A regioselective one-pot, three component synthesis of 6-Aryl-4-cyano-3(2H) -pyridazinones in water

Article abstract of DOI:10.1071/CH09602

A series of 4-cyano-3(2H)-pyridazinones bearing different aryl substituents in the 6-position of the pyridazinone ring was synthesized regioselectively using a novel efficient one-pot three component reaction of alkyl 2-cyanoacetates with arylglyoxals in the presence of hydrazine hydrate at room temperature in water. CSIRO 2010.

Full text of DOI:10.1071/CH09602

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2010, 63, 1396–1401
www.publish.csiro.au/journals/ajc
A Regioselective One-Pot, Three Component Synthesis
of 6-Aryl-4-cyano-3(2H)-pyridazinones in Water
Mehdi Rimaz,A Jabbar Khalafy,A,B and Peyman Najafi MoghadamA
AChemistry Department, Urmia University, PO Box 57154, Urmia, Iran.
BCorresponding author. Email: j.khalafi@mail.urmia.ac.ir
A series of 4-cyano-3(2H)-pyridazinones bearing different aryl substituents in the 6-position of the pyridazinone ring
was synthesized regioselectively using a novel efficient one-pot three component reaction of alkyl 2-cyanoacetates with
arylglyoxals in the presence of hydrazine hydrate at room temperature in water.
Manuscript received: 23 November 2009.
Manuscript accepted: 17 May 2010.
Introduction
One of the most common approaches to pyridazinone syn-
thesis is the condensation of 1,4-keto-esters or 1,4-keto-acids
with hydrazine.[23–29] The major drawbacks of recently reported
synthetic routes are the strong reaction conditions required for
cyclization, oxidation (use of boiling ethanol and hot acetic acid
for extended times) and the limited availability of substituted
1,4-keto-esters. The classical approach to 1,4-keto-esters is the
condensation of enolates with phenacyl chlorides,[28] thus lim-
iting the preparation to pyridazinones with aryl substituents.
Therefore, mild reaction conditions that overcome some of the
shortcomings of previous methods are necessary. One-pot mul-
ticomponent processes have recently gained a considerable and
steadily increasing academic, economic and ecological interest
because they address very fundamental principles of synthetic
efficiency and reaction design.[6,30,31] As part of our interest
in the synthesis of pyridazine systems,[32–34] we report herein
the one-pot regioselective synthesis of 6-aryl-4-cyano-3(2H)-
pyridazinone 7 via reaction of alkyl 2-cyanoacetates 8 with
arylglyoxals 9 in the presence of excess hydrazine hydrate
(Scheme 1). Previous methods of synthesis involved either the
condensation of β,β-dicyanopropiophenone with hydrazine[35]
or the reaction of arylglyoxals with hydrazine and ethyl cyano-
acetate in a two-step procedure.[36] The method reported in this
communication has the advantage of using an efficient one-pot
synthetic strategy, applying water as a green solvent and offering
milder conditions for the formation of 6-aryl-4-cyano-3(2H)-
pyridazinones. Of these compounds, only the synthesis of 22
has been previously reported.[35,36]
Organic reactions in aqueous media have attracted much atten-
tion in synthetic organic chemistry, not only because water is
one of the most abundant, cheap, and environmentally friendly
solvents, but also because water exhibits unique reactivity and
selectivity, properties that are different from those of conven-
tional organic solvents. Thus, development of novel reactivity
as well as selectivity that cannot be attained in conventional
organic solvents is one of the challenging goals of aqueous
chemistry.[1] Of all the existing areas of chemistry, medicinal
and pharmaceutical chemistry, with their traditionally large vol-
ume of waste/product ratio, could benefit the most from green
aqueous techniques.[2]
In recent years, almost every part of the drug discovery pro-
cesses has undergone a radical change. However, one of the
few things that has not changed is the fact that the major-
ity of medicines are still small organic molecules and a high
proportion of these contain a heterocyclic ring.[3] As a conse-
quence, low molecular weight heterocycles have gained a central
role in the high throughput synthesis of libraries of drug-like
compounds.[4,5]
Of such small heterocycles, substituted pyridazinones
are useful compounds with a broad array of biological
activities.[6–12] They have been used as herbicides, such as
Norflurazon 1 and as insecticides, like Pyridaben 2 for crop
protection.[13] In drug discovery, pyridazinones were identi-
fied as selective COX-2 inhibitors (ABT-963 3[14] and CK
−126[15]) and α4 integrin receptor antagonists.[16] Pyridazinone
derivatives are also cyclooxygenase-2 inhibitors 4, thereby act-
ing as anti-inflammatory drugs,[17,18] and show strong affinity
for α1-adrenergic receptors.[19,20] Most of the 6-aryl-3(2H)-
pyridazinones are active in the cardiovascular system. For
example, zardaverine 5 and imazodan 6 have been developed
as phosphodiesterase type III inhibitors (PDE III) in the search
for new antiplatelet or cardiotonic agents[21] (Fig. 1).
Results and Discussion
The arylglyoxals 9 were prepared by oxidation of the correspond-
ing aryl methyl ketones 10 according to the standard literature
procedure (Scheme 2).[37]
The reactions were performed under two conditions. In pro-
cedure A, arylglyoxals 11–18 and cyanoacetates 8 were mixed
in water and stirred at room-temperature for several minutes,
then excess hydrazine hydrate was added to the reaction mixture,
which led to formation of 6-aryl substituted cyanopyridazinones,
isolated as a single product in good yields (Scheme 1). The
Several studies have indicated that the NH group adjacent
to the carbonyl group in the azine system may be an essential
structural requirement in the binding of 3(2H)-pyridazinones to
a variety of biological receptors.[22]
© CSIRO 2010
10.1071/CH09602
0004-9425/10/091396

Regioselective Synthesis of 6-Aryl-4-cyano-3(2H)-pyridazinones
1397
F
F
CF3
O
O
O
Cl
O
N
N
N
N
HO
O
Cl
N
N
S
MeHN
S
1
2
3
O
H
O
N
SO2Me
O
N
NH
N
N
N
O
OCHF2
N
O
N
OMe
4
5
6
Fig. 1. Some important substituted pyridazinone compounds.
CN
O
singlet at δ 13.93 ppm, but two singlets for the CH of the pyri-
dazinone ring, one at δ 8.82 ppm with high intensity due to
H5 of the 6-aryl isomer 22 which is accordant with its litera-
ture value (i.e. 8.85 ppm),[35] and the other at δ 8.24 ppm with
low intensity due to H6 of 5-arylisomer 27 (Ar = Ph) which
is consistent with its literature value of δ 8.28, as reported by
Braña and coworkers,[36] and a multiplet at δ 7.47–7.88 ppm
for the phenyl protons of both 5-phenyl and 6-phenyl isomers,
which overlap each other, but their range is consistent with the
corresponding literature values.[35,36] These results show the
formation of two isomeric 4-cyanopyridazinones. Generally,
the average chemical shift for the CH of a pyridazinone ring
in 6-arylcyanopyridazinones occurrs at δ 8.67 ppm, whereas in
5-arylcyanopyridazinones, this proton is shielded and its sig-
nal occurrs at δ 8.25 ppm. Indeed, the pattern of δ (H5) >
δ (H6) that is observed for related arylsubstituted cyanopyri-
dazinones is consistent with the observations made by Showalter
and coworkers for pyrimidopyridazine derivatives.[38] The prod-
uct ratios were determined by inspection of the 1H NMR spectra,
using the intensities of the signals assigned to H5 and H6 of the
pyridazinone rings. The yields and product ratios obtained from
procedure B are summarized in Table 2.
We believe that the second procedure leads to two competi-
tive reaction pathways A and B. Presumably, the initial reaction
of hydrazine with the ester group gives the corresponding
hydrazide, and when this intermediate reacts with the alde-
hyde group it leads ultimately to the 5-arylcyanopyridazinone
after cyclization (path B). In competition with this, when the
reaction of hydrazide occurs with the keto group, as might be
expected with electron withdrawing aryl groups, subsequent
cyclization leads to the 6-aryl product (pathA). Hence, mixtures
of 5- and 6-arylcyanopyridazinones were obtained by this pro-
cedure. However, such a rationalization for the regioselectivity
is shown to be oversimplistic by the observations of Showalter
and coworkers,[38] who noted that in a series of arylglyoxals,
the reaction of hydrazine with glyoxal carbonyls depended more
on the solvent and acidity of the medium than on the electronic
effects of the aryl substituent. They have also reported that in
hydroxylic solvents such as water, similar to our reaction condi-
tions, hydrazine can react with both glyoxal carbonyls and this
leads to form the mixture of regioisomers.[38] The suggested
mechanism for the formation of both 5-arylcyanopyridazinone
and 6-arylcyanopyridazinone regioisomers under condition B is
shown in Scheme 5.
O
H
NH2NH2·H2O
O
NC
R
ϩ
Ar
Water, r.t.
70–96%
NH
O
O
Ar
N
9
8 (R ϭ Me, Et, n-Bu)
7
Scheme 1. Synthesis of 6-aryl-4-cyano-3(2H)-pyridazinone.
suggested mechanism for the exclusive formation of these prod-
ucts involves the initial formation of a γ-ketoester followed by
its subsequent reaction with hydrazine (Scheme 3). The yields
of products varied slightly with the nature of the cyano ester;
as expected the smaller esters gave somewhat better yields, as
shown in Table 1.
In order to support the above suggested mechanism for the
regioselective synthesis of 6-arylcyanopyridazinones, we per-
formed the reaction under new conditions in a two stage mode
(procedure B) based on Braña’s method.[36] In this procedure,
at the first stage cyanoacetate 8 and hydrazine hydrate both in
molar ratios were mixed for an appropriate time and then at
the second stage, arylglyoxal 9 was added to this mixture to
form the arylcyanopyridazinone derivatives. Interestingly, car-
rying out the reaction under procedure B in which only the
order of mixing the reactants was varied, yielded a mixture of
both the 6-arylcyanopridazinone 7 and 5-arylcyanopyridazinone
27 regioisomers when using glyoxals 11–15. In contrast, halo-
gen substituted arylglyoxals 16–18 gave only the corresponding
6-arylcyanopyridazinone regioisomer 7 as a single product
(Scheme 4).
As mentioned above, of these pyridazinone systems only
the structure of 4-cyano-6-phenylpyridazinone 22 and 4-
cyano-5-phenylpyridazinone (27,Ar = Ph) have been previously
reported.[35,36] The spectral data for both of them are consistent
with the literature data. For example, in the 1H NMR spectrum
of 6-phenyl derivative 22, which is obtained as a sole prod-
uct via procedure A, the H5 proton of the pyridazinone ring
appears as a singlet at δ 8.82 ppm, which is close to the litera-
ture value of δ 8.85 reported by Al-Mousawi and coworkers.[35]
The 1H NMR spectra of the mixture of products which are
obtained via procedure B, showed one signal for NH but two
signals with different intensities for all of the protons attached
to carbons. For example, the spectrum of the mixture of regio-
isomers 22 and 27 (Ar = Ph) gave one signal for NH as a broad

1398
M. Rimaz, J. Khalafy, and P. N. Moghadam
O
SeO2
H
Ar
Ar
Dioxane/water
reflux
O
O
10
9
O
Ar ϭ
O
H3CO
H3CO
15
Cl
OCH3
Br
F
OCH3
11
12
13
14
16
17
18
Scheme 2. Synthesis of arylglyoxals.
O
NC
NC
O
Ar
O
NH2NH2
Ar
O
O
R
O
Ar
R
CN
R
CN
O O
ϪROH
ϪH2O
ϪH2O
HN N
O
OH
Scheme 3. Suggested mechanism for regioselective formation of 6-arylcyanopyridazinones.
Attempts to alter the product ratio by stirring the reaction
mixture for a long time or by heating failed.
δC ([D6]DMSO) 114.4, 128.9, 130.4, 131.2, 131.7, 136.4, 138.2,
149.3, 158.2. νmax (KBr)/cm−1 3134, 3067, 2229, 1661, 1592,
1243, 1121, 1091, 1013, 927, 835, 635. m/z (%) 233 (M+ + 2,
79), 231 (M+, 100), 174 (56), 140 (61), 136 (71). Anal. Calc.
for C11H6ClN3O: C 57.04, H 3.61, N 18.14. Found: C 57.15,
H 3.69, N 18.00%.
In conclusion, we have demonstrated a novel and efficient
regioselective arylglyoxal-mediated synthesis of new 6-aryl-
4-cyano-3(2H)-pyridazinones from alkyl 2-cyanoacetates and
hydrazine at room temperature in water. Considering the avail-
ability of the starting materials, the simple procedure at room
temperature, and the robust nature of this chemical process, this
provides a very straightforward route to obtain various 6-aryl
substituted 4-cyanopyridazinones without the use of acidic or
metal catalysts. Moreover, the NH group adjacent to the car-
bonyl group in the azine system of these products supplies the
essential structural requirement for their binding to a variety of
biological receptors.
6-(4-Bromophenyl)-4-cyano-3(2H)-pyridazinone (20)
A pale pink solid, mp 348◦C (dec.) δH ([D6]DMSO) 7.71 (d,
J 8.7, 2H), 7.83 (d, J 8.7, 2H), 8.24 (s, 1H), 13.95 (br s, 1H). δC
([D6]DMSO) 110.7, 114.3, 125.7, 131.1, 131.6, 132.6, 137.2,
149.3, 158.2. νmax (KBr)/cm−1 3134, 3065, 2227, 1664, 1586,
1171, 1120, 1072, 1009, 926, 833. m/z (%) 277 (M+ + 2, 100),
275 (M+, 94), 196 (26), 140 (46). Anal. Calc. for C11H6BrN3O:
C 47.85, H 2.19, N 15.22. Found: C 47.74, H 2.30, N 15.29%.
Experimental
6-(4-Fluorophenyl)-4-cyano-3(2H)-pyridazinone (21)
General Procedures
A white solid, mp 293◦C (dec.) δH ([D6]DMSO) 7.31–7.37
(m, 2H), 7.91–7.95 (m, 2H), 8.82 (s, 1H), 13.99 (br s, 1H). δC
([D6]DMSO) 114.5, 115.0, 116.2, 116.5, 128.5, 128.6, 130.4,
130.5, 138.8, 143.2, 157.3, 161.8, 165.1. νmax (KBr)/cm−1 3103,
3052, 2239, 1675, 1607, 1515, 1242, 1167, 1137, 911, 841, 553.
m/z (%) 215 (M+, 100), 187 (20), 158 (91), 120 (28).Anal. Calc.
for C11H6FN3O: C 61.40, H 2.81, N 19.53. Found: C 61.45,
H 2.73, N 19.41%.
Melting points were determined on a Philip Harris C4954718
apparatus and are uncorrected. Infrared spectra were recorded
on aThermonicolet (Nexus 670) FourierTransform (FT) infrared
spectrometer, and measured as KBr discs. 1H (300 MHz) and 13
C
(75.5 MHz) NMR measurements were recorded on a Bruker 300
spectrometer in [D6]DMSO usingTMS as the internal reference.
Mass spectra were recorded on a Varian Matt 311 spectrometer
and relative abundances of fragments are quoted in parentheses
after the m/z values. Microanalyses were performed on a Leco
Analyzer 932.
6-Phenyl-4-cyano-3(2H)-pyridazinone (22)
A pink solid, mp 311◦C (dec.) δH ([D6]DMSO) 7.43–7.52 (m,
3H), 7.88 (dd, J1 7.8, J2 1.8, 2H), 8.82 (s, 1H), 13.98 (br s, 1H).
δC ([D6]DMSO) 114.6, 115.0, 126.2, 129.4, 130.1, 133.8, 138.8,
144.0, 157.4. νmax (KBr)/cm−1 3145, 3050, 2234, 1660, 1593,
1439, 1236, 1132, 911, 778, 693. m/z (%) 197 (M+, 100), 169
(50), 140 (93), 114 (24), 102 (26). Anal. Calc. for C11H7N3O: C
67.00, H 3.58, N 21.31. Found: C 67.12, H 3.51, N 21.20%.[35,36]
Procedure A for Pyridazinone Synthesis
To a mixture of alkyl 2-cyanoacetate (1 mmol) and arylglyoxal
(1 mmol) in water (5 mL), was successively added hydrazine
hydrate (100%, 4 mmol) at room temperature; the resultant
mixture was stirred for 15–30 min. After an appropriate time,
the precipitation of product ceased. The obtained solid was
then filtered, washed with water (4 × 10 mL) and purified by
recrystallization from methanol.
6-(4-Methoxyphenyl)-4-cyano-3(2H)-pyridazinone (23)
A yellow solid, mp 304◦C (dec.) δH ([D6]DMSO) 3.80 (s,
3H), 7.03 (d, J 8.7, 2H), 7.83 (d, J 8.7, 2H), 8.78 (s, 1H), 13.85
(br s, 1H). δC ([D6]DMSO) 55.7, 114.6, 114.8, 115.0, 126.2,
127.7, 138.6, 143.8, 157.2, 161.0. νmax (KBr)/cm−1 3149, 3025,
6-(4-Chlorophenyl)-4-cyano-3(2H)-pyridazinone (19)
A pale yellow solid, mp 336◦C (dec.) δH ([D6]DMSO) 7.69
(d, J 8.7, 2H), 7.79 (d, J 8.7, 2H), 8.25 (s, 1H), 13.91 (br s, 1H).

Regioselective Synthesis of 6-Aryl-4-cyano-3(2H)-pyridazinones
1399
Table 1. Synthesis of 6-aryl-4-cyano-3(2H)-pyridazinones via
2894, 2237, 1660, 1596, 1518, 1388, 1250, 1182, 1021, 834,
565. m/z (%) 227 (M+, 100), 170 (83), 127 (28). Anal. Calc. for
C12H9N3O2: C 63.43, H 3.99, N 18.49. Found: C 63.56, H 4.10,
N 18.37%.
procedure A
Pyridazinone
Yields with cyanoacetate 8
R = Me
R = Et
R = n-Bu
6-(3-Methoxyphenyl)-4-cyano-3(2H)-pyridazinone (24)
CN
A white solid, mp 265◦C (dec.) δH ([D6]DMSO) 3.81 (s,
3H), 7.04 (dt, J1 8.7, J2 2.4, 1H), 7.37–7.48 (m, 3H), 8.84
(s, 1H), 13.98 (br s, 1H). δC ([D6]DMSO) 55.7, 111.3, 114.9,
116.1, 118.5, 130.6, 135.2, 138.9, 143.7, 157.4, 160.2. νmax
(KBr)/cm−1 3150, 3033, 2897, 2239, 1665, 1599, 1577, 1495,
1447, 1265, 1027, 780, 691. m/z (%) 227 (M+, 100), 170 (82),
156 (24), 132 (39).Anal. Calc. for C12H9N3O2: C 63.43, H 3.99,
N 18.49. Found: C 63.40, H 4.03, N 18.40%.
O
O
80
82
72
NH
N
19
Cl
CN
NH
77
78
70
N
Br
20
6-(3,4-Dimethoxyoxyphenyl)-4-cyano-3(2H)-
pyridazinone (25)
CN
A yellow solid, mp 223◦C (dec.) δH ([D6]DMSO) 3.79 (s,
3H), 3.80 (s, 3H), 7.03 (d, J 8.4, 1H), 7.41–7.50 (m, 2H), 8.83
(s, 1H), 13.85 (br s, 1H). δC ([D6]DMSO) 56.0, 56.1, 109.2,
112.2, 114.6, 119.1, 122.8, 138.6, 143.8, 149.2, 150.7, 152.1,
158.5. νmax (KBr)/cm−1 3146, 3036, 2941, 2231, 1676, 1595,
1515, 1269, 1148, 1011, 855, 763. Anal. Calc. for C13H11N3O3:
C 60.70, H 4.31, N 16.33. Found: C 60.76, H 4.37, N 16.20%.
O
93
90
90
96
82
80
NH
N
21
F
CN
O
NH
N
6-(3,4-Methylenedioxyphenyl)-4-cyano-3(2H)-
pyridazinone (26)
22
A yellow solid, mp 350◦C (dec.) δH ([D6]DMSO) 6.09 (s,
2H), 7.02 (dd, J1 8.7, J2 2.4, 1H), 7.41–7.43 (m, 2H), 8.76 (s,
1H), 13.87 (br s, 1H). δC ([D6]DMSO) 102.0, 106.2, 109.0,
114.6, 114.9, 120.8, 138.7, 143.6, 148.5, 149.1, 157.2. νmax
(KBr)/cm−1 3147, 3028, 2899, 2240, 1664, 1592, 1503, 1446,
1247, 1229, 1034, 877, 563. m/z (%) 241 (M+, 100), 184 (85),
146 (44), 57 (53). Anal. Calc. for C12H7N3O3: C 59.75, H 2.93,
N 17.42. Found: C 59.56, H 2.98, N 17.49%.
CN
O
O
O
79
90
91
95
81
93
93
92
75
81
85
83
NH
N
23
MeO
MeO
CN
NH
N
Procedure B for Synthesis of a Mixture of Pridazinones
24
A mixture of alkyl 2-cyanoacetate (4 mmol) and hydrazine
hydrate 100% (4 mmol) in water (5 mL) was stirred at room
temperature for 10 min then the arylglyoxal (1 mmol) was added
and the resultant mixture was stirred for 15–30 min. As in
procedureA, after the appropriate time, the precipitation of prod-
uct ceased. The product was collected and washed with cold
methanol.
CN
MeO
MeO
NH
N
25
CN
O
6-Phenyl-4-cyano-3(2H)-pyridazinone (22) and
5-Phenyl-4-cyano-3(2H)-pyridazinone (27, Ar = Ph)
NH
O
O
N
A cream solid. δH ([D6]DMSO) 7.47–7.88 (m, 10H in two
26
isomers), 8.24 (s, 1H in 5-Ar), 8.82 (s, 1H in 6-Ar), 13.93 (br s,
O
CN
CN
Ar
H5
Ar
O
Ar
O
O
O
9
NC
R
ϩ
ϩ
NH2NH2·H2O
NH
NH
Water, r.t.
71–94%
O
N
H6
N
8
7 (6-Ar)
27 (5-Ar)
Scheme 4. Synthesis of 5- and 6-arylcyanopyridazinone.

1400
M. Rimaz, J. Khalafy, and P. N. Moghadam
1H). δC ([D6]DMSO) 110.4, 114.5, 114.6, 115.0, 126.2, 129.0,
129.4, 129.5, 130.1, 131.8, 132.4, 133.8, 137.5, 138.8, 144.0,
150.3, 157.4, 158.3. νmax (KBr)/cm−1 3138, 3061, 2955, 2886,
2233, 1667, 1592, 1439, 1237, 1132, 909, 778, 755, 693. Anal.
Calc. for C11H7N3O: C 67.00, H 3.58, N 21.31. Found: C 67.15,
H 3.55, N 21.25%.[35,36]
8.24 (s, 1H in 5-Ar), 8.76 (s, 1H in 6-Ar), 13.82 (br s, 1H).
δC ([D6]DMSO) 55.7, 56.0, 114.6, 114.9, 115.1, 124.3, 126.2,
127.7, 131.0, 137.4, 138.6, 143.6, 149.7, 157.2, 161.0, 162.4.
νmax (KBr)/cm−1 3148, 3024, 2953, 2894, 2237, 1660, 1597,
1518, 1389, 1259, 1183, 1140, 1021, 909, 835, 566. Anal. Calc.
for C12H9N3O2: C 63.43, H 3.99, N 18.49. Found: C 63.50,
H 4.14, N 18.32%.
6-(4-Methoxyphenyl)-4-cyano-3(2H)-pyridazinone (23)
and 5-(4-Methoxyphenyl)-4-cyano-3(2H)-pyridazinone
(27, Ar = 4-MeOPh)
6-(3-Methoxyphenyl)-4-cyano-3(2H)-pyridazinone (24)
and 5-(3-Methoxyphenyl)-4-cyano-3(2H)-pyridazinone
(27, Ar = 3-MeOPh)
A yellow solid. δH ([D6]DMSO) 3.79 (s, 3H in 6-Ar), 3.84
(s, 3H in 5-Ar), 7.15 (d, J 8.7, 2H in 5-Ar), 7.43 (d, J 8.7, 2H
in 6-Ar), 7.77 (d, J 9, 2H in 5-Ar), 7.82 (d, J 8.4, 2H in 6-Ar),
A cream solid. δH ([D6]DMSO) 3.81 (s, 3H in 5-Ar), 3.83 (s,
3H in 6-Ar), 7.04–7.54 (m, 8H in two isomers), 8.26 (s, 1H in
5-Ar), 8.84 (s, 1H in 6-Ar), 13.92 (br s, 1H). δC ([D6]DMSO)
55.7, 55.8, 111.3, 114.3, 114.4, 116.1, 117.6, 118.5, 121.2,
130.6, 130.8, 133.6, 137.5, 138.8, 150.1, 158.3, 159.8. νmax
(KBr)/cm−1 3149, 3054, 2959, 2234, 1663, 1596, 1578, 1263,
1227, 1038, 838, 803. Anal. Calc. for C12H9N3O2: C 63.43,
H 3.99, N 18.49. Found: C 63.50, H 4.10, N 18.34%.
Table 2. Synthesis of (5 or 6)-aryl-4-cyano-3(2H)-pyridazinones via
procedure B
Ar
Yields with cyanoacetate 8
6-Ar:5-Ar ratio [%]
R = Me
R = Et
R = n-Bu
6-(3,4-Dimethoxyoxyphenyl)-4-cyano-3(2H)-
pyridazinone (25) and 5-(3,4-Dimethoxyoxyphenyl)-
4-cyano-3(2H)-pyridazinone (27, Ar = 3,4-(MeO)2Ph)
83
75
81
75
72
100:0
100:0
Cl
Br
F
A yellow solid. δH ([D6]DMSO) 3.79 (s, 3H in 6-Ar), 3.80
(s, 3H in 6-Ar), 3.82 (s, 3H in 5-Ar), 3.83 (s, 3H in 5-Ar),
7.03 (d, J 8.4, 1H in 6-Ar), 7.05 (d, J 8.4, 1H in 5-Ar), 7.38–
7.50 (m, 2H in two isomers), 8.30 (s, 1H in 5-Ar), 8.83 (s, 1H
in 6-Ar), 13.81 (br s, 1H). δC ([D6]DMSO) 56.0, 56.1, 109.2,
112.2, 114.6, 119.1, 122.8, 138.6, 143.8, 149.2, 150.7, 152.1,
158.5. νmax (KBr)/cm−1 3146, 3036, 2941, 2223, 1676, 1595,
1515, 1269, 1148, 1011, 855, 763. Anal. Calc. for C13H11N3O3:
C 60.70, H 4.31, N 16.33. Found: C 60.81, H 4.39, N 16.18%.
77
88
83
86
85
74
71
100:0
36:64
77
85
80
84
73
76
80:20
20:80
H3CO
6-(3,4-Methylenedioxyphenyl)-4-cyano-3(2H)-
pyridazinone (26) and 5-(3,4-Methylenedioxyphenyl)-
4-cyano-3(2H)-pyridazinone (27, Ar = 3,4-OCH2OPh)
A yellow solid. δH ([D6]DMSO) 6.02 (s, 2H in 5-Ar), 6.08 (s,
2H in 6-Ar), 6.95–7.03 (m, 2H in two isomers), 7.31–7.42 (m,
4H in two isomers), 8.21 (s, 1H in 5-Ar), 8.75 (s, 1H in 6-Ar),
13.86 (br s, 1H). δC ([D6]DMSO) 102.0, 102.7, 106.2, 108.3,
109.0, 109.4, 114.6, 114.9, 120.8, 125.3, 128.0, 138.7, 143.6,
148.5, 149.1, 157.2, 160.3. νmax (KBr)/cm−1 3148, 3060, 2899,
2222, 1664, 1590, 1502, 1445, 1363, 1229, 1032, 926, 877.Anal.
Calc. for C12H7N3O3: C 59.75, H 2.93, N 17.42. Found: C 59.64,
H 3.01, N 17.35%.
OCH3
88
94
90
93
77
80
61:39
77:23
H3CO
OCH3
O
O
N
N
HN
HN
Path B
R
O
ϪH2O
O
Ar
H
O
O
Path B
ϪH2O
Ar
O
O
N
O
CN
O
ϪROH
NH2
NH2NH2
ϩ
CN
ϩ
Path A
Ar
NC
5-Ar
NC
Path A
HN
N
Ar
N
Ar
ϪH2O
HN
O
O
CN
O
CN
6-Ar
Scheme 5. Plausible pathways for synthesis of 5 and 6-arylcyanopyridazinone under condition B.

Regioselective Synthesis of 6-Aryl-4-cyano-3(2H)-pyridazinones
1401
Acknowledgements
Financial support from the University of Urmia is gratefully acknowledged.
We also thank Mr. M. Qavidel for taking NMR and FT-IR spectra.
[17] V. K. Chintakunta, V. Akella, M. S. Vedula, P. K. Mamnoor, P. Mishra,
S. R. Casturi, A. Vangoori, R. Rajagopalan, Eur. J. Med. Chem. 2002,
37, 339. doi:10.1016/S0223-5234(02)01336-3
[18] C. S. Li, C. Brideau, C. C. Chan, C. Savoie, D. Claveau, S. Charleson,
R. Gordon, G. Greig, J. Y. Gauthier, C. K. Lau, D. Riendeau,
M. Thérien, E. Wong, P. Prasit, Bioorg. Med. Chem. Lett. 2003, 13,
597. doi:10.1016/S0960-894X(02)01045-4
[19] Review: F. Manetti, F. Corelli, F. Strappaghetti, M. Botta, Curr. Med.
Chem. 2002, 9, 1303.
References
[1] P. Anastas, T. Williamson, Green Chemistry, Frontiers in Benign
Chemical Synthesis and Procedures 1998 (Oxford Science Publica-
tions: New York, NY).
[20] For references for the biological activity of arylpyridazinones, see:
R. Salives, G. Dupas, N. Plé, G. Que’guiner, A. Turck, P. George,
M. Servin, J. Frost, A. Almario, A. Li, J. Comb. Chem. 2005, 7, 414.
doi:10.1021/CC049845N
[2] As estimated by determination of E-factor: R. A. Sheldon, Chem. Ind.
1997, 12.
[3] I. Choong, J. Ellman, Annu. Rep. Med. Chem. 1996, 31, 309.
doi:10.1016/S0065-7743(08)60470-4
[21] W. V. Curran, A. Ross, J. Med. Chem. 1974, 17, 273. doi:10.1021/
JM00249A004
[4] A. A. Patchett, R. P. Nargund, Annu. Rep. Med. Chem. 2000, 35, 289.
doi:10.1016/S0065-7743(00)35027-8
[22] W. H. Moos, C. C. Humblet, I. Sircar, C. Rithner, R. E. Weishar, J. A.
Bristol, A. J. McPhail, J. Med. Chem. 1987, 30, 1963. doi:10.1021/
JM00394A006
[23] W. G. Overend, L. F. Wiggins, J. Chem. Soc. 1947, 239. doi:10.1039/
JR9470000239
[24] J. D. Albright, F. J. McEvoy, D. B. Moran, J. Heterocycl. Chem. 1978,
15, 881. doi:10.1002/JHET.5570150601
[25] W. J. Coates, A. McKillop, Synthesis 1993, 334. doi:10.1055/
S-1993-25861
[26] E. A. Steck, R. P. Brundage, L. T. Fletcher, J. Am. Chem. Soc. 1953,
75, 1117. doi:10.1021/JA01101A032
[27] J. J. Bourguignon, C. G. Wermuth, J. Org. Chem. 1981, 46, 4889.
doi:10.1021/JO00337A013
[28] C. G. Wermuth, G. Schlewer, J. J. Bourguignon, G. Maghioros, M. J.
Bouchet, C. Moire, J. P. Kan, P. Worms, K. Biziere, J. Med. Chem.
1989, 32, 528. doi:10.1021/JM00123A004
[29] J. M. Contreras, Y. M. Rival, S. Chayer, J. J. Bourguignon, C. G.
Wermuth, J. Med. Chem. 1999, 42, 730. doi:10.1021/JM981101Z
[30] G. H. Posner, Chem. Rev. 1986, 86, 831. doi:10.1021/CR00075A007
[31] L. Weber, K. Illgen, M. Almstetter, Synlett 1999, 366. doi:10.1055/
S-1999-2612
[5] R. V. A. Orru, M. De Greef, Synthesis 2003, 10, 1471. doi:10.1055/
S-2003-40507
[6] I. Ugi, A. Dömling, B. Werner, J. Heterocycl. Chem. 2000, 37, 647.
doi:10.1002/JHET.5570370322
[7] S. Colletti, J. L. Frie, E. C. Dixon, S. B. Singh, B. K. Choi, G. Scapin,
C. E. Fitzgerals, S. Kumar, E. A. Nichols, S. J. O’Keefe, E. A.
O’Neill, G. Porter, K. Samuel, D. M. Schmatz, C. D. Schwartz, W. L.
Shoop, C. M. Thompson, J. E. Thompson, R. Wang, A. Woods, D. M.
Zaller, J. B. Doherty, J. Med. Chem. 2003, 46, 349. doi:10.1021/
JM025585H
[8] M. P. Giovannoni, C.Vergelli, C. Ghelardini, N. Galeotti,A. Bartolini,
V. D. Piaz, J. Med. Chem. 2003, 46, 1055. doi:10.1021/JM021057U
[9] M. Van der Mey, K. M. Bommelé, H. Boss, A. Hatzelmann, M. V.
Slingerland, G. J. Sterk, H. Timmerman, J. Med. Chem. 2003, 46,
2008. doi:10.1021/JM030776L
[10] L. Costantino, G. Rastelli, C. Gamberini, M. P. Giovannoni,V. D. Piaz,
P. Vianello, D. Barlocco, J. Med. Chem. 1999, 42, 1894. doi:10.1021/
JM981107O
[11] V. Dal Piaz, M. P. Giovannoni, C. Castellana, J. Med. Chem. 1997, 40,
1417. doi:10.1021/JM970105L
[12] L. Costantino, G. Rastelli, K. Vescovini, G. Gignarella, P. Vianello,
A. D. Corso, M. Cappiello, U. Mura, D. Barlocco, J. Med. Chem. 1996,
39, 4396. doi:10.1021/JM960124F
[32] M. Rimaz, J. Khalafy, N. Noroozi Pesyan, R. H. Prager,Aust. J. Chem.
2010, 63, 507. doi:10.1071/CH09569
[33] M. Rimaz, J. Khalafy, Arkivoc 2010, ii, 110.
[34] M. Rimaz, N. Noroozi Pesyan, J. Khalafy, Magn. Reson. Chem. 2010,
48, 276. doi:10.1002/MRC.2573
[35] S. M. Al-Mousawi, M. S. Moustafa, H. Meier, H. Kolshorn,
M. H. Elnagdi, Molecules 2009, 14, 798. doi:10.3390/MOLECULES
14020798
[36] M. F. Braña, M. Cacho, M. L. Garcıa, E. P. Mayoral, B. Lopez,
B. de Pascual-Teresa, A. Ramos, N. Acero, F. Llinares, D. Munoz-
Mingarro, O. Lozach, L. Meijer, J. Med. Chem. 2005, 48, 6843.
doi:10.1021/JM058013G
[13] T. M. Stevenson, B. A. Crouse, T. V. Thieu, C. Gebreysus, B. L.
Finkelstein, M. R. Sethuraman, C. M. Dubas-Cordery, D. L.
Piotrowski, J. Heterocycl. Chem. 2005, 42, 427. doi:10.1002/
JHET.5570420310
[14] F. A. Kerdesky, M. R. Leanna, J. Zhang, W. Li, J. E. Lallaman, J. Ji,
H. E. Morton, Org. Process Res. Dev. 2006, 10, 512. doi:10.1021/
OP060016V
[15] G. C. Y. Chiou, Drugs Future 1999, 24, 979. doi:10.1358/DOF.1999.
024.09.858628
[16] Y. Gong, J. K. Barbay, A. B. Byatkin, T. A. Miskowski, E. S. Kimball,
S. M. Prouty, M. C. Fisher, R. J. Santulli, C. R. Schneider, N. H.
Wallace, S. A. Ballentine, W. E. Hageman, J. A. Masucci, B. E.
Maryanoff, B. P. Damiano, P. Andrade-Gordon, D. J. Hlasta, P. J.
Hornby, W. He, J. Med. Chem. 2006, 49, 3402. doi:10.1021/
JM060031Q
[37] G. Fodor, O. Kovacs, J. Am. Chem. Soc. 1949, 71, 1045. doi:10.1021/
JA01171A079
[38] A. J.Turbiak, J. W. Kampf, H. D. H. Showalter,Tetrahedron Lett. 2010,
51, 1326. doi:10.1016/J.TETLET.2010.01.007