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|Title: ||Oxime derivatives : versatile reagents for radical-mediated syntheses of heterocycles|
|Authors: ||Portela-Cubillo, Fernando|
|Supervisors: ||Walton, J. C.|
|Issue Date: ||2009|
|Abstract: ||A summary of tin hydride mediated reactions in generating radicals in organic synthesis is presented, together with some of the many alternative methods now available for conducting radical
reactions. Particular attention has been given to the iminyl radical and the development of tin-free
organic radical precursors. This introduction is followed by three chapters describing research on
the development of two new sources of iminyl radicals and their application in syntheses of aza-
O-Phenyl oxime ethers are the first iminyl radical precursors described in the thesis.
Microwave thermolyses of oxime ethers released iminyl and phenoxyl radicals under comparatively
mild conditions and with short reaction times. Few microwave-assisted synthetic methods, based
around radical intermediates, are known. The mild and neutral conditions associated with radical
chemistry, and the ability of radicals to perform intramolecular cyclisations, together with the
virtues of MAOS, make their combination a very useful tool in syntheses of aza-heterocycles. A
comprehensive study of intramolecular additions of iminyl radicals onto several radical acceptors,
alkenes, alkynes, phenyl rings and indoles, is described. Furthermore, a wide range of nitrogen
heterocyles with potential biological activity was prepared making use of this methodology.
Intramolecular iminyl radical cyclisation onto imines via microwave irradiation was another
process extensively studied. Microwave assisted syntheses of dihydroquinazolines and quinazolines
are described. The precursor O-phenyl oxime ethers enable imine formation to be assimilated with
iminyl radical generation before subsequent cyclisation. Clean, fast and high yielding methodology
was therefore developed for the syntheses of these highly interesting heterocycles which form the
basis of many pharmaceutical products.
Dioxime oxalates were the second type of precursor investigated as sources of iminyl
radicals. Homolytic cleavage of their N-O oxime bonds occurred on photolysis releasing two
molecules of CO₂ and two iminyl radicals in a clean and atom-efficient process. A facile route to
dioxime oxalates with a range of radical acceptors in suitable positions is described.
ESR spectroscopy was used to demonstrate that dioxime oxalates dissociate on photolysis to
give iminyl radicals in the presence of photosensitizer. This technique also confirmed the proposed
mechanisms of radical cyclisation onto double bonds and several 2-azacyclopentylmethyl radicals
were characterized by ESR spectroscopy. In several instances both the uncyclized iminyl radical,
and the cyclised C-radical, could be simultaneously detected, and their concentrations determined. ESR spectroscopy was then profitably used to determine 5-exo-cyclization rate constants of iminyl
radicals onto double bonds.
Finally, the syntheses of several heterocycles from dioxime oxalates are described.
Photolytic dissociation of dioxime oxalates containing alkenyl groups yielded iminyl radicals that
ring closed to 3,4-dihydro-2H-pyrroles in toluene solution. The syntheses of phenanthridines, and
the natural product trisphaeridine, were also accomplished by UV irradiation of dioxime oxalates
containing aromatic rings as the radical acceptor.|
|Publisher: ||University of St Andrews|
|Appears in Collections:||Chemistry Theses|
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