Silver-catalysed hydroamination : synthesis of functionalised pyrroles.
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Date
2004
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Abstract
The aim of this project was a broad one, namely to develop general methods for the preparation of nitrogen-containing heterocycles. This topic also encompasses the preparation of precursors to heterocycles with the goal of obtaining compounds that can undergo various transformations to give different cyclic products (general synthetic precursors). Workers in our group have previously reported the preparation of indolizinones from N-propargyl enaminones. Immediate goals were to elucidate the mechanism of this transformation, optimise its yields and explore its generality. Initial work revealed a possible reaction intermediate in the form of isomeric N-allenyl enaminones. These compounds can be easily prepared from N-propargyl enaminones using potassium tertbutoxide. Although parallels between the two reactions were noted, the presence of N-allenyls as reaction intermediates was not substantiated. In spite of this, N-allenyl enaminones were considered to be potentially valuable compounds in their own right and their chemistry was briefly explored. It was shown that they undergo hydroboration smoothly yielding only one hydroboration product. This was observed using dynamic iiB NMR spectroscopy. Subsequent oxidation gave interesting results and these are discussed further. At this stage it was considered important to prepare piperidine and acyclic analogues of the N-allenyl enaminones already synthesised. Both preparations proved problematic and were ultimately abandoned. Although these attempts were not fruitful, a number of interesting observations were made en route and contribute to the discussion. Whilst attempting to prepare acyclic analogues it was found that when a mixture of a secondary enaminone and propargyl bromide was treated with silver nitrate functionalised pyrroles were formed. This method of pyrrole formation, although low yielding (~25%), was both novel and intriguing. As pyrroles are important heterocycles and common synthetic targets, further work was carried out to elucidate the mechanism in operation during this conversion. A thorough investigation led to a proposed mechanism involving silver-mediated hydro amination followed by an intramolecular nucleophilic substitution. This proposed mechanism is discussed further. Carrying out the reaction over two steps was found to improve the procedure. Carbon-carbon bond formation prior to an intramolecular silver-catalysed hydroamination provides superior overall yields. Intramolecular hydroamination can be carried out at room temperature or using microwave irradiation. Employing microwave irradiation reduces reaction times from sixteen hours to sixty seconds without any decrease in yields. This process was extended to bicyclic systems, namely N-bridgehead pyrroles. The preparation of the necessary cyclic precursors via a protection-deprotection strategy is described. N-Bridgehead pyrroles provide the framework for pyrrolizidine, indolizidine and lehmizidine alkaloids and general synthetic protocols toward the synthesis of such alkaloids is proposed.
Description
Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2004.
Keywords
Heterocyclic compounds., Pyrroles--Synthesis., Theses--Chemistry.