Synthesis of A Structure Containing Three N-Fused Heterocycles With Very High Bond Forming Through A One-Pot Reaction

Synthesis of a structure containing
three N-fused heterocycles with very

high bond forming through a one-pot
reaction
Heterocyclic chemistry seminar
Presented by : Yaqeen Alhaqq F. Ghazi
MSc. Student
(Department of Pharmaceutical Chemistry)
Supervised By : Assist.Prof. Ayad MR Raoof
Assist.Prof. Ayad K. Khan
Contents
1-Introduction
2-Results and discussion
3-Mechanism of reaction
4-Conclusion
5-Reference
Introduction
One-pot reactions are one of the useful reactions
in organic chemistry due to starting materials,
reagents, and catalysts react with each other in a
single flask and produce a final product without
separation and purification of intermediates.
These types of reactions have numerous
authorities such as sustainability, simplicity, speed
in synthesis, economical and environmental
concerns.
*The most important heterocycles are :-
1-Isoindoline ring, which has been

used as antimicrobial, NH
anticancer,anti-viral, and anti-HIV
agents. Isoindoline
-Zopiclone
2-Quinazolines have behaved as N
antiviral, anticancer, antimalarial
and antibacterial, antifungal,
N
antiinflammatory, anti-HIV, and
antituberculosis agents. Quinazoline
-Terazocin
3-Pyrazoles are in the NH
skeleton of a huge number
of natural products and N
pharmaceutical compounds. Pyrazole

-Celecoxib
4-Pyrimidine derivatives N
are the main parts of

Cytidine and Uridine which N
exist in RNA structure. Pyrimidine
-Minoxidil
Results and discussion
In order to optimize the reaction conditions,
hydrazine hydrate, 3-oxobutanenitrile,
2-phthaldehydic acid and dimedone were taken as
model reactants.
The best results were achieved in ethanol as a
solvent under reflux temperature. It was found that
when the reaction was carried out in the absence of
catalyst, the yields percentage of reactions was low.
hydrazine hydrate
dimedone
3-oxobutanenitrile
2-phthaldehydic acid
The experiments showed that the yield of
reactions was increased in the presence of acidic
catalysts. The highest yields were attained in the
presence of 0.3 mmol of 4-toluenesulfonic acid
as catalyst at reflux conditions.
The reaction proceeded with both cyclic and
acyclic CH-acids to obtain different products.
When we used cyclic CH-acids, isoindolo[2,1-
c]pyrazolo[1,5-a]quinazoline derivatives were
synthesized as the final products.
O O
O O
cyclohexane-1,3-dione 5,5-dimethylcyclohexane-1,3-dione
While, pyrazolo[5',1':2,3]pyrimido[6,1-
a]isoindol derivatives were achieved when we
used acyclic CH-acids. O O
O O
Ph
pentane-2,4-dione 1-phenylbutane-1,3-dione
O O
Ph Ph
1,3-diphenylpropane-1,3-dione
The effect of substituent's on the synthesized
pyrazole ring was investigated. It is shown that
the yield of reaction is increased if the steric
effect of the substituent at the C3 position is
reduced. Therefore, because of less hindered
effect of –CH3, the highest yields were
achieved in comparison with –Ph and
-C(CH3)3. NH
pyrazole
Mechanism Of Reaction
One possible mechanism for this one-pot four-
component reaction is shown in scheme 3
2,6,6-trimethyl-6,7-dihydroisoindolo[2,1-
c]pyrazolo[1,5-a]quinazoline-8,13(5H,8bH)-dione (5b)
O
N N
N
O
O
N N
H2N NH2 CN
N
hydrazine HN
NH2
3-oxobutanenitrile
(Z)-3-hydrazineylidenebutanenitrile
2a HN
6
(5-exo dig ring closure) 5-methyl-2,4-dihydro-
3H-pyrazol-3-imine
HN
7
N
H2N
5-methyl-1H-pyrazol-3-amine
8
2-phthaldehydic acid
5,5-dimethylcyclohexane-1,3-dione 5-exo trig ring closure
Conclusion
In conclusion, some new N-fused heterocyclic
compounds have been simply synthesized via an
efficient one-pot four-component reaction with highly
bond formation in the final products.
The most important advantage of this reaction is the
formation of all rings during the reaction time.
Moreover, 4-toluenesulfonic acid as an available and
cheap catalyst, and ethanol as a green organic solvent
have been used.
Reference
Alizadeh-Kouzehrash M, Rahmati A, Synthesis
of a structure containing three
N-fused heterocycles with very high bond-
forming through a one-pot reaction, Tetrahedron
(2020), doi:
https://doi.org/10.1016/j.tet.2020.130923.

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Synthesis of a structure containing

three N-fused heterocycles with very

1-Isoindoline ring, which has been

pharmaceutical compounds. Pyrazole

are the main parts of

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