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

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.

List of scientific papers

I. Rehn S, Bergman J, Stensland B (2004). The three-component reaction between isatin, alpha-amino acids and dipolarophiles. Eur J Org Chem. 413-18.

II. Bergman J, Rehn S (2002). Synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester and its isomer 1-oxo-2,9-dihydro-1H-beta-carboline-4-carboxylic acid ethyl ester. Tetrahedron. 45: 9179-85.

III. Rehn S, Bergman J (2004). The reaction between 3-aminocrotonates and oxiindole 3-ylidene derivatives: synthesis of highly substituted pyrroles. Tetrahedron. [Accepted]

IV. Rehn S, Bergman J (2004). Synthetic studies towards the alkaloid granulatimide: synthesis of 3-imidazolylindole and 2-imidazolyltetrahydroindole. [Manuscript]