Further studies with ethyl 5-amino-3-phenyl-lH-pyrazole-4-carboxylate 1

Article abstract of DOI:10.1002/jhet.1802

The newly synthesized ethyl 3-amino-5-phenylpyrazole-4-carboxylate 1 was diazotized and coupled with β-naphthol, active methylene reagents 6, 9, 12, 15, and the active methine 19 to afford the pyrazolo[5,1-c]triazines 5, 8, 11, 14, 17, 18, and the pyrazol

Full text of DOI:10.1002/jhet.1802

July 2014
Further Studies with Ethyl 5-Amino-3-phenyl-lH-pyrazole-4-carboxylate1
1179
*
Said A. S. Ghozlan, Fathy M. Abdelrazek, Mona H. Mohammed, and Khaled E. Azmy
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
*
E-mail: prof.fmrazek@gmail.com
Received May 30, 2012
DOI 10.1002/jhet.1802
Published online 17 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
_
+
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N=N Cl
EtO2C
Ph
N
Y
X
EtO2C
Ph
N
Cl
N
X
19
N
N
H
N
Z
2
8a,b; 11a,b; 18
H
H
N
EtO2C
Ph
R
N
N
N
EtO2C
Ph
CO2Et
N
R
CO2Et
Cl
N
N
H
N
O
20
RNH2
14, 17
EttOH/TEA
H
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EtO2C
Ph
H
N
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RNH2
EtO2C
Ph
N
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NHR
N
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21
22, 23
The newly synthesized ethyl 3-amino-5-phenylpyrazole-4-carboxylate 1 was diazotized and coupled with
b-naphthol, active methylene reagents 6, 9, 12, 15, and the active methine 19 to afford the pyrazolo[5,1-c]
triazines 5, 8, 11, 14, 17, 18, and the pyrazolo[5,1-c]-1,2,4-triazoles 21, 22, and 23, respectively. Structures
are elucidated and mechanisms are discussed.
J. Heterocyclic Chem., 51, 1179 (2014).
INTRODUCTION
RESULTS AND DISCUSSION
In the past two decades, we have been involved in a
program aiming at the synthesis of new heterocyclic
compounds that may possess biologically active properties
to be used as potential biodegradable agrochemicals [1–5].
Aminopyrazoles are the most extensively utilized hetero-
cyclic amines in heterocyclic synthesis because of their ready
availability as well as their stability, which makes them
useful precursors in dyes, pharmaceuticals, and agrochemical
industries [6–13].
Recently, some newly substituted pyrazolo-fused hetero-
cyclic systems were required for biological activity studies.
The pyrazole derivative 1 described earlier by us [1] seemed
a good precursor to fulfill this objective. In the present work,
we report the results of our studies on the chemistry of
the pyrazole 1 [1] and its utility for the synthesis of some
novel pyrazolo-[5,l-c]-l,2,4-triazines and pyrazolo-[5,1-c]-
1,2,4-triazole derivatives.
Thus, the pyrazole 1 was diazotized with sodium nitrite/
HCl to afford the corresponding diazonium salt 2 that was
coupled with a variety of active methine and active methy-
lene reagents to afford the corresponding azo/hydrazo
derivatives. For example, the diazonium salt 2 couples with
b-naphthol 3 to afford the pyrazolylazo-b-naphthol deriva-
tive 4, which was cyclized on reflux in glacial acetic acid into
the corresponding pyrazolo-[5,1-c]-triazine derivative 5.
Structures 4 and 5 were established on the basis of analytical
1
and spectral data. The H NMR spectrum of 4 revealed a
singlet at d = 15.9 ppm for the hydroxyl group proton beside
the expected signals. This singlet disappeared in the
1H NMR spectrum of 5. Also, the mass spectrum of 5
showed a base peak at m/z = 368 (50.2%), which is in
complete agreement with the formula C22H16N4O2, Scheme 1.
When the diazonium salt 2 was coupled with malononi-
trile 6a and benzoylacetonitrile 6b, the pyrazolo-[5,1-c]-
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Scheme 1. Synthesis of the pyrazolo[5,1-c] triazines 5, 8, 11, 14, 17, 18.
1,2,4-triazine derivatives 8a,b have been obtained. It is
apparent that 2 couples with the active methylenes 6a,b to
afford the non-isolable azo/hydrazo intermediates 7a,b that
undergoes in situ cyclization to afford 8a,b. Structures 8a,b
were suggested for these products based on analytical and
spectral evidences. The H NMR of 8a revealed a triplet
at d = 1.20ppm (J = 7.2 Hz) for methyl group, a quartet at
d = 4.25 ppm (J = 7.2Hz) for CH2 group, a multiplet at
1
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Further Studies with Ethyl 5-Amino-3-phenyl-lH-pyrazole-4-carboxylate1
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d = 7.52–7.79ppm because of the 5 phenyl protons, and a
singlet at d = 9.55 ppm for NH2 protons. Moreover, the mass
spectrum of structure 8a showed a base peak at m/z = 308
(75%), which is in agreement with the molecular mass of
the molecular formula C15H12N6O2. The IR spectrum of 8a
revealed two absorption bands υ = 3433 and 3325 cmꢀ1 for
the amino group and one band at υ = 2229 cmꢀ1 for a
cyano group. The IR spectrum of 8b showed absorption
bands at υ = 3248 and 3175 cmꢀ1 assignable to the NH2
group, and two bands at υ = 1695 and 1639 cmꢀ1 assignable
for two carbonyl groups (ester and benzoyl groups). The
hypsochromic shift of the benzoyl carbonyl may be attrib-
uted to the formation of hydrogen bonding with the amino
group. The direct formation of cyclic products 8a,b from
the reaction of the diazonium salt 2 with both malononitrile
6a and benzoylacetonitrile 6b is in accordance with the
previously reported direct formation of pyrazolo-[5,1-c]-
1,2,4-triazines on treatment of diazotized 5-aminopyrazoles
with both reagents [14,15], Scheme 1.
In contrast to the observed direct formation of pyrazolo-
[5,1-c]-1,2,4-triazines 8a,b on treating 2 with the active
methylene reagents 6a,b, the diazonium salt 2 coupled
with acetylacetone 9a and dibenzoylmethane 9b to yield
isolable coupling products that were formulated as 10a,b.
These latter compounds could be readily cyclized into
pyrazolo-[5,1-c]-1,2,4-triazines 11a,b, respectively on treat-
ment with concentrated sulfuric acid at room temperature
for 24 h presumably via water elimination.
acyclic coupling products 13 and 16, respectively. Struc-
tures 13 and 16 were assigned for these coupling products
on the basis of elemental analysis and spectral data. The
acyclic hydrazone product 13 could be cyclized upon
reflux in pyridine to afford the pyrazolotriazine 14. The
mass spectrum of this reaction product showed a high
intensity signal at m/z = 309 (84.8%), which is in agree-
ment with the molecular formula C15H11N5O3.
Refluxing 16 in pyridine for 3 h afforded a product for
which structure 17 was suggested and seemed to be formed
via ethanol elimination. Attempts to effect cyclization of
16 by action of concentrated sulfuric acid at room temper-
ature for 24 h afforded however, another product for which
the pyrazolo[5,1-c]1,2,4-triazine 18 was suggested and its
formation presumably takes place via water elimination.
Structures 17 and 18 were assigned based on the elemental
analysis and spectral data. Thus, the mass spectra revealed
signals at m/z = 388 (20.3%) and m/z = 416 (19.28%),
corresponding to the molecular ions [M+] of each of
17 (C21H16N4O4) and 18 (C23H20N4O4), respectively,
Scheme 1.
The 1HNMR spectrum of 17 indicated only one triplet at
d = 1.25 ppm (J = 7.2 Hz) and one quartet at d = 4.31 ppm
(J = 7.2 Hz) and a singlet at d = 8.06 ppm for the triazine-
1
NH proton, whereas the HNMR spectrum of 18 revealed
two triplets at d = 1.03 ppm (J = 7.2 Hz) and at d = l.20 ppm
(J = 7.2 Hz) and two quartet at d = 4.02 ppm (J = 7.2 Hz)
and d = 4.20 ppm (J = 7.2 Hz) for two ethyl ester groups
and a multiplet at d = 7.28–7.75 ppm integratable for
10 protons (2Ph-protons) (Scheme 1 and Experimental).
The diazonium salt 2 couples with ethyl 2-chloroacetoa-
cetate 19 to afford the hydrazonyl halide derivative 20 with
loss of acetyl group via the Japp–Klingmann reaction. The
reaction product 20 could be cyclized into the pyrazolo
[5,1-c]triazole derivative 21 by refluxing in ethanol and
in the presence of catalytic amount of triethylamine. The
cyclization process takes place with hydrogen chloride
elimination. Structure 21 was assigned on the basis of
1H NMR that revealed two of the triplets at d = 1.24 ppm
(J = 7.2 Hz) and d = 1.35 ppm (J = 7.2 Hz) for two methyl
groups; two quartets at d = 4.22 ppm (J = 7.2 Hz) and
d = 4.45 ppm (J = 7.2 Hz) for two CH2 groups, a multiplet
at d = 7.45–7.84 ppm integratable for five phenyl protons
and a singlet at d = 14.60 ppm for the triazole-NH. The
13C NMR of 21 revealed the signals shown in Figure 1.
On the other hand, it has been found that when the cycli-
zation process was carried out by boiling in ethanol and in
the presence of equivalent amount of 2-aminopyridine, a
reaction product was obtained for which structure 22 was
assigned on the basis of analytical and spectral analyses
where the mass spectrum of the reaction product revealed a
high intensity base peak at m/z = 376 (100%, base peak),
which is in agreement with molecular weight of the molecular
formula C19H16N6O3. The 1H NMR spectrum of this product
Structures 10a,b and 11a,b were confirmed on the basis
of analytical and spectral analyses
Thus, the mass spectrum of 10a revealed a base peak at
m/z = 342 (6.3%), which is consistent with the molecular
mass for the molecular formula C17H18N4O4. The 1H NMR
spectrum of 10a revealed a tripled at d = 0.99 ppm and a
quartet at d = 4.04 ppm (J = 7.2 Hz) for ethyl ester group,
two singlet at d = 1.75 and 2.17 ppm for two methyl groups,
a multiplet at d = 6.70–7.50 ppm integrated for six protons
that can be attributed to phenyl and NH, and a broad singlet
at d = 10.13 ppm for pyrazole-NH. Thus, the 1H NMR indi-
cated the absence of any signal for methine proton, which
means that the hydrazo form 10a predominates.
1
The H NMR spectrum of 10b revealed a singlet at
d = 5.85 ppm that is attributed to the presence of NH proton
beside the other expected signals. Also, the mass spectrum
of 10b revealed a base peak at m/z = 466 (25.3%) that is
consistent with the molecular mass for the molecular
formula C27H22N4O4. On the other hand, structures 11a,b
were confirmed also on the basis of analytical and spectral
evidences where their mass spectra revealed peaks for the
molecular ions at m/z = 324 (55.5%) and m/z = 448
(56.9%) consistent with the molecular masses of both
11a and 11b, respectively, Scheme 1.
On the other hand, compound 2 coupled with ethyl
cyanoacetate 12 and ethyl benzoylacetate 15 to afford the
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EXPERIMENTAL
The melting points were determined on a Stuart melting
point apparatus and are uncorrected. The IR spectra were
recorded as KBr pellets using an FTIR unit Bruker-Vector 22
spectrophotometer (Chem Analytical Lab, NIU, USA). The
1H and 13C NMR spectra were recorded in DMSO-d6 as
solvent at 300 and 75 MHz, respectively on Varian Gemini
NMR spectrometer (Varian, Oxford, UK) using TMS as inter-
nal standard. Chemical shifts are reported in d units (ppm).
Mass spectra were measured on a Shimadzu GCMS-QP-1000
EX mass spectrometer (Shimadzu, Kyoto, Japan) at 70 eV.
The elemental analyses were performed at the Micro analytical
Center, Cairo University.
General procedures for preparation of compounds (4), (8a,b),
(10a,b), (13), (16) and (20). The diazonium chloride 2 [prepared
by diazotization of the amino pyrazole 1 (10 mmol) in the
appropriate amount of mixture of hydrochloric acid and glacial
acetic acid with cold sodium nitrite solution] was added
dropwise while stirring and keeping the temperature below 5ꢁC
to a cold solution of b-naphthol 3 or the active methylenes 6a,
b, 9a,b, ethyl cyanoacetate 12, ethyl benzoylacetate 15, or
ethyl 2-chloroacetoacetate 19 (10 mmol) in ethanol (50 ml)
containing sodium acetate (10 mmol). After complete addition,
the reaction mixture was left for further 2 h. The formed
precipitated solid products were filtered off and crystallized
from the proper solvents.
21
Figure 1. 13C NMR values of compound
showed only one triplet at d = 1.26 ppm (J = 7.5Hz) and only
one quartet at d = 4.24 ppm (J = 7.5 Hz) for one ethyl ester
group beside the expected peaks, Scheme 2.
Moreover, an authentic sample of 22 could be synthe-
sized via the reaction of 21 with 2-aminopyridine in boiling
ethanol for 3 h (melting point and mixed melting point).
Refluxing 20 with hydrazine hydrate in ethanol afforded
the pyrazolo[5,1-c]triazole-6-hydrazide derivative for which
structure 23 was assigned on the basis of analytical and
spectral data. The same product 23 was obtained via treat-
ment of 21 with hydrazine hydrate in ethanol solution
(melting point and mixed melting point) (Scheme 2 and
Experimental).
Scheme 2. Synthesis of the pyrazolo[5,1-c]-1,2,4-triazoles 21, 22, 23.
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Yellow crystal (80%), mp 224ꢁC. υmax/cmꢀ1 = 1695 (CO).
MS: m/z 368 [M+]. Anal. calcd for C22HI6N4O2 (368.40): C,
71.72; H, 4.37; N, 15.20. Found: C, 71.67; H, 4.31; N, 15.14.
General procedure for preparation of compounds 11a,b
5-(2-Hydroxynaphthalen-1-yl-azo)-3-phenyl-1H-pyrazole-4-
carboxylic acid ethyl ester (4). Red crystals (70%), mp 145ꢁC
(EtOH). υmax/cmꢀ1 3430 (br, OH), 3225 (NH), 1700 (CO). MS:
m/z 386 [M+]. dH = 1.27 (t, 3H, J = 7.2Hz, CH3), 4.27 (q, 2H,
J = 7.2Hz,CH2), 6.72 (d, 1H, J =9.6 Hz, Naphthyl-H4), 7.45–
7.72 (m, 10H, Ar–H and NH), 7.90 (d, 1H, J = 9.6Hz,
naphthyl-H3), 15.90 (s, 1H, OH). Anal. calcd for C22H18N4O3
(386.41): C, 68.38; H, 4.69; N, 14.49. Found C, 68–31; H,
(Cyclization of 10a,b).
To each of compounds 10a and 10b
(10 mmol) was added 10mL of concentrated sulfuric, and the
mixture was warmed to 40ꢁC for 2 h and left overnight. The
reaction mixture was then neutralized using sodium carbonate and
the precipitated solid products were collected by filtration and
recrystallized from ethanol.
4.63; N, 14.40.
4-Amino-3-cyano-7-phenyl-pyrazolo[5,1-c]l,2,4-triazine-8-
carboxylic acid ethyl ester (8a).. Pale brown crystal (70%),
mp 234ꢁC. υmax/cmꢀ1 = 3433, 3325 (NH2), 2229 (CN), 1689
(CO). MS: m/z = 308 [M+]. dH = 1.20 (t, 3H, J = 7.2 Hz,
CH3), 4.25 (q, 2H, J = 7.2 Hz, CH2), 7.52–7.79 (m, 5H,
Ar–H), 9.55 (s, 2H, NH2). Anal. calcd for CI5H12N6O2
(308.30): C, 58.43; H, 3.92; N, 27.75. Found: C, 58.38., H,
3.86; N, 27.65.
Ethyl 3-aceyl-4-methyl-7-phenyl-pyrazolo[5,1-c]-1,2,4-triazine-
8-carboxylate (11a).
Yellow crystal (65%), mp 212ꢁC. υmax
/
cmꢀ1 = 1710, 1675 (2CO). MS: m/z 324 [M+]. Anal. calcd for
C17H16N4O3 (324.34): C, 62.95; H, 4.97; N, 17.27. Found: C,
62.88; H, 4.82; N, 17.18.
Ethyl 3-benzoyl-4,7-diphenylpyrazolo[5,1-c]-1,2,4-triazine-8-
carboxylate (11b). White crystal (70%), mp 217ꢁC. υmax
/
cmꢀ1 = 1722, 1680 (2CO). MS: m/z 448 [M+]. Anal. calcd for
C27H20N4O3 (448.49): C, 73.30; H, 4.49; N, 12.49. Found: C,
73.21; H, 4.38; N, 12.34.
4-Amino-3-benzoyl-7-phenyl-pyrazolol[5,l-c]l,2,4-triazine-8-
carboxylic acid ethyl ester (8b). Green crystal (65%), mp 186ꢁC.
υ
max/cmꢀ1 = 3348, 3293 (NH2) 1693, 1639 (2CO). MS: m/z 387
[M+]. Anal. calcd for C21H17N5O3 (387.40): C, 65.10; H, 4.42; N,
18.07. Found: C, 64.95; H, 4.39; N, 17.96.
Ethyl 3-cyano-4-oxo-7-phenyl-l,4-dihydro-pyrazolo[5,1-c]-
1,2,4-triazine-8-carboxylate 14. (Cyclization of 13). Compound
13 (3.55 g, 10 mmol) was refluxed in pyridine (25mL) for 3 h and
allowed to cool to room temperature then poured into cold water
and neutralized with dilute HCl. The resulting product was
collected by filtration and crystallized from ethanol.
Pale brown crystal (65%), mp 258ꢁC. υmax/cmꢀ1 = 3444 (NH),
2218 (CN), 1735, 1666(2CO). MS: m/z = 309 [M+]. Anal. calcd
for C15H11N5O3 (309.29): C, 58.25; H, 3.58; N, 22.64. Found:
C, 58.16; H, 3.42; N, 22.58.
5-[N0-(l-Acetyl-2-oxopropylidene)-hydrazino]-3-phenyl-lH-
pyrazole-4-carboxylic acid ethyl ester (10a)..
Yellow crystal
(70%), mp 160ꢁC. υmax/cmꢀ1 =3410, 3298 (NH), 1724, 1678
(CO). MS: m/z = 342 [M+]. dH = 0.99 (t, 3H, J = 7.2Hz, CH3),
1.75 (s, 3H, CH3), 2.17 (s, 3H, acetyl CH3), 4.04 (q, 2H,
J = 7.2Hz, CH2), 6.70–7.50 (m, 6H, Ar.H+ hydazino-NH),
10.13 (s, 1H, pyrazole NH). dC = 12.01 (CH3, ester), 14.30
(CH3, acetyl), 24.92 (CH3, acetyl), 57.31(CH2, ester), 57.76
(CH-viny1), 59.54 (C-4 pyrazole), 113.66 (CN), 125.28,
126.76, 127.51, 128.12 and 129.04 (aromatic C), 138.71
(CO, ester), 161.45 (CO, acetyl). Anal. calcd for C17H18N4O4
(342.36): C, 59.64; H, 5.30; N, 16.37. Found: C, 59.44; H, 5.1;
N, 16.29.
Ethyl 3-benzoyl-4-oxo-7-phenyl-1,4-dihydro-pyrazolo[5,l-c]-
l,2,4-triazine-8-caboxylate (17).
A solution of compound 16
(4.34 g, 10 mmol) in pyridine (25 mL) was refluxed for 3 h and
then left to cool to room temperature. The reaction mixture was
then poured into cold water and neutralized with dilute HCl.
The resulting precipitate was collected by filtration and
crystallized from ethanol.
Ethyl 5-[N0-(l-benzoyl-2-oxo-2-phenylethylidene)-hydrazino]-
3-phenyl-lH-pyrazole-4-carboxylate (10b). Pale yellow crystal
(75%), mp 183ꢁC. υmax/cmꢀ1 = 3344, 3278 (NH), 1662, 1631
(2CO). MS: m/z 466 [M+]. dH = 1.25 (t, 3H, J = 7.2 Hz, CH3), 4.28
(q, 2H, J = 7.2 Hz, CH2), 5.85 (s, 1H, NH), 7.33–7.92 (m, 15H,
3Ph-H), 10.18 (s, 1H, pyrazole NH). Anal. calcd for C27H22N4O4
(466.50): C, 69.52; H, 4.75; N, 12.01. Found: C, 69.39; H, 4.60;
N, 11.90.
White crystal (55%), mp 220ꢁC. υmax/cmꢀ1 = 3223 (MH),
1732, 1663 (2CO). MS: m/z 388 [M+]. dH = 1.25 (t, 3H,
J = 7.2 Hz, CH3), 4.31 (q, 2H, J = 7.2 Hz, CH2), 7.50–7.82
(m, 10H, 2Ph-H), 8.04 (s, IH, triazine NH). Anal. calcd for
C21H16N4O4 (388.39): C, 64.944; H, 4.15; N, 14.42. Found: C,
64.82; H, 4.04; N, 14.33.
Ethyl 5-[N0-(cyano-ethoxycarbonyl-methylene)-hydrazino]-3-
4,7-diphenyl-pyrazolo[5,l-c]-l,2,4-triazine-3,8-dicarboxylic acid
diethyl ester (18). A mixture of compound 16 (4.34 g, 10 mmol)
and (10 mL) concentrated sulfuric acid was warmed at 40ꢁC for 2 h
and left overnight. The reaction mixture was neutralized cautiously
with sodium carbonate solution and the resulting product was
collected by filtration and crystallized from ethanol.
phenyl-lH-pyrazole-4-carboxylate 13.
Pale brown crystal
(70%), mp 165ꢁC. υmax/cmꢀ1 = 3395, 3215 (NH), 2206 (CN),
1720, 1674 (2CO). MS: m/z = 355 [M+]. dH = 1.16 (t, 3H,
J = 7.2 Hz, CH3), 1.33 (t, 3H, J = 7.2 Hz, CH3), 4.17 (q, 2H,
J = 7.2 Hz, CH2), 4.3 1 (q, 2H, J = 7.2 Hz, CH2), 7.50–7.65 (m,
5H, Ph-H), 13.67 (s, 2H, 2NH), Anal. calcd for C17H17N5O4
(355.36): C, 57.45; H, 4.82; N, 19.70. Found: C, 57.41; H,
Yellow crystal (65%), mp 129 C. υmax/cmꢀ1 = 1727, 1659
(2CO). MS: m/z = 416 [M+]. dH = 1.03 (t, 3H, J = 7.2 Hz, CH3),
1 .20 (t, 3H, J = 7.2 Hz, CH3), 4.02 (q, 2H, J = 7.2 Hz, CH2),
4.20 (q, 2H, J = 7.2 Hz, CH2), 7.28–7.75 (m, 10H, 2Ph-H). Anal.
calcd for C23H20N4O4 (416.44): C, 66.33; H, 4.84; N, 13.45.
Found: C, 66.25; H, 4.73; N, 13.31.
4.78; N, 19.65.
Ethyl 5-[N0-(l-ethoxycarbonyl-2-oxo-2-phenyl-ethylidene)-
hydrazino]-3-phenyl-lH-pyrazole-4-carboxylate 16. White crystal
(70%), mp 191ꢁC. υmax/cmꢀ1 = 3363 (NH), 1724 (CO). MS: m/
z = 434 [M+]. Anal. calcd for C23H22N4O5 (434.46): C, 63.58; H,
5.10; N, 12,89. Found: C, 63.52; H, 4.95; N, 12.81.
Phenyl-11,12,14,15-tetraazacyclopenta[a]phenanthrene-17-
carboxylic acid ethyl ester (5) (Cyclization of 4). Compound 4
(3.86 g, 10 mmol) was refluxed in glacial acetic acid (25 mL) for
2 h, then allowed to cool at room temperature. The formed solid
product was crystallized from ethanol.
Ethyl 5-[N0-(chloro-ethoxycarbonyl-methylene)-hydrazine]-3-
phenyl-1H-pyrazole-4-carboxylate (20). Pale brown crystals
(65%), mp 116ꢁC. υmax/cmꢀ1 = 3328, 3232 (NH), 1705 (CO).
MS: m/z = 364 and 366 [Mꢂ]. dH = 1.13 (t, 3H, J = 7.2 Hz, CH3),
1.26 (t, 3H, J = 7.2Hz, CH3), 4.17 (q, 2H, J = 7.2 Hz, CH2), 4.32
(q, 2H, J = 7.2 Hz, CH2), 7.33–7.65 (m, 6H, Ph-H + pyrazole NH),
10.04 (s, 1H, hydrazone NH). Anal. calcd for C16H17Cl N4O4
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(364.79): C, 52.68; H, 4.69; N, 15.35; Cl, 9.71. Found: C, 52.61; H,
4.63; N, 15.28; Cl, 9.65.
10mmol.) in ethanol (20mL) for 3 h, allowed to cool and then
poured into cold water. The resulting solid product was collected
by filtration and crystallized from ethanol.
Method (2). A solution of 21 (3.28 g, 10mmol) and hydrazine
hydrate were refluxed in ethanol (25 mL) for 3 h, left to cool and
then poured into cold water. The resulting solid product was
collected by filtration and crystallized from ethanol.
Yellow crystal (75%), mp 195ꢁC. υmax/cmꢀ1 = 3356, 3331, 3286
(NH and NH2), 1648, 1592 (2CO). MS: m/z = 312 (M+ ꢀ 2). Anal.
calcd for C14H14N6O3 (314.31): C, 53.49; H, 4.48; N, 26.73. Found:
C, 53.40; H, 4.39; N, 26.64.
6-Phenyl-lH-pyrazolo[5,1-c]-1,2,4-triazole-3,7-dicarboxylic
acid diethyl ester (21). To a suspension of 20 (3.64 g, 10mmol)
in ethanol (25mL) was added 0.5mL of triethylamine. The
reaction mixture was refluxed for 3 h and allowed to cool to room
temperature, then poured into ice-cold water and neutralized with
dilute HCl. The resulting product was collected by filtration and
crystallized from ethanol.
Pale brown crystal (60%), mp 204ꢁC. υmax/cmꢀ1 = 3110 (NH),
1736, 1649 (2CO). MS: m/z = 328 [M+]. dH = 1.24 (t, 3H,
J = 7.2 Hz, CH3), 1.35 (t, 3H, J = 7.2 Hz ,CH3), 4.22 (q. 2H,
J = 7.2 Hz, CH2), 4.45 (q. 2H, J = 7.2 Hz, CH2), 7.45–7.84
(m, 5H, Ph-H), 14.6 (s, 1H, triazole NH). dC = 14.07, 14.46
(2CH3), 59.55, 62.18 (2CH2), 86.81 (C-7), 127.80, 129.12,
129.46, 132.04 (Ph C), 132.25 (C-6), 149.15 (C-3), 155.59 (C-
8), 160.24, 161.34 (2CO). Anal. calcd for C16H16N4O4
(328.33): C, 58.53; H, 4.87; N, 17.06. Found: C, 58.42; H,
4.80; N, 16.92.
REFERENCES AND NOTES
[1] Ghozlan, S. A. S.; Abdelrazek, F. M.; Mohammed, M. H.;
Azmy, K. E. J Heterocylic Chem. 2010, 47, 1379.
[2] Abdelrazek, F. M.; Ghozlan, S. A. S.; Michael, F. A. J
Heterocyclic Chem. 2007, 44, 63.
Ethyl 6-phenyl-3-(N0-pyridine-2-yl-hydrazinocarbonyl)-1H-
pyrazolo [5,1-c]-1,2,4-triazole-7-carboxylate (22). Method (1).
2-Aminopyridine (0.94 g, 10mmol) was added to a solution of 20
(3.64 g, 10 mmol) in ethanol. The reaction mixture was refluxed
for 3 h, left to cool and then poured into cold water. The
resulting solid product was collected by filtration and crystallized
from ethanol/dioxane.
Method (2). 2-Aminopyridine (0.94 g, 10 mmol) was added
to a solution of 21 (3.28 g, 10 mmol) in ethanol. The reaction
mixture was refluxed for 3 h, left to cool and then poured into
cold water. The resulting solid product was collected by
filtration and crystallized from ethanol/dioxane.
Red crystal (70%), mp > 300ꢁC. υmax/cmꢀ1 = 3402, 3 175
(NH), 1678, 1650 (2CO). MS: m/z = 376 [M+]. dH = 1.26 (t, 3H,
J = 7.5 Hz, CH3), 4.24 (q, 2H, J = 7.5 Hz, CH2), 7.17–7.20
(m, 4H, pyrid-H), 7.47–7.65 (m, 5H, Ph-H), 7.83 (s, 1H, amide
NH), 8.35 (s, 1H, triazole NH). Anal. calcd for C19H16N6O3
(376.38): C, 60.63; H, 4.28; N, 22.32. Found: C, 60.57; H, 4.22;
N, 22.27.
[3] Ghozlan, S. A. S.; Hafez, E. A. A.; El-Bannany, A. A. Arch
Pharm 1987, 320, 850.
[4] Ghozlan, S. A. S.; Hassanien, A. Z. A. Tetrahedron 2002, 58,
9423.
[5] Abdelrazek, F. M.; Michael, F. A.; Mohamed, A. E. Arch
Pharm Chem life Sciences (Weinheim) 2006, 339(6), 305.
[6] Blass, B. E.; Srivastava, A.; Coburn, K. R.; Fanlkner, A. L.;
Seibel, W.L.; Tetrahedron Lett 2003, 44, 3009.
[7] Domagala, J. M.; Peterson, P. J Heterocyclic Chem 1989, 26,
1147 and references therein.
[8] Gilman, A.G.; Goodman, L. S. The Pharmaceutical Basis of
Therapeutics. Macmillan; New York, 1985, 1109.
[9] Fanger, F.; Nicklen, S.; Coulson, A. R. Proc Natl Acad Sci U S
A 1977, 74, 5463.
[10] Wellinga, K.; Grosscurt, A. C.; Van Hes, R. J Agric Food
Chem 1977, 25, 987.
[11] Grosscurt, C.; Van Hes, R.; Wellinga, K. J Agric Food Chem
1979, 27, 406.
[12] Elbannany, A.; Ghozlan, S. A. S. Egypt J Chem 1988, 31(5), 587.
[13] Rzepecki, P.; Wehner, M.; Molto, O.; Zadmard, R.; Harms, K.;
Schrader, T. Synthesis 2003, 1815.
[14] Elnagdi, M. H.; Zayed, E. M.; Khalifa, M. A. E.; Ghozlan, S.
A. S. Monatsch Chem 1981, 112, 245.
Ethyl 3-hydrazinocarbonyl-6-phenyl-1H-pyrazolo[5,1-c]-1,2,4-
triazole-7-carboxylate (23).
(3.64 g, 10 mmol) was refluxed with hydrazine hydrate (0.50mL,
Method (1).
Compound 20
[15] Zayed, E. M.; Ghozlan, S. A. S.; Ibrahim, A. A. H. Monatshefte
für Chemie 1984, 115, 431.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet