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Title: Natural Isocoumarin Analogues, Functionalized Pyrazoles, N-Substituted Dihydropyridinones, Iminothiazolidinones, Iminothiazolines and Related Heterocycles: Synthesis and Characterization
Authors: Rafique, Hummera
Keywords: Natural Sciences
Chemistry & allied sciences
Physical chemistry
Techniques, equipment & materials
Analytical chemistry
Inorganic chemistry
Organic chemistry
Issue Date: 2012
Publisher: Quaid-i-Azam University Islamabad, Pakistan
Abstract: The work presented in this thesis consists of synthesis and characterization of natural isocoumarin analogues and novel heterocyclic compounds. For convenience, the work has been divided into two parts, part one deals with the synthesis of various structural analogues of well known bioactive natural 3,4-dihydroisocoumarins viz. Annulatomarin, Montroumarin, Scorzocreticin, Typharin, and Hiburipyranone, along with the total synthesis of natural products 8-hydroxy-7-hydoxymethyl-6-methoxy-3,4- dihydroisochromen-1-one (Stellatin) and (±) 7-butyl-6,8-dihydroxy-3-pentyl-1H-3,4- dihydroisochromen-1-one have been carried out, starting from 3,5-dimethoxy-4-methyl homophthalic acid precursor. The synthesis of 3,5-dimethoxy-4-methylhomophthalic acid was carried out starting from commercially available p-toluic acid. It was then condensed with various aryl/alkyl acid chlorides to afford the corresponding 6,8-dimethoxy-7-methyl-3- aryl/alkylisochromen-1-ones (5a-j). These isochromen-1-ones were hydrolysed to keto- acids (6a-j) and then reduced to corresponding hydroxyacids, followed by cyclodehydration with acetic anhydride into corresponding 6,8-dimethoxy-7-methyl-3- aryl/alkyl-3,4-dihydroisochromen-1-ones (7a-j). Finally, demethylation of 3,4- dihydroisochromen-1-ones was carried out to afford 6,8-dihydroxy-7-methyl-3- aryl/alkyl-3,4-dihydroisochromen-1-ones (8a-j). Biological screening of all the synthesized compounds were carried out against ten bacterial strains, six were gram negative viz. Pseudomonas aeroginosa, Escherichia coli, Salmonella typhi, Shigella specie, Salmonella para typhi, Proteus mirabilis and four were gram positive viz Bacillus subtilus, Micrococcus aureus, Staphylococcus aureus and Streptococcus specie, bacterial strains, it was concluded that isochromen-1-ones (5a- j) and 3,4-dihydroisochromen-1-ones (7a-j) are more active against gram positive bacteria then gram negative. However, the 6,8-dihydroxy-3,4-dihydroisochromen-1-one derivatives (8a-j) are more active against gram negative then gram positive bacteria. Part two describes the synthesis of novel heterocyclic systems: functionalized pyrazoles, N-substituted dihydropyridinones, iminothiazolidinones and iminothiazolines. N-Methyl-3,4,5-tribromopyrazole was prepared by treating commercially available 3,4,5-tribromopyrazole with triethyl amine and methyl iodide indibromoethane. A variety of N-protected 3,4,5-triaryl-pyrazoles, 3,5-diaryl-4- bromopyrazoles, and 5-aryl-3,4-dibromopyrazoles were efficiently prepared by Suzuki Miyaura reactions. All the reactions were proceed with excellent site-selectivity with good yields. N-Substituted aza-bicyclo[3.1.0]hexan-1-ols were prepared via Kulinkovich reaction by treating titanium isopropoxide with variously substituted amino ester derivatives in anhy. Et 2 O/THF (1:1), followed by the addition of Grignard’s reagent (isopropylmagnesium bromide in ether). These bicyclo compounds were then stirred with the suspension of anhy. FeCl 3 in diethyl ether to afford dihydropyridinones in good yields. N-Substituted dihydropyridinones were subjected to [2+2] photochemically induced cycloaddition reactions, in order to explore the mechanism of unexpected rearranged product of N-benzyl dihydropyridinone while going through [2+2] photo cycloaddition reaction. 1-[Benzo[d]thiazol-2-yl)-3-(substituted] thioureas and ethyl 4-(3-benzoylthiour- eido) benzoates are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic compounds. These thioureas were converted into novel five membered heterocycles like methyl 2-[2-benzamido-3-(2-benzothiazolyl)-4-oxothia- zolidin-5-ylidene] acetates and ethyl 4-[2-benzamido-5-(2-methoxy-2-oxoethylidene)-4- oxothiazolidin-3-yl] benzoates in good yields, by the direct cyclization of these thioureas with dimethyl but-2-ynedioate (DMAD) in methanol. Ethyl 4-(3-benzoylthioureido) benzoates and 1-(benzo[d]thiazol-2-yl)-3- (substituted) thioureas serves as precursors for the synthesis of variety of biologically significant heterocyclic compounds like N-[3-(2-benzothiazolyl)-4-methylthiazol-2(3H)- ylidene] benzamides and N-[3-(benzo[d]thiazol-2-yl)-4-methylthiazol-2(3H)-ylidene] benzamides. These heterocycles were efficiently synthesized by the base-catalyzed cyclization of corresponding thioureas with 2-bromoacetone and triethylamine in moderate to good yields. Benzo[d]thiazol-2-amines, 1-(benzo[d]thiazol-2-yl)-3-(substituted) thioureas and ethyl 4-(3-benzoylthioureido) benzoates were examined in vitro for antibacterial activity against gram positive and gram negative bacteria and were found to exhibit good to potent activity as compared to the standard drugs. Benzo[d]thiazol-2-amines and 1- (benzo[d]thiazol-2-yl)-3-(substituted) thioureas were tested in vitro for their antifungalactivity against various fungal strains and were found to exhibit moderate activity as compared to the standard drug. The structures of all the synthesized compounds were confirmed by physical data, FTIR, 1 H NMR, 13 C NMR, mass spectrometry and elemental analysis.
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