On the Synthesis of [1,3]Azaphospholo[4,5-f]quino(xa)lines and 2,3-Dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line 1-oxides

Abstract

Despite their potential in areas such as medicinal chemistry and organic materials, scaffolds in which quinoline and quinoxaline are fused to phosphacycles such as 1,3-oxaphosphole, 1,3-azaphosphole, P-arylated and P-alkoxylated 2,3-dihydro-1,3-azaphosphole P-oxides have, to our knowledge, never been reported. In this study we have developed a synthetic approach to [1,3]azaphospholo[4,5-f]quinolines and -quinoxalines from quinolin-6-amine and quinoxalin-6-amine. These were converted to 5-phosphanylquino(xa)lin-6-amines by regioselective iodination in position 5, cross-coupling with diethyl phosphite and reduction. Formation of the azaphosphole ring was then achieved by reaction with N,N-dimethylformamide dimethyl acetal. Attempts at C−H arylation in position 2 did not lead to the desired derivatives but rather to 1-arylated 2,3-dihydro-[1,3]azaphospholo[4,5-f]quino(xa)line 1-oxides. Access to 1-alkoxylated 2,3-dihydro-[1,3]azaphospholo[4,5-f]quinoline 1-oxides was also developed using as key steps cross-coupling with ethyl phosphinate formed in situ and the subsequent Kabachnik-Fields reaction. The resulting tricyclic compounds were finally tested against a panel of disease-related protein kinases.