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Abstract
The primary aim of this project was to synthesize novel 4,6-dihydroxyindoles and 5,7-dihydroxyquinolin-2-ones and to study their reactivity. 4,6-Dibenzyloxyindoles were synthesised from 3,5-dibenzyloxyaniline. The synthesis of 3,5-dibenzyloxyaniline was initially attempted using a modified Curtius reaction. However, this method was not efficient due to the requirement of multiple steps and a low yield in the penultimate step. To overcome this, an alternative synthesis starting from phloroglucinol was optimised which gave 3,5-dibenzyloxyaniline in four steps in 84% overall yield.
By employing 3,5-dibenzyloxyaniline, a variety of indoles were prepared using methods such as the Bischler, modified Bischler and Hemetsberger indole syntheses. A one-pot reaction for the synthesis of 2-substituted indoles, 2,3-disubstituted indoles and 3-substituted indoles was investigated. The reactivity studies on 4,6-dibenzyloxyindoles included formylation, bromination, the Mannich reaction, the synthesis of indolylmethanes and biindolyls. Using 4,6-dihydroxyindoles a new class of heterocyclic pyrano[2,3-g]indoles was prepared via the von Pechmann reaction in 60-73% yield. Pyrano[2,3-f]indoles were also prepared from 5-aminoresorcinol employing the Bischler indole synthesis in 62-65% yield. Selected pyranoindoles were tested and found to have anti-cancer and anti-fungal activity in the in vitro assays.
The secondary aim of the project was to construct fused heterocyclic systems derived from 4,6-dihydroxyindoles and 5,7-dihydroxyquinolin-2-ones. Furoindoles were synthesised using two different methods. In the first method, the hydroxy group of 4,6-dihydroxyindole at C4 was reacted with α-haloketones to give acyl intermediates which were readily cyclised at C5 by trifluoroacetic acid to give furoindoles in 72-83% yield. In the second method 4-hydroxy-2,3-diphenylindole was used to make a variety of substituted furoindoles in 73-78% yield following a similar method.
Dihydropyranoindoles were prepared in four steps with average yield of 71-77% using a modification of the Hemetsberger indole synthesis. These reactions generated four different kinds of novel dihydropyranoindoles.
5,7-Dihydroxyquinolin-2-ones were synthesised from phloroglucinol in good 73-76% yield over two steps. 5,7-Dihydroxyquinolin-2-ones were reacted further with α-haloketones followed by cyclization in trifluoroacetic acid to give difuroquinolones in 58-86% yield.
Mannich adducts were obtained in 65-67% yield through the reaction of 5,7-dihydroxyquinolin-2-ones with bis(dimethylamino)methane, whereas oxazinoquinolones were obtained in 63-73% yield when 5,7-dihydroxyquinolin-2-ones were reacted with benzylamine and formaldehyde.
Pyrroloquinolines were prepared in a one-step method using indole-7-carbaldehyde and acrylonitrile. This is demonstrated to be a facile method to generate pyrroloquinolines in 70-84% yield.