Synthesis of functionalized pyridine derivatives by an amidoalkylation/Staudinger/aza-Wittig sequence

A new efficient methodology for the preparation of 3,4-difunctionalized pyridine derivatives by an amidoalkylation/Staudinger/aza-Wittig sequence has been developed. The synthesis includes condensation of 3-azidopropanal with urea and p-toluenesulfinic acid followed by reaction of the N-[(3-azido-1-tosyl)propyl]urea obtained with Na-enolates of tosylacetophenone or acetyl acetone to give N-[(5-azido-1-oxo-1-phenyl-2-tosyl)pent-3-yl]urea and 5-acetyl-6-(2-azidoethyl)-4-hydroxy-4-methylhexahydropyrimidin-2-one, respectively. These compounds are transformed into 6-phenyl-5-tosyl-4-ureido- and 5-acetyl-6-methyl-4-ureido-1,2,3,4-tetrahydropyridines by treatment with PPh3. The former is aromatized under the action of MnO2 or reduced by NaBH4/CF3COOH system to provide 2-phenyl-3-tosylpyridine and 2-phenyl-3-tosyl-4-ureidopiperidine.