الفهرس 
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Abstract
This work reported the synthesis of some novel thienopyrimidines and annulated heterocycles for evaluation of their antimicrobial properties.
Condensation of thieno[2,3-d]1,3-oxazine 1 with 2-cyanoacetohydrazide 2 in dioxane resulted in the formation of thieno[2,3-d]pyrimidine derivative 3. (Scheme 1)
The functionalities in 2-methyl-3-cyanoacetamido-5,6,7,8-tetrahydro-4H-benzothieno[2,3-d]pyrimidin-4-one 3 made it valuable key precursors for the formation of fused heterocyclic compounds. The reactivity of compound 3 towards various chemical reagents was investigated with the aim to producing thienopyrimidine derivatives with potential biological activities. Thus, the reaction of 3 with salicylaldehyde gave the coumarin derivative 5. On the other hand, the reaction of 3 with either 1,3-diphenyl pyrazole-4-carboxaldehyde or p-anisaldehyde yielded the arylidene derivatives 6 and 7, respectively. (Scheme 1)
Treatment of compound 6 with hydrazine hydrate in boiling dioxane afforded the unexpected product which was identified as 1E, 2E-1,2-bis [(1,3-diphenyl-1H-pyrazol-4-yl) methylene] hydrazine 8. The azine structure 8 was confirmed by comparison (TLC, IR, m.p) with authentic sample prepared from the condensation of 1,3-diphenyl pyrazol-4-carboxaldehyde with hydrazine hydrate in refluxing ethanol. (Scheme 1)
The reactivity of 3 towards active methylene reagents was investigated. Thus, the reaction of compound 3 with malononitrile in presence of a catalytic amount of piperidine in boiling dioxane afforded the 2-pyridone derivative 9. The same reaction was repeated with ethyl acetoacetate under similar condition yielded the 2-pyridone derivative 11. (Scheme 2)
Also, treatment of compound 3 with 4-methoxy benzylidene malononitrile in refluxing dioxane in the presence of catalytic amount of piperidine afforded the 2-pyridone derivative 12 with elimination of the heteryl group. (Scheme 2)
Our study moved to the reactivity of active methylene of the key precursor 3 towards phenyl isothiocyanate in basic dimethylformamide. Thus, subjecting 3 to react with phenyl isothiocyanate followed by acidification of the potassium sulphide salt yielded (Z)-2-methyl-3-(2-cyano-3-mercapto-3-(phenylamino)acrylamido)-5,6,7,8-tetrahydro-4H-benzothieno[2,3-d]pyrimidin-4-one 13. Moreover, the reaction of 3 with phenyl isothiocyanate in ethanolic potassium hydroxide, dimethylformamide and chloroacetyl chloride was added yielded the thiazolidinone derivative 14. (Scheme 2)
2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile 15 has attracted a great deal of interest over the years. The most efficient protocols for carrying out the synthesis of such thiophene derivatives are the Gewald method. The reaction of 15 with triethylorthoformate in the presence of freshly distilled acetic anhydride yielded (E)-ethyl N-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl formimidate 16 which when subjected to react with 2-cyanoacetohydrazide in refluxing dioxane afforded 2-cyanomethyl-8,9,10,11-tetrahydrobenzothieno[3,2-e][1,2,4] triazolo[1,5-c]pyrimidine 17. (Scheme 3)
The structure of compound 17 got a further chemical support through its reaction with aromatic and heterocyclic aldehydes. Thus, the reaction of 17 with 1,3-diphenyl pyrazol-4-carboxaldehyde and/or 4-chlorobenzaldehyde afforded the corresponding condensation products 18a,b. On the other hand, the reaction of 17 with salicylaldehyde gave the coumarin derivative 19. (Scheme 3)
Stirring compound 17 with one carbon donor such as carbon disulphide in ethanolic potassium hydroxide in dimethylformamide afforded the dipotassium sulphide salt 20 which in situ reacted with dimethyl sulphate and/or 1,3-dibromopropane to give compound 21 or 22, respectively. (Scheme 3)
Recently, hydrazide-hydrazones have gained great importance due to their diverse biological properties. With the aim of obtaining novel hydrazide-hydrazones with a wide spectrum of pharmaceutical applications, we report here the synthesis of a series of hydrazide-hydrazones together with their use in heterocyclic transformation.
2-Cyanoacetohydrazide reacts with 2-acetyl naphthalene to give the hydrazide-hydrazone derivative 23. (Scheme 4)
Cyclocondensation reaction of 23 with salicylaldehyde in dioxane containing triethylamine or ammonium acetate furnished smoothly the 2-imino chromene derivative 24. (Scheme 4)
When compound 23 was stirred with one carbon donor such as carbon disulphide in potassium hydroxide and dimethylformamide at room temperature for 30 minutes gave the potassium dithiocarbazate salt 25 which separated in pure crystalline form. The reaction of this salt with dihalide and α-halocarbonyl compounds was investigated. Thus, treatment of 25 with 1,2-dibromoethane and/or chloroacetyl chloride in dimethylformamide afforded the 1,3-dithiolane derivative 26 or the dithiolone derivative 27, respectively. (Scheme 4)
Similarly, the reaction of potassium dithiocarbazate 25 with ω-bromo-4-nitroacetophenone under the same condition yielded the thiophene derivative 28. (Scheme 5)
The reaction of the potassium salt 25 with ethyl chloroacetate in refluxing dioxane gave the uncyclized S-alkylation product (E)-ethyl 2-(2-cyano-3-(2-(1-(naphthal-en-2-yl)ethylidene)hydrazinyl)-3-oxopropanethioylthio) acetate 29. (Scheme 5)
Hydrazinolysis of 23 using hydrazine hydrate (80%) in refluxing dioxane yielded a crystalline product which by spectral data identified as the azine of 2-acetyl naphthalene 31 as a clear cut product in good yield without affording the expected pyrazole structure of type 32. (Scheme 5)
The reaction of 23 with 4-methoxybenzylidene malononitrile in refluxing dioxane in the presence of a catalytic amount of piperidine afforded the unexpected structure 34. The structure 34 was confirmed by authentic sample prepared from the reaction of 2-cyanoacetohydrazide with 4-methoxybenzylidene malononitrile in boiling dioxane in presence of piperidine. (Scheme 5)