Isomerisation and ring closing metathesis reactions towards benzo-fused heterocyclic compounds

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dc.contributor.author Aderibigbe, Blessing Atim
dc.date.accessioned 2006-11-01T07:47:09Z
dc.date.available 2006-11-01T07:47:09Z
dc.date.issued 2006-11-01T07:47:09Z
dc.identifier.uri http://hdl.handle.net/10539/1556
dc.description Student Number : 0410864E - MSc dissertation - School of Chemistry - Faculty of Science en
dc.description.abstract The aim of the project described in this dissertation is to explore the application of ring closing metathesis (RCM) to the synthesis of 6-, 7-, 8- and 9-membered N,N-, N,O- and O,O-benzo-fused heterocyclic compounds which are interesting structural motifs in medicinal chemistry. In recent times, their structures have been widely used as molecular scaffolds. Some of these heterocycles have been identified as antitumour agents, antibiotics and anti-HIV agents. In our laboratories, a variety of 6-, 7- and 8-membered nitrogen- and oxygen- containing benzo-fused rings have been synthesized through ruthenium-mediated isomerisation and RCM in moderate to good yields. The first step in the present project was N-protection of suitable 2-aminophenols or o-phenylenediamines followed by allylation. Rutheniummediated isomerisation followed by RCM was then used for the synthesis of the 6- membered ring system tert-butyl 4H-1,4-benzoxazine-4-carboxylate 91 and the 7- membered ring system tert-butyl 1,5-benzoxazepine-5(4H)-carboxylate 103 while only RCM was used for the 8-membered ring systems, di(tert-butyl) 2,3,4,5-tetrahydro-1,6- benzodiazocine-1,6-carboxylate 130, di(tert-butyl) 2,5-dihydro-1,6-benzodiazocine-1,6- dicarboxylate 129, 1,6-dibenzoyl-1,2,5,6-tetrahydro-1,6-benzodiazocine 132, 7-methoxy- 2,5-dihydro-1,6-benzodioxocine 137 and the 9-membered ring system 1,6-bis[(4- methylphenyl)sulfonyl]-2,5,6,7-tetrahydro-1H-1,6-benzodiazonine 159. In the synthesis of the 7-membered ring systems, based on established methodology, we encountered problems with the RCM from suitable benzylamine or benzyl alcohol precursors. The reasons for this are not clear but we suspect this could be as a result of electronic and kinetic factors. Nevertheless, we were able to synthesize a 7-membered ring system, tert-butyl 1,5-benzoxazepine-5(4H)-carboxylate 103, from a readily available precursor using a different methodology. Approaches to the synthesis of the 8-membered ring systems, di(tert-butyl) 2,3,4,5- tetrahydro-1,6-benzodiazocine-1,6-carboxylate 130, di(tert-butyl) 2,5-dihydro-1,6- benzodiazocine-1,6-dicarboxylate 129, 1,6-dibenzoyl-1,2,5,6-tetrahydro-1,6- benzodiazocine 132 and 7-methoxy-2,5-dihydro-1,6-benzodioxocine 137, as described in this dissertation, made extensive use of RCM in moderate to good yields, but the deprotection of the Boc group after hydrogenation proved to be a problem. The synthesis of the 9-membered nitrogen containing benzo-fused compounds, 1,6- bis[(4-methylphenyl)sulfonyl]-2,5,6,7-tetrahydro-1H-1,6-benzodiazonine 159 by RCM was successful but in the synthesis of the N,O-benzo-fused compound by RCM, we suspect that polymerization, which is a side reaction in RCM reactions that are slow, occurred. In the synthesis of the 9-membered O,O-benzo-fused compounds, we only isolated the starting material. The final approach in this dissertation involved the use of ruthenium-mediated isomerisation to afford internal isomerisation of the double bond within the heterocyclic rings of the 8-membered and 9-membered benzo-fused compounds previously prepared in our laboratory. This gave a mixture of regioisomers of 10-methoxy-2,3-dihydro-1,6- benzodioxocine 163 and 7-methoxy-2,3-dihydro-1,6-benzodiazocine 164, 1,6-bis[(4- Methylphenyl)sulfonyl]-1,2,3,6-tetrahydro-1,6-benzodiazocine 166, a regioisomeric mixture of 6-[(4-methylphenyl)sulfonyl]-3,6-dihydro-2H-1,6,-benzoxazocine 161 and 6-[(4-methylphenyl)sulfonyl]-5,6-dihydro-4H-1,6,-benzoxazocine 162, and the 9- membered benzo-fused ring system, 1,6-bis[(4-methylphenyl)sulfonyl]-2,3,6,7- tetrahydro-1H-1,6-benzodiazonine 170. The yields were good and the solid state structures of these isomerised compounds were examined by X-ray crystallography. Xray diffraction was also performed on the solid state 8- and 9-membered benzo-fused ring systems. We also compared the crystal structures of the 8- and 9-membered benzo-fused compounds with their isomerised compounds. en
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dc.language.iso en en
dc.subject ring closing metathesis en
dc.subject heterocyclic compounds en
dc.subject isomerisation en
dc.subject RCM en
dc.subject 7-membered ring system en
dc.subject 8-membered ring system en
dc.title Isomerisation and ring closing metathesis reactions towards benzo-fused heterocyclic compounds en
dc.type Thesis en


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