الفهرس 
Synthesis of five membered heterocycles containing enaminonitriles moietyOnly 14 pages are availabe for public view
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Abstract
The present investigation deals with the role of enaminonitriles in the synthesis of new heterocyclic systems from readily available materials, the biological activity (antimicrobial activity by diffusion disk method, minimum inhibitory concentration “MIC” and minimum bactericidal concentration “MBC”) of these systems were also investigated.
Our target compound was obtained when 3-methyl-1H-pyrazol-5(4H)-one 1 was allowed to react with 2-(4-chlorobenzylidene)malononitrile 2 in refluxing ethanol in presence of few drops of piperidine; the Michael adduct 6-amino-4-(4-chlorophenyl)-3-methyl-1,4-dihydro pyrano[2,3-c]pyrazole-5-carbonitrile 3 was isolated.
The behavior of starting compound 3 toward different electrophiles and nuleophiles had been studied. So, when pyranopyrazole 3 was heated in acetic anhydride at refluxing temperature the unexpected methyl oxazinone derivative 4 was obtained [cf. scheme 1].
The reaction of our starting pyranopyrazole 3 with oxalyl chloride in dry toluene afforded the oxoacetyl derivative 5 which has been allowed to react with appropriate alcohol or amine without purification in some coming reactions. Also the reaction of starting compound 3 with carbon disulphide gave the dithione derivative 6, and when compound 3 was submitted to react with formic acid, the pyrimidinone derivative 7 was isolated [cf. scheme 1].
The reaction of enaminonitrile 3 with sulphuric acid was investigated. Thus when compound 3 was stirred in concentrated sulphuric acid at 0 oC, the carboxamide derivative 8 was isolated.
The reaction of starting compound 3 with formamide at 100 oC afforded the aminopyrimidine derivative 9. On the other hand, the reaction of starting compound 3 with benzoyl chloride in boiling toluene afforded the phenyloxazinone derivative 10 while the reaction of starting pyranopyrazole 3 with ethyl chloroacetate gave the unexpected ethyl acetate pyranopyrazole derivative 11.
The reaction of pyranopyrazole 3 with chloroacetic acid gave the pyrrole carboxylic acid derivative 12 while when starting enaminonitile 3 reacted with diethyl malonate in dry methanol and sodium methoxide, the amino pyridine carboxylic acid derivative 13 was obtained. The reaction of starting compound 3 with urea and / or thiourea in refluxing toluene gave the amino hydroxy pyrimidine derivative 14a and / or amino pyrimidine thiol derivative 14b respectively [cf. scheme 2].
The reaction of starting enaminonitrile 3 with 4-chlorobenzaldehyde gave the corresponding Schiff base derivative 15.
The reaction of pyranopyrazole 3 with refluxing trimethyl orthoformate and triethyl orthoacetate resulted in the corresponding formimidate derivative 16 and acetimidate derivative 17 respectively.
when oxazinone derivative 4 was allowed to react with formamide at 120 oC, the methyl pyrimidinone derivative 18 was obtained. On the other hand; compound 4 reacted with hydrazine hydrate in refluxing ethanol to give the acetamide derivative 19 [cf. scheme 3].
The oxoacetyl derivative 5 reacted directly with refluxing dry methanol and refluxing dry ethanol to afford the oxoacetate derivatives 20a and 20b respectively.
Also, when the oxoacetyl derivative 5 was allowed to react with anthranilic acid in dry pyridine, the reaction product was the oxoacetamidobenzoic acid derivative 21 which was cyclized in refluxing acetic anhydride to yield the benzooxazinyl oxazinone derivative 22 [cf. schemes 4].
The carboxamide derivative 8 was submitted to react with urea and / or thiourea in boiling toluene to give the pyrimidine diol 23a and pyrimidine thiol 23b derivatives respectively. On the other hand, reaction of 8 with formamide at 120 oC led to the pyrimidinone derivative 7, which has been identified as the same product resulted from reaction of the starting enaminonitrile compound 3 with formic acid [cf. scheme 5].
Chlorination of pyrimidinone derivative 7 with phosphorous oxychloride afforded the chloropyrimidine derivative 24. The later derivative 24 was reacted with hydrazine hydrate in refluxing ethanol to give the hydrazinopyrimidine derivative 25. Also; chloropyrimidine derivative 24 reacted with sodium ethoxide; the resulted product was the ethoxypyrimidine derivative 26.
When acetimidate derivative 17 was subjected to react with hydrazine hydrate in refluxing ethanol, it afforded the hydarzino methyl pyrimidine derivative 27 which reacted with carbon disulphide in dry pyridine to give the triazolopyrimidine thione derivative 28 while the reaction of 27 with refluxing acetic anhydride afforded the pyrimidine acetohydrazide derivative 29 [cf. scheme 6].
Tetrafused heterocyclic systems have been synthesized via hydarzinopyrimidine 27. Thus, reaction of 27 with benzoyl chloride in refluxing toluene afforded the phenyl triazolopyrimidine derivative 30, while the reaction of 27 with sodium nitrite in the presence of concentrated hydrochloride acid / glacial acetic acid mixture at 0 oC gave the tetrazolopyrimidine derivative 31 [cf. scheme 6].
Antibacterial and antifungal activities of some detected synthesized compounds were screened using the following methods and techniques:
1- Diffusion disk method.
2- Determination of the minimum inhibitory concentration (MIC) using tube dilution assay technique.
3- Determination of the minimum bactericidal concentration (MBC).
The experiments were performed using test bacterial organisms belonging to the Gram -positive bacteria (Staphylococcus aureus, Bacillus subtilis, Bacillus cereus and Kocuria rhizophila) and Gram negative bacteria (Salmonella typhimurium, Klebsiella pneumoniae and Pseudomonas aeruginosa) respectively as well as Candida albicans as yeast and Aspergillus niger as mould. The active compounds were compared with standard antibiotics Novobiocin and Chloramphenicol and the antifungal drug Nystatin.
The final results of biological activity can summarized as follows:
1- Compounds 3, 6, 7, 9, 12, 13, 14a and 16 are active compounds.
2- The above compounds have activity towards the tested gram positive bacteria, yeast and mould varied according to each compound.
3- The mixture of compounds 3+9, 9+16 and 6+16 were found to be active against tested gram negative bacteria.
4- Most of active compounds ranged from moderate to good bactericidal agents with more advantage to compound 9 which exceeds the compared antibiotics in some cases.