| Summary: | Student Number : 0410864E -
MSc dissertation -
School of Chemistry -
Faculty of Science === 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.
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