The preparation and properties of annelated pyridines and related heterocyclic systems



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A series of monoannelated pyridines has been prepared in which a four, five or six-membered ring is fused at either the 2,3- or 3,4-position of the pyridine ring. The partial hydrogenation of isoxazole and substituted isoxazoles provides a convenient source of [beta]-amino-[alpha],[beta]-unsaturated carbonyl compounds. The [beta]-amino-[alpha], [beta]-unsaturated aldehydes react with five or six-membered cyclic ketones in a normal Friedlander type of reaction leading to the formation of 2,3-mono-annelated pyridines whereas [beta]-amino-[alpha],[beta]-unsaturated ketones are found to yield rearranged 2,3-mono-annelated pyridines. Condensation reactions were employed to prepare a similar series of bis-annelated pyridines in which all possible combinations of five and six-membered rings are fused to the pyridine nucleus. The reaction between [beta]-aminomethylenecycloalkanones and cyclic ketones leads to the formation of [2,3:5,6]-bisannelated pyridines rather than expected [2,3:4,5]bisannelated pyridines. The [2,3:4,5bisannelated pyridines have been prepared by condensation between cyclic ketones, formaldehyde and ammonium acetate. Utilizing the Friedlander condensation between 2-aminonicotinaldehyde and cyclic ketones a series of 2,3-fused 1,8-napthyridines have also been prepared. Cyclobutapyridines are found to undergo catalytic hydrogenation at room temperature and one atmosphere of hydrogen to the corresponding azabicyclo[4.2.0]octanes. The [raised 1]H and [raised 13]C NMR spectra of annelated pyridines have been determined. As the size of the ring fused to pyridine is decreased, the chemical shifts of "bridgehead carbons increase, while the chemical shift of the carbon ortho to the fused ring decreases. The proton attached to this ortho carbon moves down-field except in the case of cyclobutapyridines. The basicities of annelated pyridines and of 2,3-fused,-1,8-napthyridines have been determined as half neutralization potentials by titration in acetic anhydride using 0.1 N perchloric acid in acetic acid as titrant. Decreasing the size of the ring fused at the 2,3-position of pyridine decreases the basicity of the molecule, whereas ring fusion at the 3,4-position of pyridine has only a minor and apparently inconsistent influence on the basicity. For 1,8-napthyridines, decreasing the size of the fused ring also results in a decrease in the basicity, but due to the presence of two nitrogen atoms, the overall basicity of the molecule is not affected dramatically. The gas phase basicities and photoelectron spectra of mono-annelated pyridines has been determined in collaboration with Dr. Donald Aue of the University of California at Santa Barbara.