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A novel, efficient and simple one pot- five component synthesis of pyrazolopyranopyrimidines using Imidazole in aqueous medium

Ar O N N H NH O N

Aisha Siddekha
Assistant Professor, Department of Chemistry, Smt. V. H. D. Central Institute of Home Science, Bangalore560 001

Abstract
A novel one-pot five component synthesis of pyrazolopyranopyrimidines by the condensation of aromatic aldehydes, malononitrile, ethylacetoacetate, hydrazine hydrate 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 not involve any tedious work-up or purification; avoids hazardous reagents/byproducts and results in good yields.
O O + Ar H O + O CN CN + H2N NH2 . H2O + HCOOH imidazole N H2O, 80oC N H O N Ar O NH

Aisha Siddekha, Aatika Nizam and M. A. Pasha* Department of Studies in Chemistry, Central College Campus, Bangalore University, Bangalore560 001, INDIA

Green-Chemistry

Environmentally compatible reactions Fast and facile reactions Atom economy Easy separation and purification of products No/ minimum byproducts or waste generation

Green protocols

Microwave irradiation Ultrasonic irradiation Multi-component reactions Solvent-free reactions Solid state synthesis Tandem reactions/Domino reactions etc

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

Heterocycles:
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

Pyrazolo-pyrido(pyrano) pyrimidines
Pyrimidine derivatives exhibit antiviral, anticancer , anti-inflammatory, antimicrobial, anti-fungal, and antihistaminic activities, antiplatelet agents with analgesic activity and as a new drug for treatment of insomnia. Pyrazoles are an important class of heterocyclic compounds form the parent skeleton of pyrine drugs and other pharmaceutical compounds. Pyrazolo-pyrido (or pyrano) pyrimidines have known to show the antimicrobial activity .

Background of the present work

Synthesis of pyrano [2,3-c]pyrazole ring system fused to a pyrimidine moiety has been reported by El-Assiery et al and Zaki et al using -enaminonitrile precursor and acetic anhydride. Al-Thebeiti has reported a method wherein Pyrano derivatives were cyclized to pyranopyrimidines with acetic anhydride/pyridine, formamide and formamide /formic acid by Al-Matar et al

Reported methods
Ar CN N N H O NH2 Ac2O N N H O N NH Ar O

Zaki et al

H3C R N N Ar

Ar CN Ac2O/pyridine, O NH2 R H3C N N H

Ar

O NH

Al-Assierry et al

Table 1. The condensation reaction of 2chlorobenzaldehyde under different catalyst loading.

Amount of Imidazole (mmol) 0.1 0.2 0.5 0.75 1

Yield (%)

40 51 89 90 90

TABLE 2: Synthesis of pyrazolopyranopyrimidines from various aromatic aldehydes, malononitrile, ethylacetoacetate, hydrazine hydrate and formic acid.
O O + Ar H O + O CN CN + H2N NH2 . H2O + HCOOH imidazole N H2O, 80oC N H O N Ar O NH

Entry

Aromatic aldehydes (1)


O H

Time (min)

Yield (%)

a
b
MeO

30
30
H

83
85 83

O H Cl

30
O

d
NO2

30

80

O H OMe

30

83

Plausible Mechanism for the formation of pyrazolopyranopyrimidines


.. N H H CN CN N H Ar O + CN CN OH HN NH2 .. EtO O + Ar CN CN H+ N H O NH Ar + N N N H O N H OH H H2O N N H O N H N N H O .. NH2 + H O O OH H + N OH H N N H O N -H2O N N H O Ar N H OH N H .. H2N NH2 Ar H + NH N H H Ar OH Ar O OEt H N N H O N H+ H Ar CN CN -H2O H O CN CN + C N H+ O OEt HO H Ar Ar O CN OEt N CN O

Ar

CN CN

Ar

Ar H O

Ar

O NH

N H

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

References

S. A. El-Assiery, G. H. Sabed, A. Fonda. Synthesis of some new annulated pyrazolo-pyrido (or pyrano) pyrimidine, pyrazolopyridine and pyranopyrazole derivatives. 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 Pot Solvent-Free Synthesis of Pyrano [2,3-c]-Pyrazoles and Pyrazolo[1,5a]Pyrimidines, Molecules, (2010), 15, 6619

Acknowledgement

The Principal and my colleaguesSmt. V. H. D. Central Institute of Home Science, Bangalore

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