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Selective formation of α-methylene-β-amino acid derivatives through the aza version of the baylis-Hillman reaction
Stockholm University, Faculty of Science, Department of Organic Chemistry.
2001 In: The Journal of Organic Chemistry, Vol. 66, 6498-6501 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2001. Vol. 66, 6498-6501 p.
URN: urn:nbn:se:su:diva-25675OAI: diva2:200213
Part of urn:nbn:se:su:diva-84Available from: 2004-03-26 Created: 2004-03-26Bibliographically approved
In thesis
1. The three-component aza-Baylis-Hillman reaction: development and application
Open this publication in new window or tab >>The three-component aza-Baylis-Hillman reaction: development and application
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The current thesis presents the optimization and generalization of the Baylis-Hillman reaction applied to in situ generated imines, i.e. a three-component aza- Baylis-Hillman reaction. We found that the title reaction proceeds most efficiently in the presence of a combination of catalysts, i.e. 3-hydroxyquinuclidine (0.15 equiv) and titanium isopropoxide (0.02 equiv), together with molecular sieves (4 Å; activated powder; 200 mg/mmol substrate) at ambient temperature.

Our study of the scope and limitations of this reaction, revealed that arylaldehydes and sulfonamides are the only imine precursors which both generate the corresponding imines in situ and facilitate a further reaction with the Michael acceptor in a Baylis-Hillman fashion. Among the Michael acceptors tested, acrylates and acrylonitrile demonstrate high reactivity, while acrylamides and β-substituted acrylates do not participate in the reaction.

The optimized conditions applied to the above range of substrates results in good-to-excellent yields of the desired amine-products (53-94%) and very high chemoselectivity (83- >99%). Furthermore, the reaction times observed under these conditions are considerably shorter than those previously reported for the aza-Baylis-Hillman reaction.

In the development of a stereoselective version of the title reaction, the use of a chiral catalyst proved to be most effective. Thus, an enantiomeric excess up to 74% can be obtained with β-Isocupreidine. With chiral imine precursors or chiral acrylates, the diastereoselectivity attained was poor. No asymmetric induction was observed when chiral Lewis acids were employed as a co-catalyst.

The α-methylene-β-amino acid derivatives obtained via the three-component aza-Baylis-Hillman reaction were subjected to further transformation. Carbon chain elongation at the olefinic end of the amine-adduct was attempted. For this purpose, the Miyaura borylation protocol could be successfully applied. The subsequent Suzuki-type cross-coupling reaction resulted predominantly in hydrolysis of the boronate intermediate, together with formation of the amine-adduct via β-hydride elimination. The optimal conditions for this latter reaction remain to be found.

Finally, 2,5-dihydropyrroles have been synthesized from aza-Baylis-Hillman adducts, via a short and efficient route in which the key step is a microwave-assisted ring-closing metathesis of the N-allylated amine-adducts.

Place, publisher, year, edition, pages
Stockholm: Institutionen för organisk kemi, 2004. 61 p.
National Category
Organic Chemistry
urn:nbn:se:su:diva-84 (URN)91-7265-848-7 (ISBN)
Public defence
2004-04-16, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Available from: 2004-03-26 Created: 2004-03-26Bibliographically approved

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