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.
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Synthesis and Reactions of 3-Unsubstituted 2-Isoxazolines

Antti Pohjakallio

Doctoral dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the School of Chemical Technology for public examination and debate in Auditorium KE2 (Komppa Auditorium) at the Aalto University School of Chemical Technology (Espoo, Finland) on the 9th of April 2011 at 12 noon.

Overview in PDF format (ISBN 978-952-60-4070-7)   [1006 KB]
Dissertation is also available in print (ISBN 978-952-60-4069-1)

Abstract

2-Isoxazolines are five-membered heterocyclic compounds that serve as versatile synthetic intermediates in organic chemistry. A number of important functional groups, including 1,3-hydroxycarbonyl compounds, β-hydroxynitriles, 1,3-diamines and α,β-unsaturated carbonyl compounds can be accessed via these heterocycles. The powerful 1,3-dipolar cycloaddition reaction between nitrile oxides and alkenes has long served as the most important method to synthesize 2-isoxazolines.

This thesis describes the discovery and development of a new synthetic approach to 3-unsubstituted 2-isoxazolines via subsequent conjugate addition and oxime transfer reactions. Small organic amines combined with various acids were found to catalyze the conjugate additions of oximes and N-hydroxycarbamates to α,β-unsaturated aldehydes. In the case of oximes, the conjugate addition intermediates underwent intramolecular oxime transfer reactions that resulted in the formation of 3-unsubstituted 2-isoxazoline products. Mechanistic studies verified that the isoxazoline formation proceeds via the conjugate addition intermediate and pointed out to acid catalysis in the oxime transfer process. The best catalyst, N-methylanilinium diphenylphosphate, enabled the synthesis of a broad range of racemic 3-unsubstituted 2-isoxazolines from enals with good efficiency. The acid mediated oxime transfer process was combined with a known enantioselective oxime conjugate addition reaction to provide the first enantioselective method for the synthesis of 3-unsubstituted 2-isoxazolines.

The 3-unsubstituted 2-isoxazolines can be converted to β-hydroxynitriles by a base catalyzed isomerization reaction. An improved method for the isomerization process was developed, and combining this with the newly developed enantioselective 2-isoxazoline synthesis was shown to enable an easy two-step synthesis of highly enantioenriched β-hydroxynitriles.

This thesis consists of an overview and of the following 4 publications:

  1. Antti Pohjakallio and Petri M. Pihko. 2008. A versatile entry to 3-unsubstituted 2-isoxazolines. Synlett, volume 2008, number 6, pages 827-830. © 2008 Georg Thieme Verlag. By permission.
  2. Antti Pohjakallio and Petri M. Pihko. 2009. Enantioselective synthesis of 2-isoxazolines by a one-flask conjugate addition/oxime-transfer process. Chemistry - A European Journal, volume 15, number 16, pages 3960-3964.
  3. Antti Pohjakallio, Petri M. Pihko, and Ulla M. Laitinen. 2010. Synthesis of 2-isoxazolines: Enantioselective and racemic methods based on conjugate additions of oximes. Chemistry - A European Journal, volume 16, number 37, pages 11325-11339.
  4. Antti Pohjakallio, Petri M. Pihko, and Jun Liu. 2010. Base-catalyzed isomerization of 2-isoxazolines enables a two-step enantioselective synthesis of β-hydroxynitriles from enals. The Journal of Organic Chemistry, volume 75, number 19, pages 6712-6715.

Keywords: 2-isoxazoline, enantioselective synthesis, oxime transfer, amine catalysis, acid catalysis

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Last update 2012-07-10