Highly regioselective Friedländer annulations with unmodified ketones employing novel amine catalysts: syntheses of 2-substituted quinolines, 1,8-naphthyridines, and related heterocycles.

ABSTRACT

Catalysts were evaluated on the preparation of 2-substituted quinolines, 1,8-naphthyridines, and chromone derivatives from unmodified methyl ketones and o-aminoaromatic aldehydes. While oxide catalysts yielded the 2,3-dialkyl substituted products, cyclic secondary amines provided the 2-alkylsubstutited products regioselectively. In particular, pyrrolidine derivatives provided the highest regioselectivity favoring the 2-substituted products. The most reactive and regioselective catalyst was the bicyclic pyrrolidine derivative, TABO (1,3,3-trimethyl-6-azabicyclo[3.2.1]octane), yielding 1,8-naphthyridines with as high as 964 regioselectivity. Regioselectivity increased with slow addition of the methyl ketone substrate to the reaction mixture, and was positively related to temperature. Isolated yields of single regioisomers were typically 65-84%, while observed regioselectivities were > or =9010 for 1,8-naphthyridines and > or =8416 for quinolines.