The doctoral dissertations of the former Helsinki University of Technology (TKK) and Aalto University Schools of Technology (CHEM, ELEC, ENG, SCI) published in electronic format are available in the electronic publications archive of Aalto University - Aaltodoc.
Aalto

Modifications of Carboxyindoles on Solid Phase

Jan Tois

Dissertation for the degree of Doctor of Philosophy to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium KE 2 (Komppa Auditorium) at Helsinki University of Technology (Espoo, Finland) on the 24th of October, 2003, at 12 o'clock noon.

Overview in PDF format (ISBN 951-22-6893-0)   [502 KB]
Dissertation is also available in print (ISBN 951-22-6751-9)

Abstract

Different solid phase modifications were studied in order to develop new and simple routes for pharmaceutically interesting highly substituted carboxyindoles. A convenient method for the preparation of 5-substituted 2-carboxyindoles and three novel direct functionalization methods for carboxyindoles were developed during this study.

5-Nitro-2-carboxyindole was synthesized easily in three steps from commercially available inexpensive 4-nitro-aniline. Through attachment of this template to solid phase followed by reduction, reductive amination, N-alkylation and cleavage, a small library of differently substituted carboxyindoles were obtained.

Solid phase brominations were studied followed by palladium catalyzed Suzuki-coupling. This technology offers an efficient and selective method to introduce bromine and a new C-C-bond to 3-position of polymer bound 2-carboxyindoles.

Formylation studies were also succesfull. By utilizing Vilsmeier formylation a new C-C-bond was obtained direcly and selectively at the 3-position of polymer bound 2-carboxyindoles.

In solid phase metalation studies of 5-carboxyindoles a 4-position functionalization was achieved in 80 % regioselectivity. Despite the moderate regioselectivity it is obvious that ring lithiation can be adopted to solid phase.

This thesis consists of an overview and of the following 5 publications:

  1. Tois J., Franzén R., Aitio O., Huikko K. and Taskinen J., 2000. Preparation of 5-substituted 2-carboxyindoles on solid support. Tetrahedron Letters 41, No. 14, pages 2443-2446.
  2. Tois J., Franzén R., Aitio O., Laakso I., Huuskonen J. and Taskinen J., 2001. Solid-phase bromination and Suzuki coupling of 2-carboxyindoles. Combinatorial Chemistry & High Throughput Screening 4, No. 6, pages 521-524.
  3. Tois J., Franzén R., Aitio O., Laakso I. and Kylänlahti I., 2001. Vilsmeier formylation of 2-carboxyindoles and preparation of O-benzylhydroxyureas on solid phase. Journal of Combinatorial Chemistry 3, No. 6, pages 542-545.
  4. Tois J. and Koskinen A., 2003. Solid-phase lithiation of 5-carboxyindoles. Tetrahedron Letters 44, No. 10, pages 2093-2095.
  5. Tois J., Franzén R. and Koskinen A., 2003. Synthetic approaches towards indoles on solid phase recent advances and future directions. Tetrahedron 59, No. 29, pages 5395-5405.

Keywords: carboxyindoles, solid phase synthesis, direct functionalization, Vilsmeier formylation, lithiation, bromination

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© 2003 Helsinki University of Technology

Last update 2011-05-26