الفهرس 
Acknowledgment
Synthesis and reactions of thienopyrazole compoundsOnly 14 pages are availabe for public view
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Abstract
5-Chloro-3-methyl-1-phenyl-1H-pyrazole-3-carboxaldhyde (8) was prepared by a Vilsmeier–Haack reaction for compound 43. The latter compound was subjected to react with hydroxyl amine hydrochloride followed by dehydration to give the chloro-nitrile 33. (Scheme i)
Aminocarbonitrile IIa and aminocarboxamide IIb was synthesized by an innovative method according to literature procedure using Thorpe-Zeigler cyclization for pyrazole sulfanyl acetonitrile and acetamide derivatives Ia,b. (Scheme ii)
Diazotization of the amino carbonitrile compound IIa with sodium nitrite solution (10%) in a mixture of acetic acid and conc. HCl at 0-5oC afforded chlorotriazine III. The chloride ion in compound III underwent nucleophilic substitution reactions with various primary and secondary amines under neat conditions followed by refluxing in ethanol to give the N-substituted pyrazolothienotriazine derivatives IV-VI. (Scheme iii)
Moreover, hydrazinolysis of the chlorotriazine compound III with hydrazine under neat conditions followed by reflux in ethanol yielded the hydrazinotriazine compound VII. The hydrazino compound VII was used as a versatile precursor for synthesis of other heterocyclic rings attached or fused to pyrazolothienotriazine moiety VIII-XI. Consequently, the reaction of the hydrazino compound VII with triethyl orthoformate in presence of a catalytic amount of acetic acid afforded the triazolothienotriazine compound VIII. Moreover, nucleophilic addition of NH2 group of hydrazino compound to carbon disulfide yielded the corresponding triazolothione derivative IX. On the other hand, condensation of the hydrazinotriazine VII with acetyl acetone and benzaldehyde gave the corresponding pyrazolyl and Schiff”s base X and XI respectively. (Scheme iv)
Aminocarbonitrile compound IIa was chloroacetylated using chloroacetyl chloride in dioxane on a steam bath followed by neutralization to afford the chloroacetamide dervative XII, which underwent nucleophilic substitution reactions with various amines by fusion then reflux in ethanol afforded N-alkyl(aryl)aminomethyl-pyrimidine dervatives XIIIa-c. (Scheme v)
Aniline derivative XIIIa undergoes Mannich reaction upon treatment with formaldehyde to give compound XIV, also it can react with triethylorthoformate and POCl3 to give compounds XV, XVI respectively. (Scheme vi)
Subsequentely, condensation of o-aminocarbonitrile IIa with triethyl orthoformate in presence of drops of acetic acid produced the corresponding the ethoxymethyleneamino XVII. Which upon stirring with hydrazine hydrate, the aminoiminopyrimidine XVIII was obtained. Condensation of the amino-imino XVIII with triethyl orthoformate and/or benzaldehyde in presence of piperidine produced the corresponding triazolopyrimidine XIX and phenyl dihydro-triazolopyrimidine XX respectively. Amino-imino XVIII reacts with different 1,3-dicarbonyl compounds to give a novel tetracyclic compounds. Thus, condensation with diethyl malonate and acetyl acetone afforded the ethyl triazolopyrimidinyl acetate and the methyl triazolopyrimidine XXI, XXII respectively. (Scheme vii)
In a similar manner, condensation of the amino-imino XVIII with ethyl acetoacetate and ethyl benzoyl acetate afforded the corresponding triazepinones XXIII, XXIV. When the amino-imino XVIII was subjected to react with phenacyl bromide in refluxing ethanol and triethyl amine yielded the 8-phenyl triazine XXV not XXVI. Subsequently, on fusion of amino-imino XVIII with diethyl oxalate under neat conditions produced the corresponding triazindione XXVII. Also, heating of XVIII with carbon disulfide in pyridine on a steam bath, the corresponding triazolothione XXVIII was obtained. (Scheme viii)
The reaction of compound IIb with diethyl malonate in acetic acid afforded the ethyl ester compound XXIX. When o-aminocarboxamide compound IIb reacted with phthalic anhydride in boiling acetic acid, 3-phthalimido derivative XXX was produced, while in boiling DMF, the pyrimidoisoindoledione XXXI was formed. (Scheme ix)
The ethyl ester derivative XXIX reacted with hydrazine hydrate and gave the corresponding carbohydrazide derivative XXXII, that was used as a versatile starting material for the synthesis of other heterocyclic compounds. Thus, reaction of carbohydrazide XXXII with triethyl orthoformate in presence of acetic acid yielded triazepinedione compound XXXIII. Also, condensation with benzaldehyde gave the corresponding Schiff’s base XXXIV.
(scheme x)
Condensation of carbohydrazide derivative XXXII with different bifunctionally compounds namely: diethylmalonate, acetyl acetone, ethyl acetoacetate and ethyl cyanoacetate under neat conditions yielded the non-isolated hydrazones as intermediate which underwent ring closure under the reaction conditions (in situ) to give compounds XXXV-XXXVIII. (Scheme xi)
When the aminocarboxamide compound IIb, was subjected to react with triethyl orthoformate in the presence of catalytic amount of acetic acid, thienopyrimidinone XXXIX was obtained, which was converted to the corresponding chloropyrimidine compound XL, by reaction with phosphorus oxychloride. The chlorine atom in the chloro compound XL underwent nucleophilic substitution reactions with hydrazine hydrate by reflux in ethanol to afford the corresponding hydrazino compound XLI. Hydrazino compound XLI was used as a key intermediate for synthesis of new fused heterocyclic systems condensed with pyrazolothienopyrimidine moiety. Thus, when react with triethyl orthoformate in the presence of catalytic amount of acetic acid afforded triazolopyrimidine XLII. While the reaction with sodium azide in DMF produced the tetrazoloderivative XLIII. (Scheme xii)
Condensation of the hydrazino derivative XLI with different bifunctionally compounds namely: ethyl benzoylacetate, diethylmalonate, acetyl acetone and ethyl cyanoacetate under neat conditions followed by addition of ethanol and reflux, yielded the non-isolated hydrazones as intermediate which underwent ring closure under the reaction conditions (insitu) to give compounds XLIV-XLVII. (Scheme xiii)
Condensation of the hydrazino compound XLI with benzaldehyde in refluxing ethanol produced Schiff’s base XLVIII. The hydrazino compound XLI reacted with carbon disulphide in pyridine to afford triazolopyrimidinethione XLIX. Also, compound XLI was reacted with ethoxymethylene ethylcyanoacetate in ethanol to give compound L. Finally, condensation of hydrazino compound with ethyl acetoacetate afforded compound LI. (Scheme xiv)
Heating of the amino carboxamide compound IIb with chloro acetyl chloride in a water bath under neat conditions followed by neutralization afforded the chloromethyl pyrimidothienopyrazole LII, which was converted into the corresponding mercaptomethyl derivative LIII upon refluxing with thiourea followed by treatment with sodium hydroxide then acidification with HCl. Mercaptomethylpyrazolothienopyrimidine LIII was alkylated using halogenated compounds namely: ethyl chloroacetate, phenacyl bromide and chloro acetone to give S-alkylated mercaptomethyl pyrazolothienopyrimidine drivatives LIV-LVI respectively. While in the case of 2-chloro-4,6-dimethylnicotinonitrile it gave thienopyridyl derivative LVII. (Scheme xv)