Multicomponent Synthesis of Polysubstituted Pyridines

Significance

Reported is the synthesis of polysubstituted pyridines through the multicomponent reaction of 1,3-dicarbonyls, aromatic aldehydes, malononitrile, and alcohols. The reaction requires the use of a base (sodium hydroxide) and also proceeds in a stepwise fashion, if the aldehyde and malononitrile are first mixed together in DMF and the intermediate product is isolated. Treatment with base (triethylamine) and with a 1,3-dicarbonyl compound in alcohol gives the desired pyridine. A mechanism can thus be proposed, whereby the aldehyde and malononitrile undergoes a Knoevenagel condensation, the product of which undergoes a Michael-type condensation with the 1,3-dicarbonyl species. The ­final pyridine is provided after tautomerization, attack by the alcohol, and oxidation. Although this mechanism seems plausible, caution must always be exerted when applying the knowledge gained from step-wise reactions to multicomponent systems.