Theses and dissertations (Applied Sciences)
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Item Microwave synthesis and molecular re-arrangement of a grisadienone and its derivatives(2011) Ngcobo, Thandekile Sithembile; Gengan, Robert Moonsamy; Shode, F. O.ortho-Deoxygrisan (38), a spirodienone was synthesised from bisphenol (42) using both conventional and microwave assisted methods. The bisphenol (42) was synthesised from phenol (52) by conventional and microwave assisted methods. Benzophenone (43) was synthesised from compound (49) which in turn was synthesised from compound (53) by chromic acid oxidation in acetic anhydride or acetic acid. Compound (53) was synthesised from bisphenol (42) by mono-acetylation method.Acid-catalysed rearrangement of ortho-deoxygrisan (38) in the absence of light was investigated. Chromatography of the reaction mixture afforded compound (D) as a major component. Attempts to synthesise ortho-grisan (50) from benzophenone (43) were unsuccessful. Microwave assisted selenium dioxide oxidation of compound (53) gave a yellow compound C. The spectra of this compound were very similar to the spectra of ortho-deoxygrisan (38). However, selenium dioxide was reacted with compound (53) in the absence of microwave to give a yellow solid B. The 1H NMR spectral data of this compound led to the proposed structure B for it.Item Synthesis of bisquinolines through conventional and unconventional energy sources(2011) Makhanya, Talent Raymond; Gengan, Robert MoonsamyMalaria, the most prevalent parasitic disease, is considered a neglected disease owing to insufficient research and development in synthesis and therapy worldwide. Therapy failures are frequent and are due to a variety of factors such as the intrinsic characteristics of the disease, conditions of transmission, and the difficult control of spreading through tropical areas. Primary factors are the complexity of the parasite life cycle and the development of drug resistance. Another critical factor is the increasing number of immune-compromised patients that suffer from malaria and human immunodeficiency virus (HIV) co-infections. Most of the drugs currently available to treat malaria are quinoline derivatives modelled on the quinine molecule, found in the bark of Cinchona trees. Over the last 50 years the use of quinine has declined owing to the development of synthetic 4-aminoquinolines such as chloroquine. However, the malaria parasite is rapidly becoming resistant to the drugs currently available. Recently bisquinoline compounds were found more potent than chloroquine against both chloroquine-sensitive and resistant strains of malaria; this improved efficacy and prompted an increased interest in the design of these anti-malarial drugs. Although several synthetic methods are available to synthesise bisquinolines, we report the synthesis of bisquinolines from simple, readily available and cost- effective starting compounds. The synthesis was accomplished in four reaction steps using the Claisen condensation, Vilsmeir-Haack reaction, formation of a Schiff base and thermal cyclization, sequentially. We used a conventional energy source and microwave irradiation for the synthesis, wherever possible, of 2, 4-dichloro-3, 4'-biquinoline and 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline. In the first step, 3-acyl-2, 4-dihydroxyquinoline is synthesised from an equimolar mixture of methyl-2-aminobenzoate and ethyl acetoacetate by microwave irradiation for 3 minutes; the yield is 90 % whereas by 6 hours refluxing the yield is 75 %. This is followed by the synthesis of 3-chloro-3-(2,4-dichloroquinolin-3yl) acrylaldehyde, by combining DMF and POCl3 at 00C to form the electrophile which reacts with 3-acyl-2,4-dihydroxyquinoline under microwave irradiation for 5 minutes; the yield is 65 % whereas by 6 hours refluxing the yield is 50 %. In the next step, several protocols to prepare a Schiff base 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene aniline are investigated with the best yield of 75% obtained by microwave irradiation for 5 minutes. Subsequently three aniline derivatives viz, 4-methoxyaniline, 4-chloroaniline and 4-methylaniline, are used as substrate to prepare 3-chloro-3-(2,4-dichloroquinolin-3-yl) allylidene-4-methoxyaniline, 3-chloro-3-(2 ,4-dichloroquinolin-3-yl) allylidene-4-methylaniline and 3-chloro-3-(2, 4-dichloroquinolin-3-yl) allylidene-4-chloro aniline at 68, 78 and 64 % yield, respectively. In the final step, 2, 4-dichloro-3, 4'-biquinoline is prepared; several methods were investigated, however, the best yield is 24 % which is obtained under alkaline conditions in the presence of K2CO3 and DMF by microwave irradiation for 10 minutes. The 2, 4-dichloro-7'-methoxy-3, 4'-biquinoline derivative is also prepared in 18 % yield under the same alkaline conditions. The outline of the total synthesis of bisquinoline is presented graphically below.Item Microwave as an energy source in the synthesis of 2-aryl-4-quinolone alkaloids and naphthyridines(2011) Ndaba, Hlengiwe Glenrose; Gengan, Robert MoonsamyOne of the greatest medical challenges facing mankind is the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) which has now become a major epidemic with more than 40 million people infected worldwide. Of equal concern is its implication in high mortality and the onset of a number of opportunist mycobacterial infections, principally tuberculosis. In spite of the discovery of some relatively effective antiretroviral (ARV) drugs such as Azido Thymidine (AZT), Nevirapine (NVP) and Efavirenz (EFV), its’ application as either a single or combinational form causes side effects by harming the bone marrow. Drug resistance is a key cause of failure for treatment of HIV infection. Hence greater interdisciplinary efforts, involving both natural and social sciences, are needed urgently to combat this HIV/AIDS pandemic. Heterocyclic nitrogen based compounds, obtained from either natural sources or synthesis are adequately documented to have increased biological activity against several diseases. Recently a study of drugs containing the naphthyridine scaffold has acquired increasing attention because of its potential against HIV/AIDS. Generally, naphthyridines demonstrate good potency in both the enzyme and cellular systems and this prompted our interest in the synthesis of naphthyridine derivatives from simple and readily available starting compounds. Furthermore we wanted to form an intermediate quinolone moiety since it has good biological potential. In this study we report the synthesis of three naphthyridine derivatives, i.e. 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2- methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine from easily available chemicals such as aniline, ortho-toludine, para-toluidine and ethyl benzoylacetate via a five step reaction scheme using either conventional reflux, microwave irradiation or both methodologies. It was found that microwave irradiation was several folds faster than conventional reflux methodology and the yield of the product was higher. The first step of the reaction scheme is a simple condensation reaction: three acrylate derivatives, viz. ethyl-3-aniline-3-phenyl acrylate, ethyl-3-phenyl-3-(ortho-tolylamino) acrylate and ethyl-3-phenyl-3-(para-tolylamino) acrylate were synthesized by refluxing ethyl benzoylacetate in an acidified ethanolic solution with aniline, ortho-toluidine and paratoluidine respectively for three hours; the yields were 95, 87.5 and 80 % respectively. Page v In the second step, thermal cyclisation was achieved for the synthesis of three quinoline derivatives, viz. 2-phenylquinoline-4(1H)-one, 8-methyl-2-phenylquinoline-4(1H)-one and 6- methyl-2-phenylquinoline-4(1H)-one from their respective acrylates under microwave irradiation for 5 minutes at 180 °C and 250 watts; the yields were 92, 84 and 80 % respectively. In the third step of the reaction, synthesis of 4-chloro-2-phenylquinoline, 4- chloro-8-methyl- 2-phenylquinoline and 4- chloro-6-methyl-2-phenylquinoline was achieved from a mixture of POCl3 and their respective quinolines via microwave irradiation for 3 minutes at 75 °C and 150 watts and via conventional reflux for 5 hours. It was found that under microwave irradiation, the reaction occurred nearly 100 fold faster but the % yield of the product was marginally higher. The fourth step of the reaction resulted in the formation of three schiff’s base, viz. 4-(Nphenyl)- 2-phenyl-4-aminoquinoline, 8-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline and 6-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline from their respective quinolines via microwave irradiation for 20 minutes at 180 °C and 180 watts and via conventional reflux for 2 hours. It was found that under microwave irradiation, the reaction occurred nearly 6 fold faster and the % yield of the product was over 10 % higher. The final step of the reaction was achieved by a Vilsmeir Haack reaction and in situ base catalyzed thermal cyclisation: 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6- phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine were synthesized from their respective schiffs base via microwave irradiation for 20 minutes at 75 °C at 120 watts and via conventional reflux for 21 hours. It was found that under microwave irradiation, the reaction occurred over 60 fold faster and the % yield of the product was over 20 % higher.The outline for the five step synthesis of the three naphthyridines is presented graphically below: Page vi Key: (a) R1= H; R2=H (b) R1 = H; R2 = CH3 (c) R1 = CH3; R2 =H Reaction Conditions: 1) conc.HCl, EtOH, 3hrs, 50 °C; 2) conc. HCl, hand stirring 10 min; 3) 180 °C, MWI, 250 watts, 5 min; 4) POCl₃, MWI, 75 °C, 150 watts, 2 min; 5) POCl₃, 100 oC, 5 hrs; 6) aniline, t-BuOH, MWI, 180 °C, 180 watts, 20 min; 7) aniline, t-BuOH, 80 °C, 3 hrs; 8) DMF, POCl₃, MWI, 75 °C,120 watts 20 minute; 9) DMF, POCl3, 100 oC, 21 hrs.