Reducing catalyst loadings in radical cyclisation reactions and investigating atropisomerism in enamides

• Main Author: Wilson, Paul
• Published: University of Warwick 2010
• Subjects: 547.5; QD Chemistry
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533205

The bulk of the work presented in this thesis represents an evolution of copper-mediated atom transfer radical cyclisation. Chapter 1 provides introduction to radical cyclisation methods and applications and is followed by the shortest results chapter that discusses the outcome of 1,4-dimethylpiperazine mediated radical cyclisation of monobromoacetamides. Cyclisation was possible but competing reduction and elimination pathways are prevalent when less reactive substrates are used. Chapters 3 and 4 focus on the evolution of copper-mediated atom transfer radical cyclisation. A number of additives were screened in the hope of achieving catalyst regeneration which would allow catalyst loadings to be reduced without loss of efficiency and negate the need for an inert atmosphere throughout the reaction. In chapter 3, AIBN was found to be the optimum additive and efficient cyclisation was possible using copper (I) (Cu(TPA)Br) and copper (II) (Cu(TPA)Br2) complexes (1 mol%) in DCM and toluene (at 50 and 110 oC respectively) suggesting AIBN could activate and reactivate the catalyst in situ. In chapter 4 an alternative, highly efficient process was developed using copper (II) in the presence of potassium borohydride in MeOH. Reaction times were significantly reduced (10-30 min) and reactions were performed at room temperature even at decreased catalyst loadings (0.1 mol%). The mechanism for the process is likely to differ from that of conventional atom transfer radical cyclisation. UV analysis of the catalyst complex and the reactions progress, compared to literature data, suggest the active catalyst could be a copper borohydride (CuBH4) complex. Finally chapter 5 compiles a structural analysis of a variety of enamides to determine the feasibility of chiral induction during 5-endo trig radical cyclisation. A number of N-cycloalkenyl and N-cyclohexenyl enamides, which share an axis of chirality about the N-C(cycloalkenyl) bond, were analysed by variable temperature NMR to determine the rate and barrier of rotation of the chiral axis. Although none of the enamides studied had barriers great enough to achieve chiral induction it was recognised that the barrier to rotation could be significantly increased if tetrasubstituted enamides were accessible. Tetrasubstituted enamides were prepared and their barriers were determined by chiral HPLC, with barriers predicted to be great enough for chiral induction. Cyclisation was attempted but to no avail with unexpected oxidation products being obtained. Despite this, a more comprehensive understanding of the enamide structure has paved the way for potential chiral induction in 5-endo trig radical cyclisation.