Work

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

Year: 2025

Type: article

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.

Source: European Journal of Organic Chemistry

DOI: 10.1002/ejoc.202500080