Substituted pyridines are important as natural products and components of natural products and as unnatural compounds, yet their synthesis is still a challenge as there are very few general methods available. The aza-Diels-Alder method provides rapid access to highly substituted pyridines.
This research project studies the synthesis of substituted pyridines via aza-DielsAlder reactions of novel aza-dienes and dienophiles. The synthesis of novel azadienes involved the investigation of oxime, enamine and hydrazone synthesis.
Oximes were studied using ethyl acetoacetate as the starting material; this was reacted to give ethyl oximino acetoacetate. The OH group of the oxime was then reacted with trimethylsilyl chloride, 1 butyldimethylsilyl chloride and dimethyl sulphate to give the corresponding oxime ethers, these oximes were further reacted with pyrrolidine in an attempt to make the corresponding enamine/aza-diene, these reactions were unsuccessful and the oximes would undergo a Beckmann rearrangement. Hydrazones were synthesised from 2,3-butanedione and N,N-dimethylhydrazine, the hydrazone was then reacted with pyrrolidine in an attempt to form an aza-diene, the reaction was repeated under various conditions but the desired product was never formed and starting materials were recovered. Various reactions were done in an
attempt to react the carbonyl functional group present in the hydrazone, these reactions were also unsuccessful. The bis-hydrazone could however be formed from 2,3-butanedione but not from the mono-hydrazone.
Ethyl oximino acetoacetate was then reacted with excess trimethylsilyl chloride to form an aza-diene. This aza-diene was heated under reflux with dimethylacetylene dicarboxylate in toluene for 3 weeks to form a highly substituted pyridine, the azadiene was then reacted with various other dienophiles but no products were isolated after 6 weeks of heating under reflux. Some of the reactions were repeated by heating in a sealed tube but these were also unsuccessful. The reaction with the aza-diene and dimethylacetylene dicarboxylate was repeated using microwave irradiation this also formed the substituted pyridine and reduced the reaction time from 3 weeks to ½ hour.