The Synthesis of Pyrido-fused 8-Methoxy Carbazoles by Using a Light-Assisted, Base Mediated Cyclization Reaction
| dc.contributor.author | Magagula, Bongi Florence | |
| dc.contributor.supervisor | Ntsimango, Songeziwe | |
| dc.contributor.supervisor | De Koning, Charles B. | |
| dc.date.accessioned | 2024-10-26T09:38:27Z | |
| dc.date.available | 2024-10-26T09:38:27Z | |
| dc.date.issued | 2023 | |
| dc.description | A dissertation submitted in fulfilment of the requirements for the degree of Master of Science, to the Faculty of Science, School of Chemistry, University of the Witwatersrand, Johannesburg, 2023. | |
| dc.description.abstract | Nitrogen-containing compounds such as indoles and carbazoles are significant classes of the N-heterocycles that show great promise as anti-cancer compounds. Indoles such as 2,3-diarylindole, 3-pyranyl indole and carbazoles such as 9-methoxyellipticine are compounds which possess anticancer or antitumor properties. Due to the favourable biological activities of N-heterocyclic compounds, medicinal and synthetic chemists have developed numerous methodologies for their synthesis. In this research project, the broad aim was to synthesize pyrido-fused carbazoles from 5-methoxyindole using methodologies that have been previously used in our laboratories and by other chemists while changing the position of the nitrogen atom on the pyrido-fused carbazoles. The first step in the synthesis of these carbazoles was the treatment of 5-methoxyindole with di-tert-butyl dicarbonate in the presence of 4-dimethylaminopyridine (DMAP) which gave the desired protected indole, tert-butyl 5-methoxy-1H-indole-1-carboxylate in excellent yields (90-99%). Exposure of the tert-butyl 5-methoxy-1H-indole-1-carboxylate to lithium 2,2,6,6-tetramethypiperidide followed by quenching with triisopropyl borate and hydrochloric acid gave (1-(tert-butoxycarbonyl)-5-ethoxy-1H-indol-2-yl)boronic acid. Using this and various halogen substituted pyridines, for example 3-bromo-4-methylpyridine in the Suzuki-Miyaura coupling reaction gave tert-butyl 5-ethoxy-2-(4methylpyridin-3-yl)-1H-indole-1-carboxylate (83% yield). This was further reacted with paraformaldehyde and iron (III) chloride or phosphorus oxychloride and DMF. After the removal of tert-butoxycarbonyl protecting group utilizing various methods this produced 5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde (48% yield). 5-Methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde possesses all the carbons of the final compounds and is suitably functionalized to partake in the key photo-induced and ase-mediated cyclization reaction. Previous studies pointed to the necessity of an alkyl protecting group on the indole-N atom. As a result, the indole nitrogen atom was then protected again with a methyl or a benzyl group; where the N-benzyl could be removed at a later stage. For example, reaction of 5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde dissolved in THF, potassium hexamethyldisilazide and benzyl bromide furnished 1-benzyl-5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde (83% yield). The key step in this synthesis was the light-assisted, base-mediated cyclization reaction which has been reported by de Koning and co-workers, where a solution of 1-benzyl-5-methoxy-2-(4-methylpyridin-3-yl)-1H-indole-3-carbaldehyde dissolved in dry DMF and potassium tert-butoxide was heated and irradiated with medium mercury lamp yielding the desired pyrido fused carbazole, 11-benzyl-8-methoxy-11H-pyrido[3,4-a]carbazole in a good yield of 70%. Following the outlined synthetic procedure depicted above, we were able to synthesize 5 analogues of 11-benzyl-8-methoxy-1H-pyrido[3,4-a]carbazole. | |
| dc.description.sponsorship | National Research Foundation (NRF-Thuthuka). | |
| dc.description.submitter | MM2024 | |
| dc.faculty | Faculty of Science | |
| dc.identifier | 0000-0003-0488-2277 | |
| dc.identifier.citation | Magagula, Bongi Florence. (2023). The Synthesis of Pyrido-fused 8-Methoxy Carbazoles by Using a Light-Assisted, Base Mediated Cyclization Reaction. [Master's dissertation, University of the Witwatersrand, Johannesburg]. https://hdl.handle.net/10539/41974 | |
| dc.identifier.uri | https://hdl.handle.net/10539/41974 | |
| dc.language.iso | en | |
| dc.publisher | University of the Witwatersrand, Johannesburg | |
| dc.rights | ©2023 University of the Witwatersrand, Johannesburg. All rights reserved. The copyright in this work vests in the University of the Witwatersrand, Johannesburg. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of University of the Witwatersrand, Johannesburg. | |
| dc.rights.holder | University of the Witwatersrand, Johannesburg | |
| dc.school | School of Chemistry | |
| dc.subject | N-heterocyles | |
| dc.subject | Carbazoles | |
| dc.subject | Anti-cancer | |
| dc.subject | Cyclization reaction | |
| dc.subject | UCTD | |
| dc.subject.other | SDG-3: Good health and well-being | |
| dc.title | The Synthesis of Pyrido-fused 8-Methoxy Carbazoles by Using a Light-Assisted, Base Mediated Cyclization Reaction | |
| dc.type | Dissertation |