Synthesis of coumarins in search of better nonpeptidic HIV protease inhibitors

3-Substituted-4-hydroxycoumarins have been recently identified as active no npeptidic HIV pretense inhibitors. In order to get more potent inhibitors, synthesis of a number of 3-substituted-4-hydroxycoumarins have been designe d. Nucleophilicity of C-3 in 4-hydroxycoumarin is exploited by reacting wit h an electrophile3-carbethoxycoumarin to achieve a new C-3 substituted-4-hy droxycoumarin. But the product identified is a benzopyranodicoumarin (2), w hich is also obtained by the reaction of 4-hydroxycoumarin with salicylalde hyde. However, the reaction of 4-hydroxycoumarin with a number of 2-oxygena ted aldehydes 4b-e affords dicoumarols (5a-d) only. On the contrary, with 2 ,4,5-trimethoxybenzaldehyde (4f), a benzopyranodicoumarin (6a) is formed. T he reaction of 4-hydroxycoumarin with 6-bromo-3,4-methylenedioxybenzaldehyd e (4g) and 6-bromo-3,4-dimethoxybenzaldehyde (4h), when treated separately, furnisher benzopyranodicoumarin (Gb) and benzopyranocoumarin (7) respectiv ely. In both the eases, unusual nucleophilic aromatic substitution of bromi ne occurs in electron-rich aromatic systems without any catalyst.