No description available.

This thesis is concerned with the development of three new synthetic routes to highly functionaliscd imidazo[4,5-b]pyridinone derivatives of biological interest as purine antagonists. The first synthetic route developed was based on the construction of 5-nitro-6-methylthiopyridine derivatives by annulation of readily available l-amino-l-methylthio-2-nitroethenes with 1,3-bis-clectrophiles (e.g. mal-onyl dichloride). Although this new type of ring formation was successful, the yields of the new pyridine derivatives obtained were disappointingly low and studies to improve the efficiency of the cyclisation met with little success. Subsequent displacement of the methylthio group in the new pyridine derivatives with benzylamines, and base catalysed cyclisation of the resulting amino-nitropyridines provided an efficient new route to otherwise inaccessible and usefully functionaliscd imidazo[4,5-b]pyridinone derivatives. The second new synthetic route to imidazo[4,5-b)pyridinone derivatives investigated was concerned with reductive cyclisation reactions of 4-nitro-imidazol-5-ylcarbonylmethine derivatives accessible by the previously un-described acylation reactions of activated mcthylene compounds with 4-nitroimidazole-5-carbonyl chlorides. This synthetic approach was largely successful and allowed the efficient general synthesis of highly function-alised and otherwise unavailable imidazo[4,5-b]pyridinone derivatives. The chemistry of the novel compounds thereby made available was also studied and their utility as starting materials for the synthesis of other imidazopyridine derivatives by functional group manipulation, investigated. The third synthetic pathway to imidazo[4,5-b]pyridinone derivatives explored, involved as a key step, the successful displacement of the halogen atom in 5-chloro-4-nitroimidazoles by anions derived from activated methylene compounds. The resulting 4-nitroimidazol-5-ylacetate derivatives were converted smoothly on heating into 3-substituted imidazo[4,5-c] isoxazoles in high yield. Reductive opening of the isoxazole ring in these compounds provided a viable high yielding method for the synthesis of 4-amino-5-ethoxalylimidazole derivatives. The latter were in turn successfully converted into usefully functionaliscd imidazo[4,5-b]-pyridinone derivatives in moderate to good yield by cyclisation with activated methylene compounds in high boiling solvents. This method complements the second route developed in the present studies by allowing the synthesis of 6-substituted derivatives as distinct from the 5-and 7-substituted imidazo[4,5-b]pyridinones available through imidazolyl-carbonylmethine precursors.

No description available.

The preparation of phosphoranes and their uses in the synthesis of non-phosphorus containing molecules are reviewed. The photolysis and vacuum flash thermolysis (V.F.T.) of two new oxazaphospholans, 5,9-diphenyl-2,3-benzo-9-aza-1,4,6-trioxa -5-phosphaspiro-[4,4]-nonane and 9-methyl-5-phenyl-2,3-benzo-9-aza-l,4,6-trioxa-5-phosphaspiro-[4,4]-nonane are outlined. The V.F.T. and photolysis of some 1,3,2-dioxa-phospho1ans are also mentioned. A review of pheny1phosphinidene, pheny1phosphinothioylidene and pheny1phosphinylidene is given. 2,3-Diphenyl-1,3,2-oxazaphospholene is investigated as a possible precursor to pheny1phosphinylidene. The results of a number of attempted trapping reactions upon this species are discussed. The photolysis of 1,2-dihydronaphthalenes, chromenes, isochromenes, thiochromenes and related compounds is reviewed. Work showing that the photolysis of 1-substituted-dihydrophosphinoline oxides gives similar products is included. The syntheses of phosphorinans, phosphorindienes, phosphinolines and isophosphinolines are discussed. The products obtained from the photolysis of a number of new 1-substituted-(1,2)-dihydrophosphinoline oxides are identified. Attempts to trap out the intermediate species in these reactions with other trapping reagents although unsuccessful are discussed. A short review is given of monometaphosphate and similar species. Finally preparations of 1,2-oxaphosphol-3-ene 2-oxides are reviewed and the reactions of some of them outlined.

The flash vacuum thermolysis and photolysis of a number of cyclic sulphones have been studied with a view to developing these reactions as possible synthetic processes. A number of 2- substituted thietan sulphones have been shown to give the appropriately substituted cyclopropanes in high yields. The corresponding reactions of 3-substituted theitan sulphones are not quite so clean however, and a number of products are formed. Attempts have been made to synthesise sulphoximides based on the thiochroman nucleus; however, without success. The flash thermolyses of thiochroman-4-one sulphones have been studied. The products of these reactions are generally ?,?- unsaturated ketones, and the mechanism has been probed by deuterium labelling experiments. The flash thermolyses of some substituted ?-sultines have been studied in detail. Generally, sulphur dioxide is extruded and the products are derived from the remaining biradical species. In one case however, one of the products is derived from a loss of sulphur monoxide from the starting material. The conformational equilibria of various cis and trans 3-substituted thietan 1-oxides have been studied using n.m.r. spectroscopy and a lanthanide shift reagent technique. In general it has been found that the oxygen atom prefers to adopt an equatorial position in all of the compounds studied.

3-Substituted thietane 1-oxides have been investigated by proton, carbon-13, and lanthanide induced shift, magnetic resonance studies, and for the two isomers of 3-p-bromophenylthietane 1-oxide, by X-ray crystallography. It has been concluded that it is reasonable to interpret the physical properties of a solution of the cis-isomers in terms of the single conformer in which both substituents occupy equatorial positions, and those of the trans-isomers in terms of approximately equal amounts of both possible conformers. cis and trans-3-Methylthietane 1-oxide react with toluene-p- -sulphonyl isocyanate to give the thietane imides with epimerisation. In polar solvents the reaction involves prior equilibration of the sulphoxides, but in non-polar solvents this does not occur. Pentamethyl-1-phenylphosphetan 1-oxides react with toluene-p- -sulphonyl isocyanate to give the phosphetan imides with retention of configuration. The reaction has been shown to be first order in both reactants. Optically active acyclic phosphine oxides however react to give racemic phosphine imides. The first step of this reaction involves racemisation of the phosphine oxide. Kinetic studies have shown this process to be first order in phosphine oxide and second order in isocyanate. Investigations suggest that if a reaction involves putting a formal positive charge on sulphur in a thietane or its 1-oxide, and if there is a good nucleophile in solution, then nucleophilic attack will occur at the a-carbon and ring opened products will result. The photolysis and flash thermolysis of a series of 4?-electron cyclic sulphones have been investigated. These reactions are thought to involve an unsaturated sulphene which rearranges to give a series of cyclic sulphinate esters. In the thermolysis reaction these then fragment. A number of novel organo-platinum complexes have been prepared and their structures have been determined by n.m.r. and infrared spectroscopy. Attempts to generate stable sulphene-metal complexes by rearrangement of the above complexes induced by thermal, photochemical, and chemical means, have not been successful.

Within a number of industries, and particularly within the pharmaceutical industry, there is a desire for reliable, high yielding routes towards large numbers of valuable small molecules that allow a wide range of products to be synthesised. Heterocyclic compounds are particularly sought after as useful compounds, with an estimated 70% of pharmaceutical products being based on heterocyclic structures. A drawback of many traditional routes towards heterocyclic compounds is that the range of substituents that may be placed around the ring is limited. This is especially limiting if ring substituents have to be placed early in a synthesis, reducing the opportunities for elaboration at a late stage. Our approach is to take highly halogenated heterocyclic systems and use them as scaffolds for the synthesis of novel compounds by the sequential replacement of halogen atoms with other functionalities. This approach has led to the generation of a number of novel highly substituted heterocyclic species.

The work contained in this thesis was intended to study the rearrangement of <i>o</i>-nitrotoluene to anthranil which has previously been shown to occur under a variety of conditions. Flash Vacuum Pyrolysis (FVP) of nitrotoluene over zeolite 13X was carried out. <i>o</i>-Nitrotoluene was found to give conversion to toluene in 5.5% yield with recovery of starting material (12%). FVP of <i>m</i>-nitrotoluene gave recovery of toluene in 8% yield and starting material (7%). FVP of <i>p</i>-nitrotoluene gave only a trace of toluene with mainly recovery of unreacted starting material (12%). FVP of 1-ethyl-2-nitrobenzene over zeolite 13X gave conversion to ethylbenzene in 13% yield and styrene in 4% yield along with recovery of a trace of starting material. FVP of nitrotoluene was also carried out over the zeolites A, Y, ZSM-5 and mordenite as well as alumina and silica. <i>o-</i>Nitrotoluene was found to give conversion to aniline by a combined reduction and dealkylation in yields from 5-41% with unreacted starting material (0-515); <i>o</i>-toluidine and toluene were identified as minor products in several of the pyrolyses. <i>m-</i>Nitrotoluene over alumina gave aniline and <i>m</i>-toluidine. <i>p-</i>Nitrotoluene over zeolite Y alumina gave conversion to aniline and <i>p</i>-toluidine. FVP of 1-ethyl-2-nitrobenzene over these zeolites, silica and alumina gave conversion to aniline and indole in varying amounts; minor products of styrene, 2-vinylaniline and ethylaniline were also observed. FVP of 3-methylanthranil with no catalyst at 700°C gave conversion to 1<i>H</i>-indol-3(2<i>H</i>)-one in 86% yield. FVP of 3-methylanthranil over zeolite mordenite at 500°C gave conversion to 1<i>H-</i>indol-2(2<i>H</i>)-one in 11% yield along with unreacted starting material (6%). FVP of 1<i>H-</i>indol-3(2<i>H</i>)-one over zeolite mordenite at 500°C gave rearrangement to 1<i>H</i>-indol-2(2<i>H</i>)-one in 37% yield. FVP of anthranil over zeolite Y at 500°C gave conversion to aniline in 28% yield.

The cycloaddition reactions of a number of triene-conjugated nitrile ylides and diazoalkanes were studied. In all cases the a,b unsaturation was part of a benzene or thiophene ring and the g,d;e,ζ double bonds were olefinic. The nitrile ylides in which the trienyl system was in the <i>trans</i> configuration reacted exclusively <i>via </i>1,1-cycloadditions to yield the corresponding 1-alkenyl-<i>exo</i>-cyclopropa[<i>c</i>]isoquinolines. These primary products were found to undergo intramolecular rearrangement reactions of three types to yield 4-alkenyl-1<i>H</i>-2-azepines, propenyl-bridged isoquinolines (or the thiophene analogue) or azabenzobabaralanes. It was found that the proportions of these products obtained were dictated by the substitution pattern of the precursor cyclopropa[<i>c</i>]isoquinoline, and, in each case, the observed reaction modes are rationalised in terms of substituent effects. Triene-conjugated diazoalkanes where the <i>cis </i>d substituent was hydrogen were found to yield exclusively the 4-alkenyl-1<i>H</i>-2,3-diazepines, presumably <i>via</i> a 1.7-electrocyclisatoin process. Where the <i>cis </i>d substituent was a phenyl ring and the ζ-substituent was an aryl group a 1,1-cycloaddition occurred, ultimately yielding the pyrrolophthalazines. Where either the d- or ζ-substituent of the diazoalkane was non-aromatic, carbene-derived products were formed <i>via</i> intermolecular reactions. Where the trienyl system was in the <i>cis</i> configuration at the g,d-bond the 1,1-cycloaddition process became less competitive and the major or exclusive products were the carbene-derived cyclopropa[<i>a</i>]naphthalenes. Greater proportions of the phthalazines were obtained where the ζ-substituent was aromatic. This effect is rationalised in terms of the stability of a proposed diradical intermediate for rearrangement of the primary cycloaddition product.

This thesis is concerned with the synthesis and reactivity of condensed polyaza heterocycles as potential new DNA binding/intercalating agents. In particular, the use of isoxazoles as key intermediates in the synthesis of polyfunctionalised quinoline derivatives followed by the annulation of these latter derivatives is described. 1,3-Dipolar cycloaddition reactions of 2-nitrobenzonitrile N-oxide with conjugated alkynes or alkenes or its conjugate addition with activated methylene anions gave 3-(2-nitrophenyl)isoxazole derivatives. Reduction of the nitro-group and cyclisation through a suitable substituent in the 4 position of the isoxazole ring afforded functionalised isoxazoloquinoline derivatives, reductive cleavage of the isoxazole ring in which released masked ortho-amino-carbonyl functionality thus providing access to a variety of novel polyfunctionalised quinoline derivatives. Heteroannulation reactions of 4-amino-1,2-dihydro-2-oxoquinoline-3-carboxamide and of its 1-hydroxy analogue gave functionalised pyrimido[5,4-c]quinoline and 6-hydroxyprimido[5,4-c]quinoline derivatives respectively, while heterocyclisation reactions of ethyl 3-(4-amino-1,2-dihydro-2-oxoquin-3-yl)-3-oxopropionate and of its 1-hydroxy analogue afforded pyrido[3,2-c]quinoline and 6-hydroxypyrido[3,2-c]quinoline derivatives respectively. The reactivity of these potential new DNA binding/intercalating agents was also briefly examined. The nucleophilic displacement reactions of the peri substituted 4,5-dichloropyrimido[5,4-c]quinoline with a variety of mono- and dinucleophilic agents were the subject of substantial investigations yielding a variety of novel 4,5-disubstituted and 4,5-annulated pyrimido[5,4-c]quinoline derivatives. In addition, nucleophilic substitution reactions of 2,4,5-trichloropyrimido[5,4-c]quinoline and 2,4,5-trichloropyrido[3,2-c]quinoline were the subject of a brief examination in the course of which they were converted into a number of new 2,4,5-trisubstituted pyrimido[5,4-c]quinoline and pyrido[3,2-c]quinoline derivatives respectively.