UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis in the pyridine series : Part 1. The synthesis of new 3,4,5-trialkylated pyridines ; part 2. The synthesis of new 3,5 dimethyl-4-substituted pyridines ; steric effects as an aid to synthesis Tabata, Takao


PART I A synthetic sequence leading to new and inaccessible 3,4-,5-trialkylated pyridines has been developed 3,4-Dimethyl-5-cyanopyridine was converted to 3,4-dimethyl-5-acetylpyridine on treatment with methylmagnesium iodide and the acetylpyridine was subsequently treated with ethylmagnesium iodide to yield 3,4-dimethyl-5(2-hydroxy-2-butyl)pyridine. Removal of the hydroxyl group was accomplished by means of red phosphorus and hydriodic acid and the resulting olefinic compounds were catalytically hydrogenated to 3,4-dimethyl-5-s-butylpyridine. For further studies in this area, 3,4-dimethyl-5-acetylpyridine was reduced to 3,4-dimethyl-5-ethylpyridine by the Wolff-Kishner reaction and the latter was condensed with benzaldehyde to afford 3-methyl-4-styryl-5-ethyl-pyridine. This, on ozonolysis, was converted to 3-methyl-5-ethyl isonicotinic acid which was subsequently methylated with diazomethane to methyl 3-methyl-5-ethyl-4-pyridine-carboxylate. The nature of the synthesis allows the preparation of virtually any type of 3,4-,5-trialkylated pyridine by straightforward variations at the appropriate stage. PART II In relation to Part I, the synthesis of 3,5-dimethyl-4-substituted pyridines was undertaken. 3,5-Lutidine was reacted with acetic anhydride and zinc to afford in good yield the unexpected 3,5-dimethyl-4-acetyl-pyridine. This was then conveniently converted to 3,5-dimethyl-5-ethylpyridine on reduction with acetic acid and zinc thereby confirming the structure of the acetylpyridine. The acetylpyridine was also reduced with lithium aluminum hydride to 3,5-dimethyl-4-(1-hydroxyethyl)pyridine which in turn was readily dehydrated with phosphorus pentoxide to 3,5-dimethyl-4-vinylpyridine. Both the hydroxypyridine and the vinylpyridine on treatment with hydrobromic acid yielded 3,5-dimethyl-4(2-bromoethyl)-pyridine hydrobromide. This was then converted to 3,5-dimethyl-4-(2-cyanoethyl)pyridine. The preparation of these compounds was possible due to the utilization of the steric effects enforced by the two neighbouring methyl groups at the 3 and 5 positions of the pyridine ring. This sequence of reactions provides a valuable method by which 3,5-dimethyl-4-substituted pyridines can be synthesized owing to the availability of the starting material and to the relatively high yielding reactions.

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