Synthesis of C-3 functionalised 1-pyrroline 1-oxides
Chapter 1 introduces the phenomenon of oxygen toxicity and the central role played by oxygen free radicals, most notably the superoxide radical anion. The technique of spin trapping, whereby reactive free radicals are studied and identified, is then introduced. The synthesis of improved spin traps for superoxide by the preparation of 1-pyrroline 1-oxides bearing a C-3 ester or alkyl halide substituent is then discussed. Chapter 2 describes the preparation of 2-(prop-2-enyl)-aldehydes, 2-dimethoxymethylaldehydes and a 2-phenylthiomethylaldehyde. Bromination of 5,5-dimethyl-1-(prop-2-enyl)-1-pyrroline 1-oxide did not give rise to addition at the C=C double bond but recovery of the nitrone and a hydroxamic acid. Similarly, hydrohalogenation of the alkenyl-nitrone did not lead to addition at the C=C double bond. The preparation and utility of 3-(ethoxycarbonylprop-2-enyl)-5,5-dimethyl-1-pyrroline 1-oxide is then described. Chapter 3 details the preparation of 3-dimethoxymethyl-1-pyrroline 1-oxides. Acid-catalysed deprotection of these nitrone acetals did not result in the formation of the expected 3-aldehydo-5,5-dimethyl-1-pyrroline 1-oxides. Chapter 4 deals with the preparation of 5,5-dimethyl-3-phenylthiomethyl-1-pyrroline 1-oxide. Conversion of the phenylthiomethyl group to an iodomethyl group led to the loss of the nitrone. Chlorination of the nitrone gave 4-methyl-4-nitro-2-phenylthiomethylpentanoic acid. Oxidation of 5,5-dimethyl-3-ethoxycarbonyl-1-hydroxypyrrolidine resulted in the dimeric nitrone 3,3'-bis(ethoxycarbonyl)-5,5,5',5'-tetramethyl-3,3'-bi-1-pyrrolinyl 1,1-dioxide being isolated. Chapter 5 concerns the synthetic utility of α-bromoaldehydes. The preparation of 5,5-dimethyl-3-benzenesulphonyl-1-pyrroline 1-oxide is then described. Alkylation of the nitrone in the presence of sodium hydride with methylbromoacetate gave the C-3 disubstituted nitrone, 3-benzenesulphonyl-5,5-dimethyl-3-methoxycarbonylmethyl-1-pyrroline 1-oxide. Chapter 6 concerns the spin trapping reactions of the nitrones prepared in this thesis. The ESR spectra of the hydrogen atom adducts showed the magnetic non-equivalence of the β-hydrogens owing to the presence of the C-3 substituent. Spin trapping of the t-butoxy radical was found to be stereospecific. Apparent selectivity for the hydroxyl radical was found as no spin adducts were detected with the superoxide radical anion.