The synthesis of 3-substituted-2-(nitromethylene)-piperidines

The class of insecticides known collectively as the nitromethylene heterocycles (NMHs) were discovered in the late 1970's. The NMHs are a group of compounds that are particularly active against certain insects, exhibit low toxicity to vertebrates and are non-persistent in the environment. Their site of action is on the cholinergic synapse where they act as agonists at the post-synaptic nicotinic acetylcholine receptors. Research into developing these types of compounds has led to a wide range of analogues being synthesised, resulting in a wide variety of activities. Analogues of 2- (nitromethylene)piperidine with small group substituents at the 3-position (e.g. halogens or small alkyl groups), in general, were found to have increased levels of activity. The work reported in this thesis is the synthesis of some novel 3-substituted-2- (nitromethylene)piperidines. Initially a series of 3-substituted-2-piperidones was synthesised via the catalytic decomposition of 3-diazo-2-piperidone. Rhodium(II) acetate and methyl trioxorhenium were found to be particularly efficient catalysts. The 1,3-dipolar cycloaddition of electron deficient olefins to 3-diazo-2-piperidone resulted in a range of 3-substituted pyrazolines being formed. Nitrogen could be eliminated from these pyrazolines to give spirocyclopropanes. 3-Alkoxy-2-(nitromethylene)piperidines were synthesised by the nitromethylenation of 3-alkoxy-2-piperidones. However the nitromethylenation of the 3-spirocyclopropyl derivatives was not successful due to steric effects. To overcome the problems of steric hindrance, 3-diazo-2-(nitromethylene)piperidine was synthesised via a six step synthesis from 2-piperidone. This was the first compound to be synthesised which contains a 3-diazo-l-nitropropene group. Although this diazo compound acted as a 1,3-dipole with electron deficient olefins to give the corresponding pyrazolines, the rhodium catalysed decomposition was found to form 3-oxo-2-(nitromethylene)piperidine as the major product even in the presence of other carbenoid trapping agents. Further investigation into this reaction has led to a proposed mechanism which is outlined in the thesis