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Current Organic Chemistry
ISSN: 1385-2728
Current Organic
Chemistry
Volume 10, Number 3, February 2006
Contents
Hot Topics in Diazine Chemistry
Guest Editor: Péter Mátyus
Editorial Pp. 257
Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine
Template: Organic and Medicinal Chemistry Approach
Pp. 259-275
Pier Giovanni Baraldi, Mojgan Aghazadeh Tabrizi, Romeo Romagnoli,
Hussein El-Kashef, Delia Preti, Andrea Bovero, Francesca Fruttarolo,
Marina Gordaliza and Pier Andrea Borea
[Abstract]
Use of Polyfunctionalized Pyridazines as Reactive
Species for Building Chemical Diversity Pp.
277-295
J.J. Bourguignon, S. Oumouch and M. Schmitt
[Abstract]
Dihydroazines Based on α,β-Unsaturated
Ketones Reactions Pp. 297-317
V.A. Chebanov and S.M. Desenko
[Abstract]
Recent Advances in the Area of Pyridodiazinium Systems
Containing Bridgehead-Nitrogen Atom Pp. 319-322
György Hajós
[Abstract]
An Overview of Diazine Nucleoside Analogues Pp.
333-362
Luigi A. Agrofoglio
[Abstract]
Diazine Analogues of the Pyridocarbazole Alkaloids
Pp. 363-375
Norbert Haider
[Abstract]
Palladium-Catalyzed Reactions on 1,2-Diazines
Pp. 377-417
Bert U.W. Maes, Pál Tapolcsányi, Caroline
Meyers and Péter Mátyus
[Abstract]
Abstracts
[Back to top]
Editorial
This special issue of Current Organic Chemistry is devoted
to several current synthetic and biological aspects of the
chemistry of diazines to illustrate the considerably increasing
interest in and complexity of this research area. The wide
range of the synthetic procedures and strategies recently
developed and described in this issue for the syntheses of
diazine derivatives may also have broader applicability in
the heterocyclic chemistry, and thereby it may be useful for,
and may stimulate further work in other fields of heterocyclic
chemistry.
I am very grateful to all authors for their efforts to contribute
to this issue with highly informative and well-organized surveys.
The first contribution by Baraldi et al. (University
of Ferrara, Italy) describes the synthesis and medicinal chemistry
of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines,
and the optimization process, including structure-activity
relationship analysis, to develop new selective antagonists
for the A2A and A3 adenosine receptors.
The study may illustrate a systematic way how to identify
structural motives of complex structures which could be responsible
for selective receptor-ligand interactions.
In the medicinal chemistry, one of the most typical and extensively
studied approaches to hit and/or lead identification is based
on the syntheses of libraries of compounds with high chemical
diversity. Bourguignon et al. (University Louis Pasteur,
Strasbourg, France) have developed a particularly efficient
pathway to the preparations of large number of polyfunctionalized
pyridazines by the application of amination and palladium
cross coupling reactions in tandem combination. Pyridazines
containing two, three and four halogens, without or with further
functional groups could be efficiently used as starting materials.
Chebanov and Desenko (Institute for Scintillation Materials
of National Academy of Science of Ukraine) reports on the
heterocyclization reaction of unsaturated ketones with urea
and structurally related derivatives to give dihydropyrimidines
in good yields. Moreover, an interesting procedure with wide
scope has also been developed to obtain dihydroazolopyrimidines
by cyclocondensation of aminoazoles and unsaturated ketones.
Pyridodiazonium systems are of interest per se representing
new types of zwitterionic compounds, and as intermediates
for the syntheses of otherwise hardly accessible substituted
pyridines. Hajós (Chemical Research Center, Hungarian
Academy of Sciences) provides a broad survey on the synthetic
and theoretical aspects of the pyrido[1,2-a]pyrimidinium,
pyrido[1,2-a]pyrazinium, pyrido[1,2-c]pyrimidinium, and pyrido[1,2-b]pyridazinium
ring systems, and their transformations.
Pyrimidine nucleosides are of great importance in the medicinal
chemistry of antiviral, antibacterial and anticancer compounds.
Agrofoglio (Université d’Orléans, France)
focuses particularly on the carbocyclic, acyclic, and C-5
pyrimidine nucleosides, and illustrates the recent development
in the field by numerous examples.
Haider (University Vienna, Austria) reviews of the medicinal
chemistry of diazinocarbazoles as aza analogues of naturally
occurring pyridocarbazoles, such as e.g. ellipticine, with
significant anticancer activity. Some diazine analogues are
bioisosters, whereas some of them are well beyond the principles
of classical bioisosterism. Nevertheless, from both types
there could be identified several compounds with interesting
biological activities. Moreover, several elegant synthetic
procedures, including Diels-Alder approach, have also been
elaborated to these classes of compounds.
Maes (University Antwerp) et al. extensively surveyed
the most efficient methods for C- and N-functionalization
of pyridazines via palladium-catalyzed cross coupling reactions
including Suzuki, Stille, Sonogashira, Heck, carbonylation
and Buchwald-Hartwig reactions. The review well demonstrates
the wide scope of these reactions to the syntheses of a broad
range of pyridazines including fused ring systems.
Péter Mátyus
Semmelweis University
Department of Organic Chemistry
Budapest
Hungary
[Back to top]
Pyrazolo[4,3-e][1,2,4]Triazolo[1,5-c]Pyrimidine
Template: Organic and Medicinal Chemistry Approach
Pier Giovanni Baraldi, Mojgan Aghazadeh Tabrizi, Romeo Romagnoli,
Hussein El-Kashef, Delia Preti, Andrea Bovero, Francesca Fruttarolo,
Marina Gordaliza and Pier Andrea Borea
Here we report our medicinal chemistry approach on the synthesis
of the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines
and related compounds that have permitted us to complete the
SAR analyses on this class of chemical molecules. Evaluating
their pharmacological profiles, we planned several structural
modifications to modulate the biological activity versus the
different adenosine receptor subtypes. Efforts made by our
research group led to the discovery of a variety of selective
antagonists for the A2A and A3 receptors,
performing modifications at the N7, N8,
N5, C9, C2-position of the
pyrazolo-triazolo-pyrimidine core and by the replacement of
the 2-(2-furyl)[1,2,4]triazole molecular part with substituted
2-thioxotriazole, dioxotriazine, oxotriazine, and 1,2,4-triazepine
moieties. Modifications at the N7-pyrazole performed
by the introduction of different alkyl or arylalkyl chains,
led us to the discovery of very potent and selective A2A
receptor antagonists, whereas, functionalisations at the N5-position
together with the modulation of the pattern of substitution
on the N8-pyrazole nitrogen revealed new A3
antagonists (40, 41) suitable to represent candidate for the
pharmacological and clinical investigations. Other modifications
performed to the tricyclic nucleus, such as the introduction
at the C9-position of thioethyl, aminoalkyl and
(cyclo)alkylamino radicals (compounds 50-66) and the replacement
of the 2-furyl moiety with substituted aromatic rings (compounds
48 a-f and 49a, b) led to a diminished receptor affinity.
Also the replacement of the 2-(2-furyl)triazolo template with
new heterocycles revealed inactive molecules but allowed us
to real understand what structural modifications introduced
on the pyrazolo-triazolo-pyrimidine structure played an important
role on ligand-receptor interaction. In this way, we notice
what position of the heterocyclic structure is not allowed
to be modified and, on the contrary, what position is susceptible
of modifications or functionalizations.
[Back to top]
Use of Polyfunctionalized Pyridazines as Reactive
Species for Building Chemical Diversity
J.J. Bourguignon, S. Oumouch and M. Schmitt
Efficient chemical pathways leading to differently substituted
3-aminopyridazines have been reviewed with the general objective
to help to design the most straightforward chemical pathways
to produce libraries of compounds with largest chemical diversity.
Thus 3-chloropyridazines bearing at different positions halogens
may offer opportunities, when submitted two tandem of selected
reactions leading to the expected compounds (amination vs.
palladium cross coupling reactions (PCCR)). As a result of
its electron-deficient system, the commercially available
3,6-dichloropyridazine offers a large panel of reactivities
in particular the access to 4-functionalized systems (vicarious
nucleophilic substitution, halogenation, metalation/alkylation,
arylation using Lewis acid catalyst). In other cases, the
functionalized pyridazin-3-one precursors may be helpful as
the free amide could also deal with PCCR by means of its O-Triflate
derivative. A particular attention was given to opportunities
offered by electron deficient 3,6, 3,4,6, 3,4,5, and 3,4,5,6-polychloropyridazines.
However increasing the number of chlorines increased the number
of possible combinations toward both amination and PCCR, and
in general, led to a loss of regioselectivity. Thus introduction
of different functionalities (bromine, iodine, enol, nitro,
cyano, methyl and other carbon acids) at the pyridazine ring
significantly increased their potentials, (increased reactivity
and regioselectivity). Finally tetra-functionalized pyridazines
were briefly introduced. They may constitute the most suitable
scaffolds for building in an expeditive manner different 3-aminopyridazine
sub-series by means of combinatorial chemistry.
[Back to top]
Dihydroazines Based on α,β-Unsaturated
Ketones Reactions
V.A. Chebanov and S.M. Desenko
The present review is devoted to heterocyclizations of unsaturated
carbonyl compounds which result in the formation of six-membered
partially hydrogenated heterocycles. Three main pathways of
such reactions are discussed: syntheses of dihydropyridines
by preliminary transformation of unsaturated ketone, cyclocondensations
of unsaturated carbonyl compounds with nitrogen containing
1,3–binucleophiles and heterocyclizations with participation
of additional functional groups of enones.
In the first part of review reactions of cyclic and acyclic
enamines with unsaturated ketones are observed. The participation
of cyclic, noncyclic enamines and enaminonitriles in formation
of various dihydroazoles is described.
The significant part of the review is concerned with reactions
of unsaturated ketones with urea and its analogs such as thiourea,
guanidine and amidines leading to dihydropyrimidine-2-thiones,
dihydrothiazines, dihydropyrimidin-2-ones, dihydropyrimidine-2-ilamines
and 2-alkyl(aryl) substituted 1,4- or 1,6-dihydropyrimidines
respectively. The mechanisms of the interaction of urea and
its analogs with aromatic unsaturated ketones are also discussed.
The reactions of malonic acid derivatives, e.g. malononitrile,
malonamide, thiomalonamide, cyanoacetamide, thiocyanacetamide
and cyanoacetic ester are described in the next part of the
review. Some features of these reactions and their possible
mechanisms observed in details.
The last part is concerned with cyclocondensation of aminoazoles
and α,β-unsaturated
carbonyl compounds or Mannich bases as the most common method
of synthesis of dihydroazolopyrimidines with a nodal nitrogen
atom. The reactions of synthetic precursors of chalcones -
substituted benzaldehydes and acetophenones as well their
mechanisms are also observed.
[Back to top]
Recent Advances in the Area of Pyridodiazinium Systems
Containing Bridgehead-Nitrogen Atom
György Hajós
A survey is provided on new synthetic pathways to pyrido[1,2-a]pyrimidinium,
pyrido[1,2-a]pyrazinium, pyrido[1,2-c]pyrimidinium,
and pyrido[1,2-b]pyridazinium systems and their partially
saturated derivatives appeared during the recent years. Reaction
mechanisms of these ring closure methodologies are also discussed.
Some representative further transformations of these ring
systems are also summarized. Thus, alkylation of olates and
thiolates, ring opening reactions, photochemical transformations
and flash vacuum pyrolytic reactions are reviewed.
[Back to top]
An Overview of Diazine Nucleoside Analogues
Luigi A. Agrofoglio
Early work on antiviral agents focused on traditional nucleoside
analogues in which the base was linked to one or other of
the naturally occurring sugars. Some of these were indeed
shown to possess anti-metabolic properties, but it became
apparent that their usefulness was severely limited by instability
and poor selectivity. Since the discovery of the first successful
anti-viral drug, acyclovir, in 1974 by Gertrude “Trudy”
Elion, interest has diversified towards compounds in which
the heterocycle and sugar components of the nucleoside differ
significantly from the natural form. These novel types of
nucleosides act as anticancer, antiviral or antibacterial
drugs. The intense search for clinically useful nucleoside
derivatives has resulted in a wealth of new approaches for
their synthesis. In this review, we will give an overview
of the synthesis of some pyrimidine nucleosides according
to their structural types (e.g., acyclics, carbocyclics, and
C5-substituted pyrimidine nucleosides), including compounds
having "unnatural" L-stereochemistry, along with
the synthetic routes of some selected examples. The article
also refers to other relevant review articles that have covered
particular areas of investigation or have dealt in depth with
a single compound.
[Back to top]
Diazine Analogues of the Pyridocarbazole Alkaloids
Norbert Haider
The pyrido[4,3-b]carbazole alkaloids, ellipticine
and olivacine, have been attracting considerable
interest since many years due to their pronounced antitumour
activity. Among the large number of structural variations
of these lead compounds which have been performed in search
of new agents with enhanced pharmacological profiles, a remarkable
proportion of work has been devoted to the synthesis of diazine-fused
carbazoles as “aza” analogues (in a broader sense)
of the natural products. The present article will give a detailed
overview of the literature from the past two decades in this
field of medicinal heterocyclic chemistry.
[Back to top]
Palladium-Catalyzed Reactions on 1,2-Diazines
Bert U.W. Maes, Pál Tapolcsányi, Caroline
Meyers and Péter Mátyus
In this report, we review the C- and N-functionalization
of the pyridazine nucleus via palladium-catalyzed
reactions (Suzuki, Stille, Sonogashira, carbonylation, Heck,
Buchwald-Hartwig) in which carbon atoms of the pyridazine
nucleus are involved. The efficient use of these reactions
in synthetic strategies to build up polycyclic 1,2-diazines
is also included.
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