). Anal. Calcd for
C12H11N5O (241.25): C, 59.74; H, 4.60; N, 29.03%. Found: C,
59.82; H, 4.66; N, 29.12%.
2-Benzylidene-1-(5-phenyl-5H-1,2,4-triazol-3-yl)hydrazine
(18). An equimolar mixture of 2 (1.75 g, 10 mmol) and benzaldehyde
(1.06 g, 10 mmol) in ethanol (30 mL) in the presence of
piperidine (0.3 mL) was refluxed for 6 h. The reaction mixture
was concentrated and poured into acidified cold water. The
solid product formed was filtered off, washed with cold
water, dried, and recrystallized with ethanol/H2O (3:1) to yield
3-Methyl-5-phenyl-1H-[1,2,4]triazolo[3,4-c][1,2,4]triazole (9).
A mixture of 2 (1.75 g, 10 mmol) and acetic anhydride
(15 mL) was heated at reflux for 4 h and then allowed to cool.
The solid product was collected by filtration and recrystallized
from methanol. Yield 60%, 0.12 g, mp 130–132ꢀC; IR (nmax
,
brown powder. Yield 45%, 0.12 g, mp 230–232ꢀC; IR (nmax
,
cmÀ1): 3140 (NH). 1H NMR (300 MHz, CDCl3): d ppm 1.32
(s, 3H, CH3), 7.22–7.94 (m, 6H, Ar-H + NH). 13C NMR
(75 MHz, CDCl3): d ppm 15.88, 126.84, 128.75, 129.59,
cmÀ1): 3134 (NH). 1H NMR (300 MHz, CDCl3): d ppm 6.12
(s, 1H, –N═CH), 7.23–7.88 (m, 12 H, Ar-H + NH + H-3
triazole). MS, m/z (%) = 263 ([M]+, 50). 159 ([M]+–PhCHN,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. A. El Rady
Vol 000
[7] Demirbas, A.; Sahin, D.; Demirbas, N.; Alpay-Karaoglu, S.
Eur J Med Chem 2009, 44, 2896.
20). Anal. Calcd for C15H13N5 (263.30): C, 68.42; H, 4.98; N,
26.60%. Found: C, 68.55; H, 5.06; N, 26.77%.
[8] Salgın-Göksen, U.; Gokhan-Kelekci, N.; Goktas, O.;
Köysal, Y.; Kılıc, E.; Isık, S.; Aktay, G.; Ozalp, M. Bioorg Med
Chem 2007, 15, 5738.
[9] Labanauskas, L.; Udrenaite, E.; Gaidelis, P.; Bruk, A. Il
Farmaco 2004, 59, 255.
[10] Todoulou, O. G.; Papadaki-Valiraki, A. E.; Ikeda, S.;
De Clercq, E. Eur J Med Chem 1994, 29, 611.
[11] Al-Soud, Y. A.; Al-Dweri, M. N.; Al-Masoudi, N. A. Il Farm-
aco 2004, 59, 775.
2-Phenyl-3-[(3-phenyl-3H-1,2,4-triazol-5-yl) amino]-1,3-
thiazolidin-4-one (20). An equimolar mixture of 18 (0.32 g,
2 mmol) and thioglycolic acid (0.28 mL, 2 mmol) in dry benzene
(20 mL) was refluxed for 10 h. The reaction mixture was evaporated
to dryness under reduced pressure. The thiazolidinone was
separated off, washed with ether, and recrystallized from ethanol as
brown powder. Yield 45%, 0.15 g, mp 224–226ꢀC; IR (nmax
,
cmÀ1): 3130 (NH), 1695 (CO). 1H NMR (300 MHz, CDCl3): d
ppm 3.39 (s, 2H, CH2 thiazole), 5.96 (s, 1H, CH thiazole),
7.23–7.88 (m, 12 H, Ar-H + NH + H-3 triazole). 13C NMR
(75 MHz, CDCl3): d ppm 36.73, 57.45, 76.62, 125.82, 127.54,
128.75, 128.99, 129.53, 129. 89, 133.78, 139.43, 163.89, 168.67.
MS, m/z (%) = 337 ([M]+, 50), 309 ([M]+–CO, 30), 305 ([M]+–S,
20), 260 ([M]+–Ph, 25). Anal. Calcd for C17H15N5OS (337.40): C,
60.52; H, 4.48; N, 20.76%. Found: C, 60.63; H, 4.59; N, 20.79%.
3-Chloro-4-phenyl-1-[(3-phenyl-3H-1,2,4-triazol-5-yl)amino]
azetidin-2-one (22). To a well-stirred solution of 18 (0.32 g,
2 mmol) and triethylamine (0.1 mL) in dry dioxane (20 mL),
chloroacetyl chloride (0.22 mL, 2 mmol) was added dropwise at
room temperature, then the reaction mixture was refluxed for
8 h. The precipitate of triethylamine hydrochloride was filtered
and washed thoroughly with dioxane. The filtrate was
evaporated to one third of its original volume, cooled and
poured into acidified ice/water, and the precipitate formed
washed with water thoroughly, dried, and recrystallized
from methanol as brown powder. Yield 47%, 0.16 g, mp
[12] Subrahmanya, B. K.; Boja, P.; Jagadeesh, P. D.; Prashantha,
N. B.; Shivarama, H. Eur J Med Chem 2009, 44, 5066.
[13] Declercq, E. J Clin Virol 2004, 30, 115.
[14] Naito, Y.; Akahoshi, F.; Takeda, S.; Okada, T.; Kajii, M.;
Nishimura, H.; Sugiura, M.; Fukaya, C.; Kagitani, Y. J Med Chem
1996, 39, 3019.
[15] Saha, A. K.; Liu, L.; Simoneaux, R.; Decorte, B.; Meyer, C.;
Shrzat, S.; Breslin, H. J.; Kukla, M. J.; End, D.-W. Bioorg Med Chem Lett
2005, 15, 5407.
[16] Géza, S.; Tamás, S.; Éva, B.; József, L.; Gábor, N.; József, R.;
Judit, J.; Ferenc, A. Eur J Med Chem 1990, 25, 95.
[17] İlkay, K. Ş.; Güniz, K.; Sevim, R.; Gülten, Ö.-S.; Osman, Ö.;
İbrahim, B.; Tuncay, A.; James, P. S. Il Farmaco 2004, 59, 893.
[18] Chen, J.; Sun, X. Y.; Chai, K. Y.; Lee, J. S.; Song, M. S.;
Quan, Z. S. Bioorg Med Chem 2007, 15, 6775.
[19] Suresh, K. G. V.; Rajendraprasad, Y.; Mallikarjuna, B. P.;
Chandrashekar, S. M.; Kistayya, C. Eur J Med Chem 2010, 45,
2063.
[20] Navin, B. P.; Imran, H. K.; Smita, D. R. Eur J Med Chem
2010, 45, 4293.
[21] Sztanke, K.; Tuzimski, T.; Rzymowska, J.; Pasternak, K.;
Kandefer-Szerszeń, M. Eur J Med Chem 2008, 43, 404.
[22] Alexander, A.; Lilli, A.; Lucinda, S.; Stefan, T.; Walter, V.;
Michael, D. G. Bioorg Med Chem Lett 2004, 14, 817.
[23] Akio, K.; Takeshi, S.; Takahiko, T.; Atsuo, T.; Shuichi, S.;
Shinichi, T. Bioorg Med Chem 2002, 10, 1905.
1
228–230ꢀC; IR (nmax, cmÀ1): 3132 (NH), 1697 (CO). H NMR
(300 MHz, CDCl3): d ppm 5.12 (d, 1 H, H-4 azetidine), 5.29
(d, 1H, H-3 azetidine), 7.23–7.88 (m, 12 H, Ar-H + H-3
triazole+ NH). 13C NMR (75 MHz, CDCl3): d ppm 62.47, 63.63,
76.68, 125.82, 127.87, 128.79, 128.99, 129.44, 129.89, 133.78,
144.43, 163.67, 164.34. MS, m/z (%) = 339 ([M]+, 52), 303
([M]+–Cl, 30), 311 ([M]+–CO, 20), 185 ([M]+–2Ph, 15). Anal.
Calcd for C17H14ClN5O (339.78): C, 60.09; H, 4.15; N, 20.61%.
Found: C, 60.15; H, 4.25; N, 20.74%.
[24] Marie-Odile, C.-G.; Alban, S.; Pascale, P.; Pierre, R. Bioorg
Med Chem Lett 2005, 15, 3555.
[25] Kucukguzel, I.; Tatar, E.; Kucukguzel, S. G.; Rollas, S.;
De Clercq, E. Eur J Med Chem 2008, 43, 381.
[26] Michael, M. D.; Sarah, R. G.; Sidath, C. K.; Marjan, J.; Jeffrey,
B. A.; Kathryn, A. H. Antiviral Res 2010, 87, 78.
[27] Padmavathi, V.; Sudhakar, R. G.; Padmaja, A.; Kondaiah, P.;
Ali, S. Eur J Med Chem 2009, 44, 2106.
[28] Anelia, T. M.; Diana, W.; Yordan, A. T.; Pavletta, D. Eur J
Med Chem 2009, 44, 63.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet