Tallant, Neil Antony; (1992) The cyclisation of unsaturated peroxides. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The reactions of several γ,δ-unsaturated hydroperoxides with tert-butyl hypochlorite have been investigated, and it has been shown that this provides a general synthesis of 3-(1-chloroalkyl)-1,2-dioxolanes. It is believed that in general the reaction proceeds via a mixture of polar and radical pathways, but in the presence of silica the reaction appears to be entirely polar. If acetone is used as the solvent, this provides a new synthesis of substituted 1,2,4-trioxepanes which are formed as a minor product in the reaction. The treatment of 3-cyclooctenyl hydroperoxide with fert-butyl hypochlorite in the presence of silica affords a chloro-substituted bicyclic peroxide, but under identical conditions 4-cyclooctenyl hydroperoxide produces very little of the expected bicyclic ether. Instead, the major product is 4-chlorocyclooctanone, which is probably formed via a transannular 1,5-hydride shift. We further found that the observation of 1,2,4-trioxepane formation is not general, and that under similar conditions 1,2-dioxolanes are the exclusive products. However, it has recently been shown that under these conditions allylic hydroperoxides can form 1,2,4-trioxanes, and further investigation has found that the product formed is largely dependent on the nature of the substitution on the double bond. Thus, 3-phenylallyl (cinnamyl) hydroperoxide forms 1,2-dioxolanes, whereas 1-phenylallyl hydroperoxide forms 1,2,4-trioxanes with high stereoselectivity. One such trioxane has been found to show in vitro activity against malarial parasites. Good stereoselectivity was also found in the formation of 1,2,4-trioxanes from 2-methyl-2-buten-1-yl hydroperoxide. Additionally, the possibility of incorporating aldehydes derived from amino acids into the trioxanes has been demonstrated. Investigations of the 13C nmr spectra of the trioxanes synthesised showed that these compounds exhibit a reversed Perl in Effect i.e. 1J(C-Hax) is found to be greater than 1J(C-Heq). This was rationalised via a homoanomeric effect from the β-oxygen. A general synthesis of 2-substituted 3-buten-l-yl hydroperoxides proved impossible to find. The 2-methyl compound could be synthesised by perhydrolysis of the corresponding trifluoromethanesulphonate ester (triflate), but other analogues proved impossible to make due to the instability of the triflates. On cyclisation, 2-methyl-3-buten-l-yl hydroperoxide forms 3,4-disubstituted-1,2-dioxolanes, but generally with no stereoselectivity. However, if mercuric nitrate is used as the electrophile, then the trans isomer is found to be favoured.

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