The development of catalytic methods for the synthesis of saturated nitrogen heterocycles

Thesis

Chapter 1: Introduction

The introduction gives a description of the applications of azetidines, pyrrolidines and piperidines, as well as a brief overview of existing methods for their synthesis. Selected examples from the chemical literature are discussed. This chapter also reviews the history and development of hydrogen borrowing catalysis for nitrogen alkylation.

Chapter 2: Photoredox Catalysis for the Synthesis of Azetidines

The development of visible light mediated photoredox catalysis for azetidine synthesis was explored. A Ru(bpy)₃²⁺ catalyst system was employed to induce single electron reduction of 1 phenylbut 2 en 1 one and reaction of the resulting radical anion was attempted with a number of nitrogen containing electrophiles. Subsequently, a tethered substrate featuring an enone and an oxime portion was designed, synthesised and subjected to a screen of photoredox catalysts, with the hope of effecting an intramolecular azetidine formation.

Chapter 3: Hydrogen Borrowing Catalysis for the Synthesis of Piperidines

Hydrogen borrowing catalysis enabled the generation of a wide range of substituted piperidine scaffolds. Diols are employed as double alkylating agents and overall the process forms two new C–N bonds to furnish the heterocycle. A range of diols and amines were subjected to the reaction conditions to synthesis piperidines. The synthesis of pyrrolidines, azetidines and heterocycles bearing more than one heteroatom were also investigated under the hydrogen borrowing conditions.

Chapter 4: Stereoselective Synthesis of Piperidines using Hydrogen Borrowing Catalysis

Hydrogen borrowing catalysis for the synthesis of piperidines with stereogenic centres at the C2, C3 and C4 positions was investigated. The use of an enantiopure amine was explored for stereoinduction at the C2 centre. Through extensive optimisation, water was discovered to be an optimum reaction solvent and a new set of reaction conditions were developed enabling stereoretention in up to 93:7 er at the C3 position. Piperidines bearing a stereogenic centre at the C4 position could be synthesised from enantioenriched starting materials as this centre was found to be unharmed during the hydrogen borrowing reaction.

Chapter 5: Experimental

This chapter contains the experimental procedures and spectroscopic data for all of the compounds described within the thesis.

Chapter 6: Appendix

The X-ray crystallographic data for compound 240 can be found in the appendix.

Chapter 7: References

The references cited within the thesis can be found in this chapter.

Authors: Chamberlain, A.E.R.

• DOI: 10.5287/ora-wr5mk5vgj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English