Synthesis, tautomeric forms, specific intermolecular interactions, and lipophilicity of methylated 6-hydroxypyridazine-3-carboxylic acid and its 4,5-dihydro analogs

Article abstract of DOI:10.1016/j.molstruc.2011.05.016

Effects of methylation for intermolecular interactions and lipophilicity have been studied for a series of methylated 4,5-dihydro-6-hydroxypyridazine-3- carboxylic and 6-hydroxypyridazine-3-carboxylic acids (1 and 2). In solution they exist in equilibrium of the lactam and lactim tautomers, with the reverse preferences for analogs 1 and 2, which affect the syntheses of their methylated derivatives. Carboxylic acid 2 preferably crystallizes as a hydrate, built of carboxylate anions and hydronium cations 2^-·H ₃O⁺, hydrogen bonded into catemeric patterns involving both ions. In methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate (4A) the molecules are NH?O hydrogen bonded into chains. In both structures 2 ^-·H₃O⁺ and 4A, there are relatively strong CH?O hydrogen bonds, arranging the molecules into sheets. The increased lipophilicity of the methylated derivatives has been correlated with the formation of CH?O bonds.

Full text of DOI:10.1016/j.molstruc.2011.05.016

Journal of Molecular Structure 998 (2011) 84–90
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, tautomeric forms, specific intermolecular interactions, and lipophilicity
of methylated 6-hydroxypyridazine-3-carboxylic acid and its 4,5-dihydro analogs
a
b
Anna Katrusiak a, , Paweł Piechowiak , Andrzej Katrusiak
⇑
a Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan´, Poland
b Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 April 2011
Received in revised form 10 May 2011
Accepted 10 May 2011
Available online 14 May 2011
Effects of methylation for intermolecular interactions and lipophilicity have been studied for a series of
methylated 4,5-dihydro-6-hydroxypyridazine-3-carboxylic and 6-hydroxypyridazine-3-carboxylic acids
(1 and 2). In solution they exist in equilibrium of the lactam and lactim tautomers, with the reverse pref-
erences for analogs 1 and 2, which affect the syntheses of their methylated derivatives. Carboxylic acid 2
preferably crystallizes as a hydrate, built of carboxylate anions and hydronium cations 2ÀÅH3O+, hydrogen
bonded into catemeric patterns involving both ions. In methyl 4,5-dihydro-6-oxopyridazine-3-carboxyl-
ate (4A) the molecules are NHÁ Á ÁO hydrogen bonded into chains. In both structures 2ÀÅH3O+ and 4A, there
are relatively strong CHÁ Á ÁO hydrogen bonds, arranging the molecules into sheets. The increased lipophil-
icity of the methylated derivatives has been correlated with the formation of CHÁ Á ÁO bonds.
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Pyridazine–carboxylic acids
Lactam–lactim tautomers
Methylation
Lipophilicity
Crystal structure
1. Introduction
the lactam and lactim tautomers of 1 and 2 present in the reaction
solution and stabilized in the reactions of methylation.
Pyridazine derivatives exhibit biological activity of a broad
spectrum, such as anticonvulsant and sedative, which stimulates
research on reactivity and properties of this group of compounds
[1]. Pyridazinone and its derivatives can transform between lactam
and lactim tautomers, also characteristic of many organic sub-
stances. Their chemical and biological properties are associated
with these tautomeric forms. It also applies to 6-hydroxypyrid-
azine-3-carboxylic acid derivatives, exhibiting tautomeric
transformations, which in turn affect their methylation and lipo-
philicity. 6-Hydroxypyridazine-3-carboxylic acid (2) was described
2. Results and discussion
2.1. Tautomers of 1 and 2 as anchored by methylation
Both compounds 1 and 2 exhibit lactam–lactim tautomers
resulting from the hydrogen atom migration between nitrogen
N1 in pyridazine ring to O (C6) shown in Scheme 1. However, the
X-ray diffraction analysis of compound 2 (see below) revealed that
it preferably forms a hydrate, where the molecule dissociates into
the ionic complex 2ÀÅH3O+.
in 1909 by Gabriel [2] who obtained it by treating
acid with hydrazine sulfate. The Gabriel’s synthesis of 2 was a mul-
tistep reaction: condensation of -ketoglutaric acid with hydrazine
a-ketoglutaric
The substitution of the acidic proton by an alkyl group was per-
formed as an attempt of anchoring one of the lactam–lactim forms.
It was shown [4,5] that methyl group can be introduced by using
either of the following methods: (i) treatment with dimethyl sul-
fate at 140–150 °C; (ii) treatment with methyl iodide in dry DMF
at room temperature; and (iii) treatment with dimethyl sulfate in
20% aq. natrium carbonate at room temperature. It was further
established [4,5] that methylation method (i) anchors the lactam
form, so N-methyl pyridazinone arises. However, method (iii) leads
to the lactim form and O-methyl derivatives are obtained.
Methods (i) and (ii) applied for the methylation of 1 and 2
yielded a mixtures of compounds difficult to separate. Only meth-
od (iii) gave well crystallized methylated products of 1 and 2. The
course of reaction was controlled by TLC. The MS spectrum of the
reaction 1 product showed that only one methyl group was intro-
duced. Three mono-methylated derivatives could be formed:
a
hydrate was the first step leading to 4,5-dihydro-6-hydroxypyrid-
azine-3-carboxylic acid (1), which in the second step was treated
with bromine in acetic acid, yielding 2. In 1948 Homer et al. [3]
synthesized 2 by the oxygenation of 6-methyl-3-pyridazinone
with either diluted HNO3 or K2Cr2O7/H2SO4 [3]. The lipophilicity
of 1 and 2 is low compared to the values of drugs penetrating into
the nervous system. Therefore it has been undertaken to obtain
new methylated derivatives of 1 and 2 and to investigate the role
of methylation site for the lipophilicity of these compounds. The
methylation sites in the products can be also used for studying
⇑
Corresponding author.
E-mail address: akatrus@ump.edu.pl (A. Katrusiak).
0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2011.05.016

A. Katrusiak et al. / Journal of Molecular Structure 998 (2011) 84–90
85
O
OH
O
OH
O
OH
O
OH
O
OH
O
OH
N
N
N
N
N
N
N
N
O
H2NNHCH3
NH
NH
OH
CH3
OH
OH
O
O
O
3A
1
2
O
Scheme 1. Lactam and lactim molecular H-tautomers of 1 and 2.
Scheme 3. Alternative direct synthesis of standard 3A.
4,5-dihydro-1-methyl-6-oxopyridazine-3-carboxylic acid (3A),
4,5-dihydro-6-methoxypyridazine-3-carboxylic acid (3B) and
methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate (4), all shown
in Scheme 2.
O
OH
O
OH
In order to identify the structure of obtained methylated prod-
uct of 1, we synthesized 3A by treating
a-ketoglutaric acid with
N
methylhydrazine in 10% HCl (Scheme 3).
N
N
Then the isolated methylation product of 1 treated with di-
methyl sulfate was compared to methylated the lactam form 3A
and showed that compound 3A has not been stabilized by method
(iii). The melting points, 1H NMR spectra and TLC of both samples
were compared where compound 3A synthesized according to
Scheme 3 was used as a standard. In the 1H NMR spectrum of
3A, the signal of the methyl group was observed at 3.27 ppm. Four
protons at C4 and C5 appear at about 2.46 and 2.75 ppm as triplets.
The carboxylic proton gives a wide signal at about 12.94 ppm.
It was difficult to discriminate between products 3B and 4 basic
only on their 1H NMR spectra, because the chemical shift of
O-methyl protons at carboxylic group (4) is similar to that of
O-methyl protons at hydroxylic group (3B). Therefore it has been
studied by X-ray diffraction and established that methyl 4,5-dihy-
dro-6-oxopyridazine-3-carboxylate (4A) was synthesized during
the methylation of 1. The signals in 1H NMR spectrum of 4A have
been assigned to the methyl protons at 3.74 ppm, and C4/C5 pro-
tons at about 2.40 and 2.75 ppm.
In the analogous way as the C4–C5 saturated pyridazinone acid
1, also unsaturated acid 2 has been treated with dimethyl sulfate at
room temperature in 20% aq. natrium carbonate. A mixture of two
products, methyl 1-methyl-6-oxopyridazine-3-carboxylate 5A and
methyl 6-methoxypyridazine-3-carboxylate 5B, was obtained
(Scheme 4). The identity of isolated products, separated by column
chromatography, was determined by MS, 1H NMR and 13C NMR.
The MS spectrum of the products of the methylation of 2 was con-
sistent with two methyl groups introduced to the molecule. In the
1H NMR spectrum of 5A, a pair of doublets from protons at C4 and
C5 at approximately 7 ppm (J = 9.6 Hz) were observed. The N-
methyl protons were shifted to 3.36 ppm, while O-methyl protons
NH
O
OH
2
(CH3)2SO4
O
OCH3
O
OCH3
N
N
N
N
CH3
O
OCH3
5A
5B
Scheme 4. Methylation method (iii) of 2 with dimethyl sulfate.
signaled their presence at 3.85 ppm. In the 1H NMR spectrum of 5B,
apart from a pair of doublets (H–C4 and H–C5), also signals of two
O
OH
O
OH
O
O
O
O
CH3
CH3
N
N
N
N
N
N
N
NH
CH3
O
O
O
OH
CH3
3A
3B
4A
4B
Scheme 2. Three mono-methylated derivatives of 4,5-dihydropyridazinecarboxylic acid (1): only the ester exhibits lactam 4A and lactim 4B tautomers.

86
A. Katrusiak et al. / Journal of Molecular Structure 998 (2011) 84–90
Table 1
methyl groups were present. The signal of the methyl protons in
methoxy group at C6 was close to the signal of methyl protons at
the ester group: 3.78 ppm and 3.86 ppm, respectively.
Heats of formation HOF (kcal/mole) of the lactam A and lactim B tautomers of 1–5.
Compound
HOF
Compound
HOF
In order to confirm structure 5A, this product has been obtained
directly in another chemical reaction. Acid 2 was treated with
selectively methylated N,N-dimethylformamide dimethyl acetal
(DMF–DMA). In this way 6-hydroxy-1-methylpyridazine-3-car-
boxylic acid (6) was synthesized. Compound 6 was also obtained
in the reaction of 3A treated with bromine in acetic acid, however
its yield was very small. The 1H NMR spectrum of 6 consists of a
pair of doublets from the protons at C4 and C5 and N-methyl group
at 3.32 ppm. Compound 6 was methylated under typical reaction
conditions and 5A was obtained with a small yield (Scheme 5).
1A
2A
3A
4A
5A
À91.49
À38.15
À83.44
À83.37
À30.75
1B
2B
3B
4B
5B
À48.02
À72.42
À43.58
À45.26
À53.14
2.2. Heat of formation of lactam and lactim forms
The heat of formation (HOF) of tautomers A and B of com-
pounds 1–5 have been calculated by the molecular orbital AM1
procedure with the standard parameters implemented in the MO-
PAC program in the precise mode [6]. The calculated HOF magni-
tudes have been compiled in Table 1. The HOF magnitudes of
saturated acids 1, 3, 4 in lactam tautomers A are smaller than of
their lactim form B, indicating that the lactam forms are more sta-
ble than the lactim tautomers. The calculations indicate that the
reverse HOF energy preference applies to the unsaturated acid
derivatives 2 and 5. Their HOF magnitudes are smaller for the lac-
tim tautomers B.
2.3. Crystal structures
The structures of 2 and methyl 4,5-dihydro-6-oxopyridazine-3-
carboxylate 4A have been determined by single-crystal X-ray
diffraction.
Acid 2 preferably crystallizes as a hydrate, and in the crystalline
state it transforms into the ionic form 2ÀÅH3O+, as shown in Fig. 1.
The 2À and H3O+ ions are hydrogen bonded (Table 2) into pairs by a
short hydrogen bond O(1w)–H(1w)Á Á ÁO(1) of 2.498(2) Å. The
hydronium cation forms further H-bonds O(1w)–H(2w)Á Á ÁN(2i) of
Fig. 1. The formula unit of hydrate 2ÁH2O, in the ionic form of 2ÀÅH3O+ constituting
an asymmetric part of the crystal. The thermal ellipsoids have been drawn at the
50% probability level, and the H-bond has been indicated by the dashed line.
3.001(2) Å and O(1w)–H(3w)Á Á ÁO(3ii) of 2.787(2) Å. Together with
bonds N(1)–H(1)Á Á ÁO(2iii) of 2.783(2) Å, two per one molecule, they
connect the lactim nitrogen and carboxyl groups. These OHÁ Á ÁO,
OHÁ Á ÁN and NHÁ Á ÁO bonds link the ions into slightly corrugated
tapes, shown in Fig. 2, along crystal direction [0 1 0]. These tapes
are parallel to crystal planes (1 0 1). The tapes are further con-
nected into sheets extending along planes (1 0 1), by C(4)–
H(4)Á Á ÁO(5iv) and C(5)–H(5)Á Á ÁO(1v) of 3.337(3) Å and 3.501(3) Å,
respectively (Fig. 3). The shortest contact between the sheets in-
volves atoms C(3) and C(4vi), the latter at (x À 1, y, z), 3.332(4) Å
apart. The hydronium cations are characteristic of very strong acids
[7] and their hydrogen salts [8].
The molecular ring of 4,5-dihydro-6-oxopyridazine-3-carboxyl-
ate (4A) is in a strongly distorted half-chair conformation (Fig. 4),
with the smallest torsion angle N(1)–N(2)–C(3)–C(4), and the larg-
est one C(3)–C(4)–C(5)–C(6); the Cremer–Pople puckering param-
eters for the ring are: puckering amplitude q2 = 0.3937(14) Å, and
O
OH
O
OH
O
OH
N
N
N
1
2
N
N
NH
CH3
CH3
O
O
O
3A
6
2
3
angles h2 = 111.58(19)° and
u2 = 24.4(2)°. In the crystal structure
molecules are arranged into sheets parallel to crystal plane
(À1 0 1). Hydrogen bonds NHÁ Á ÁO (Table 3) involve the lactim
atoms and link the molecules into chains along crystal direction
[0 1 0]. It is an unusual type of hydrogen bonding, because the lac-
tim groups most frequently bind the maleic hydrazide molecules
by a pair of NHÁ Á ÁO bonds into dimers [9]. The ester groups form
an aggregate resembling the catemers of carboxylic acids, but with
the OHÁ Á ÁO bonds replaced with OCH3Á Á ÁO contacts (Table 3, Fig. 5).
O
O
CH3
CH3
N
N
O
5A
2.4. Lipophilicity of methyl derivatives
The introduction of methyl groups increases the size of mole-
cules and changes their interactions, which affects properties of
Scheme 5. Reaction 1: Br2/CH3COOH, small yield; reaction 2: DMF–DMA, good
yield; reaction 3: (CH3)2SO4/Na2CO3/rt, small yield.

A. Katrusiak et al. / Journal of Molecular Structure 998 (2011) 84–90
87
Table 2
Hydrogen bonds and short C–HÁ Á ÁO contacts (Å and °) in the crystal structure of 2ÀÅH3O+.
D–HÁ Á ÁA
D–H
HÁ Á ÁA
DÁ Á ÁA
D–HÁ Á ÁA
Symmetry code
N1–H1Á Á ÁO2
0.84(3)
1.03(3)
0.85(2)
1.09(2)
1.11(3)
1.06
1.95(3)
1.56(2)
2.16(2)
1.72(2)
2.39(3)
2.47(3)
2.783(2)
2.498(2)
3.001(2)
2.787(2)
3.337(2)
3.500(2)
168(3)
149(3)
170(3)
163(3)
142(2)
163(3)
1 À x, y + 0.5, 2 À z
x, y, z
O1w–H1wÁ Á ÁO1
O1w–H2wÁ Á ÁN2
O1w–H3wÁ Á ÁO3
C4–H4Á Á ÁO3
1 À x, y À 0.5, 2 À z
x, y À 1, Àz
2 À x, y À 0.5, 1 À z
2 À x, y + 0.5, 1 À z
C5–H5Á Á ÁO1
Fig. 2. The ionic aggregation within H-bonded sheets of 2ÀÅH3O+.
the compounds and can be significant for its pharmaceutical activ-
ity. Such modifications of molecular structure are termed as the
methylene shuffle, and this method is often aimed at increasing
the hydrophobicity of compounds. Larger lipophilicity, which rep-
resents the affinity of a molecule or a moiety for a lipophilic envi-
ronment, facilitates penetration of drugs into the central nervous
system. Therefore the lipophilicity control is essential in designing
new active pharmaceutical ingredients. Lipophilicity has been
measured for 1, 2, 3A, 4A, 5A, 5B and 6 by thin-layer chromatogra-
phy (Table 4). Higher or positive RM values are characteristic of the
compounds more lipophilic than those exhibiting lower RM magni-
tudes. A correlation between the lipophilicity and the number of
methyl substituents in the acid derivatives is apparent. The unme-
thylated acids 1 and 2 have the lowest RM value.
It has been established, that the C4–C5 bond saturation reverses
the preference of lactam–lactim tautomers. The methylation of
tautomers of 1 and 2 can be used as alternative reactions for
obtaining compounds 3A, 4, 5A, 5B, 6 that were described in liter-
ature [11–17]. Compound 3A was obtained in 1961 by Kline and
Cox obtained by treating a-ketoglutaric acid with methylhydrazine
sulfate [11]. Synthesis of 4 was published by Teotino in 1959. It
consisted in reaction between dimethyl 2-oxoglutarate and hydra-
zine with acid catalysis in refluxing methanol [12,13].
5A was synthesized by Homer in 1948 from methyl 6-oxopyrid-
azine-3-carboxylate using methyl iodide [3]. 5B is known also in
literature [14–16]. It was obtained from ethyl 6-chloropyrid-
azine-3-carboxylate with sodium methylat [14], or from 6-meth-
oxypyridazine-3-carboxylic acid with thionyl chloride (stage 1)
and methanol (stage 2) [15], or by cyclization of cis-phospharene
[16].
3. Conclusions
Compound 6 was obtained by King and Mc Millan in 1952. This
was prepared by 1:1 hydrochloric acid hydrolysis of a small
amount of its ethyl ester [17]. It was also prepared by Homer, Greg-
ory and Wiggins by oxidation of 2,6-dimethyl-3-pyridazinone [3].
The lactam–lactim tautomers of 6-hydroxypyridazine-3-car-
boxylic acid (1) and its 4–5 saturated analog 2 have been methyl-
ated and the methylation products correspond to the tautomers of
1 and 2. Acid 2 crystallized of aqueous solution forms hydrates,
with the acidic proton transferred and hydronium cation formed:
4. Experimental
2
ÀÅH3O+. In the crystal structures, the methylation leads to the
replacement of strong OHÁ Á ÁN and NHÁ Á ÁO hydrogen bonds, with
weaker CHÁ Á ÁO interactions, which correlates with increasing lipo-
philicity of the methylated derivatives. This has been confirmed by
the measurements of lipophilicity of the investigated compounds.
Melting points were determined on a Boetius apparatus and
were uncorrected. 1H NMR (300 MHz) and 13C NMR (75 MHz)
spectra were recorded in CDCl3 or DMSO with TMS as an
internal standard and chemicals shifts are expressed as d (ppm).

88
A. Katrusiak et al. / Journal of Molecular Structure 998 (2011) 84–90
Fig. 3. The pattern of hydrogen bonds, including the CHÁ Á ÁO bonds, in 2ÀÅH3O+.
Fig. 4. Two perpendicular projections of methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate (4A) molecule perpendicular to the N1-N2 bond. Thermal ellipsoids have been
drawn at the 50% probability level.
The J-values are given in Hz. Mass spectra were obtained on an
AMD 604 Inectra GmbH instrument. The products were separated
by a column chromatography using as a mobile phase acetone/
hexane mixture (3:2). The column was filled by silica gel
(0.040–0.063 mm, 230–400 mesh ASTM, Merck). The lipophilicity
measurement was done according to the literature [18]. Separation

A. Katrusiak et al. / Journal of Molecular Structure 998 (2011) 84–90
89
Table 3
Table 4
Hydrogen bonds and short contacts in methyl 4,5-dihydro-6-oxopyridazine-3-
carboxylate (4A) (Å and °). Apart from the C8–H8nÁ Á ÁO2 (n = 1, 2, 3) contacts
involving the carboxyl methyl hydrogens and oxygen atoms, also the next shortest
C–HÁ Á ÁO contact dimensions have been given for comparison.
Lipophilicitiy of 1 and 2 and their methylated derivatives. The RM values have been
calculated from the experimental Rf values, according to formula RM = log[1/Rf À 1].
Compound
1
2
3A
4
5A
5B
6
RM
À1.28
À1.69
À1.06
1.56
0.31
0.75
0.27
D–HÁ Á ÁA
D–H
HÁ Á ÁA
DÁ Á ÁA
D–HÁ Á ÁA Symmetry code
N1–H1Á Á ÁO3
0.89(3) 1.91(3) 2.791(2) 168.6(3) 1 À x, y À 0.5, 0.5 À z
C8–H81Á Á ÁO2 0.96
C8–H82Á Á ÁO2 0.96
C8–H83Á Á ÁO2 0.96
C5–H51Á Á ÁO3 0.96
3.01
3.06
2.82
3.137(2) 88.9
3.137(2) 85.6
3.137(2) 100.5
Àx, y À 0.5, À0.5 À z
Àx, y À 0.5, À0.5 À z
Àx, y À 0.5, À0.5 À z
evaporated. Crude product was crystallized from ethanol. Yield
52%; m.p. 143–145 °C; 1H NMR (CDCl3) d 2.46 (t, J = 8.5 Hz, 2H),
2.75 (t, J = 8.5 Hz, 2H), 3.27 (s, 3H); 13C NMR d 25.8, 36.6, 39.0,
143.4, 164.3, 173.9. MS(m/z, M+): 156.0 (100%). Anal. Calcd for
C6H8N2O3 (156.14): C, 46.15; H, 5.16; N, 17.94. Found C, 46.03;
H, 5.13; N, 17.52.
2.72(3) 3.593(2) 150.8(3) 1 À x, y + 0.5, 0.5 À z
was carried out on precoated RP-TLC plated of RP-18F 254s (Merck,
Darmstadt, Germany). The polar mobile phase was a mixture
methanol/water (8:2). Each compound was dissolved in methanol
4.1.1. General procedure of methylation reaction
To a stirred mixture of 10 mmol of acid 1 or 2 in 30 mL of 20%
Na2CO3 13 mL of dimethylsulfate was added at room temperature.
The reaction mixture was stirred for 2 h then poured into water
and extracted with dichloromethane. The extracts dried with
MgSO4 and evaporated. Crude products were purified by column
chromatography and crystallization from ethanol.
(1 mg/mL) and the solution (5 lL) was applied onto the plate with
aid of a HAMILTON syringe. After development, the plates were
dried and the spots were localized in UV 254 nm.
4.1. 4,5-Dihydro-1-methyl-6-oxopyridazine-3-carboxylic acid 3A
1.46 g (10 mmol) of
a-Ketoglutaric acid was dissolved in 10%
HCl and 0.46 g (10 mmol) of methylhydrazine was added drop-
wise. Then the reaction mixture was refluxed for 3 h. After cooling
the reaction mixture was extracted with dichloromethane. The ex-
tracts were washed with water, dried (anhydrous MgSO4) and
4.2. Methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate 4A
Yield 67%; m.p. 115–118 °C; 1H NMR (CDCl3) d 2.40 (t, J = 8.1 Hz,
2H), 2.75 (t, J = 8.1 Hz, 2H), 3.74 (s, 3H); 13C NMR d 24.6, 37.8, 39.5,
Fig. 5. Autostereographic projection [10] of the H-bonding pattern within the sheets in methyl 4,5-dihydro-6-oxopyridazine-3-carboxylate (4A) structure, viewed
perpendicular to crystal plane (À1 0 1).

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A. Katrusiak et al. / Journal of Molecular Structure 998 (2011) 84–90
143.7, 159.6, 173.6. MS(m/z, M+): 156.0 (100%). Anal. Calcd for
C6H8N2O3 (156.14): C, 46.15; H, 5.16; N, 17.94. Found C, 45.92;
H, 5.08; N, 17.34.
solution by evaporation. The diffraction data were recorded using
a 4-circle KUMA KM4-CCD diffractometer. The structures were
solved by direct methods with program Shelxs-97 and refined with
Shelxl-97 [19]. The crystal data of 2ÀÅH3O+ and 4A have been listed
in Table 2. The crystal structures have been also deposited with the
Cambridge Crystallographic Database Centre as supplementary
publications Nos. CCDC 771942 and CCDC 771943 copies can be
obtained free of charge on request from www.ccdc.cam.ac.uk/da-
ta_request/cif. The crystallographic details of these structures are
tabulated in Supplementary information, Tables S1–S12.
4.3. Methyl 1-methyl-6-oxopyridazine-3-carboxylate 5A and methyl
6-methoxypyridazine-3-carboxylate 5B
For 5A: Yield 37%; m.p. 189–191 °C; 1H NMR (CDCl3) d 3.36 (s,
3H), 3.85 (s, 3H), 6.97 (d, J = 9.9 Hz, 1H), 7.84 (d, J = 9.9 Hz, 1H);
13C NMR d 38.9, 52.6, 129.4, 132.1, 136.1, 160.6, 162.6. MS(m/z,
M+): 168.0 (7%). Anal. Calcd for C7H8N2O3 (168.15): C, 50.00; H,
4.80; N, 16.66. Found C, 49.95; H, 4.61; N, 16.34.
Appendix A. Supplementary material
For 5B: Yield 67%; m.p. 99–100 °C; 1H NMR (CDCl3) d 3.89 (s,
3H), 3.98 (s, 3H), 6.97 (d, J = 9.6 Hz, 1H), 7.86 (d, J = 9.6 Hz, 1H);
13C NMR d 40.5, 52.6, 128.4, 131.7, 135.3, 159.6, 162.3. MS(m/z,
M+): 168.0 (9%). Anal. Calcd for C7H8N2O3 (168.15): C, 50.00; H,
4.80; N, 16.66. Found C, 49.87; H, 4.72; N, 16.51.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2011.05.016.
References
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(a) To 1.56 g (10 mmol) of 3A in acetic acid 0.79 g (10 mmol) of
bromine was added dropwise. The reaction mixture was stir-
red for 2 h at 70 °C then poured into water, alkalized with
NH4OH and extracted with dichloromethane. The extracts
dried with MgSO4 and evaporated. Crude products were
purified by crystallization from ethanol. Yield 7%; subl.
220 °C; m.p. 295 °C; 1H NMR (CDCl3) d 3.32 (s, 3H), 6.95 (d,
J = 9.8 Hz, 1H), 7.82 (d, J = 9.8 Hz, 1H); 13C NMR d 39.7,
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MgSO4 and evaporated. Crude products was crystallized
from ethanol. Yield 62%.
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4.4.1. X-ray diffraction
The single crystals of compounds 2ÀÅH3O+ and 4A for X-ray dif-
fraction measurements were grown from the dichloromethane