Studies in the Chemistry and Properties of 7, 8, 9, 10-Tetrahydro Pyrido (1, 2-A) Aquinoxalin-6-Ones
This thesis reports the results of investigations into the chemistry and properties of the new heterotricycle: 7, 8, 9, 10-tetrahydropyrido (1, 2-a) aquinoxalin-6-one. The chemistry and properties of quinoxalines, pyrrolo (1,2-a) quinoxalines and pyrido (1,2-a) quinoxalines are reviewed. A re-investigation of the methods of synthesis of the title compound and some of its derivatives was undertaken. Condesation of pipecolinic acid with the appropriately substituted 1-fluoro-2-nitrobenzene in ethanol basified wih 10% sodium hydrogen carbonate solution followed by cyclization of the resulting N-(2 - nitrophenyl) piperdine-2- carboxylic and with alkaline sodium dithionite was developed as the optimum method. The 2-fluoro-and 3-methyl- derivatives of the heterotricycle were prepared in this manner. The sodium dithionite reductive cyclization method, however, proved ineffective when there was another reducible group in the acid adduct. In this case, selective hydrogen transfer reductive cyclization of the methyl ether of the carboxylic acid, via palladium on carbon, was the preferred method. The 3-nitro derivative of the heterotricycle was available only by this method. The reactions of 7, 8, 9, 10-tetrahydropyrido (1,2-a) quinoxalin-6-one with electrophilic reagents have been studied. The tetrahydropyioxalinone was found to be completely unreactive to some reagents and in several other instances, intractable mixtures of compounds were obtained. Nitration of the heterocycle was however achieved with a mixture of potassium nitrate and sulphuric acid, giving the 2-nitro compound. Attempted nitration with concentrated nitric acid alone, or in other solvents, gave ring-opened products, as the tricyclic skeleton is readily cleaved under these conditions. Bromination of the heterocycle was examined under four different conditions in order to delineate the role played by the amine and amide nitrogen atoms in directing electrophilic substitution into the aromatic ring. With one mole equivalent bromine in acetic acid and with bromine in bioling hydrobromic acid, two different monobromo derivatives were obtained. Mixtures of products were obtained, on the other hand, from the reactions of the heterocycle with N-bromosuccinimide in 50% sulphuric acid and also with excess bromine in acetic acid. 1H-NMR nuclear Overhauser enhancement studies involving the amide N-H of the 7,8,9,10-tetrahydropyrido (1,2-a) quinoxalin-6-ones have been used to fully assign for the first time, the aromatic proton signals of the pyrido (1,2-a)quinoxalin-6-ones as well as to unambiguously characterize the products of nitration with potassium nitrate/sulphuric acid and bromination with one mole equivalent bromine in glacial acetic acid as the 2-nitro-; and 3-bromo compounds respectively. Attempted N-alkylations of 7,8,9,10-tetrahydropyrido(1,2-a) quinoxalin-6-one by the conventional methods of reaction with an alkyl halide in the presence of a strong base such as sodium hydride or sodium methoxide were unsuccessful. A convenient and mild method of N-alkylation of the heterocyclic compounds via a phase transfer process was however developed. N-alkylation of the tetrahydropyridoquinoxalinones were accomplished in a solid-liquid two-phase system consisting of powdered sodium hydroxide/potassium carbonate suspended in benzene, in the presence of a catalytic amount of tetra-n-butylammonium hydrogen sulphate. Good yields of the relatively more soluble N-alkyl products were obtained. Several attempts at selective replacement of the 6-oxo group in the title compound with chlorine by reaction with phosphoryl chloride were unsuccessful and gave rise to a suspected polychlorinated compound. Products of attempted oxidation with manganese dioxide and alkaline potassium ferricyanide are described. Full assignments of the 1H and 13C-NMR resonance of the new heterocycle 7,8,9,10-tetrahydropyrido (1,2,-a) quinoxalin-6-one and some of its derivatives are reported for the first time. Unambiguous assignments were made by extensive NOE experiments in conjunction with the use of 2D one-bond and long rage 13C:1H chemical shift correlations. The replacement of hydrogen with deuterium has been known to produce shifts in the position of the neighbouring carbon-13 NMR signals. The magnitude of these effects has recently been shown to possess a stereochemical dependance. Exchange of the amide N-of the7,8,9,10-tetrahydropyrido (1,2-a) quinoxalin-6-ones with deuterium induces shifts in the carbon-13 resonances of the heterocycle. Evidence is presented in this work to show that the magnitude of the deuterium isotope effect on these carbon-13 NMR resonance bears a geometrical relationship to the N-H. Fungicide activity of the tetrahydropyridoquinoxalinones, their precursors and N-alkyl derivatives are also reported for the first time.