New heterocyclic systems derived from activated indoles

Abstract

This thesis explores the use of activated 3-substituted-4,6-dimethoxyindoles in the preparation of new indole-based heterocyclic systems. Novel pyrrolo[a]indole dimers were synthesized via acid catalysed condensation of 3-substituted-4,6-dimethoxyindoles with acetone and p-substituted acetophenones. General activation of the indole scaffold was found to improve the efficiency and versatility of the reaction when compared to the parent skatole, though a steric limitation was apparent. The bis-indole nature of this system was also exploited to produce a range of mixed indole dimers. The formation of the reaction product was found to be dependent upon the acidity of the reaction mixture, with a spiropyrrolo[a]indole dimer preferentially forming in the presence of a weak acid. 9H-Pyrrolo[1,2-a]indoles were prepared through acid catalysed condensation of 3-substituted-4,6-dimethoxyindoles with a range of chalcones. Conversely, condensations with alkyl α,β-unsaturated ketones were preferentially found to undergo polymerization. General activation of the indole scaffold was found to improve the reaction time and product yield when compared to the parent system. The C2 position was identified as the most reactive position of these 9H-pyrrolo[1,2-a]indoles and the inability to introduce a C5-carbaldehyde functionality hindered subsequent oxidation to the 4,7-indoloquinone scaffold. The ability of 4,6-dimethoxyindoles to specifically activate the indole C7 position was exploited to develop innovative synthetic routes to indoles 1,7-annulated with medium sized rings. In particular, a ring closing metathesis strategy was employed to prepare indoles fused with eight and nine membered cycloalkanes and lactones. Ring closure of larger rings proved unfavourable, hindering the synthesis of ten and eleven membered cycloalkane and glyoxylic ester analogues. Similarly, the development of indole fused lactams was hampered by several of the pathway intermediates displaying undesirable reactivities. A new type of indole flavonoid hybrid was prepared though treatment of 7-nitrovinylindoles with salicylaldehyde in the presence of 1,4-diazabicyclo[2.2.2]octane. However, the reaction was found to be unable to tolerate changes to the reactivity of the aldehyde.