Synthesis of mono- and bicyclic azacycles via palladium- and ruthenium-catalysed enynamide cycloisomerisation

Thesis

The initial aim of this project was to investigate ways of synthesising fused, spirocyclic and linked bicyclic amines. We built on methodology previously developed within our group, employing cyclic dienamides, prepared using the reductive cyclisation of bromoenynamides, as key structural building blocks for further annulation.

In the course of investigating the reactivity of these cyclic dienamides, we discovered a new efficient and general route to their synthesis, by employing palladium- or ruthenium-catalysed enynamide cycloisomerisation. A wide range of attractive dienamide scaffolds were synthesised from simple enynamide precursors in rapid, high yielding and operationally simple reactions, underlining their potential utility as an atom-economical source of azacycles.

Chiral enynamide substrates were used to generate 1,4-dienamides as a single diastereomer at the newly formed (quaternary) stereocentre. This relay of stereochemistry was exploited not only in the formation of monocyclic dienamides, but even in the formation of a spirocyclic product, and this bodes well for further stereocontrolled synthesis of polysubstituted azacycles.

Finally the palladium- and ruthenium-catalysed cycloisomerisation of enynamides was discussed and investigated mechanistically, utilising ¹H NMR spectroscopy, timecourse and deuterium-labelling experiments.

Authors: Walker, PR

• Publication date: 2014
• DOI: 10.5287/ora-j5npd1zm1
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: heterocycles; palladium; cyclisation; homogeneous catalysis; ynamide; cycloisomerisation
• Subjects: Organic chemistry; Organic synthesis; Heterocyclic chemistry; NMR spectroscopy; Chemistry & allied sciences; Catalysis