Pyridazine derivatives. XXIV. Efficient N-methylation of diversely substituted 3(2H)-pyridazinones using N,N-dimethylformamide dimethylacetal

Article abstract of DOI:10.1081/SCC-120004258

A series of diversely substituted 3(2H)-pyridazinones were efficiently N-methylated at position 2 by treatment with N,N-dimethylformamide dimethylacetal in DMF.

Full text of DOI:10.1081/SCC-120004258

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PYRIDAZINE DERIVATIVES. XXIV. EFFICIENT N-
METHYLATION OF DIVERSELY SUBSTITUTED 3(2H)-
PYRIDAZINONES USING N,N-DIMETHYLFORMAMIDE
DIMETHYLACETAL
Eddy Sotelo a & Enrique Raviña a
a Departamento de Química Orgánica, Laboratorio de Química Farmacéutica, Facultad de
Farmacia, Universidad de Santiago de Compostela, Santiago de Compostela, 15782, Spain
Version of record first published: 16 Aug 2006
To cite this article: Eddy Sotelo & Enrique Raviña (2002): PYRIDAZINE DERIVATIVES. XXIV. EFFICIENT N-METHYLATION OF
DIVERSELY SUBSTITUTED 3(2H)-PYRIDAZINONES USING N,N-DIMETHYLFORMAMIDE DIMETHYLACETAL, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:11, 1675-1680
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SYNTHETIC COMMUNICATIONS, 32(11), 1675–1680 (2002)
PYRIDAZINE DERIVATIVES. XXIV.[1]
EFFICIENT N-METHYLATION
OF DIVERSELY SUBSTITUTED
3(2H)-PYRIDAZINONES USING
N,N-DIMETHYLFORMAMIDE
DIMETHYLACETAL
*
Eddy Sotelo and Enrique Ravina
Departamento de Quımica Organica, Laboratorio de
Quımica Farmaceutica, Facultad de Farmacia,
Universidad de Santiago de Compostela, 15782,
Santiago de Compostela, Spain
ABSTRACT
A series of diversely substituted 3(2H)-pyridazinones were
efficiently N-methylated at position 2 by treatment with
N,N-dimethylformamide dimethylacetal in DMF.
In recent years the 3(2H)-pyridazinone nucleus has been extensively
studied in the search for new and selective medicinal agents.[2] It has proved
to be an important pharmacophore in the search for drugs acting on the
cardiovascular system.[3] Although the presence of the NH group adjacent
*Corresponding author. E-mail: pyrisymp@usc.es
1675
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1676
SOTELO AND RAVINA
to the strong (C¼O) dipole in the azine system was formerly regarded as a
structural requirement for these activities,[4] alkylation at this position has
recently been reported to enhance biological activity.[5]
For several years, we have been involved in a program aimed at study-
ing the pharmacological exploitation of the 6-aryl-3(2H)-pyridazinone
system in medicinal chemistry.[6–9] As part of this work, we were interested
in evaluating the effect of the 2-methylation on the biological activity of
several 3(2H)-pyridazinones.
The N-alkylation of ambident 6-membered heterocycles possessing a
tautomeric or mesomeric structure is usually inefficient and non-regioselec-
tive,[10] the N-alkylpyridazinone, normally being accompanied by a variable
amount of the corresponding alkoxypyridazine. N-methylation of the NH
group of 3(2H)-pyridazinones is usually effected with methyl iodide[11] or
dimethyl sulphate.[12] The drawback of these reagents is that they generally
require treatment of the heterocycle with inorganic bases with the result that
the overall yield can be reduced because of undesirable reactions of the
functional groups present in the molecule.
The use of formamide acetals for alkylation and formylation of
organic compounds is well documented.[13] In particular dimethylforma-
mide dimethylacetal (DMFDMA) is an effective methylating reagent that
is widely used for synthesis of esters from carboxylic acids[14] and for the
preparation of ethers or thioethers.[15] Curiously, they appear not to have
been used in pyridazine chemistry. We report here the use of DMFDMA for
efficient N-methylation of a series of diversely substituted 3(2H)-pyridazi-
nones under neutral conditions (Scheme 1).
DMFDMA was found to be an extremely efficient reagent, able to
carry out the successful methylation of different series of 3(2H)-pyridazi-
nones 1a–n. Refluxing a 1.5 : 1 mixture of DMFDMA and a (3H)-pyridazi-
none in dry DMF afforded the corresponding N-methylated product 2 in
yields of 89–98% (Table 1), usually within 1–2.5 h. All products were iden-
tified by comparison of their physical data and NMR and IR spectra with
those of authentic samples.
Scheme 1. Methylation of substituted 3(2H)-pyridazinones employing DMFDMA.

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PYRIDAZINE DERIVATIVES. XXIV
1677
Table 1. Chemical Structure and Experimental Results of the N-Methylation of
3(2H)-Pyridazinones Employing DMFDMA
Yield
(%)
M.P.
(ꢀC)
Compound
R4
R5
R6
Formula
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
H
H
H
H
H
H
H
H
H
H
H
CN
H
Br
H
H
Cl
Br
Me
SMe
OMe
OEt
N3
Ph
N(CH2)5
COOMe
NH2
NH2
H
96
98
98
oil
112–113
135–137C
C
172–174
C5H6N2O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C11H10N2O
11H9ClN2O
11H9BrN2O
C12H12N2O
12H12N2OS
C12H12N2O2
C13H14N2O2
C11H9N5O
C17H14N2O
C16H19N3O
C14H11N3O3
C11H11N3O
C11H10BrN2O
97164–164
95
97165–16C7
92
93
94
98
98
89
88a
74a
132–133
140–142
90–91
155–156
121–122
143–145
154–155
262–263
aOverall yield (see Scheme 2).
In the case of compounds 1m and 1n, which bear an amino group at
position 5, reaction with DMFDMA gave the corresponding N,N-dimethyl-
formamidino derivatives 3m and 3n in yields of 97and 82%, respectively
(Scheme 2). Treatment of compounds 3m and 3n with the Lewis acid zinc
chloride in refluxing absolute ethanol[16] removed the formamidino group at
position 5 affording the desired 5-amino-2-methylpyridazinones 2m and
2n in high yield (91%). Reaction of DMFDMA with 4,5-dichloro-3(2H)-
pyridazinone (1o, Scheme 2) gave 4-chloro-5-methoxy-2-methyl-3-pyridazi-
none (2o), probably through the highly reactive chlorine atom at position 5
undergoing nucleophilic attack by methoxide anion formed during the
generation of the aza-oxo-stabilized carbene ion.
In summary, reaction with DMFDMA is a straightforward alter-
native procedure for clean and efficient N-methylation of substituted

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1678
SOTELO AND RAVINA
Scheme 2.
3(2H)-pyridazinones. The operational simplicity, high yields and mild reac-
tion conditions are the main characteristic features of this process.
EXPERIMENTAL PART
Melting points were measured on a Gallenkamp melting point
apparatus and are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer 1640 FTIR spectrophotometer. 1H-NMR spectra were
obtained on a Bruker AMX-300 Hz spectrophotometer using tetramethylsi-
lane as the internal standard. The progress of the reactions was monitored
by thin layer chromatography on 2.5 mm Merck silica gel GF 254 strips.
Typical procedure for the N-methylation of 3(2H ) pyridazinones 1 using
DMFDMA: A mixture of 3(2H)-pyridazinone 1 (5 mmol) and DMFDMA
(7.5 mmol) was refluxed in dry DMF (5 ml) for 1–2.5 h. On cooling, the
mixture was poured onto ice and the solid thus obtained was filtered out
and washed with water to give the expected N-methyl compound, which
then was recrystallized from an appropriate solvent.
Cleavage of the N,N-dimethylformamidino group using zinc chloride: A
mixture of the N,N-dimethylformamidinopyridazinone (3m or 3n) (5 mmol)
and anhydrous zinc chloride (20 mmol) in absolute ethanol was refluxed for
24 h. On cooling, the solvent was removed under reduced pressure and the
mixture was poured onto ice. The solid thus obtained was filtered out and
recrystallized from an appropriate solvent to obtain compounds 2m and 2n.
4-Chloro-5-methoxy-2-methyl-3-pyridazinone (2o): M.p.: 153–155ꢀC.
IR (KBr/cmꢁ1): 1636 (CO), 1110 (C-O). 1H-NMR (DMSO-d6): 3.66 (s, 3H,
CH3), 4.04 (s, 3H, CH3), 8.18 (s, 1H, CH).

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PYRIDAZINE DERIVATIVES. XXIV
ACKNOWLEDGMENTS
1679
Financial support of this work by the Xunta de Galicia under Project
XUGA 8151389 is gratefully acknowledged.
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Received in the Netherlands April 20, 2001