Loughborough University
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Novel free radical synthesis of heterocycles

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posted on 2014-05-14, 13:06 authored by Emma Mann
The use of tri-n-butyltin hydride and an initiator to mediate free radical cyclisation as a synthetic organic process is well documented throughout the chemical literature. By using BU3SnH, and developing new 'catalytic' BU3SnH methods, many new heterocyclic compounds have been synthesised successfully. The search for new 'tin-free' radical reagents is important in order to provide a non-toxic alternative to tin. We have started initial studies on the replacement oftriorganotin hydrides with germanium analogues. An interesting number of reactions using BU3SnH do not give reduced products and have an oxidation step in the mechanism. These BU3SnH mediated cyclisations provide a useful synthetic method. Our studies were aimed at developing the synthetic protocol as well as determining the mechanism. 'Shilajit' is an ancient tribal panacea, believed to have many advantageous biological properties. The active constituents are based upon a benzochromenone skeleton. The key component of the natural product Shilajit, 3-methoxy-6H-benzo[c]chromen-6-one, as well as several analogues have been synthesised using this BU3SnH mediated 'oxidative' free radical approach. The mechanism proposed for these reactions by Bowman et ai, the pseudo SRN I mechanism, has also been studied in order to try to determine the presence of the radical anion intermediates which are essential for the pseudo SRN 1 mechanism to be correct. The BU3SnH mediated 'oxidative' cyclisation protocol was successfully applied to electron deficient pyrroles, i.e. pyrroles with electron withdrawing substituents. Radicals generated on N-substituted chains readily undergo cyclisation onto the pyrrole ring. The protocol was also applied to cyclisation reactions of analogous imidazoles. The imidazole reactions were used for an extensive examination of the mechanism of the 'oxidative' BU3SnH protocol. The studies have disproved the pseudo SRN 1 mechanism (where BU3SnH is the oxidising agent) and suggest possible alternative oxidising agents. The importance of the functionality on the heterocyclic ring is also emphasised. Free radicals have been generated using photolytic methods, and the results are contrasted with those from traditional BU3SnH reactions. The synthesis of several substituted pyrazoles and radical cyclisation reactions were attempted on various pyrazole systems with the aim of synthesising the natural product withasomnine.



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© Emma Mann

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A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.

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