Oxime derivatives : versatile reagents for radical-mediated syntheses of heterocycles

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- heterocyles. 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

The oxime portmanteau motif : released heteroradicals undergo incisive EPR interrogation and deliver diverse heterocycles

OA funded through the RCUK OA block grant.Selective syntheses are now available for compounds of many classes, based on C-centered radicals, exploiting a diverse range of mechanisms. The prospect for chemistry based around N- and O-centered radicals is probably more favorable because of the importance of heterocycles as biologically active materials. Heteroradical chemistry is still comparatively underdeveloped due to the need for safe and easy ways of generating them. Oxime esters appeared promising candidates to meet this need because literature reports and our EPR spectroscopic examinations showed they readily dissociated on photolysis with production of a pair of N- and O-centered radicals. It soon became apparent that a whole suite of benign oxime-containing molecules could be pressed into service. The bimodality of the oxime motif meant that by suitable choice of functionality the reactions could be directed to yield selectively products from either the N-centered radicals or from the O-centered radicals. We found that on one hand photolyses of acetophenone oxime esters of carboxylic acids yielded alicyclics. On the other hand, aromatic and heteroaromatic acyl oximes (as well as dioxime oxalates) afforded good yields of phenanthridines and related heterocycles. Easily prepared oxime oxalate amides released carbamoyl radicals, and pleasingly, β-lactams were thereby obtained. Oxime carbonates and oxime carbamates, available via our novel 1,1'-carbonyldiimidazole (CDI)-based preparations, were accessible alternatives for iminyl radicals and hence for phenanthridine preparations. In their second modes, these compounds proved their value as precursors for exotic alkoxycarbonyloxyl and carbamoyloxyl radicals. Microwave-assistance was shown to be a particularly convenient procedure with O-phenyl oxime ethers. The iminyl radicals generated from such precursors with alkene, alkyne, and aromatic acceptor substituents furnished pyrrole, quinoline, phenanthridine, benzonaphthiridine, indolopyridine, and other systems. Microwave irradiations with 2-(aminoaryl)alkanone O-phenyl oximes enabled either dihydroquinazolines or quinazolines to be obtained in very good yields. The fine quality of the EPR spectra, acquired during photolyses of all the O-carbonyl oxime types, marked this as an important complement to existing ways of obtaining such spectra in solution. Quantifications enabled SARs to be obtained for key reaction types of N- and O-centered radicals, thus putting mechanistic chemistry in this area on a much firmer footing. Surprises included the inverse gem-dimethyl effect in 5-exo-cyclizations of iminyls and the interplay of spiro- with ortho-cyclization onto aromatics. Insights into unusual 4-exo-cyclizations of carbamoyl radicals showed the process to be more viable than pent-4-enyl 4-exo-ring closure. Another surprise was the magnitude of the difference in CO2 loss rate from alkoxycarbonyloxyl radicals as compared with acyloxyl radicals. Their rapid 5-exo-cyclization was charted, as was their preferred spiro-cyclization onto aromatics. The first evidence that N-monosubstituted carbamoyloxyls had finite lifetimes was also forthcoming. It is evident that oxime derivatives have excellent credentials as reagents for radical generation and that there is ample room to extend their applications to additional radical types and for further heterocycle syntheses. There is also clear scope for the development of preparative procedures based around the alkoxyl and aminyl radicals that emerge downstream from oxime carbonate and oxime carbamate dissociations.Publisher PDFPeer reviewe

Oxime derivatives : versatile reagents for radical-mediated syntheses of heterocycles

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- heterocyles. 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.EThOS - Electronic Theses Online ServiceGBUnited Kingdo