ABSTRACT
In the past couple of years, a few articles have been published on the solid-phase synthesis of pyridazine derivatives [1–9]. These methods apply to intermediates weakly bound to polymers, as a result of which the ester bond is cleaved easily, either during the ring closure or right after it. While these approaches have some advantages if someone wants to have quick success in a few steps while just only touching on solid-phase chemistry, these inhibit exploitation of the field (e.g., optimization of solid-phase synthetic steps is not possible because the product is immediately cleaved from the polymer). Moreover, many slow reactions are used in these methods [1–5, 8, 9] and it is disadvantageous to react or prepare sensitive substrates by reactions taking place over days. Since polymers are not dispersed generally in the whole volume of the reaction mixture, local concentrations of the polymer-supported substrates may be 5 to 20 times higher than that of the reagents (if an equimolar amount is used), depending on the swelling ability of the polymer in the solvent used. Low reaction rates are usually due to low concentrations of the reagents, because more vigorous conditions cannot be used due to the lability of the linker, and because physical properties (like swelling) of the polymers are considered neither by these methods nor by a related solid-phase strategy [10]. Supports of low loading (below 0.6 mmol/g) are used [1–10], but this is insufficient for preparative purposes. Multistage sequences of reaction steps with 2various nucleophiles present elegant approaches [3, 6, 8, 9], but only till the point where optimization is not needed. Otherwise, multistage sequences just cover the fact that simultaneous presence of multiple nucleophiles always results in a product mixture and that the optimum conditions have not been found yet.
