Synthesis of Pyridazine Derivatives through the Unexpected Intermediate 5-Amino-4-Cyano-2,3-Dihydro-Furan-2,3-Disulfonic Acid Disodium Salt

Article abstract of DOI:10.1002/jhet.5570400615

An unexpected compound (5-amino-4-cyano-2,3-dihydrofuran-2,3-disulfonic acid disodium salt, 4) was isolated from the reaction of glyoxale bis hydrogen sulfite disodium salt with malononitrile. Its structure was undoubtly identified through crystal structure analysis. Compound 4 was highly stable and it was isolated easily and in a very high yield. Its reactivity was studied in the reactions with some hydrazine derivatives in order to obtain different pyridazine analogs.

Full text of DOI:10.1002/jhet.5570400615

Nov-Dec 2003
1065
Synthesis of Pyridazine Derivatives through the Unexpected Intermediate
5-Amino- 4-Cyano -2,3-Dihydro-Furan-2,3-Disulfonic Acid Disodium Salt
#
§
‡
Barbara Cacciari*, Giampiero Spalluto, Valeria Ferretti*
#
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, 44100 Ferrara, Italy
§
Dipartimento di Scienze Farmaceutiche, Piazzale Europa 1, Trieste, Italy
‡
Dipartimento di Chimica and Centro di Strutturistica Diffrattometrica, V. Luigi Borsari 46, 44100 Ferrara, Italy
Received March 5, 2003
An unexpected compound (5-amino-4-cyano-2,3-dihydrofuran-2,3-disulfonic acid disodium salt, 4) was
isolated from the reaction of glyoxale bis hydrogen sulfite disodium salt with malononitrile. Its structure was
undoubtly identified through crystal structure analysis. Compound 4 was highly stable and it was isolated
easily and in a very high yield. Its reactivity was studied in the reactions with some hydrazine derivatives in
order to obtain different pyridazine analogs.
J. Heterocyclic Chem., 40, 1065 (2003).
The pyridazine nucleus is a very common feature in
many compounds of biological interest. Its employment
gave good results in several fields of medicinal chem-
solubility or create possible hydrogen bonds with the
receptor. In the literature, different functionalized pyri-
dazine derivatives are reported; in particular, the 3-
amino-4-cyano-pyridazine 1 was selected as ideal start-
ing material for our purposes. Its preparation was
reported starting from the hydrazide of ethyl cyanoac-
etate and glyoxale bis hydrogen sulfite disodium salt to
furnish the 4-cyano-2H-pyridazin-3-one (2), followed by
many steps to afford the desired amino nitrile derivative
(Scheme 1) [4-8].
In order to obtain quickly and easily the desired pyri-
dazine derivative, in analogy to the reported strategy, we
tried to react the glyoxale bis hydrogen sulfite disodium
salt, characterized by a more controlled reactivity with
respect to the glyoxale itself, with malononitrile in an
attempt to obtain a possible intermediate suitable for the
reaction with hydrazine to afford compound 1 (Scheme 2)
istry, such as PDE inhibitors for inflammatory diseases
4
[1], as endothelin-A receptor antagonists [2], in the
development of active compounds toward α and α
1
2
adrenoceptors [3], as central analgesics and aldose
reductase inhibitors [4].
Due to this wide use of pyridazine based structures,
great attention has been paid to the development of differ-
ent methodologies for the preparation of pyridazine itself
and its functionalized derivatives.
During a study on the synthesis of bicyclic heteroaro-
matic structures for a random screening program for
searching new adenosine receptors antagonists, the pyri-
dazine nucleus represented a classical bioisosteric substi-
tution of phenyl ring which could confer a better water

1066
B. Cacciari, G. Spalluto, V. Ferretti
Vol. 40
This pathway was necessary because the simple reaction
ononitrile anion, whose generation is derived by treatment
with sodium hydroxide or sodium hydrogen carbonate, on
the carbon of the glyoxale bis hydrogen sulfite. This step did
not seem to induce sulfur group to leave as expected, but the
elimination of the hydroxy group. Subsequently, an intramol-
ecular cyclization of the second oxygen atom of the carbon
of the glyoxale on the cyano group produced compound 4,
again without elimination of the sulfur group (Scheme 3).
The unexpected formation of this stable intermediate led
us to investigate the reaction with hydrazine. The reaction
of 4 with hydrazine monohydrate produced in a good yield
the compound 5 (3-amino-1H-pyrazolo[3,4-c]pyridazine)
through a possible presumed pathway reported in Scheme
4. This mechanism involves a double attack of the
hydrazine with the opening of the ring, followed by a
Michael addition to the α,β unsatured nitrile to form the
pyridazine ring with water and ammonia elimination, and
subsequent intramolecular cyclization on the cyano group
to furnish the bicyclic final structure (5) (Figure 2).
of glyoxale, malononitrile and hydrazine led to a complex
mixture of different and unidentified products, as reported
in the literature [6]. The other possibility to react the
hydrazine with malononitrile as analog of the hydrazide of
the ethyl cyanoacetate, was known to furnish 3-
cyanomethyl-4-cyano-5-aminopyrazole (3) [9].
Surprisingly, the reaction of malononitrile with the gly-
oxale bis hydrogen sulfite disodium salt gave in a high
yield a crystal intermediate (4), whose structure was char-
acterized undoubtly by NMR and X-ray studies (Figure 1).
Compound 5 has already been reported in the literature,
but its synthesis was based on the reactivity of 2,5-
dichloro-3-cyano-pyridazine, prepared through several
steps [7,10]. This attractive reactivity of compound 4,
Figure 1. ORTEP [13] view of compound 4 displayng the thermal
ellipsoids at 40% probability
Actually, the characterization through a crystal structure
analysis of compound 4 was necessary due to the difficult
1
interpretation of the simple H NMR, performed in D O
2
which showed just two doublet coupled signals.
The hypothesized reaction mechanism involved in the
formation of this compound starts from the attack of the mal-
Figure 2. ORTEP [13] view of compound 5 displaying the thermal
ellipsoids at 40% probability

Nov-Dec 2003
5-Amino- 4-Cyano -2,3-Dihydro-Furan-2,3-Disulfonic Acid Disodium Salt
1067
Scheme 4
prompted us to investigate the reaction with a substituted
hydrazine, such as methyl hydrazine, in order to verify if
the sulfur groups were good leaving groups even in these
conditions.
With methyl hydrazine the synthetic conditions utilized
for unsubstituted hydrazine (Method A) gave comparable
results, from a mechanistic point of view, but in a very low
yield (27%), permitting recovery of the starting material.
This different result could be attributed to the non-aro-
matic character of the final compound, which most proba-
bly could be considered the driving force of the process.
great importance as analog of purine bases as possible
ligands for adenosine receptor subtypes [11], while the
simultaneous presence of carbonyl and carboxamido func-
tions on compound 6, could permit the synthesis of sys-
tems of policyclic compounds based on pyridazine nucleus
of potential biological interest.[1-4]
Moreover, we isolated in a high yield a really interesting
compound, 5-amino-4-cyano-2,3-dihydro-furan-2,3-disul-
fonic acid disodium salt (4), which is worthy of further
investigations regarding its reactivity. In fact, it could be a
suitable intermediate to obtain other heteroaromatic rings
through its reaction with different nucleophiles.
Nevertheless, forcing the reaction conditions (AcOH/H O,
2
reflux 24 hours, Method B) the yield was significantly
increased from 27 to 78%. The simple pyridazine ring (6)
so formed was easily hydrolized in the acqueous reaction
enviroment (Scheme 5). Whereas the attempt with the
phenyl hydrazine did not furnish any compounds in the
same conditions, probably due to steric hindrance and
lower nucleophilicity which hampered a similar pathway.
Compound 6 (2-methyl-3-oxo-pyridazine-4-carboxam-
1
ide) was characterized by H NMR and X-ray studies
(Figure 3). The supposed mechanism shows the possible
double attack by the less sterically hindered nitrogen of the
hydrazine rather than the more basic one, with water elim-
ination to give the pyridazine structure. Then, a rearrange-
ment of the structure led to the hydrolysis of imino and
cyano groups probably due to the impossibility of aromati-
zation, as already mentioned.
In conclusion, we synthesized and characterized some
pyridazine derivatives (5,6) which could represent versa-
tile building blocks for the construction of more complex
heterocyclic systems. In particular, the 3-amino-1H-pyra-
zolo[3,4-c]pyridazine (5), so easily obtained, can be of
Figure 3. ORTEP [13] view of compound 6 displaying the thermal ellipsoids
at 40% probability (for the sake of clarity only one molecule is showed)
Scheme 5

1068
B. Cacciari, G. Spalluto, V. Ferretti
Vol. 40
EXPERIMENTAL
amino-group and of the water molecules are implied in a compli-
cated three-dimensional net of hydrogen bonds.
Reaction courses and product mixtures were routinely moni-
tored by TLC on silica gel (precoated F Merck plates) and
3-Amino-1H-pyrazolo[3,4-c]pyridazine (5).
254
To a solution of compound 4 (300 mg, 0.81 mmol) in EtOH
(20 mL) and water (10 mL) was added hydrazine monohydrate
(0.12 mL, 3 eq.) and the mixture was stirred at room temperature
for 12 h and then 2 h at 50 °C. The solvent was then removed and
the residue was purified by flash chromatography (EtOAc/ Hex
50%) to give compound 5 as a pale yellow solid (yield 57%);
melting point 257-259 °C. IR (KBr): 3327, 3049, 1623, 1591,
visualized, when necessary, with aqueous KMnO . IR spectra
4
1
were measured on a Perkin-Elmer 500 instrument. H NMR were
obtained with a Bruker AC 200 spectrometer, peak positions are
given relative to TMS as internal standard, and J values are given
in Hz. Melting points were determined on a Buchi-Tottoli instru-
ment and are uncorrected. Chromatography was performed with
Merck 40-63 mesh silica gel. All products reported showed IR
1
1169, 1110, 1027, 752. H NMR (DMSO-d ): δ 5.96 (bs, 2H),
1
6
and H NMR spectra in agreement with the assigned structures.
7.99 (d, 1H, J = 6), 8.91 (d, 1H, J = 6), 12.64 (bs, 1H).
Crystal Structure Analysis.
Anal. Calcd. for C H N : C, 44.44; H, 3.73; N, 51.83. Found:
5
5 5
C, 44.44; H 3.74; N, 51.87.
X-ray diffraction data were collected on a Nonius Kappa CCD
diffractometer at room temperature using graphite-monochro-
mated MoKα radiation (λ = 0.71073 Å) with a φ scan followed
by ω scan to fill the sphere. Intensities were corrected for Lorentz
and polarization. Structures were solved by direct methods with
the SIR92 program [12] and refined by full-matrix least squares
with anisotropic non-H and isotropic H atoms using the
SHELX97 program [13]. ORTEP [14] views of the molecules are
showed in Figures 1-3.
Crystal Structure Analysis.
3-Amino-1H-pyrazolo[3,4-c]pyridazine, C H N , Mr =
135.13, tetragonal, space group P42/n, Z = 8, a = 17.5850(7), c =
5
5
5
3
-3
3.7465(1) Å, V = 1158.54(8) Å , ρ = 1.549 Mg m , F(000)=
calc
-1
560, µ = 0.110 mm , λ = 0.71069 Å. Total number of reflections
measured 8655, unique 1696 (R = 0.043), 1165 with I ≥ 2σ(I)
used in the refinement. No. Parameters = 111, final R index =
0.0473.
int
5-Amino-4-cyano-2,3-dihydro-furan-2,3-disulfonic Acid
Disodium Salt (4).
The molecule is almost perfectly planar, with a dihedral angle
between the calculated mean-planes of the two fused rings of
1.08(5)°. Molecules related by a centre of symmetry are linked
by N3-H…N2 bonds (N…N distance = 2.907(2) Å, N-H…N
angle= 169(2)°) and form dimeric units. The N5 aminic nitrogen
connects the dimers acting as both a donor and acceptor of hydro-
gen bonds (N5-H….N4 [y+1/2, -x, z+1/2] = 3.059(2) Å, N5-
H….N5[-y, x-1/2, z+1/2] = 3.253(2) Å].
A solution of malononitrile (500 mg, 0.075 mol) in ethanol (10
mL) was added to a suspension of glyoxale bis hydrogen sulfite
disodium salt (2.15 g, 0.075 mol) in water (25 mL) and the pH
was adjusted around 9 with some drops of aqueous 10% NaOH.
The mixture was stirred at room temperature for 4 h; the solvent
was removed and the residue was suspended in ethanol (30-40
mL) and the precipitate was collected by filtration to furnish
compound 4 (yield 89%); melting point >300 °C; IR (KBr):
2-Methyl-3-oxo-2,3-dihydro-pyridazine-4-carboxamide (6).
Method A.
1
3382, 2185, 1681, 1599, 1455, 1215, 1054, 1036, 779, 694. H
13
NMR (D O): δ 4.57 (d, 1H, J = 2), 5.53 (d, 1H, J = 2). C NMR
To a solution of compound 4 (300 mg, 0.81 mmol) in EtOH
(20 mL) and water (10 mL) the methyl hydrazine (0.13 mL, 3
eq.) was added and the mixture was stirred at room temperature
for 12 h and 2 h at 50 °C. The solvent was then removed and the
residue was purified by flash chromatography (EtOAc/ Hex
50%) to give compound 6 as an off-white solid (yield 27%).
2
(D O): δ 51.97, 66.84, 93.17, 122.36, 173.11.
2
Anal. Calcd. for C H N S O Na •3H O: C, 17.39; H, 2.92; N,
5
4
2
2
7
2
2
8.11. Found: C, 17.37; H, 2.92; N, 8.14.
Crystal Structure Analysis.
4-Cyano-5-amino-2,3-dihydrofuran-2,3-disulfonic acid dis-
Method B.
2-
+
odium salt, [C H N S O ] •2Na •3H O, , Mr = 368.24, tri-
5
4
2
2
7
2
clinic, space group P-1, Z = 2, a = 8.1060(2), b = 9.3210(3), c =
9.8840(3) Å, α = 66.9280(14), β = 89.8960(15), γ =
To a solution of compound 4 (300 mg, 0.81 mmol) in glacial
AcOH (20 mL) and water (10 mL), methyl hydrazine (0.086
mL, 3 eq.) was added and the mixture was stirred at reflux for
24 h. The solvent was then removed and the crude was purified
by flash chromatography (EtOAc/Hexane 50%) to give com-
pound 6 as an off-white solid (yield 78%); melting point: 156-
3
-3
75.0110(14)°, V = 659.56(3) Å , ρ = 1.854 Mg m , F(000)=
calc
-1
376, µ = 0.523 mm , λ = 0.71069 Å. Total number of reflections
measured 8871, unique 3785 (R = 0.031), 3054 with I ≥ 2 σ (I)
int
used in the refinement, No parameters = 230, Final R index =
0.0358.
1
158 °C. IR (KBr): 3256, 1692, 1621, 1173, 1115. H NMR
The asymmetric unit consists of a sodium disulfonate salt and
three water molecules. Both Na cations are hexa-coordinated,
(CDCl ): δ 3.91 (s, 3H), 7.99 (d, 1H, J = 6), 8.21 (d, 1H, J = 6),
9.42 (bs, 1H).
3
+
the geometry of the complexes being slightly distorted octahe-
dral, as shown in Figure 1. Na1 binds two water molecules and
two sulfonylic oxygens, its coordination being completed by two
N1 nitrogens of different asymmetric units, while Na2 is coordi-
nated to six oxygens belonging to three different asymmetric
units. Na-O distances are in the range 2.32-2.63 Å and are typical
for this type of bond; Na-N distances of 2.344(3) and 2.569(3) Å
compare well with those found in hexa-acetonitrile Na complex
[15] that are in the range 2.478-2.519 Å. The hydrogens of the
Anal. Calcd. for C H N O : C, 47.06; H, 4.61; N, 27.44.
Found: C, 47.03; H, 4.62; N, 27.43.
6
7 3 2
Crystal Structure Analysis.
2-Methyl-3-oxo-2,3-dihydropyridazine-4-carboxamide,
C H N O , Mr = 153.14, triclinic, space group P-1, Z = 2 (two
6
7 3 2
molecules in the asymmetric unit), a = 7.500(1), b = 8.172(2), c =
11.182(3) Å, α = 92.178(8), β = 94.316(7), γ = 96.029(14)°, V =
3
-3
-1
678.9(2) Å , ρ = 1.508 Mg m , F(000)= 320, µ = 0.123 mm ,
calc

Nov-Dec 2003
5-Amino- 4-Cyano -2,3-Dihydro-Furan-2,3-Disulfonic Acid Disodium Salt
1069
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λ = 0.71069 Å. Total number of reflections measured 3079,
unique 2151 (R = 0.069), 1476 with I ≥ 2σ(I) used in the refine-
int
ment. No. parameters= 255, final R index = 0.0661.
In both molecules forming the asymmetric unit the amidic
group shows the characteristic delocalization with C-N distances
intermediate between double and single bonds (C-N bond lengths
= 1.312(4) and 1.318(4) Å). The amidic N forms a short intramol-
ecular hydrogen bond with O2 (N3…O2 = 2.694(4) and 2.696(4)
Å, in the two molecules) and an intramolecular N-H…O bonds
with O1 (N3….O1a [x, 1-y, -z] = 2.872(4); N3a…O1[-x-1, 1-y, -
z] = 2.881(4) Å) linking molecules in infinite antiparallel chains.
Supplementary Material.
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[13] G. M. Sheldrick, SHELX97, Program for Crystal Structure
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[14] C. K. Johnson, ORTEP-II, Report ORNL-5138, Oak Ridge
National Laboratory, Oak Ridge, TN, (1976).
Crystallographic data for the structures reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication n. CCDC 203816 (4),
CCDC 203817 (5) and CCDC 203818 (6), respectively. Copies
of the data can be obtained free of charge on application to the
CCDC, 12 Union Road, Cambridge CB21EZ, UK (Fax: Code +
(44) 1223 336-033; e-mail: deposit@ccdc.cam.ac.uk)
Acknowledgments.
We thank Prof. Augusto C. Veronese for the helpful discus-
sions on the spectral data and the mechanistics considerations.
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