Synthesis of some new pyrazole, pyrimidine, pyridazine, and their fused derivatives from 3-oxo-3,n-diphenylpropionamide

Article abstract of DOI:10.1002/jhet.1700

The title compounds were obtained from the reactions of 3-oxo-3,N-diphenylpropionamide 3 with dimethylformamide dimethylacetal followed by hydrazine to afford the pyrazole 7, condensation with benzaldehyde followed by cyclocondensation with guanidine to afford the pyrimidine derivative 13, condensation with active methylenes followed by azo coupling of the products followed by cyclization to afford the pyridazines 17a, 17b. The pyridazinone 17b was explored for the synthesis of some novel pyridazine-fused heterocyclic compounds 19, 21, 24a, 24b, 24c, and 26. All structures were proved via their elemental analyses and spectral data.

Full text of DOI:10.1002/jhet.1700

824
Synthesis of Some New Pyrazole, Pyrimidine, Pyridazine, and Their Fused
Derivatives from 3-Oxo-3,N-diphenylpropionamide
Vol 51
a
b
b
b
c
*
Fathy M. Abdelrazek, Yehia M. Elkholy, Ali M. Salah, Nagwa M. Abdelazeem, and Peter Metz
aChemistry Department, Faculty of Science, Cairo University, Giza, Egypt
bChemistry Department, Faculty of Science, Helwan University, Helwan, Egypt
cInstitute of Organic Chemistry, TU Dresden, Dresden 01062, Germany
*
E-mail: prof.fmrazek@gmail.com
Received January 31, 2012
DOI 10.1002/jhet.1700
Published online 9 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
Ph
O
O
O
O
O
N
O
NH
Ph
N
PhHN
Ph
N
PhHN
Ph
NHPh
H2N NH2
Ph
NHPh
NH2NH2
12
NH2
Ph
N
H
N
H
4
11
13
7
DMFDMA
PhCHO
10
O
O
X
CN
CN
O
+
-
Ph
Ph
NHPh
O
O
X
PhN=N Cl
N
Ph
NHPh
N
H
8
Ph
NHPh
14, a,X=CN
b,X=CO2Et
15a,b
3
18
CN
Ph
O
Ph
O
NC
X
X
14a,b
CN
Y
PhHN
NHPh
+ -
PhN=N Cl
NaOEt
N
N
N
HN
Ph
8
Ph
a, Y=NH
b, Y=O
16a,b
17
The title compounds were obtained from the reactions of 3-oxo-3,N-diphenylpropionamide 3 with
dimethylformamide dimethylacetal followed by hydrazine to afford the pyrazole 7, condensation with benzaldehyde
followed by cyclocondensation with guanidine to afford the pyrimidine derivative 13, condensation with
active methylenes followed by azo coupling of the products followed by cyclization to afford the pyridazines
17a,b. The pyridazinone 17b was explored for the synthesis of some novel pyridazine-fused heterocyclic
compounds 19, 21, 24a–c, and 26. All structures were proved via their elemental analyses and spectral data.
J. Heterocyclic Chem., 51, 824 (2014).
INTRODUCTION
agrochemicals [9–12]. In the context of this program and
because of the abovementioned stunning biological activities
of pyridazine derivatives, we have reported several novel
syntheses of some new pyridazine and fused-pyridazine deri-
vatives [12–15]. Recently, some new substituted pyrazoles,
pyrimidines, pyridazines, and their fused derivatives
were required for biological activity studies. 3-Oxo-3,N-
diphenylpropionamide 3 (Scheme 1) seemed a suitable
candidate to fulfill this objective.
Pyridazine derivatives have received considerable attention
in the last two decades because of their diverse biological
activities [1,2]. This class of compounds is reported to show
aldose-reductase inhibitory effect [3]. They are also used
as antihistaminic, analgesic, anti-inflammatory, [4] and
cardiotonic agents with vasodilator activity [5]. In addition,
these compounds were also reported to possess a good binding
affinity toward a1,a2-adrenergic and 5-HT1A serotoninergic
receptors [6] and to show herbicidal and fungicidal [7,8]
activities. In the last two decades, we have been involved in
a program aiming at the synthesis of heterocyclic compounds
of expected biological activity to be tested as biodegradable
RESULTS AND DISCUSSION
3-Oxo-3,N-diphenylpropanamide 3 was obtained from
the reaction of ethyl benzoylacetate 1 with aniline 2 in
© 2013 HeteroCorporation

May 2014
Synthesis of Some New Pyrazole, Pyrimidine, Pyridazine, and Their Fused
Derivatives from 3-Oxo-3,N-diphenylpropionamide
825
Scheme 1. Synthesis of compounds 3,4,7,9,11 and 13.
O
O
O
O
OH
N
O
Ph
N
Ph
N
Ph
Ph
PhHN
PhHN
N N
+
-
PhN=N Cl
NH
N
N
N
H
8
N
H
9
H
Ph
7
6
-H2O
-PhNH2
O
Ph
O
Ph
PhHN
O
PhHN
OH
NH2
H2NHN
N
NH2NH2
-NM
A
B
5
e2
O
O
O
O
O
O
DMF
DMFDMA
Dioxane, Reflux
PhNH2
+
OEt
Ph
NHPh
Ph
NHPh
Ph
3
1
2
N
4
PhCHO
10
Ph
NH
O
O
O
PhHN
Ph
N
H2N
NH2
Ph
NHPh
12
NH2
N
H
Ph
11
13
refluxing DMF. The formation of compound 3 is assumed
to proceed via the elimination of ethanol. Structure 3 was
established based on elemental and spectral data. The IR
spectrum of 3 revealed the presence of amide carbonyl at
cyclization to the carbonyl group leaving the amide or ester
groups is well known in the literature [16].
Compound 7 was allowed to couple with the diazotized
aniline 8 to afford 3-Phenyl-5-phenylazo-1H-pyrazole-4-
carboxanilide 9 (Scheme 1).
1
1687 cmÀ1, and the H NMR revealed the presence of NH
group at d = 10.2 ppm. (cf. Experimental).
Compound 3 was allowed to react with dimethylformamide
dimethylacetal in refluxing dioxane to afford 2-benzoyl-3-
The condensation of 3 with benzaldehyde 10 by
using piperidine as the catalyst afforded the expected
2-benzoyl-3,N-diphenylacrylamide 11. Compound 11 reacts
with guanidine 12 in the presence of piperidine to afford
the desired 2-amino-4,6-diphenyl-1,4-dihydro- pyrimidine-
5-carboxanilide 13. Compound 13 was established based on
elemental and spectral data (Scheme 1; Experimental).
Compound 3 underwent condensation reaction with the
active methylene compounds 14a,b to afford the condensa-
tion products 15a,b, respectively. These latter compounds
couple with 8 to afford the hydrazo compounds 16a,b.
Analytical and spectral data are in complete agreement
with structures 15a,b and 16a,b (cf. Experimental).
Compounds 16a,b could be readily cyclized to the
desired pyridazine derivatives 17a,b upon reflux in ethanol
containing sodium ethoxide as a basic catalyst. The cyclization
presumably involves the addition of the hydrazone NH to
(dimethylamino)-N-phenylacrylamide
4
in quantitative
yield. Compound 4 reacts with hydrazine hydrate in
refluxing ethanol to afford the intermediate 5A/5B
(Scheme 1). Cyclization of the intermediate 5 can take
place via the elimination of aniline from 5A to give the
hydroxy-pyrazole/pyrazolone derivative 6 or via elimination
of water from 5B to give 3,N-diphenyl-1H-pyrazole-4-
carboxamide 7.
The IR spectrum of this reaction product revealed the
presence of an amide carbonyl at 1652 cmÀ1. The 1H NMR
seemed of no help in discriminating 6 and 7; however, the
elemental analysis showed a high carbon content and the
mass spectrum showed m/z = 263 that is in favor of structure 7
who was established to this reaction product. Such selective
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

826
F. M. Abdelrazek, Y. M. Elkholy, A. M. Salah, N. M. Abdelazeem, and P. Metz
Vol 51
by the Microanalytical Center at Cairo University and a consider-
able part of the spectra were carried out in the Institute of Organic
Chemistry, Technical University of Dresden, Germany.
one of the CN groups to afford the imino pyridazine 17a or
elimination of ethanol to afford the pyridazinone 17b,
respectively. The structures of compounds 17a,b were estab-
lished based on analytical and spectral data (cf. Experimen-
tal; Scheme 2).
On the other hand, compound 3 was coupled smoothly
with benzene diazonium salt 8 to afford the nicely colored
hydrazo product 18. This latter compound 18 was fused
with malononitrile 14a or ethyl cyanoacetate 14b on an oil
bath at 170 ꢀC to afford directly the pyridazine derivatives
17a and 17b, respectively, presumably via the intermediacy
of 16a,b that underwent cyclization in situ without being
isolated (Scheme 2).
3-Oxo-3,N-diphenylpropanamide 3.
A mixture of ethyl
benzoyl acetate 1 (1.92 g; 0.01 mole) and aniline 2 (0.93 g;
0.01 mole) in dimethylformamide (25 mL) was refluxed for 3 h,
whereby a homogeneous solution was obtained then left to cool
to room temperature. The reaction mixture was then poured on
ice-cold water. The solid precipitate that appeared was filtered
off and recrystallized from ethanol to afford the pure product.
Yellowish white crystals; yield 85%, mp: 111 ꢀC (EtOH).
υ
max = 3260 (NH), 1687 (CO), and 1663 (CO) cmÀ1; MS: m/z= 239
[M+]. dH = 4.14 (s, 2H, CH2), 7.35À7.99 (m, 10H, 2Ph-H), 10.2
(s, 1H, NH). Anal. Calcd for C15H13NO2 (239.26): C, 75.30; H,
5.48; N, 5.85. Found: C, 75.36; H, 5.54; N, 5.80.
2-Benzoyl-3-(dimethylamino)-N-phenylacrylamide 4.
A
The obtained pyridazinone derivative 17b was explored
to synthesize some other fused pyridazine derivatives.
Thus, it was allowed to react with hydrazine hydrate,
hydroxyl amine hydrochloride 20, urea derivatives 12,
22, and 23 and 1,2-phenylenediamine 25 to afford the
pyrazolo pyridazine 19, isoxazolo pyridazine 21, pyrimido
pyridazines 24a–c, and pyridazino benzo[b]diazepine 26
derivatives, respectively. Analytical and spectral data are in
complete agreement with these structures (cf. Experimental,
Scheme 3).
mixture of (2.39 g; 0.01 mole) and dimethylformamide
3
dimethylacetal (1.19 g; 0.01 mole) in dioxane (25 mL) was refluxed
for 3 h (TLC control), and then left to cool at room temperature.
The contents of the flask were poured on ice-cold water. The
precipitated solid was collected by filtration and recrystallized to
give 4 as pale yellow crystals; yield 87%, mp. 86 ꢀC (EtOH).
υ
max = 3262 (NH), 1600 (CO), and 1660 (CO) cmÀ1; MS: m/z= 294
[M+]. dH =3.33 (s, 6H, 2CH3), 7.18–7.99 (m, 10H, 2Ph-H), 7.75 (s,
1H, CH), 10.15 (s, 1H, NH). Anal. Calcd for C18H18N2O2 (294.35):
C, 73.45; H, 6.16; N, 9.52. Found: C, 73.48; H, 6.12; N, 9.58.
3-Phenyl-1H-pyrazole-4-carboxanilide 7. A mixture of 4
(2.94 g) and hydrazine hydrate (0.5mmol) in ethanol (25 mL) was
refluxed for 3 h (TLC control) and left to cool overnight. The
reaction mixture was then poured on ice cold water. The
precipitated solid was filtered off and recrystallized from ethanol.
White crystals; yield 68%, mp: 185 ꢀC (EtOH). υmax = 3303, 3242
(NH), 1652 (CO) cmÀ1. MS: m/z = 263 [M+]. dH = 6.2 (s, 1H,
CH), 7.17À7.76 (m, 10H, 2Ph-H), 10.1 (s, 1H, NH amide), 14.30
(s, 1H, NH ring). Anal. Calcd for C16H13N3O (263.29): C, 72.99;
H, 4.98; N, 15.96. Found: C, 73.05; H, 5.10; N, 15.90.
EXPERIMENTAL
Melting points were determined on an electrothermal (9100)
(Kleinfeld, Gehrden, Germany) apparatus and are uncorrected.
IR spectra were recorded as KBr pellets on a Perkin Elmer 1430
spectrophotometer (Waltham, MA). The 1H NMR and 13C
NMR spectra were taken on a Varian Gemini 300 MHz spectrom-
eter (Varian, inc., Palo Alto, CA) in DMSO-d6 using TMS as
internal standard and chemical shifts are expressed in d (ppm)
values. Mass spectra were taken on a Shimadzu GCMS-GB 1000
PX (70eV) (Kyoto, Japan). Elemental analyses were carried out
3-Phenyl-5-phenylazo-1H-pyrazole-4-carboxanilide 9.
Diazonium salt was freshly prepared by adding a solution of
(0.7 g; 0.01 mole) of sodium nitrite in 5 mL of H2O to a
Scheme 2. Synthesis of compounds 15,16,17 and 18.
O
O
X
CN
CN
O
+
-
Ph
Ph
NHPh
O
O
X
PhN=N Cl
N
Ph
NHPh
N
H
8
Ph
NHPh
14, a,X=CN
15a,b
3
b,X=CO2Et
18
CN
X
14a,b
Ph
Ph
O
O
NC
CN
Y
PhHN
NHPh
+
-
NaOEt
X
PhN=N Cl
N
N
N
HN
Ph
8
Ph
a, Y=NH
b, Y=O
17
16a,b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Some New Pyrazole, Pyrimidine, Pyridazine, and Their Fused
Derivatives from 3-Oxo-3,N-diphenylpropionamide
827
Scheme 3. Synthesis of compounds 19,21,24 and 26.
NH2
Ph
N
Ph
NH2
N
O
O
NH2
NH2
N
PhHN
PhHN
NH2NH2.H2O
N
N
N
25
N
N
Ph
Ph
19
26
Ph
O
Ph
CN
O
NH2
NH
O
O
Ph
O
PhHN
Z
PhHN
NH2OH.HCl
20
PhHN
N
N
N
H2N
NH2
N
N
N
N
Ph
Z
N
N
12,Z=NH
22,Z=O
23,Z=S
Ph
17b
Ph
21
24
a, Z=NH
b, Z=O
c , Z=S
cold solution of aniline hydrochloride (3 mL of conc.
HCl + 1 mL of aniline) with stirring. The resulting solution
of the diazonium salt was added to a cold solution of 7
(2.63 g; 0.01 mole), in ethanol (30 mL) containing sodium
acetate (2 g). The reaction mixture was stirred at room
temperature for 1 h and the solid products, so formed, was
collected by filtration and recrystallized from ethanol. Brown
crystals; yield 81%, mp195 ꢀC (EtOH). υmax = 3303, 3240
(2NH), 1652 (CO) cmÀ1. MS: m/z = 367 [M+]. dH = 6.75–7.76
(m, 15H, 3Ph-H), 10.15 (s, 1H, NH amide), 14.22 (s, 1H, NH
ring). Anal. Calcd for C22H17N5O (367.40): C, 71.92; H, 4.66;
N, 19.06. Found: C, 71.98; H, 4.56; N, 19.00.
Reaction of 3 with the active methylenes 14a,b: Preparation
of 15a,b. To a mixture of 3 (2.39 g; 0.01 mole) and
malononitrile 14a (0.66 g; 0.01 mole) or ethyl cyanoacetate 14b
(1.13 g; 0.01 mole) in ethanol (25 mL), few drops of
triethylamine were added as catalyst. The reaction mixture was
refluxed for 3 h in each case then left to cool overnight. The
reaction mixture was poured on ice cold water and neutralized
with few drops of HCl. The precipitated solids were collected by
filtration and recrystallized from ethanol.
4,4-Dicyano-3-phenylbut-3-enoic acid phenylamide 15a.
Reddish brown powder; yield 85%, mp 90 ꢀC (EtOH). IR:
υ
max = 3473 (NH), 2206, 2363 (2CN), and 1662 (CO) cmÀ1
.
MS: m/z = 287 [M+]; dH = 2.78 (s, 2H, CH2), 7.05–7.65
(m, 10H, 2Ph-H), 10.1 (s, 1H, NH). Anal. Calcd for
C18H13N3O (287.32): C, 75.25; H, 4.56; N, 14.63. Found C,
75.28; H, 4.65; N, 14.50.
2-Benzoyl-3,N-diphenylacrylamide 11.
To a refluxing
mixture of 3 (2.39 g; 0.01 mole) and benzaldehyde 10 (1.06 g;
0.01 mole) in ethanol (25 mL) was added piperidine (0.5 mL)
with continuous reflux for 5 h (TLC control), then left to cool to
room temperature. The reaction mixture was then poured on
ice-cold water and neutralized by few drops of conc. HCl. The
solid precipitate that appeared was filtered off and recrystallized
from ethanol to afford 11. Pale yellow powder; yield 62%, mp.
80 ꢀC (EtOH). υmax = 3475, 3343 (NH), 1689 (2CO) cmÀ1. MS:
m/z = 327 [M+]. dH = 7.15–7.68 (m, 15H, 3Ph-H), 7.94 (s, 1H,
CH), 10.25 (s, 1H, NH amide). Anal. Calcd for C22H17NO2
(327.38): C, 80.71; H, 5.23; N, 4.28. Found: C, 80.65; H, 5.28;
Ethyl 2-cyano-3-phenyl-4-phenylcarbamoyl-but-2-enoate
15b.
White crystals; yield 76%, mp 105 ꢀC (EtOH). IR:
max = 3262 (NH), 2236 (CN), and 1705, 1663 (2CO) cmÀ1
.
υ
MS: m/z = 334 [M+]. dH = 1.18 (t, 3H, CH3), 2.75 (s, 2H, CH2),
3.81 (q, 2H, CH2), 6.98–7.60 (m, 10H, 2Ph-H), 10.12 (s, 1H,
NH). Anal. Calcd for C20H18N2O3 (334.37): C, 71.84; H, 5.43;
N, 8.38. Found: C, 71.90; H, 5.48; N, 8.28.
Azo coupling of 15a,b: Preparation of 16a,b. Diazonium
salt 8 was freshly prepared by adding a solution of (0.7 g;
0.01 mole) of sodium nitrite in 5 mL of H2O to a cold
solution of aniline hydrochloride (3 mL of conc. HCl + 1 mL
of aniline) with stirring. The resulting solution of the
diazonium salt was added to a cold solution of 15a or 15b
(0.01 mole) in ethanol (25 mL) containing sodium acetate
(2 g). The reaction mixture was stirred at room temperature
for 1 h and the solid product, thus formed, was collected by
filtration and recrystallized from ethanol to afford 16a and
16b, respectively.
N, 4.42.
2-Amino-4,6-diphenyl-1,4-dihydropyrimidine-5-carboxanilide
13. To a refluxing mixture of 11 (3.27 g; 0.01 mole) and guanidine
hydrochloride (0.96g; 0.01 mole) in ethanol (25 mL) was added
piperidine (0.5 mL) with continuous reflux for 4 h (TLC control),
then left to cool to room temperature. The reaction mixture was
then poured on ice-cold water and neutralized by few drops of
conc. HCl. The solid precipitate that appeared was filtered off and
recrystallized from ethanol to afford 13. Yellow powder; yield
72%, mp.88ꢀC (EtOH). υmax = 3261, 3198, and 3137 (NH and
NH2), 1687 (CO)cmÀ1; MS, m/z = 366 [M+-2 ]. dH = 3.85 (s, 1H,
4-H), 4.28 (s, 2H, NH2), 7.05–7.58 (m, 15H, 3Ph-H), 7.84 (s, 1H,
ring NH), 10.12 (s, 1H, NH amide). Anal. Calcd for C23H20N4O
(368.43): C, 74.98; H, 5.47; N, 15.21. Found: C, 74.95; H, 5.54;
N, 15.29.
4,4-Dicyano-3-phenyl-2-(phenyl-hydrazono)-but-3-enoic acid
phenylamide 16a.
υ
Brown crystals; yield 96%, mp. 152 ꢀC.
max = 3455, 3219 (2NH), 2231 (CN), 1654 cmÀ1 (CO); MS:
m/z = 391 [M+]. dH = 6.8–7.6 (m, 15H, 3Ph-H), 10.33 (s, 1H,
NH amide), 12.53 (s, 1H, hydrazo NH). Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

828
F. M. Abdelrazek, Y. M. Elkholy, A. M. Salah, N. M. Abdelazeem, and P. Metz
Vol 51
C24H17N5O (391.42): C, 73.64; H, 4.38; N, 17.89. Found: C,
73.68; H, 4.45; N, 17.98.
The reaction mixture was refluxed for 3 h (TLC control)
and left overnight. The reaction mixture was then poured
on ice cold water. The precipitated solid was filtered off
and recrystallized from ethanol to give 19. Yellow
crystalline product; yield 86%, mp. 161 ꢀC. υmax = 3439, 3220,
2298 (NH and NH2), 1654 (CO)cmÀ1. MS: m/z = 406 [M+].
dH = 6.65–7.70 (m, 15H, 3Ph-H), 10.35 (s, 1H, NH amide),
11.1 (s, 2H, NH2). dc = 115.15 (d), 115.66 (s), 118.55 (d),
120.33 (d), 124.46 (d), 127.66 (d), 128.19 (d), 128.97
(d), 129.49 (d), 130.01 (d), 131.6 (s), 137.46 (s), 138.51 (s),
142.04 (s), 153.25 (s), 161.99 (s), 162.88 (s). Anal. Calcd for
C24H18N6O (406.44): C, 70.92; H, 4.46; N, 20.68. Found: C,
71.12; H, 4.50; N, 20.52.
Ethyl 2-cyano-3-phenyl-4-phenylcarbamoyl-4-(phenyl-
hydrazono)-but-2-enoate 16b. Brown crystals; yield 96%, mp.
158 ꢀC. υmax = 3455, 3219 (2NH), 2231 (CN), 1654 cmÀ1 (CO);
MS: m/z = 438 [M+]. dH = 6.8–7.6 (m, 15H, 3Ph-H), 10.33 (s, 1H,
NH amide), 12.53 (s, 1H, hydrazo NH). Anal. Calcd for
C26H22N4O3 (438.48): C, 71.22; H, 5.06; N, 12.78. Found: C,
71.32; H, 4.96; N, 12.70.
Cyclization of 16a,b: Synthesis of the pyridazines
17a,b.
To a solution of each of compounds 16a and 16b
(0.01 mole) in ethanol (25 mL) was added 3 mL of freshly
prepared sodium ethoxide (1.15 g, 0.05 mole of sodium metal
dissolved in 10 mL of absolute ethanol). The reaction
mixture was refluxed for 2 h and left overnight to cool, poured
on ice-cold water and drops of conc. HCl were added till just
neutral (pH 7). The precipitated solids were filtered off and
3-Imino-4,7-diphenyl-3,7-dihydroisoxazolo[3,4-c]pyridazine-
5-carboxanilide 21.
To a refluxing mixture of 18b (3.92g;
0.01 mole) and hydroxylamine hydrochloride 20 (0.7g;
0.01 mole) in ethanol (25 mL) piperidine (0.01mole) was
added. The reflux was continued for 4 h (TLC control) and
then the reaction mixture was left to cool to room temperature.
The reaction mixture was then poured on ice cold water and
neutralized by few drops of conc. HCl. The solid precipitates
that appeared were filtered off and recrystallized from ethanol
to afford 21 as yellow crystalline product; yield 67%, mp.
recrystallized from ethanol to afford 17a and 17b.
5-Cyano-6-imino-1,4-diphenyl-1,6-dihydropyridazine-3-
carboxanilide 17a. Brown crystals; yield 96%, mp. 152 ꢀC
(EtOH); IR: υmax = 3455–3219 (2NH), 2231 (CN), and1654
(CO) cmÀ1; MS: m/z = 391 [M+]; dH = 6.65À7.62 (m, 15H,
3Ph-H), 10.33 (s, 1H, amide), 12.53 (s, 1H, imine). Anal.
Calcd for C24H17N5O (391.42): C, 73.64; H, 4.38; N, 17.89.
Found: C, 73.70; H, 4.15; N, 17.80.
161 ꢀC.
υmax = 3451, 3378, 3295, 3232 (2NH), 1656
(CO) cmÀ1. MS: MS: m/z = 407 [M+]. dH = 6.60–7.72 (m, 15H,
3Ph-H), 10.35 (s, 1H, NH amide), 12.15 (s, 1H, imine NH).
Anal. Calcd for C24H17N5O2 (407.42): C, 70.75; H, 4.21; N,
17.19. Found: C, 70.65; H, 4.25; N, 17.30.
5-Cyano-6-oxo-1,4-diphenyl-1,6-dihydropyridazine-3-
carboxanilide 17b.
Yellow crystals; yield 83%, mp. 158 ꢀC
(EtOH); IR: υmax = 3315, 3226 (NH), 2235 (CN), 1727 (CO),
1654 (CO) cmÀ1. MS: m/z = 392 [M+]. dH =6.90À7.62 (m, 15H,
3Ph-H), 10.20 (s, 1H, amide). Anal. Calcd for C24H16N4O2
(392.41): C, 73.46; H, 4.11; N, 14.28. Found: C, 73.55; H, 4.25;
N, 14.15.
Synthesis of the dihydropyrimido[4,5-c]pyridazine-3-
carboxanilide derivatives 24a–c.
To a mixture of 18b
(3.92 g; 0.01 mole) and guanidine hydrochloride 12 (0.96 g;
0.01 mole) or urea 22 (0.6 g; 0.01 mole) or thiourea 23 (0.76 g;
0.01 mole) in ethanol/dimethylformamide mixture 4:1 (25 mL)
few drops of triethylamine were added as catalyst (molar amount
in case of 12). The reaction mixture was refluxed for 3 h, then left
to cool to room temperature, diluted with cold water and acidified
with few drops of HCl till just neutral. The precipitated solids
were collected by filtration, washed thoroughly with cold water
3-Oxo-3,N-diphenyl-2-(phenyl-hydrazono)-propionamide
18. Diazonium salt was freshly prepared by adding a solution
of (0.7g; 0.01 mole) of sodium nitrite in 5 mL of H2O to a
cold solution of aniline hydrochloride (3 mL of conc.
HCl+ 1 mL of aniline) with stirring. The resulting solution of
the diazonium salt was added to a cold solution of 3 (2.39 g;
0.01 mole) in ethanol (25 mL) containing sodium acetate (2 g).
The reaction mixture was stirred at room temperature for 1 h
and the solid product, so formed, was collected by filtration
and recrystallized from ethanol. Yellow crystalline product;
yield 76%, mp: 140ꢀC (EtOH). υmax = 3448, 3220 (2NH),
1731, and 1654 (2CO) cmÀ1. MS: m/z = 343 [M+]; dH = 7.0–7.89
(m, 15H, 3Ph-H), 11.08 (s, 1H, NH anilide), 13.56 (s, 1H,
hydrazo NH). Anal. Calcd for C21H17N3O2 (343.38): C, 73.45; H,
and recrystallized from DMF/ethanol to afford 24a–c, respectively:
5-Amino-7-imino-1,4-diphenyl-1,7-dihydropyrimido[4,5-c]
pyridazine-3-carboxanilide 24a. Dark yellow crystals; yield
85%, mp. 163 ꢀC (EtOH). υmax = 3440, 3220 (NH and NH2),
1654 cmÀ1 (CO). MS: m/z =433 [M+]. dH =6.52–7.38 (m, 17H,
3Ph-H + NH2), 11.12 (s, 1H, amide NH), 12.05 (s, 1H, imine NH).
dc =114.10 (s), 115.56 (d), 118.56 (d), 120.43 (d), 124.16
(d), 126.26 (d), 127.79 (d), 128.57 (d), 128.82 (d), 129.45
(d), 134.81 (s), 138.5 (s), 142.26 (s), 145.91 (s), 153.04 (s),
160.25 (s), 162.79 (s), 164.85 (s). Anal. Calcd for
4.99; N, 12.24. Found: C, 73.55; H, 5.09; N, 12.14.
The reaction of 18 with the active methylenes 14a,b:
C
25H19N7O (433.46): C, 69.27; H, 4.42; N, 22.62. Found:
Alternative synthesis of 17a,b.
To a mixture of 18 (3.43g;
0.01 mole) and malononitrile 14a (0.66g; 0.01 mole) or ethyl
cyanoacetate 14b (1.13g; 0.01 mole) few drops of triethylamine
were added as catalystꢀ. The reaction mixture was fused together
on an oil bath at 170 C for 3 h then left overnight to cool. The
solid product obtained in each case was triturated with ethanol
and poured on ice cold water and neutralized with few drops of
HCl. The precipitated solids were collected by filtration and
recrystallized from ethanol to afford directly the pyridazine
C, 69.35; H, 4.40; N, 22.68.
5-Amino-7-oxo-1,4-diphenyl-1,7-dihydropyrimido[4,5-c]
pyridazine-3-carboxanilide 24b.
Yellow crystalline product;
yield 66%, mp. 164 ꢀC. υmax = 3437, 3129 (NH and NH2), 1687
and 1654cmÀ1 (2CO). MS: m/z = 434 [M+]. dH = 6.75–7.82
(m, 17H, 3Ph-H+ NH2), 11.1 (s, 1H, NH). Anal. Calcd for
C25H18N6O2 (434.45): C, 69.11; H, 4.18; N, 19.34. Found: C,
69.15; H, 4.28; N, 19.55.
5-Amino-1,4-diphenyl-7-thioxo-1,7-dihydropyrimido[4,5-c]
derivatives 17a,b respectively.
3-Amino-4,7-diphenyl-7H-pyrazolo[3,4-c]pyridazine-5-
pyridazine-3-carboxanilide 24c.
product; yield 67%, mp. 167 ꢀC. υmax = 3443, 3220, 3129
(NH and NH2), 1655 (CO) cmÀ1 MS: m/z = 450 [M+].
Pale yellow crystalline
carboxanilide 19.
To compound 18b (3.92 g; 0.01 mole)
in ethanol (20 mL) hydrazine hydrate (0.5 mL) was added.
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Synthesis of Some New Pyrazole, Pyrimidine, Pyridazine, and Their Fused
Derivatives from 3-Oxo-3,N-diphenylpropionamide
829
dH = 6.79–7.65 (m, 17H, 3Ph-H + NH2), 11.08 (s, 1H, NH).
Anal. Calcd for C25H18N6OS (450.52): C, 66.65; H, 4.03; N,
18.65; S, 7.12. Found: C, 66.63; H, 4.13; N, 18.60; S, 7.17.
(5-Amino-1,4-diphenylhydrobenzo[b]pyridazino[3,4-e]-1,4-
diazepin-3-yl)N-benzamide 26. To a refluxing mixture of
18b (3.92 g; 0.01 mole) and 1,2-phenylenediamine 25 (1.08 g;
0.01 mole) in ethanol (25 mL) piperidine (0.5 mL) was added.
The reflux was continued for 4 h (TLC control) and then the
reaction mixture was left to cool to room temperature. The
reaction mixture was then poured on ice cold water and
neutralized by few drops of conc. HCl. The solid
precipitates that appeared were filtered off and recrystallized
from ethanol to afford 26 as pale yellow crystals; yield 62%,
Cinnolines and Phthalazines; Castle, R. N., Ed.; John Wiley & Sons,
Inc.: New York, 1973; pp. 968–1012 and references within.
[2] a) Frank, H.; Heinisch, G. Pharmacologically active pyrida-
zines Part I. In Progress in Medicinal Chemistry; Ellis, G.P., West, G.
B., Eds.; Elsevier: Amsterdam, 1990; Vol. 27, 1.; b) Frank, H.; Heinisch,
G. Pharmacologically active pyridazines Part II. In Progress in Medicinal
Chemistry; Ellis, G.P., Luscombe, D.K., Eds.; Elsevier: Amsterdam,
1992; Vol. 29, 141.
[3] Mylari B. L., Zembrowski W. J. US Pat. 4 1990, 954, 629;
Chem Abstr 1991, 114, 62105 u.
[4] Sahin M. F.; Badicoglu B.; Goekce M.; Kuepeli E. Arch
Pharm Pharm Med Chem (Weinheim) 2004, 337, 445.
[5] Barrett J. A.; Woltmann R. F.; Swillo R. S.; Kasiewski C. J
Cardiovascular Pharm 1990, 16, 537.
[6] Betti L.; Zanelli M.; Gannaccini G.; Manetti F.; Schenone S.;
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[8] Stevenson T. M.; Crouse B. A.; Thieu T. V.; Gebreysus C.;
Finkelstein B. L.; Sethuraman M. R.; Dubas-Cordery C. M.; Piotrowski
D. L. J. Heterocyclic Chem. 2005, 42, 427.
mp. 169 ꢀC.
υmax = 3437, 3357 (NH and NH2), 1654
(CO) cmÀ1. MS: m/z = 482 [M+]. dH = 6.65–7.65 (m, 21H,
arom. + NH2), 11.12 (s, 1H, amide NH) Anal. Calcd for
C30H22N6O (482.54): C, 74.67; H, 4.60; N, 17.42. Found:
C, 74.63; H, 4.65; N, 17.55.
[9] Abdelrazek F. M.; Fathy A. E. M. Arch. Pharm. Chem. Life
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Acknowledgments. We thank the Alexander von Humboldt
Foundation (Germany) for granting a research fellowship (July
2011) to F. M. Abdelrazek; during this time, a considerable part
of the spectra of this work was carried out. This work has been
abstracted in part from the M. Sc. Thesis of Mrs. Nagwa M.
Abdelazeem.
[10] Abdelrazek F. M.; Metz P.; Metwally N. H.; El-Mahrouky S.
F. Arch Pharm Chem life Sciences (Weinheim) 2006, 339(8), 456.
[11] Abdelrazek F. M.; Metz P.; Kataeva O.; Jaeger A.; El-Mahrouky S.
F. Arch Pharm Chem Life Sciences (Weinheim) 2007, 340(10), 543.
[12] Abdelrazek, F. M.; Metwally, N. H. Synthetic Communications
2009, 39, 4088.
[13] Elkholy, Y. M. Heterocyclic Commun 2005, 11(1), 89.
[14] Abdallah, T. A.; Metwally, N. H.; Abdelrazek, F. M. Afinidad
2008, 65(537), 393.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet