Lithiation of 4-methoxy-2-pyridones. Synthetic entry to tenellin and funiculosin, and related natural 3,5-disubstituted 4-oxy-2-pyridones

Lithiation of 4-methoxy-2-pyridone with butyllithium at –78 °C occurs at the C-3 position exclusively. Subsequent reactions with MeOD, Mel, CO2, benzaldehyde or (E)-but-2-enal then lead to the corresponding C-3-substituted derivatives. In a one-pot procedure, treatment of 1,2-dihydro-4-methoxy-1-methyl-2-oxopyridine-3-carboxylic acid with ammonia in the presence of a polyphosphate buffer at 80 °C produced natural ricinine in 58% overall yield.A convenient three-step synthesis of 5-aryl- and 5-alkyl-substituted 4-methoxy-2-pyridones is described. Lithiation of these substrates, followed by reaction with electrophiles, provided a convenient route to 3,5-disubstituted 4-oxy-2-pyridones, and a synthetic entry to natural products, e.g. tenellin and funiculosin, containing this structural feature.