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Title: Synthesis of nitrogen containing heterocycles via radical cyclisation
Author: Filik, Robert Paul
ISNI:       0000 0001 3464 8620
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2000
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O-benzoyl hydroxamic acids were found to be suitable precursors for the generation of amidyl radicals. A stereoselectivity study was performed to investigate the 5-exo cyclisations of the amidyl radicals formed. Hence a range of methyl and phenyl 2- substituted N-alkyl-Af-benzoyloxy-pent-4-enamides were synthesised and cyclised using tributyltin hydride and AIBN. A small preference for the Irons isomer was observed in all cases (10-36%) with the phenyl pendant series giving the highest selectivities. The observed Irons isomer was not that expected by current theories (Beckwith and Houk model). The effect of the N-substituent was found to exert little or no influence on the stereoselectivity of any of the reactions. Due to the difficulties in removing toxic tin residues from the reaction mixture alternative methods for the generation and 5-exo cyclisation of amidyl radicals utilising A-acyl hydroxamic acids were investigated using Cu(OTf)2 and Sml2. The effect of concentration, solvent and nature of the O-acyl group was found to be significant for the Cu(OTf)2 mediated reactions. Then using copper again this time in the form of CuCl(N-pentyl-2-pyridylmethanimine) under atom transfer conditions the cyclisation of prochiral N-benzyl/N-tosyl-dichloroacetamides in the 5-exo mode was investigated. The dichloro-acetamide precursors were readily cycliscd with yields and diastereoselectivities generally higher than those previously reported. The methodology was extended to include mono-halogenated precursors with results indicating that tertiary monohalogcnted precursors cyclised efficiently while primary monohalogented precursors did not, even under forcing conditions. The success of the CuCl(N-pentyl-2-pyridylmethanimine) then led to the development of a solid supported version. The ligand was immobilised on aminopropylated silica and used to study the 5-exo and 5-endo cyclisation of haloacetamidcs. The sense and degree of selectivity observed was comparable to that observed for the homogenous catalyst although elevated temperatures were required. A screening program was devised to furnish new more active atom transfer catalysts. The program established that aliphatic amine derived ligands proved to be more efficient atom transfer catalyst than the aromatic pyridine/imine derived ligands. TrenMe6 proved to be the best and was used to investigate the cyclisation of prochiral monohaloacetamides in the 5-exo mode with good selectivities observed (9:1-25:1) in favour of the tram isomer. Another useful alternative to tributyltin hydride proved to be 1-ethylpiperidine hypophosphite-AIBN and it was used to cyclise various haloacetamides with good diastereoselectivities being observed. However, when using secondary monohaloacetamides significant amounts of reduction and cleaved products were observed in the reaction mixture.
Supervisor: Not available Sponsor: Knoll Pharmaceutical Company
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry