New approaches to nitrogen heterocycles via radical cyclisations

Doctoral thesis English OPEN
Guy, Collette S.
  • Subject: QD

The work presented in this thesis focuses on the use of radical cyclisations to synthesise nitrogen heterocycles. Chapter 1 provides an introduction to radical cyclisations and the development of conditions over the past couple of decades. It also gives an introduction to atropisomerism, a phenomenon present in a number of cyclisation precursors, and how this has been exploited to achieve chirality transfer in the cyclisation of acrylanilides.\ud \ud Chapter 2 describes investigations into the effects of alkene substitution on the barrier to rotation about the N-alkenyl bond in enamides. A range of enamides were synthesised and their barriers to rotation were investigated by both 1H VT NMR and racemisation of an enriched atropisomer. Tetrasubstituted enamides were found to have significantly higher barriers to rotation, and in some cases it was possible to separate the two atropisomers at room temperature by chiral HPLC.\ud \ud Chapter 3 describes the results of 5-endo cyclisations of tetrasubstituted enamides. Dependant on the starting material, cyclisations were carried out mediated by both Bu3SnH and copper. Cyclisations of tetrasubstituted enamides proved to be more challenging than previous reported cyclisations of less hindered substrates with a number of by products produced.We have also examined the possibility of whether chirality transfer would be possible in the cyclisation of an enamide with a high barrier to rotation.\ud \ud In Chapter 4 studies into the cyclisations of 2-bromobenzyl enamides are presented. Initial cyclisations were carried out into the Bu3SnH mediated cyclisation of a trisubstituted enamide and the rate of both the 5-exo and 6-endo cyclisation was calculated. The cyclisation of tetrasubstituted 2-bromobenzyl enamides was then attempted, however it proved less successful. The hindered nature of the tetrasubstituted enamides was found to slow the rate of cyclisation significantly leading to the formation of other products.\ud \ud Chapter 5 describes studies into the synthesis of oxindoles via radical cyclisation. Reactions in methanol with CuBr and TPA at 50 oC gave three main products, a reduced compound, an eliminated compound and the target oxindole. Reactions repeated in toluene at 110 oC were much cleaner giving the oxindole product in high conversions.
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