Multicomponent synthesis of pyridazine and pyridazinoquinazoline derivatives in the presence of catalysts such as magnesium oxide (MgO) and 12-tungstophosphoric acid (PW)

Article abstract of DOI:10.1002/jhet.355

A series of 3-amino-2,5-dihydropyridazines and fused pyridazinoquinazolines have been prepared in a one-step procedure from three-component reactions of (arylhydrazono)-propan-2-ones, aldehydes and malononitrile or ethyl cyanoacetate in the presence of ma

Full text of DOI:10.1002/jhet.355

1122
Multicomponent Synthesis of Pyridazine and
Pyridazinoquinazoline Derivatives in the Presence of Catalysts
Such as Magnesium Oxide (MgO) and 12-Tungstophosphoric
Acid (PW)
Vol 48
Hassan Sheibani* and Zeinab Esfandiarpoor
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran
*E-mail: hsheibani@mail.uk.ac.ir
Received September 7, 2009
DOI 10.1002/jhet.355
Published online 1 June 2011 in Wiley Online Library (wileyonlinelibrary.com).
A series of 3-amino-2,5-dihydropyridazines and fused pyridazinoquinazolines have been prepared in a
one-step procedure from three-component reactions of (arylhydrazono)-propan-2-ones, aldehydes and
malononitrile or ethyl cyanoacetate in the presence of magnesium oxide (MgO) and 12-tungstophos-
phoric acid (PW) as highly effective heterogeneous catalysts. The salient features of these methods
include high conversions, short reaction times, cleaner reaction profiles, and the use of inexpensive and
readily available catalysts.
J. Heterocyclic Chem., 48, 1122 (2011).
INTRODUCTION
of pyridazines encourage the development of methods
for their synthesis and functionalization. In our continu-
ing interest in the synthesis of heterocycles containing
nitrogen and sulfur atoms [7,8], we decided to investi-
gate the three-component reaction of a-oxohydrazone 1,
aldehydes, and malononitrile or ethyl cyanoacetate,
which is extended to the formation of 3-amino-2,5-dihy-
dropyridazine derivatives. It has been recently shown
that the CH of aldehydehydrazone is electron rich and
reacts with electrophiles. The reactivity of compound 1
toward a, b-unsaturated nitriles has recently been uti-
lized to develop a new synthetic approach for dihydro-
pyridazines, using pyridine or piperidine as base cata-
lysts [9].
Increasing attention during the last decades for envi-
ronmental protection has led to both modern academic
and industrial groups to develop chemical process with
maximum yield and minimum cost. One of the tools
used to combine economic aspects with the environmen-
tal ones is the multicomponent reaction (MCR) strategy;
this process consists of two or more synthetic steps
which are carried out without isolation of any intermedi-
ate thus reducing time, saving money, energy, and raw
materials [1].
The chemistry and pharmacology of pyridazines have
recently received considerable interest. This can be read-
ily realized from the vast number of papers and patents
dealing with synthesis, chemistry, and biological activ-
ities of pyridazine derivatives [2]. The pyridazine ring is
often encountered as a structural component of com-
pounds possessing biological activity: analgesic, antibac-
terial, anti-inflammatory, antihypertensive, or antihista-
minic activities have all been reported [3–5]. These
compounds could also be used as semi-conductor mate-
rials and as materials with nonlinear optical properties
[6]. These pharmacological and technological properties
In recent years, there has been increasing emphasis
on the design and use of environmentally friendly solid
acid and base catalysts to reduce the amount of toxic
waste and by products arising from chemical processes
prompted by stringent environment protection laws.
Magnesium oxide (MgO), obtained using a novel but
simple procedure, was systematically investigated as a
heterogeneous base catalyst for reactions taking place in
the liquid phase, specifically the Michael addition and
C
V
2011 HeteroCorporation

September 2011 Multicomponent Synthesis of Pyridazine and Pyridazinoquinazoline Derivatives in the
Presence of Catalysts Such As Magnesium Oxide (MgO) and 12-Tungstophosphoric Acid (PW)
1123
Scheme 1
it avoids the drawbacks of environmental pollution and
existing technologies are being corroded [11].
RESULTS AND DISCUSSION
In continuing our interest in the synthesis of heterocy-
clic compounds [12–15], in this article, we wish to
report a one-pot synthesis of 6-acetyl-3-amino-2,5-dia-
ryl-2,5-dihydro-4-pyridazincarbonitrile derivatives 4a–i
and substituted pyridazinoquinazolines 4j–m which were
prepared in a three-component reaction of arylhydra-
zones 1a–c, malononitrile or ethyl cyanoacetate, and
aldehydes at ambient temperature in the presence of cat-
alysts such as magnesium oxide MgO and 12-tungsto-
phosphoric acid (PW) along with catalytic amount of
triethylamine (Scheme 1).
the Knoevenagel condensation. The catalytic activity of
MgO for both Knoevenagel condensation and Michael
additions (active methylene compounds such as malono-
nitrile and 1,3-dicarbonyl compounds with a,b-unsatu-
rated carbonyl compounds) was found to compare favor-
ably with previous studies using more complicated and
expensive catalysts. Indeed the simplicity of the prepara-
tion and the ease of reactivation after use may offer suf-
ficient compensation to make MgO the base catalyst of
choice even if slightly better yields can be obtained
with alternative catalysts [10].
To optimize the reaction conditions, we used some
polar and nonpolar solvents in the three-component
reactions of benzaldehyde, malononitrile, arylhydrazones
1 (Y ¼ H or ACO2Et) in the presence of high surface
area magnesium oxide (MgO) or 12-tungstophosphoric
acid (PW) along with catalytic amount of triethylamine
as model reactions to investigate the effects of solvent
for preparing compounds 4a and 4l, respectively. In
each case, the substrates were mixed together with 0.25
g catalysts agitated with 10 mL solvent. The results are
shown in Table 2.
Heteropoly acids (HPAs) have several advantages as
catalysts which make them economically and environ-
mentally feasible. They are stronger acids than homoge-
neous acid catalysts such as sulfuric acid or ion
exchange resins. The use of HPAs as a catalyst is im-
portant in the development of clean technologies, since
As shown in Tables 1 and 2, reaction yields are mark-
edly affected by the catalyst, and optimum results were
obtained when reactions were run in acetonitrile and in
the presence of 12-tungstophosphoric acid (PW) along
with catalytic amount of triethylamine. To optimize the
reaction conditions for preparing compounds 4, the
Table 1
Synthesis of 4a-m in the presence of catalyst.
CMa (MgO)
time (yield)
[min(%)]
HSAb (MgO)
time (yield) [min(%)]
PWc time (yield)
[min(%)]
Compound
Ar
X
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
4-ClC6H4
2,4-Cl2C6H3
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
C6H5
CN
CN
50(80)
45(75)
40(78)
60(60)
45(65)
60(50)
80(65)
45(78)
48(74)
60(55)
40(75)
150(60)
120(65)
16(93)
15(90)
12(90)
18(62)
13(75)
17(65)
18(70)
16(91)
13(80)
15(60)
14(82)
75(65)
60(70)
3(95)
3(94)
6(75)
2(78)
7(80)
10(82)
7(92)
5(82)
4(65)
3(88)
8(78)
15(70)
15(72)
CN
CN
CN
CN
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
CN
4-ClC6H4
2,4-Cl2C6H3
4-NO2C6H4
4-BrC6H4
C6H5
4j
4k
4l
4m
C6H5
a Commercial MgO.
b High surface area MgO.
c 12-Tungstophosphoric acid a along with catalytic amount of triethylamine.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1124
H. Sheibani and Z. Esfandiarpoor
Vol 48
Scheme 2
Table 2
Solvent effects on the three-component reactions for the synthesis of
4a and 4l in the presence of MgO or 12-tungstophosphoric
acid (PW).
Compound
Catalyst
Solvent Time (min) Yield (%)
4a
4l
4a
4l
4a
4l
MgO(PW) Toluene
MgO(PW) Toluene
90(60)
150(95)
16(3)
75(15)
60(45)
120(70)
60(75)
45(60)
93(95)
65(70)
70(80)
50(60)
MgO(PW)
MgO(PW)
MgO(PW)
MgO(PW)
MeCN
MeCN
EtOH
EtOH
effect of catalysts for preparing compounds 4a–i under
different reaction conditions were investigated. First,
the three-component reaction was carried out in the
presence of two types of magnesium crystals [commer-
cial MgO (CM-MgO) and high-surface area MgO
(HSA-MgO)]. High-surface area MgO was found to be
more active than CM-MgO. Second, we have used 12-
tungstophosphoric acid (PW) along with catalytic
amount of triethylamine as a highly effective heteroge-
negeneous catalyst and the results of these methods are
presented in Table 1.
The compounds 4c–f and 4h–m are known in the lit-
erature [9,16,17]. The IR spectra and melting point of
all known compounds were consistent with those
reported in the literature. Structures 4a–m were estab-
lished on the basis of IR which showed the presence of
CN or carboxylate group at a region of 2235–2238 or
1650–1700 cmꢀ1, respectively, and two sharp bands at
3450–3400 and 3370–3300 cmꢀ1 which are due to the
asymmetric and symmetric vibrations of the NH2 group.
We have separately used pyridine, triethylamine as
base catalysts and 12-tungstophosphoric acid (PW) as an
acid catalyst in the three-component reaction of benzal-
dehyde, (Phenylhydrazono)-propan-2-one 1a, malononi-
trile, or ethyl cyanoacetate to prepare compounds 4a
and 4g, respectively. These reactions were too slow with
low yields. However, these reactions in the presence of
12-tungstophosphoric acid (PW) along with catalytic
amount of triethylamine can be performed in excellent
yields and in short reaction times. Our observations are
reported in Table 3.
1
The H and 13C NMR and mass spectra of compounds
(4a, 4b, 4g, and 4j) were also in accordance with the
proposed structures.
In summary, by using different catalysts, it has been
verified that the three-component reactions of (arylhy-
drazono)-propan-2-ones, aldehydes, and malononitrile or
ethyl cyanoacetate in the presence of 12-tungstophos-
phoric acid (PW) along with catalytic amount of trie-
thylamine as a highly effective heterogeneous catalyst
can be performed to yield pyridazine and pyridazinoqui-
nazoline derivatives in excellent yields and in short
reaction times.
On the basis of our results, a plausible mechanism
has been proposed for the three-component reaction of
(arylhydrazono)-propan-2-ones 1, aldehydes, and malo-
nonitrile or ethyl cyanoacetate in the presence of MgO
to yield 3-amino-2,5-dihydro pyridazine derivatives, as
shown in Scheme 2.
Table 3
Catalyst effects on the three-component reactions for the synthesis of
EXPERIMENTAL
4a and 4g.
The (arylhydrazono)-propan-2-ones 1 were known and pre-
pared according to a general procedure [16]. Melting points
were determined on an Gallenkamp melting point apparatus
and are uncorrected. IR spectra were measured on a Mattson
Compound
Catalyst
Time (h)
Yield (%)
4a
4a
4a
4g
4g
4g
Pyridine
Triethylamine
PWa
Pyridine
Triethylamine
PWa
5.5
5
60
60
75
46
45
50
1
1000 FTIR spectrometer. H NMR and 13C NMR spectra were
2.5
12
10
6
recorded on a BRUKER DRX-500 AVANCE spectrometer at
500 and 125.77 MHz, respectively. MS spectra were recorded
on a Shimadzu QP 1100EX mass spectrometer operating at an
ionization potential of 70 eV. Elemental analyses were per-
formed using a Heraeus CHN-O-Rapid analyzer.
a 12-Tungstophosphoric acid.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2011 Multicomponent Synthesis of Pyridazine and Pyridazinoquinazoline Derivatives in the
Presence of Catalysts Such As Magnesium Oxide (MgO) and 12-Tungstophosphoric Acid (PW)
1125
(C4), 58.8, 33.8 (C5), 24.5, 14.3. MS, m/z (%):363 (Mþ, 15),
320(8), 290(100), 258(24), 248(15), 181(10), 119(14), 93(15),
77(42), 65(12), 51(14). Anal. Calcd. for C21H21N3O3: C,
69.41; H, 5.82; N, 11.56; %. Found: C, 69.25; H, 5.79; N,
11.29.
2-Acety-6-amino-3-(4-chlorophenyl)-3-H-pyridazino [1,6-
a]quinazoline-4-yl cyanide (4j). Yellow crystals; mp 193–
195ꢁC; mmax(KBr): 3435, 3425 (NH2), 2223 (CN), 1690 (CO)
cmꢀ1; dH (500 MHz, DMSO-d6): 8.18–7.30(8H, m, Ar),
7.18(2H, s, NH2), 5.00(1H, s, pyridazine-H), 2.39(3H, s, CH3);
dC (125 MHz, DMSO-d6): 195.7 (CO), 156.4, 147.3, 144.6,
141.3, 139.9, 134.4, 132.2, 129.3, 128.9, 124.7, 124.3, 120.5,
114.3, 112.1 (CN), 67.6 (C4), 37.4 (C3), 25.2 (CH3), MS, m/z
(%):375 (Mþ, 18), 336(27), 333 (100), 283(24), 93(15),
77(52), 65(22), 51(18). Anal. Calcd. for C20H14ClN5O: C,
63.92; H, 3.75; N, 18.64. Found: C, 63.68; H, 3.64; N, 18.29.
Preparation of high-surface area MgO. The catalysts used
in this study were obtained by calcinations of rehydrated
Mg(OH)2 at 450ꢁC for 2 h [10].
General procedure for the preparation of 3-amino-2,5-
dihydropyridazine and pyridazinoquinazoline derivatives
(4a–m). Method I: A mixture of the (arylhydrazono)-propan-2-
one 1 (2 mmol), aldehyde (2 mmol), and malononitrile or ethyl
cyanoacetate (2 mmol) in CH3CN (25 mL) was refluxed with
stirring in the presence of commercial MgO or high-surface
area MgO (0.25 g). The reactions were continued until com-
pletion, as monitored by TLC. After completion of the reac-
tion, the catalyst was removed by filtration and the filtrate was
concentrated to obtain the crude product. The crude product
was crystallized from ethanol.
Method II: To a magnetically stirred solution of the 12-tung-
stophosphoric acid (PW) (0.1 mmol) along with catalytic
amount of Triethylamine (4–5 drops), aldehyde (2 mmol), and
malononitrile or ethyl cyanoacetate (2 mmol) in CH3CN (25
mL) was added (aryylhydrazono)-propan-2-one 1 (2 mmol) at
ambient temperature for the period of time shown in Table 1.
The reactions were continued until completion, as monitored
by TLC. After completion of the reaction, the catalyst was
removed by filtration and the filtrate was concentrated to
obtain the crude product. The crude product was crystallized
from ethanol.
Acknowledgments. The authors express appreciation to the Sha-
hid Bahonar University of Kerman Faculty Research Committee
Fund for its support of this investigation.
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CH3). dC (125 MHz, DMSO-d6): 195.6 (CO), 150.2, 143.4,
141.9, 139.9, 131.8, 129.4, 128.8, 128.6, 127.9, 125.7, 120.2
(CN), 56.4 (C4), 35.5 (C5), 24.5 (CH3). MS, m/z (%):350 (Mþ,
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m
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NH2), 5.20(1H, s, pyridazine-H), 4.04(2H,q, JHH ¼ 7.0 Hz,
3
CH2), 2.32(3H, s,CH3), 1.15(3H, t, JHH ¼ 7.0 Hz, CH3); dC
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet