A Simple and Efﬁcient Regioselective and Chemoselective Synthesis of
New Substituted 3-Methyl-6-arylpyridazine-4-carboxamides and 5-Oxo-3-
and Mehdi M. Baradarani
Faculty of Chemistry, Department of Organic Chemistry, Urmia University, Urmia 57154, Iran
Department of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran
Received August 29, 2017
Published online 8 January 2018 in Wiley Online Library (wileyonlinelibrary.com).
A facile, green, and one-pot approach is described for the regioselective synthesis of new substituted
3-methyl-6-arylpyridazine-4-carboxamides in water at room temperature. Subsequent treatment of
these products with the Vilsmeier reagent led to chemoselective and regioselective production of new
5-oxo-3-aryl-5,6-dihydropyrido[4,3-c]pyridazine-8-carbaldehydes in good to excellent yields.
J. Heterocyclic Chem., 55, 603 (2018).
The exploration of new structures for drug development
is a rapidly emerging theme in medicinal chemistry .
The pyridazine structural framework and heterofused
analogues as important privileged heterocyclic scaffolds
continue to attract attention because of their wide variety
of interesting biological properties . Pyridazines show
a diverse range of pharmacological activities, including
bronchodilatory, cardiotonic, anti-inﬂammatory, and platelet
aggregation activities . While the ﬁrst identiﬁcation of a
pyridazine ring within a natural product structure was
reported relatively recently , pyridazine heterocyclic sub-
units have been incorporated into a number of successful
pharmaceutical products such as Sulfamethoxypyridazine 1
and Nifurprazine 2 (antibacterial agents), Minaprine 3
(antidepressant) and Gabazine 4 (GABA
antagonist) (Fig. 1) . As a consequence, new
methodology that allows the rapid synthesis of libraries of
novel pyridazine derivatives bearing multiple functionality
for incorporation in drug discovery campaigns continues to
be an important target for medicinal chemists.
The development of new synthetic methods for the
efﬁcient preparation of heterocycles containing pyridazine
ring fragments is therefore an interesting challenge. As
most approaches to synthesis of pyridazine heterocycles
including inconvenient operations, a limited number of
suitable substrates, harsh reaction conditions, a high
number of steps, and poor yields, therefore, the report of
synthetic strategies with mild and efﬁcient methods can
be highly desirable.
Recently, Green chemistry has developed as an
important and expanding research area, as it avoids the
use of environmentaly hazardous compounds and
minimizes the production of waste products . The
usage of safe solvents is one approach to achieving these
aims. Water has many advantages over conventional
organic solvents, because it is cheap, readily available,
non-polluting, and non-ﬂammable .
Herein, we report the rapid formation of 3-methyl-
6-arylpyridazine-4-carboxamides 5 via three-component
condensations of arylglyoxal monohydrates 6, acetoace-
tamide 7, and hydrazine hydrate in water. Subsequently,
treatment of the resulting products 5 with the Vilsmeier
reagent led to chemoselective synthesis of 5-oxo-3-aryl-
5,6-dihydropyrido[4,3-c]pyridazine-8-carbaldehydes 8 in
excellent yields. The retrosynthesis of new products 5
and 8 is shown in Scheme 1.
RESULTS AND DISCUSSION
We have recently reported simple, efﬁcient, and
economic methods for the synthesis of a number of
heterocyclic scaffolds . Because of the high solubility
of arylglyoxal monohydrates in water and because this
solvent allows for an environmentally friendly process,
water was used as the preferred solvent for the
optimization experiments and in the ﬁnal preparative
protocol. The synthesis of 3-methyl-6-phenylpyridazine-
4-carboxamide (5a) was achieved by the one-pot three-
component reaction of phenylglyoxal monohydrate (6a),
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