Selective functionalization of the 1-imidazo[1,2-]pyrazole scaffold. A new potential non-classical isostere of indole and a precursor of push-pull dyes.

We report the selective functionalization of the 1-imidazo[1,2-]pyrazole scaffold using a Br/Mg-exchange, as well as regioselective magnesiations and zincations with TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl), followed by trapping reactions with various electrophiles. In addition, we report a fragmentation of the pyrazole ring, giving access to push-pull dyes with a proaromatic (1,3-dihydro-2-imidazol-2-ylidene)malononitrile core. These functionalization methods were used in the synthesis of an isostere of the indolyl drug pruvanserin. Comparative assays between the original drug and the isostere showed that a substitution of the indole ring with a 1-imidazo[1,2-]pyrazole results in a significantly improved solubility in aqueous media.