Synthesis of indole and oxindole derivates incorporating pyrrolidino, pyrrolo or imidazolo moieties

University dissertation from Stockholm : Karolinska Institutet, Biosciences and Nutrition

Abstract: The focus of this thesis is on the synthesis of oxindole- and indole-derivatives incorporating pyrrolidins, pyrroles or imidazoles moieties. Pyrrolidino-2-spiro-3'-oxindole derivatives have been prepared in high yielding three-component reactions between isatin, alpha-amino acid derivatives, and suitable dipolarophiles. Condensation between isatin and an alpha-amino acid yielded a cyclic intermediate, an oxazolidinone, which decarboxylate to give a 1,3-dipolar species, an azomethine ylide, which have been reacted with several dipolarophiles such as N-benzylmaleimide and methyl acrylate. Both N-substituted and N-unsubstituted alpha-amino acids have been used as the amine component. 3-Methyleneoxindole acetic acid ethyl ester was reacted with p-toluenesulfonylmethyl isocyanide (TosMIC) under basic conditions which gave (in a high yield) a colourless product. Two possible structures could be deduced from the analytical data, a pyrroloquinolone and an isomeric beta-carboline. To clarify which one of the alternatives that was actually formed from the TosMIC reaction both the beta-carboline and the pyrroloquinolone were synthesised. The beta-carboline was obtained when 3-ethoxycarbonylmethyl-1H-indole-2-carboxylic acid ethyl ester was treated with a tosylimine. An alternative synthesis of the pyrroloquinolone was performed via a reduction of a 2,3,4-trisubstituted pyrrole obtained in turn by treatment of a vinyl sulfone with ethyl isocyanoacetate under basic conditions. This molecule (the pyrroloquinolone), obtained in a low yield by a multistep procedure, proved to be identical with the product obtained easily via the TosMIC route. The reaction between 3-aminocrotonates and 3-acetonylideneoxindole in refluxing toluene resulted in 2-pyrrolo-3?-yloxindoles in high yields, (around 90 %). At room temperature the 2-pyrrolo-3'-yloxindoles exist as a mixture of keto-enol tautomers. Treatment with POCl3 yielded the corresponding 2-chloro-3-pyrrolyl indole, which gave a pyrrolo annulated indolopyrane upon basic hydrolysis of the ester function of the methyl ester. 3-Imidazolylindoles were synthesised in good yields from the corresponding benzylimine and TosMIC. Treatment of cyclohexanone benzylimine with alpha-chloroacrylonitrile yielded, after expulsion of HCN by refluxing in ethanol, 1-benzyl-4,5,6,7-tetrahydroindole. Formylation and benzylimine formation followed by treatment with TosMIC furnished the desired 2-imidazolyltetrahydroindole. Keywords: isatin, three-component reaction, a-amino acid, azomethine ylide, pyrrolidino-3-spiro-3?-oxindole derivatives, 3-methyleneoxindole derivatives, pyrroloquinolone, TosMIC, ß-carboline, tosylimine, pyrrole, keto-enol tautomerism, indolopyran-2-one, imidazole, benzylimine, tetrahydroindole.

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