Investigations into the use of Ring Closing Metathesis to form 5-, 6-, 7- and 8-membered benzo-fused heterocylces
Date
2006-11-01T12:37:49Z
Authors
Panayides, Jenny-Lee
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Abstract
The first part of the dissertation involves the use of ring closing metathesis (RCM) and
ruthenium mediated isomerisation-RCM tandem reactions to form a wide range of nitrogencontaining
benzo-fused heterocycles. Those synthesized include the 6-membered
isoquinolines, the 7-membered benzazepines and the 8-membered benzazocines. In order to
put these compounds into perspective, a review of selected naturally occurring nitrogencontaining
benzo-fused heterocycles is included along with some of their synthetic
approaches. Of major significance is our utilization of the Wits methodology allowing one to
access the 6-, 7- and 8-membered ring systems from a common synthetic intermediate. The
1,2,3,6-tetrahydro-2-benzazocines were all obtained after RCM in excellent yields (82-99%).
We were also able to show that some ofthe protecting groups used were easily removed and
that the ring could be hydrogenated after RCM to yield the 1,2,3,4,5,6-hexahydro-2-
benzazocines. The isoquinolines were synthesized in 78% and 27% yield for the Ac- and Tsprotected
compounds respectively, with no product isolated for the Boc- or SO2Bn-protected
compounds. These poor results, caused a change to our strategy and we then used a
“combinatorial-type” approach for the synthesis of the 2,5-dihydro-1H-2-benzazepines and
the 2,3-dihydro-1H-2-benzazepines with yield of 9, 47, 58 and 82% and 8, 26, 39 and 82%
obtained respectively for the RCM reaction Futhermore, we attempted the synthesis of the
substituted 4-phenyl isoquinolines and 5-phenyl benzazepines, but we found that the systems
would not undergo RCM even at high temperatures and with large amounts of Grubbs II
metathesis catalyst.
A short review is given in the second part of the dissertation concerning the naturally
occurring and pharmaceutically useful indenols, indenones and indanones. It further
highlights how our methodology was extended to include the synthesis of 4-isopropoxy-5-
methoxy-1H-inden-1-ol (X), 4-isopropoxy-5-methoxy-1H-inden-1-one (X) and 4-isopropoxy-
5-methoxy-1H-indanone (X) through the use of ruthenium-mediated isomerisation and RCM
from a similar common intermediate. We have shown the synthesis of 3-substituted indenols,
indenones and indanones using the same synthetic procedure, but by changing the reaction
temperature during RCM. This dissertation also answers many of the questions posed during
the post-doctoral work of Coyanis. Namely, we were able to support our proposed mechanism
that the conversion of the unsubstituted indenol to the indenone was occurring via a dehydrogenative-oxidation, through the use of 1H NMR studies that were coupled with an
ICP-MS analysis. To the best of our knowledge, this is the first reported use of the Grubbs II
catalyst (or its degradation products) in a tandem RCM-oxidation procedure by our group
recently.
Description
Student Number : 0002306V -
MSc dissertation -
School of Chemistry -
Faculty of Science
Keywords
ring closing metathesis, benzo-fused heterocycles, grubbs II catalyst, benzazocines, benzazephines, dihydroisoquinolines