A facile synthesis of pyrazolo[3,4-d]pyridazines via the 1,3-dipolar cycloaddition of 3-arylsydnones. Synthesis and computational studies of 1-aryl-4,5-dihydro-1h-pyrazolo[3,4-d]pyridazine-3,6-diones and their 3,6-dichloro derivatives

Article abstract of DOI:10.1002/jhet.5570430403

The synthetic utility of 1,3-dipolar cycloaddition of DMAD to sydnones has been exploited in the preparation of new 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d] pyridazine-3,6-diones 7a-j and their aromatic 3,6-dichloro analogues 8a-j. The lactam-lactim tautomer

Full text of DOI:10.1002/jhet.5570430403

Jul-Aug 2006
827
A Facile Synthesis of Pyrazolo[3,4-d]pyridazines Via the 1,3-Dipolar
Cycloaddition of 3-Arylsydnones. Synthesis and Computational
Studies of 1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-
diones and their 3,6-Dichloro Derivatives.
Sanyal R. and Bharati V. Badami*
Postgraduate Department of Studies in Chemistry
Karnatak University, Dharwad – 580 003, INDIA.
bbadami@rediffmail.com
Received June 22, 2005
Dedicated to Dr.G.S.Puranik, P.G.Department of Studies in Chemistry, Karnatak University, Dharwad, on his 75th birthday.
O
H
H
O
R1
R2
R1
R2
NH
NH
3 steps
N
N
O
N
N
O
The synthetic utility of 1,3-dipolar cycloaddition of DMAD to sydnones has been exploited in the
preparation of new 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-diones 7a-j and their aromatic
3,6-dichloro analogues 8a-j. The lactam-lactim tautomerism of compound 7a has been studied by the semi
emperical (PM3) and ab initio methods.
J. Heterocyclic Chem., 43, 827 (2006).
N
Introduction.
N
N
N
N
HN
Sydnones form a class of mesoionic compounds which
undergo a wide variety of reactions [1]. Inspite of their
aromaticity, they behave as potential 1,3-dipolar systems
undergoing cycloaddition reactions with different
dipolarophiles [1,2]. The ability of sydnone ring to
undergo 1,3-dipolar cycloaddition reactions has been
extensively used in heterocyclic ring construction [1]. It
provides a one-pot facile and convenient means of
synthesizing a wide variety of five membered ring
nitrogen heterocycles. Many such synthetic uses of
sydnones have been reported earlier from this laboratory
[3-5]. In continuation of these ongoing studies directed
towards the construction of 5-membered 1,2-diaza -
Nitrogen heterocycles mediated by sydnones, we thought
of further exploiting the 1,3-dipolar cycloaddition
chemistry of the sydnone ring for the synthesis of some
fused heterocyclic systems, which are difficult and
lengthy or inaccessible by routine methods. Now, in the
present work, we have used the 1,3-cycloadduct of
sydnone with DMAD as an important intermediate in
converting some 3-arylsydnones 1a-j to the so far
unknown 1H-pyrazolo[3,4-d]pyridazine derivatives 2 –
the 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-
diones (7a-j). Despite the similarities of the pyrazolo[3,4-
d]pyridazine system 2 with the purine analogs - 1H-
imidazo[4,5-d]pyridazines 3 [6a], the former have not
been extensively studied.
N
N
H
2
3
This has been mainly due to the scarcity of synthetic
methods and inherent difficulties in the existing ones and
so, not much work has been reported on their synthesis.
Their biological properties are also not well understood.
Only two recent reports [6b,6c] cited in the literature have
claimed in vitro antimicrobial activities for a series of
compound 2 derivatives (the former work is from our
laboratory). The key step in obtaining compounds 2 is the
synthesis of the precursors - the 3,4-functionalised
pyrazoles 4 (only C3-COR & C4-COX; C3-COCH3 & C4-
CO2Et with C5- CH3 & C6H5 are reported [7]).
5
R
N
N
4
3
The most general synthetic approach to obtain these
precursors involves the base (NaOEt) induced reaction of
alpha-hydrazinohalides and beta-carbonyl compounds,
which in turn are obtained by elaborate processes [7,7a].
Further conversion of these pyrazoles into the pyrazolo-
[3,4-d]pyridazines follows a simple cyclisation with
hydrazine hydrate. However, the hitherto unknown corre-
sponding C-5H compounds are not accessible by this

828
Sanyal R. and B. V. Badami
Vol 43
Scheme 1
method and now we demonstrate the use of sydnones for
the facile synthesis of such compounds.
H
H
CO2CH3
COOCH3
Our synthetic strategy, that we have found to be of
importance in the design of one-pot, simple and alternate
process for the synthesis of these ortho-functionalised
pyrazoles, involved the cycloaddition of DMAD to 3-
arylsydnones 1a-j to give the dimethyl-1-aryl-1H-
pyrazole-3,4-dicarboxylates 5a-j in quantitative yields and
high purity. This reaction proceeds smoothly in dry
xylene at 120 °C. The synthesis of some such substituted
aryl derivatives have been earlier reported from our
laboratory [8a,8b,8c]. These compounds are the key
intermediates in the synthesis of the title compounds 8a-j.
This approach provides a shorter route (the 3-
arylsydnones are readily obtained by simple procedure
from the easily available and inexpensive aromatic amines
[9]), useful, practical protocol for the present work and
compares favourably in terms of the use of simple
reagents and avoids the use of solvent. Hence, it is a cost
and time efficient synthesis for the pyrazolo[3,4-d]-
pyridazine system 2.
O
R1
R2
R1
R2
N
N
CO2CH3
Xylene
O
N
N
COOCH3
1a-j
5a-j
H
N
CONHNH2
R1
R2
H2NNH2
HCl
N
CONHNH2
6a-j
O
Cl
Cl
H
H
R1
R2
R1
R2
POCl3
NH
NH
N
N
N
N
N
N
O
7a-j
8a-j
(a) R1 & R2 = H; (b) R1= H; R2 = 4-Br; (c) R1 = H; R2 = 4-CH3;
(d) R1 = H, R2 = 2-Cl; (e) R1 = H; R2 = 4-Cl; (f) R1 = H, R2 = 2-
OCH3; (g) R1 = H; R2 = 4-OCH3; (h) R1 = H; R2 = 4-OCH2CH3;
(i) R1 = 3-Cl; R2 = 4-CH3; (j) R1 = 3-NO2, R2 = 4-CH3.
Results and Discussion.
The dimethyl-1-aryl-1H-pyrazole dicarboxylates 5a-j
when refluxed with hydrazine hydrate (99 %) in ethanol
gave the bishydrazides 6a-j instead of the cyclic products
7a-j. There have been conflicting reports on the
hydrazinolysis products of pyrazole diesters. While some
workers have reported the formation of bishydrazides
[10], others have reported the direct cyclisation to the
pyrazolo[3,4-d]pyridazine system [6c,7]. However, we
have observed the formation of only the bishydrazides 6a-
j for all the pyrazole diesters we have synthesised. The
cyclisation to the pyridazine system was not observed
even after prolonged heating (~ 40 hrs). The bishydra-
zides needed refluxing with hydrochloric acid to get the
desired 1-aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-
3,6-diones 7a-j. These diones 7a-j on heating with
phosphorous oxychloride aromatised to give the target
sydnones as synthons in heterocyclic synthesis and it‘s
1,3-dipolar cycloaddition reaction which provides a
prominent synthetic method for rapid construction of
functionalized heterocycles, often which are obtained with
difficulty and by lengthy procedures. The synthesis of
many more such compounds, with different heterocyclic
systems on the phenyl ring is in progress and will be
submitted as a separate paper shortly.
Spectral Characterization.
The IR spectra of all the pyrazole dicarboxylates 5a-j
show two intense bands at 1740 and 1702 cm-1 assignable
to the two ester carbonyl groups at C3 and C4 positions
respectively. The pyrazole ring ꢁC-H appears as a medium
1
intensity band at 3133 cm-1. The H-NMR (300MHz)
spectra of these compounds show two singlets at ꢂ 4.08
and ꢂ 3.85 ppm for the methyl protons of the C-3 and the
C-4 ester groups respectively and the assignment of these
signals are done on the basis of the low electron density at
the 3-position of pyrazoles [11], which is also evidenced
by the reported 13C –NMR data (C3 at ꢂ 133 & C4 at ꢂ
105 ppm) [11a]. This is also the reason why electrophilic
substitution reactions of pyrazoles take place only at 4-
position and not at 3 or 5. The pyrazole proton appears at
ꢂ 8.45 ppm, while the aryl protons resonate at ꢂ 7.50 -
compounds
–
1-aryl-3,6-dichloro-1H-pyrazolo[3,4-d]-
pyridazines 8a-j (Scheme 1).
Conclusions.
The synthetic utility of 1,3-dipolar cycloaddition to
sydnone provides a short and efficient route for the 5-
subsituted / unsubstituted pyrazolo[3,4-d]pyridazines in
good overall yields. Starting from an aromatic amine, the
precursor i.e. the ortho-functionalised pyrazoles 5a-j – the
key intermediates, are obtained in ~ 90 % yield in only
four steps via sydnones, while the reported method [7],
also starting from the primary amines involves the
multistep synthesis of substituted hydrazones and then
cyclisation to compound 2 with expensive substituted ꢀ-
diketones. This work underlines the importance of
1
7.75 ppm. The H-NMR NOE difference spectrum of one
compound – the p-chlorophenyl derivative 5e, shows an
enhancement in the intensity of the signal for the aromatic
proton at ꢂ 7.75 (ortho to pyrazole), when the pyrazole
ring proton is double irradiated. This indicates a close

Jul-Aug 2006
A Facile Synthesis of Pyrazolo[3,4-d]pyridazines Via
829
the 1,3-Dipolar Cycloaddition of 3-Arylsydnones
proximity between the pyrazole proton and the ortho-
protons of the phenyl ring. The single crystal X-ray
studies of one such compound 5i which we have been
able to document [12] for further structural insight,
showed a distance of 2.28 Å between these two protons,
which accounts for the above NOE result. In the
displacement ellipsoids drawn at the 50% probability
level, a low torsional angle of 8.66° was observed between
the phenyl and the pyrazole rings.
8.01 and another at ꢁ 11.15 ppm which are both D2O
exchanged. The large differences in these chemical shifts
indicate that both are neither due to the two NH (7-I) or
two OH (7-IV). Hence, these two signals could be
assigned to a lactam NH and a lactim OH group. Based on
the extent of dehielding, the former signal was assigned to
the NH and the latter to the OH. Such lactam-lactim
tautomers have been reported for similar types of diones
[7]. A more detailed consideration of the tautomerism in
these systems has been studied by computational
methods. The pyrazole C-5H in these compounds is
slightly deshielded due to the proximity of OH /C=O and
resonates at ꢁ 9.15.
H
H
H
COOCH3
COOCH3
Cl
N
N
The IR spectra of the dichloro compounds (8a-j) show
the absence of CO, NH or OH bands indicating the
H
H
1
5e
aromatisation of the ring. The H-NMR spectra show the
pyrazole proton resonating at ꢁ 8.64 ppm and other
signals only for the aromatic protons.
The IR spectra of the 1-arylpyrazole-3,4-dicarbohydra-
zides (6a-j) show bands at 3395 cm-1 and 3300 cm-1 due to
ꢀN-H stretching vibrations. The pyrazole ꢀC-H band is
observed at 3180 cm-1. The amide carbonyl stretching
bands appear at 1644 and 1581 cm-1 while the ꢁN-H
bending bands are at 1521 and 1500 cm-1.
Computational Studies.
The phenomenon of tautomerism is thought to play a
major role in determining the chemical and biological
activity of several compounds and in particular the N-
heterocycles related to the nucleic acid bases. We thought
that these newly synthesized compounds – 1-aryl-4,5-
The 1H-NMR (300 MHz) spectra of all these
compounds show a broad signal at ꢁ 3.90 corresponding
to four protons of NH2, while the two NH protons
resonate at ꢁ 10.01 and ꢁ 11.40 ppm. All these signals
disappeared in the D2O exchange spectrum. The pyrazole
proton appears at ꢁ 8.95 and the aromatic protons resonate
at ꢁ 7.50 ꢁ - 7.95 ppm.
The IR spectra of the corresponding diones (7a-j) show
only one band at 1672 cm-1 assignable to CO and a broad
band in the region 3200-3450 cm-1 which could be due to
the NH and probably the OH stretchings also. These data
indicate the existence of the mono lactam form 7-II or 7-
III and not the dione 7-I or the diol 7-IV for these
compounds (Figure 1).
dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-diones
7a-j
would be ideal for the theoretical investigations since they
can theoretically exist in four tautomeric forms - the
dilactam form PP-1, two monolactam forms PP2 and
PP3a and its rotamer PP3b and the dilactim rotamers
PP4a and PP4b (Figure 2).
H
O
O
O
H
H
H
H
H
H
N
N
N
N
N
N
H
N
H
N
H N
N
N
N
H
O
O
O
H
PP1
PP2
PP3a
O
OH
NH
NH
N
NH
N
N
N
N
N
H
H
O
O
O
H
H
O
O
H
H
7-I
N
N
7-II
N
N
N
H
N
H
N
H
N
N
N
N
N
O
OH
O
O
O
H
H
NH
N
N
N
H
N
N
N
PP3b
PP4a
Figure 2
PP4b
OH
7-III
OH
7-IV
Figure 1
Such pyridazine diones have been reported [7] to exist
in the monolactam form PP3b, based on their UV, IR and
1H-NMR spectral studies. Structure PP3b was proposed
as the preferred tautomer based solely on the resemblance
This lactam-lactim tautomer (7-II or 7-III) was also
evident from the 1H-NMR spectra which show signals at ꢁ

830
Sanyal R. and B. V. Badami
Vol 43
1
of the UV and H-NMR spectra with that of compound 9.
There being a possibility of hydrogen bonding in structure
PP3b as shown in 10, this would be relatively more stable
than the monolactam form PP3a.
except the dilactam form PP1, where both the pyridazine
nitrogens are puckered from the plane of the ring. The
bond distances and the bond angles are depicted in
Scheme 2 and 3 respectively.
O
OH
Scheme 2
NH
N
N
HN
HN
N
N
N
O
NH
H
H
10
9
However, we found these studies inadequate for such
molecules, so we have used the Molecular Orbital
methods – Semiemperical (PM3) and ab initio methods to
study the tautomeric preference in these diones and we
find that our calculations to be more accurate compared to
the qualitative treatment reported earlier [7]. To our
knowledge, this appears to be the first documentation of
computational studies for such a system.
The spectral data of the pyridazine diones synthesized
in the present work, also indicate the existence of the
monolactam forms. However, the spectral studies alone
do not reveal which of the two monolactam forms is
preferred. In the present work we have used both semi
empirical (PM3) and ab initio methods to study the
tautomerism in the parent system and restricted ourselves
to a PM3 study of 1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-
d]pyridazine-3,6-dione 7a.
All the structures considered in this study were first
optimized using the PM3 [13] method as implemented in
MOPAC [14]. The PM3 optimized structures were then
subjected to energy minimization at the Restricted
Hartree-Fock (RHF) level using the standard split valence
6-31G basis set, augmented with a d polarization function
on the heavy atom [15]. All the stationary points were
characterized as minima (NIMG = 0) by their vibrational
analysis at the same level. Second order Moller-Plesset
[16] (MP2) calculations were then carried out on the
HF/6-31G* geometries to get improved energy
comparison. The zero point energy obtained at the HF/6-
31G* level were scaled by 0.9135 [17] to account for the
systematic overestimation of ZPE at this level. All the ab
initio calculations were carried out using the PC [18]
version of GAMESS [19].
Bond lengths (in Angstrongs) at HF/6-31G8
As Scheme 2 shows, we have found two minima for the
monolactam form , one when the N6-O7-O-H dihedral
angle is equal to 0 °C (PP3a) and another when it is 180
°C (PP3b). The dilactim form also shows two equilibrium
geometries, PP4a and PP4b with N6-O7-O-H dihedral
angle of 0 °C and 180 °C respectively. The relative
energies of the equilibrium geometries calculated by ab
initio method without electronic correlation (HF) differs
from that of the MP2 calculations. The energetic order is
PP1<PP3a<PP2<PP3b<PP4a<PP4b at the HF/6-31G*
Results.
A) Tautomerism in 1H-pyrazolo[3,4-d]pyridazine-3,6-
dione.
level
while
at
the
MP2
level
The
it
is
semi
PP3a<PP2<PP3b<PP1<PP4a<PP4b.
Geometries of the six equilibrium structures we have
located are shown in Scheme 2. The relative energies in
kcal mol-1 and absolute energies in Hartrees are given in
Table 1. All the minimized structures have Cs symmetry
empirical PM3 method also predicts a stability order
similar to the MP2 calculations. The dioxo form PP1
which is predicted to be more stable than PP3a at the HF

Jul-Aug 2006
A Facile Synthesis of Pyrazolo[3,4-d]pyridazines Via
831
the 1,3-Dipolar Cycloaddition of 3-Arylsydnones
Table 1
Relative Energies (Kcal mol-1) of the Tautomers of 1H-Pyrazolo[3,4-d]pyridazines-3,6-dione
PP1
PP2
PP3a
PP3b
PP4a
PP4b
PM3 a
HF/6-31G*
5.53
-0.45
3.87
1.79
3.10
0.00
3.51
2.26
3.38
15.38
9.40
19.38
(-559.147795)
0.104259
0.00
ZPE c
MP2(fc)//HF/6-31G*
0.104231
2.51
0.104239
1.02
0.104034
1.95
0.103812
11.62
0.103444
15.41
(-560.769710)
0.00
2.65
1.04
1.93
11.72
15.49
MP2(full)//HF/6-31G*
HF//HF/6-31G*+ZPE c
MP2(fc)//HF/6-
31G*+ZPEc
(-560.816474)
0.00
-0.47
2.49
1.78
1.00
2.12
1.81
15.10
11.34
18.87
14.90
0.00
MP2(full)//HF/
2.64
1.03
0.00
1.79
11.44
14.98
6-31G*+ZPE
a PM3 Heat of formation in Kcal mol-1. b The values in parentheses are absolute energies(in Hartrees). c Zero point energy obtained at
the HF/6-31G*level, scaled by 0.9135.
level by 0.47 kcal mol-1, is found to be of higher energy
Thus, the gas phase ab initio calculations indicate a
preference of pyrazolo[3,4-d]pyridazine diones to exist in
the mono lactam form PP3a. The other mono lactam form
PP2 is the next most stable tautomer. This tendency of
pyrazolo[3,4-d]pyridazines to exist in the mono lactam
form is not surprising since such a preference has been
observed in other cyclic hydrazide compounds like
phthalhydrazide [20].
(2.64 kcal mol-1) then PP3a at the MP2 (full) level.
Scheme 3
B) Tautomerism in 1-phenyl-1H-pyrazolo[3,4-d]pyri-
dazine-4,7-dione.
We have used only the computationally less demanding
PM3 semi empirical method for studying this compound.
The equilibrium geometries located are shown in Scheme
4 & 5.
We have found two minima for each of the structures
with identical bond lengths and bond angles; one in which
the phenyl ring is coplanar with the pyrazolo[3,4-d]-
pyridazine ring and another in which it is twisted by an
angle ranging between 22 to 29°. Both the structures
differ slightly in their heat of formation (ꢀHf). The heat of
formation of all the geometries are tabulated in Table 2.
The introduction of a phenyl ring does not considerably
change the geometrical parameters and the relative order
of stability of the tautomers of the pyrazolo[3,4-d]-
pyridazine-4,7-dione system. The order of stability also
remain unchanged, with the monolactam form P3a
predicted to be the most stable structure. The structure
P3b where there is a possibility of interaction between the
pyrazole N2 and lactim hydrogen is also of comparable
energy while the other mono lactam form P2 is of slightly
higher energy. The dilactam form P1 has around 1.6 kcal
mol-1 higher _Hf than the most stable structure P3a. The
dilactim forms (P4a and P4b) have the highest ꢀHf
Bond angles(in degree ) at HF/6-31G*

832
Sanyal R. and B. V. Badami
Vol 43
Table 2
PM3 Heat of Formation of 1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-dione
P1
P2
P3a
P3b
P4a
P4b
ꢁHf
34.51 (ꢂ =00.0 )
34.61 (ꢂ= 22.1)
32.89 (ꢂ = 00.0)
33.02 (ꢂ = 22.3)
32.15 (ꢂ = 00.0)
32.26 (ꢂ = 23.6)
32.57 (ꢂ = 00.0)
32.64 (ꢂ = 27.6)
37.59 (ꢂ = 00.0)
37.71 (ꢂ = 25.9)
38.63 (ꢂ = 00.0)
38.70 (ꢂ = 29.1)
1ꢂrefers to the dihedral angle between the phenyl and the pyrazolo[3,4-d]pyridazine ring
values, ~6.5 kcal mol-1 higher than P3a (Table 2). These
calculations thus indicate a general preference of the
pyrazolo[3,4-d]pyridazine-4,7-dione to exist in the mono
lactam form P3a.
Scheme 5
Scheme 4
PM3 Geometries of 1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]-
pyridazine-3,6-dione (Bond angles).
the evolution of carbon dioxide ceased (~ 1 hr). The solvent
was removed under reduced pressure and the residue
triturated with petroleum ether (60-80 °C). The white solid
obtained was recrystallised from ethanol. 5h ( yield 94 % ).
m.p. 102-104 °C. 1 H NMR (CDCl3): ꢀ 8.40 (s,1H, pyrazole
C5-H), 7.50 (d, 2H, J= 8.0 Hz), 7.42 (d, 2H, J= 8.0 Hz), 4.2
(q, 2H) 4.00 (s, 3H), 3.80 (s, 3H), 1.3 (s,3H). Mass calcd. for
C15H16N2O5: 304; found: 304.
PM3 Geometries of 1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-
3,6-dione (Bond lengths).
EXPERIMENTAL
General Procedures.
Anal. Calcd. for C15H16N2O5 C, 59.21; H, 5.26; N,9.21 %;
Found C, 59.01; H, 4.88; N,8.81 %.
Dimethyl-1-aryl-1H-pyrazole-3,4-dicarboxylates (5a-j).
5i m.p. 96-98 °C. ( yield 99 % ). 1 H NMR (CDCl3): ꢀ 8.40
(s,1H, pyrazole C5-H), 7.50 – 7.30 (m, 3H,Ar), 4.00 (s,3H), 3.80
(s,3H), 2.3 (s,3H). Mass calcd. for C14H13N2O4Cl: 308 & 310;
Found: 308 & 310.
Compounds 5a-g have been reported earlier [8,8a,8b,8c] and
now compounds 5h,i,j are also prepared by this reported
method.
To a solution of 3-arylsydnones 1a-j (0.005 mol) in dry
xylene (4 ml), dimethylacetylenedicarboxylate (0.71 g, 0.005
mol) was added and the reaction mixture heated at 120 °C till
Anal.Calcd. for C14H13N2O4Cl C, 54.54; H,4.22; N,9.09%;
Found C, 54.23; H,4.19 N,8.69 %.

Jul-Aug 2006
A Facile Synthesis of Pyrazolo[3,4-d]pyridazines Via
833
the 1,3-Dipolar Cycloaddition of 3-Arylsydnones
1
5j m.p. 122-124 °C. ( yield 96 % ). 1 H NMR (CDCl3): ꢀ 8.40
(s,1H, pyrazole C5-H), 7.90 (s, 1H,Ar), 7.60 (d,1H, J=8.1, Ar),
7.82 (d,1H, J=8.1, Ar), 4.00 (s,3H), 3.80 (s,3H), 2.3 (s,3H).
Mass Calcd. for C14H13N3O6: 319; found: 319.
Anal. Calcd. for C14H13N3O6 C, 52.67; H,4.10; N,13.16 %;
Found C, 52.39; H,4.00; N,12.79 %.
6j m.p. 281-285 °C. (yield 84%). H NMR (CDCl3): ꢀ 11.37
(br, 1H), 10.11 (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.65-7.40
(m, 3H, Ar), 3.67 (br, 4H), 2.25 (s, 3H).
Anal. Calcd. for C12H13N7O4 C, 45.14; H, 4.07; N, 30.72 %;
Found C, 45.09; H, 4.02; N 30.39 %.
1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-diones
(7a-j).
1-Arylpyrazole-3,4-dicarbohydrazides (6a-j).
To a solution of 5a-j (0.003 mol) in 10 ml of ethanol,
hydrazine hydrate (99-100%, 1.46 ml, 0.03 mol) was added and
the reaction mixture refluxed for 5 hours. The white solid that
separated on cooling was collected by filtration, washed with
water and dried. Recrystallisation was done from ethanol/DMF.
6a m.p. 210-213 °C. (yield 79 % ). 1H NMR (CDCl3): ꢀ 11.37
(br, 1H), 10.11 (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.80-7.70
(m, 5H, Ar), 3.67 (br, 4H).
1-Arylpyrazole-3,4-dicarbohydrazides (6a-j) (0.003 mol)
were suspended in 30 ml of water and the pH adjusted to 2 with
2 N hydrochloric acid. The resulting mixture was refluxed for 2
hours on a heating mantle during which time the pyridazine-
diones separated as white solids. The reaction mixture was
cooled and the solid collected by filtration, washed with water
until the washings were neutral, and dried. Recrystallisation was
done from DMF. 7a [8] m.p. 284-286 °C. (yield 70%). 1H
NMR (DMSO-d6): ꢀ 11.15 (s, 1H, OH), 9.14 (s, 1H, pyrazole C-
5H), 7.98 (s, 1H, NH), 8.02 - 7.56 (m, 5H, Ar). Mass calcd. for
C11H8N4O2: 228. Found: 228.
Anal. Calcd. for C11H12N6O2 C, 50.77; H, 4.65; N, 32.29 %;
Found C, 50.46; H, 4.22; N, 31.71 %.
6b m.p. 225-227 °C. (yield 87 %). 1H NMR (CDCl3): ꢀ 11.37
(br, 1H), 10.11 (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.50 (d,
2H, J= 8.1 Hz, Ar), 7.42 (d, 2H, J= 8.1 Hz, Ar), 3.67 (br, 4H).
Anal. Calcd. for C11H11N6O2Br C, 38.96; H, 3.27; N, 24.78 %;
Found C, 38.60; H, 3.01; N, 24.35 %.
Anal. Calcd. for C11H8N4O2 C, 57.89; H, 3.53; N, 24.55 %;
Found C, 57.79; H, 3.46; N 24.19 %.
1
7b m.p. >300 °C. (yield 74%). H NMR (DMSO-d6): ꢀ 11.15
(s, 1H, OH), 9.14 (s, 1H pyrazole C-5H), 7.98 (s, 1H, NH), 8.02
(d, 2H, J=8.6 Hz, Ar), 7.50 (d, 2H, J=8.6 Hz, Ar). Mass calcd..
for C11H7N4O2Br :306 & 308. Found: 306 & 308.
6c m.p. 201-204 °C. (yield 88 %). 1H NMR (CDCl3): ꢀ 11.37
(br, 1H), 10.11 (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.40 (d,
2H, J= 8.0 Hz, Ar), 7.35 (d, 2H, J= 8.0 Hz, Ar), 3.66 (br, 4H),
2.35 (s, 3H).
Anal. Calcd. for C11H7N4O2Br C, 42.96; H, 2.28; N, 18.24 %
Found C, 42.59; H, 1.96; N 17.89%.
1
Anal. Calcd for C12H14N6O2 C, 52.55; H, 5.14; N, 30.64 %;
Found C, 52.15; H, 5.09; N, 30.26 %.
6d m.p. 226-229 °C. (yield 90 %). H NMR (CDCl3): ꢀ 11.37
(br,1H), 10.11 (br,1H), 8.91 (s,1H,pyrazole C5-H), 7.65- 7.40
(m,4H, Ar), 3.68 (br, 4H).
7c m.p. 294 °C.(decomp) (yield 78 %). H NMR (DMSO-d6):
ꢀ 11.15 (s, 1H, OH ), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H,
NH), 8.12 (d, 2H, J=8.6, Ar), 7.60 (d, 2H, J=8.6, Ar), 2.35 (s,
3H, CH3). Mass calcd. for C12H10N4O2: 242. Found: 242.
Anal. Calcd. for C12H10N4O2 C, 59.50; H, 4.16; N,23.13 %;
Found C, 59.16; H, 4.02; N 22.83 %.
Anal. Calcd. for C11H11N6O2Cl C, 44.90; H, 3.74; N 28.57 %.
Found C, 44.56; H, 3.66; N, 28.09 %.
1
7d m.p. 272 °C.(decomp) (yield 78%). H NMR (DMSO-d6):
1
6e m.p. >300 °C. (yield 92%). H NMR (CDCl3): ꢀ 11.37
ꢀ 11.15 (s, 1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H,
NH of lactam), 8.22 - 7.80 (m, 4H, Ar). Mass calcd. for
C11H7N4O2Cl :262 & 264. Found: 262 & 264.
(br,s,1H), 10.11 (br, s, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.42 (d,
2H, J= 8.0 Hz, Ar), 7.40 (d, 2H, J= 8.0 Hz, Ar), 3.69 (br, 4H).
Anal. Calcd. for C11H11N6O2Cl C, 44.90; H, 3.74; N, 28.57 %;
Found C, 44.78; H, 3.63; N,28.21 %.
Anal. Calcd. for C11H7N4O2Cl C, 50.38; H, 2.61; N, 21.37 %;
Found C, 50.01; H, 2.41 N, 20.91 %.
1
6f m.p. 193 °C (decomp). (yield 72 %). H NMR (CDCl3): ꢀ
7e m.p. >3000 °C (yield 79%). 1H NMR (DMSO-d6): ꢀ 11.15
(s, 1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H, NH), 8.12
(d, 2H, J=8.5, Ar), 7.60 (d, 2H, J=8.5, Ar). Mass calcd. for
C11H7N4O2Cl: 262 & 264. Found: 262 & 264.
11.37 (br, s, 1H), 10.11 (br, s, 1H), 8.91 (s, 1H, pyrazole C5-H),
7.38 -7.30 (m, 4H, Ar), 3.67 (br, 4H), 3.9 (s, 3H).
Anal. Calcd. for C12H14N6O3 C, 49.65; H, 4.82; N, 28.95 %;
Found C, 49.22; H, 4.51; N, 28.59 %.
Anal. Calcd. for C11H7N4O2Cl C, 50.38; H, 2.61; N, 21.37 %;
Found C, 50.00; H, 2.28; N, 20.98 %.
6g m.p. 225-228 °C. (yield 91%). 1H NMR (CDCl3): ꢀ 11.37
(br, 1H), 10.11, (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.38 (d,
2H, J= 7.9 Hz, Ar), 7.30 (d, 2H, J= 7.9 Hz, Ar), 3.67 (br, 4H),
3.95 (s, 3H).
7f m.p. 292 °C (decomp). (yield 69 %). 1H NMR (DMSO-d6):
ꢀ 11.15 (s, 1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H,
NH of lactam), 8.10- 7.70 (m, 4H, Ar), 4.05 (s, 3H, CH3). Mass
calcd. for C12H10N4O3: 258. Found: 258.
Anal. Calcd. for C12H14N6O3 C, 49.65; H, 4.82; N, 28.95 %;
Found C, 49.26; H, 4.81; N, 28.59 %.
Anal. Calcd. for C12H10N4O3 C, 55.81; H, 3.90; N, 21.70 %;
Found C, 55.55; H, 3.68; N, 21.35 %.
1
6h m.p. 210-214 °C. (yield 78%). H NMR (CDCl3): ꢀ 11.37
1
(br, 1H), 10.11 (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.40 (d,
2H, J= 7.9 Hz, Ar), 7.35 (d, 2H, J= 7.9 Hz, Ar), 4.2 (q, 2H), 1.4
(t, 3H), 3.67 (br, 4H).
7g >300 °C. (yield 76%). H NMR (DMSO-d6): ꢀ 11.15 (s,
1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H, NH), 8.32 (d,
2H, J=8.7, Ar), 7.80 (d, 2H, J=8.7, Ar), 4.01 (s, 3H, CH3). Mass
calcd. for C12H10N4O3: 258. Found: 258.
Anal. Calcd. for C13H16N6O3 C, 51.31; H, 5.26; N, 27.62 %;
Found C, 50.75; H 5.05; N,27.41 %.
Anal. Calcd for C12H10N4O3 C, 55.81; H, 3.90; N, 21.70 %;
Found C, 55.45; H, 3.45; N, 21.37 %.
1
6i m.p. 241-244 °C. ( yield 88%). H NMR (CDCl3): ꢀ 11.37
1
(br, 1H), 10.11 (br, 1H), 8.91 (s, 1H, pyrazole C5-H), 7.40 -7.30
(m, 3H, Ar), 3.67 (br, 4H), 2.25 (s,3H).
Anal. Calcd. for C12H13N6O2Cl C, 46.75; H, 4.22; N, 27.22
%; Found C, 46.48; H, 4.07; N, 26.79 %.
7h m.p. 252-254 °C. (yield 72 %). H NMR (DMSO-d6): ꢀ
11.15 (s, 1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H,
NH), 8.34 (d, 2H, J=8.7, Ar), 7.85 (d, 2H, J=8.7, Ar), 4.15 (q,
2H), 1.55 (t, 3H). Mass calcd. for C13H12N4O3: 272. Found: 272.

834
Sanyal R. and B. V. Badami
Vol 43
Anal. Calcd. for C13H12N4O3 C, 57.35; H, 4.41; N, 20.58 %;
Found C, 57.19; H,4.04; N,20.23 %.
7i m.p. 258-260 °C. (yield 78%). H NMR (DMSO-d6): ꢀ
11.15 (s, 1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H,
NH), 8.34 -7.85 (m, 3H, Ar), 2.45 (s, 3H). Mass calcd. for
C12H9N4O2Cl: 276. Found: 276.
J=8.5, Ar), 4.20(q, 2H), 1.42 (t, 3H). Mass Calcd. for
C13H10N4OCl2: 308, 310 & 312. Found: 308, 310 & 312.
Anal. Calcd. for C13H10N4OCl2: C, 50.64; H, 3.24; N, 18.18
%; Found C, 50.22; H, 2.95; N, 17.83 %.
8i m.p. 121-123 °C. (yield 78 %). H NMR (DMSO-d6): ꢀ
8.59 (s, 1H, pyrazole C-5H), 7.50 - 7.20 (m, 3H, Ar), 2.72 (s,
3H).
1
1
Anal. Calcd. for C12H9N4O2Cl C, 52.17; H, 3.26; N, 20.28 %;
found C, 51.98; H, 3.02; N, 19.88 %.
Anal. Calcd. for C12H7N4Cl3: C, 46.15; H, 2.24; N, 17.94 %;
Found C, 45.81; H, 2.02; N, 17.57 %.
1
7j m.p. >300 °C. (yield 75%). H NMR (DMSO-d6): ꢀ 11.15
1
(s, 1H, OH), 9.14 (s, 1H, pyrazole C-5H), 7.98 (s, 1H, NH), 8.1
– 7.8 (m, 3H, Ar), 2.48(s, 3H). Mass calcd. for C12H9N5O4: 287.
Found: 287.
Anal. Calcd. for C12H9N5O4: C, 50.18; H, 3.13; N, 24.38 %;
Found C, 49.78; H, 2.82 N, 23.99 %.
8j m.p. 182 (decomp)°C. (yield 75 %). H NMR (DMSO-d6):
ꢀ 8.59 (s, 1H, pyrazole C-5H), 7.80 - 7.40 (m, 3H, Ar), 2.80 (s,
3H). Mass Calcd. for C12H7N5O2Cl2: 323, 325 & 327.
Anal. Calcd. for C12H7N5O2Cl2: C, 44.58; H, 2.16; N, 21.67
%; Found C, 44.21; H, 2.01; N, 21.35 %.
1-Aryl-3,6-dichloro-1H-pyrazolo[3,4-d]pyridazines (8a-j).
REFERENCES
1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyridazine-3,6-diones
7a-j (0.002 mol) were refluxed with POCl3 (8 ml) for 5- 8 hours.
Excess POCl3 was removed under reduced pressure and the
residue obtained was treated with an ice-cold solution of
NaHCO3. The white solid was then collected by filtration,
washed with water and dried. Recrystallisation was done from
chloroform. 8a m.p. 155-157 °C. (yield 62 %). 1H NMR
(DMSO-d6): _ 8.59 (s, 1H, pyrazole C-5H), 7.98 -7.22 (m, 5H,
Ar). Mass calcd. for C11H6N4Cl2: 264,266 & 268. Found:
264,266 & 268.
[1] M. Ohta and H. Kato, ‘Nonbenzenoid Aromatics’, ed.
Snyder, J. P., Academic Press, New York, 117 (1969); Y. Jeng-Ping,
Y. Jia-Jzong,. C. Teng-Yueh and U. Bling, Synthesis, 12, 1775 (2002).
[2] R. Huisgen, H. Gotthardt and R. Grashey, Angew. Chem.,
74, 30 (1962).
[3] B. V. Badami and G. S. Puranik, Indian Journal of
Chemistry, 12, 671-673 ( 1974).
[4] S. G. Mallur and B. V. Badami, Il. Farmaco, 55, 65-67 (2000).
[5] Raveendra K. Hunnur, Prashant S .Latthe and Bharati V.
Badami, J. Chem. Research, 9, 592 (2005).
Anal. Calcd. for C11H6N4Cl2: C, 50.00; H, 2.28; N, 21.21 %;
Found C, 49.60; H, 2.04; N, 20.76 %.
[6a] M. Tisler and B. Stonovnik, Condensed Pyridazines
including cinnolines and Phthalazines, R. N. Castle, Ed., John Wiley and
Sons, New York, 780(1970).
1
8b m.p.125-127 °C. (yield 67 %). H NMR (DMSO-d6): ꢀ
8.59 (s, 1H, pyrazole C-5H), 8.12 (d, 2H, J=8.5,Ar), 7.90 (d, 2H,
J=8.5, Ar).
[6b] U. S. Hiremath, C. V. Yelamaggad and B. V. Badami, Indian
J. Heterocyl. Chem. 5, 19 (1995).
[6c] P. S. Patel, P. S. Fernandes and K. A. Vyas, Indian J. Chem.,
29B, 966 (1990).
[7] A. S. Shawali, J. Heterocyclic Chem., 14, 375 (1977).
[8] G. Coispeau, J. Elguero and R. Jacquier, Bull. Soc. Chim. Fr.
2061 (1969)
[8a] Bharati V. Badami and G.S. Puranik, Revue Roumaine de
Chimie, 27, 281-284 (1982).
[8b] D. B. Dambal, Bharati V. Badami and G. S. Puranik, Indian
Journal of Chemistry, 21B, 865-868 (1982).
[8c] R. K. Tikare, Bharati V. Badami and G. S. Puranik, Indian
Journal of Chemistry, 22B, 673-677 (1983).
[9] J. C. Earl and A. W. Mackney, J. Chem.Soc., 899 (1935).
[10] M. Bobek, J. Farkas and F. Sorm, Tetrahedron Lett., 52,
4611 (1970).
Anal. Calcd. for C11H5N4Cl2Br: C,38.48; H,1.47; N,16.36 %;
Found C, 38.08; H,1.15; N,15.91 %.
8c m.p. 162-164 °C. (yield 70 %). H NMR (DMSO-d6): ꢀ
8.59 (s, 1H, pyrazole C-5H), 7.90 (d, 2H, J=8.5, Ar), 7.20 (d,
2H, J=8.5, Ar), 2.4 (s, 3H). Mass Calcd. for C12H8N4Cl2: 278,
280 & 282. Found: 278, 280 & 282.
1
Anal. Calcd. for C12H8N4Cl2: C,51.79; H,2.89; N,20.14 %;
Found C, 51.50; H,2.49; N,19.84 %.
1
8d m.p. 179-181 °C. (yield 69 %). H NMR (DMSO-d6): ꢀ
8.59 (s, 1H, pyrazole C-5H), 8.10 - 7.95 (m, 4H, Ar).
Anal. Calcd. for C11H5N4Cl3: C,44.29; H,1.68; N,18.70 %;
Found C, 44.00; H,1.35; N,18.25 %.
1
8e m.p. 170-172 °C. (yield 70 %). H NMR (DMSO-d6): ꢀ
[11] Handbook of Heterocyclic Chemistry, by Alan R. Katritzky,
page 91 (1985) (Pergamon Press).
8.59 (s, 1H, pyrazole C-5H), 7.90 - 7.20 (m, 4H, Ar).
Anal. Calcd. for C11H5N4Cl3: C,44.29; H,1.68; N,18.70 %;
Found C, 44.01; H,1.22; N,18.31 %.
[11a] Ref. No.11, page nos. 98 & 103.
[12] S. Thamotharan, V. Parthasarati, R. Sanyal, B. V. Badami
and A. Linden, Acta Cryst., E59, o44-o45 (2003).
[13] J. J. P. Stewart, J. Comput. Chem., 10, 209 & 221 (1989).
[14] J. J. P., Stewart, MOPAC 2000, Fujitsu Limited, Tokyo,
Japan 1999.
1
8f m.p. 142-144 °C. (yield 69 %). H NMR (DMSO-d6): ꢀ
8.59 (s, 1H, pyrazole C-5H), 8.10 - 7.95 (m, 4H, Ar), 4.05 (s,
3H). Mass Calcd. for C12H8N4OCl2 : 294,296 & 298. Found: 294,
296 & 298.
[15] P. C. Hariharan and J. A. Pople, Chem. Phys. Lett., 16, 217 (1972).
[16a] C. Moeller and M. S. Plesset, Phys. Rev., 46, 618 (1934).
[16b] J. S. Binkley and J. A. Poplej, Int. J. Quantum Chem., 9, 229
(1975).
[17] P. A. Scott and L. J. Radom, Phys. Chem., 100, 16502 (1996).
[18] A. A. Granovsky, http://classic.chem.msu.su/gran/gamess/index.html
[19] M. W. Schmidt, K. K Baldridge, J. A Boatz, S. T. Elbert,
M. S Gordan, J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, J.
S. Su, T. L. Windus, M. Dupuis, and J. A. Montgomery, J. Comput.
Chem., 14, 1347 (1993).
Anal. Calcd. for C12H8N4OCl2: C, 48.84; H, 2.73; N, 18.98 %;
Found C, 48.37; H, 2.67; N, 18.62 %.
8g m.p. 158 (decomp) °C. (yield 68 %). 1H NMR (DMSO-d6):
ꢀ 8.59 (s, 1H, pyrazole C-5H), 7.85 (d, 2H, J=8.5, Ar), 7.25 (d,
2H, J=8.5, Ar), 4.15 (s, 3H). Mass Calcd. for C12H8N4OCl2: 294,
296 & 298. Found: 294, 296 & 298.
Anal. Calcd. for C12H8N4OCl2: C,48.84; H,2.73; N,18.98 %;
found C, 48.55; H,2.43; N,18.55 %.
1
8h m.p. 128-130° (yield 72 %). H NMR (DMSO-d6): ꢀ 8.59
[20] J. A. Elvidge and A. P. Redman, J. Chem. Soc., 1711 (1960).
(s, 1H, pyrazole C-5H), 7.90 (d, 2H, J=8.5, Ar), 7.20 (d, 2H,