Novel methods for the synthesis of functionalised indoles.
The work in this thesis describes investigations into the development of a tandem
radicallDiels-Alder reaction strategy for the construction of indole alkaloids.
The synthesis of a key precursor, 2-[(4-methylphenyl)sulfonyl]indole, was investigated
and involved two main· strategies: functionalisation of the indole ring using lithiation
procedures and assembling the indole as a key step (chapter 2). A method based on the
former strategy was deemed to be the most practical and delivered the desired product in
moderate yields (35 - 45%).
The viability of the first step of the proposed tandem radicallDiels-Alder strategy was
investigated by examining the intramolecular addition of vinyl and aryl radicals to a
sulfone substituted indole (chapter 3). These studies showed that the addition of sp2
centred radicals to substituted indoles was feasible (20 - 40%). A study using an
acetylenic precursor also provided useful information about the relative rates of desulfonylation
and radical addition to acetyleneS; de-sulfonylation is a competing process.
An alternative tandem palladiumlDiels-Alder reaction was briefly examined, but was
thwarted by capricious palladium catalysed cross coupling reactions.
Further studies were carried out to extend the scope of the novel ipso substitution reaction
(chapter 4). It was found that alkyl radical cyclisations proceed efficiently to give a new
~ethod for the synthesis of fused[1,2-a]indoles (30 - 84%). The feasibility of a related
ipso substitution using phenylthio and phenylsulfinyl substituted indoles was also
examined. It was found that these reactions are also successful, but proceed in reduced
yields compared with the sulfones (24 - 51 %). These results could be attributed to the
more favoured reaction of the electron rich carbon centred radical with the more
electrophilic 1t bond. The thesis is concluded by a brief discussion of the mechanism of
these cyclisations with the available experimental evidence supporting an addition!