Synthesis and Characterization of Novel Heterocycles: pyrazoles, dihydropyrimidinones, iminothiazolidinones, quinolinyloxy oxa/thiadiazolamines and triazolones /thiones and study of palladium(0)-catalyzed cross- coupling reactions

Abstract

This thesis describes the synthesis of various classes of heterocyclic compounds like, pyrazoles, dihydropyrimidinones, iminothiazolidinones, quinolinyloxy oxa/thiadiazol amines and triazolones/thiones and in addition study of palladium(0)-catalyzed cross- coupling reactions. Michael addition of some substituted anilines to methyl acrylate in acidic medium afforded the methyl 3-(substituted anilino)propionates (96-104), which on treatment with hydrazine hydrate in methanol were converted into corresponding 3-(substituted anilino) propionohydrazides (105-113) in good yields. Microwave irradiation of the latter with pentane-2,4-dione afforded 1-(3,5-dimethyl-1H-pyrazol-1-yl)-3-(substituted anilino) propan-1-ones (114-122) under solventless conditions. A series of new 5-substituted thiobarbituric acid derivatives 5-acetyl-3-aryl-2-thioxo- dihydropyrimidine-4,6(1H,5H)-diones (133-140) were synthesized by cyclocondensation of 1-aroyl-3-arylthioureas with malonic acid in the presence of acetic anhydride. These compounds exist in equilibrium with their enolic tautomeric form 5-(1-hydroxy ethylidene)-3-aryl-2-thioxo-dihydropyrimidine-4,6-(1H,5H)-diones. Plausible mechanism for the formation of products was proposed. Compounds (133-140) were evaluated for their preliminary antibacterial activity against a representative panel of Gram positive and Gram negative bacteria and were found to exhibit promising activity towards the tested microorganisms using levofloxacin as the reference drug. Of these compounds, the derivative (134) having methoxy group at ortho position of phenyl ring showed the highest effect on pathogenic bacteria and was identified as the lead molecule for further structural modifications. An efficient, synthesis of some 1-aroyl-3-aryl thioureas (123-132) was carried out. Substituted aroyl chlorides were treated with an equimolar quantity of potassium thiocyanate in acetone to afford the corresponding isothiocyantes which were not separated followed by reaction with an equimolar amount of substituted anilines to furnish the 1-aroyl-3-arylthiourea derivatives (123-132) which were assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and were found to exhibit moderate to potent activity towards the tested microorganisms, compared to the standard drugs Tetracycline, Penicillin and Metronidazole.An efficient, regioselective synthesis of some 2-aroylimino-3-aryl-thiazolidin-4-ones (141-150) involving base-catalyzed cyclization of 1-aroyl-3-aryl thioureas with chloroacetyl chloride in dioxane is reported. Compounds (141-150) were assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and were found to exhibit promising activity towards the tested microorganisms, comparable to and in some cases better than those of the standard drugs. The cyclic condensation of 1-aroyl-3-aryl thioureas with dimethyl acetylene dicarboxylate (DMAD) in methanolic solution at room temperature resulted in the formation of methyl [4-oxo-2-(substituted benzoylimino)-3-(substituted phenyl) thiazolidin-5-ylidene] acetates (151-164) in good to excellent yield. The synthesis of bis(thioureas) was carried out by treatment of aroyl/alkyl chloride with potassium thiocyanate and as a result corresponding isothiocyanates were obtained using acetone as solvent. These isothiocyanates were treated with 1,2-phenylene diamine and 1,2-bis(thioureas) (165-172) were obtained in good yield. Similarly, these isothiocyanates were treated with 1,4-phenylene diamine and resulted in 1,4-bis(thioureas) (173-180) synthesis. These bis-(thioureas) were also treated with dimethyl acetylene dicarboxylate (DMAD) and corresponding 1,2-bis(iminothiazolidinone) acetates (181-188) and 1,4- bis(iminothiazolidinone) acetates (189-196) were synthesized in good yield. A series of quinolinyloxy oxa/thiasemicarbazide derivatives (200-207) were synthesized. Intramolecular cyclization of these quinolinyloxy oxa/thiasemicarbazide derivatives in the acidic medium of poly phosphoric acid (PPA) resulted in synthesis of quinolinyloxy 1,3,4-oxa/thiadiazolamine derivatives (208-215) while in basic medium of sodium hydroxide intramolecular cyclization of these quinolinyloxy oxa/thiasemicarbazide derivatives resulted in synthesis of quinolinyloxy 1,2,4- triazolones/thiones derivatives (216-223). A series of 1,2-difluoro-3,4,5,6-tetra substituted phenylbenzene derivatives (226-228) was reported through Suzuki-Miyaura coupling-reaction of 1,2-difluoro-3,4,5,6- tetraiodobenzene with various boronic acid derivatives using tetrakis(triphenyl phosphine) palladium(0) as catalyst. The substrate 1,2-difluoro-3,4,5,6-tetraiodobenzene (225) was also synthesized by treatment of 1,2-difluoro-benzene with molecular iodine in the presence of K2S2O8, trifluoro acetic acid and sulphuric acid.