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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Advances in Amine Catalysis: Brønsted Acids in Iminium and Enamine Activation

Anniina Erkkilä

Dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the Department of Chemical Technology for public examination and debate in Auditorium KE2 (Komppa Auditorium) at Helsinki University of Technology (Espoo, Finland) on the 26th of October, 2007, at 12 noon.

Overview in PDF format (ISBN 978-951-22-8987-5)   [660 KB]
Dissertation is also available in print (ISBN 978-951-22-8986-8)

Abstract

Condensation of aldehydes and ketones with primary and secondary amines results in the formation of reactive imines and iminium salts. Additionally, a loss of a proton form an iminium species leads to the formation another active intermediate: enamine. Iminium salts and enamines are more reactive than their parent compounds and thus their formation can be exploited in amine catalysis. In fact, activation of carbonyl compounds by iminium and enamine catalysis has attracted wide attention in the last decade and become a practical tool for the synthetic organic chemists.

In the summary part of this thesis reactions activated via iminium ion or enamine formation are reviewed focusing on the role of the Brønsted acid co-catalyst. The described catalysts consist of a primary or secondary amine iminium or enamine catalyst and an acid co-catalyst and can often be derived from nature's chiral pool. The Brønsted acid co-catalysis plays a central role in the iminium and enamine catalysis. In the iminium catalysis the co-catalyst functions as a general acid catalyst in the iminium formation and as a general base catalyst in the some times required removal of hydrogen from the nucleophile when it has reacted to form the initial iminium intermediate. In enamine catalysis these modes are already combined in the formation of the reactive enamine species. Thereafter the co-catalyst may be used to activate and orient the approaching electrophile.

In this thesis enamine catalysis was utilized in the synthesis of polypropionate building blocks by asymmetric aldol reactions. Also, combined enamine-iminium catalysis was employed in the synthesis of alpha-substituted enals, which in turn were utilized as substrates in iminium catalyzed transformations. For the iminium catalyzed transformation of alpha-substituted enals a novel aniline catalyst was developed.

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

  1. Källström, S., Erkkilä, A., Pihko, P. M., Sjöholm, R., Sillanpää, R., Leino, R. 2005. Consecutive Proline-Catalyzed Aldol Reactions and Metal-Mediated Allylations: Rapid Entries to Polypropionates. Synlett 5, 751-756.
  2. Erkkilä, A., Pihko, P. M. 2006. Mild Organocatalytic α-Methylenation of Aldehydes. Journal of Organic Chemistry 71, 2538-2541.
  3. Erkkilä, A., Pihko, P. M., Clarke, M.-R. 2007. Simple Primary Anilines as Iminium Catalysts for the Epoxidation of α-Substituted Acroleins. Advanced Synthesis & Catalysis 349, 802-806.
  4. Erkkilä, A., Pihko, P. M. 2007. Rapid Organocatalytic Aldehyde-Aldehyde Condensation Reactions. European Journal of Organic Chemistry 2007, 4205-4216.
  5. Erkkilä, A., Majander, I., Pihko, P. M. 2007. Iminium catalysis. Chemical Reviews 107, in press.

Keywords: amine catalysis, enamine, iminium, organocatalysis, Brønsted acid

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© 2007 Helsinki University of Technology

Last update 2011-05-26