Direct formylation of 2-pyridone core of 3-N-methylcytisine via Duff reaction; synthesis of 9-enyl, 9-ynyl and 9-imino derivatives

The first direct synthesis of 3-N-methyl-9-formylcytisine via electrophylic formylation is described. It is established, that Vilsmeier-Haack and Gatterman variants of this reaction are unsuccessful in the case with 3-substituted (-)-cytisine derivatives, but Duff procedure (with hexamethylenetetramine in trifluoroacetic acid) gives a possibility to obtain the target pseudo aromatic aldehyde with the 69% yield. Convenient precursors for [4 + 2]- or [3 + 2]-cycloaddition reactions are obtained by means of condensation of synthesized 3-N-methyl-9-formylcytisine with acetone, nitromethane and phosphorous ylides with yields from 70 to 87%. Alternative aprroach to alkenyl products and to 9-alkynyl-3-methylcytisine is realized using the Heck and Sonogashira cross-coupling reactions of methyl vinyl ketone, cyclohexenone or trimethylsilylacetylene with 9-bromo-3-methylcytisine (55, 70 and 60% accordingly). It is shown, that interaction of 3-N-methyl-9-formylcytisine with hydroxylamines leads to corresponding nitrone (93%) and oxime (70%). All individual compounds are isolated by column chromatography and completely characterized on the basis of NMR spectroscopy data.