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Aisha SiddekhaAssistant Professor,

Department of Chemistry,

Smt. V. H. D. Central Institute of Home Science,

Bangalore

560 001

O

Ar

N

NH

N

NH

O

A novel, efficient and simple one pot- five

component synthesis ofpyrazolopyranopyrimidines using

Imidazole in aqueous medium

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AbstractA novel one-pot five component synthesis of pyrazolopyranopyrimidines by thecondensation of aromatic aldehydes, malononitrile, ethylacetoacetate, hydrazinehydrate and formic acid catalyzed by organocatalyst imidazole is described.

The highlighting features of this protocol is its efficiency, milder reaction

condition, use of environmentally friendly catalyst. The procedure does notinvolve any tedious work-up or purification; avoids hazardousreagents/byproducts and results in good yields.

Aisha Siddekha, Aatika Nizam and M. A. Pasha*

Department of Studies in Chemistry, Central College Campus,Bangalore University, Bangalore560 001, INDIA

CN

CN O

Ar

N

NH N

NH

OO

O OH

O

NH2

NH2

Ar

++ + + HCOOH

H2O, 80oC

imidazoleH

2O

.

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Green-Chemistry

Environmentally compatible reactions

Fast and facile reactions Atom economy

Easy separation and purification of products

No/ minimum byproducts or waste generation

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Green protocols

Microwave irradiation

Ultrasonic irradiation

Multi-component reactions Solvent-free reactions

Solid state synthesis

Tandem reactions/Domino reactions etc

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Multi component reactions (MCRs) More than two different starting materials

combine to give a product in a single step

Simplified purification- all reagents

incorporated into the final product.

Good yield.

Examples-Ugi reaction, Micheal addition, etc

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Heterocyclic compounds are biologically active

and possess interesting pharmacological

properties: Pyrido[2,3-d]pyrimidine derivatives,

4H-benzo[b]pyran derivatives,

Tetrahydropyrimidines, Pyranopyrazoles,

3,4-dihydropyrimidin-2-ones etc

are synthesized by multicomponent strategy

Heterocycles:

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Pyrazolo-pyrido(pyrano) pyrimidines

Pyrimidine derivatives exhibit antiviral, anticancer ,

anti-inflammatory, antimicrobial, anti-fungal, and

antihistaminic activities, antiplatelet agents withanalgesic activity and as a new drug for treatment

of insomnia.

Pyrazoles are an important class of heterocyclic

compounds form the parent skeleton of pyrinedrugs and other pharmaceutical compounds.

Pyrazolo-pyrido (or pyrano) pyrimidines have

known to show the antimicrobial activity .

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Synthesis of pyrano [2,3-c]pyrazole ring

system fused to a pyrimidine moiety has

been reported by El-Assiery et al and Zakiet al using -enaminonitrile precursor and

acetic anhydride. Al-Thebeiti has reported a

method wherein Pyrano derivatives werecyclized to pyranopyrimidines with acetic

anhydride/pyridine, formamide and

formamide /formic acid by Al-Matar et al

Background of the present work

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Reported methods

O

Ar

NH2

CN

N

NH O

Ar

N

NH

N

NH

O

Ac2O Zaki et al

O

Ar

NH2

CN

NN

Ar

CH3

O

Ar

N

NH

CH3

N

NH

O

R RAc2O/pyridine, Al-Assierry et al

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Table 1. The condensation reaction of 2-

chlorobenzaldehyde under different catalyst loading.

Amount of Imidazole

(mmol)

Yield (%)

0.1 40

0.2 51

0.5 89

0.75 90

1 90

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Entry

Aromatic

aldehydes (1)

Time (min) Yield

(%)

a 30 83

b 30 85

c 30 83

d 30 80

e 30 83

H

O

H

O

Cl

H

O

NO2

H

O

MeO

H

O

OMe

TABLE 2: Synthesis of pyrazolopyranopyrimidines from

various aromatic aldehydes, malononitrile, ethylacetoacetate,

hydrazine hydrate and formic acid.CN

CNO

Ar

N

NH

N

NH

OO

O OH

O

NH2

NH2

Ar

++ + + HCOOH

H2O, 80oC

imidazoleH

2O

.

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OH

N

NH

H

+

CN

H

H

CNN

N

H

CNOH

Ar

HCN

H

CN

CN-Ar

O

H

Ar CN

OO

OEt

-

+

O

OEtO

CN

N

Ar

Ar

O

OCN

CN

EtO

NH2

NH2

Ar CN

CNNH

NH2

O

OEtN

NH

Ar

NO

HOH CN

HH+

NN

H

O

Ar

NH

CNH

H+ N NH

O

Ar

CN

NH2

H

O

OH NNH

O

Ar

NH H

O

N

NNH

O

Ar

NH

N

OH

H

NNH

O

Ar

N

N

OH

NNH

O

Ar

N

NH

O

NNH

O

Ar

N

N

OH

H

OHH

H

..

+

-H2O

-

H+

+

..

..

+..

+

-H2O

H2O

+

Plausible Mechanism for the formation

of pyrazolopyranopyrimidines

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Conclusion

A novel, efficient and straightforward one- pot

procedure for the synthesis of biologically active

pyrazolopyranopyrimidines is developed.

The salient features of this protocol are:

Simple procedure, short reaction time,mild reaction conditions, easier work-up,

use of water as solvent

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References

S. A. El-Assiery, G. H. Sabed, A. Fonda. Synthesis of some new annulatedpyrazolo-pyrido (or pyrano) pyrimidine, pyrazolopyridine and pyranopyrazolederivatives. Acta Pharm. (2004), 54, 143

A. H. Shamroukh, M. E. A. Zaki, E. M. H. Morsy, Faiza M. Abdel-Motti, F.M. E. Abdel-Megeid.Arch. Pharm. Chem. Life Sci. (2007), 340, 236

Al-Thebeiti, S. Marzoog. Synthesis of some new spiropyrazolo [4',5':5,6]pyrano[2,3- d]pyrimidines.Afinidad(2000), 57, 365

Al-Thebeiti, S. Marzoog. Synthesis of some new spiropyrazolo[4',5':5,6]-

pyrano[2,3-d]pyrimidines,Heterocycles, (2000), 53, 621

H. M. Al-Matar, D. K. Khaled, Y. A. Aisha, M. H. Elnagdi. Green One PotSolvent-Free Synthesis of Pyrano [2,3-c]-Pyrazoles and Pyrazolo[1,5-a]Pyrimidines,Molecules, (2010), 15, 6619

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Acknowledgement

The Principal and my colleagues-Smt. V. H. D. Central Institute of Home

Science, Bangalore

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