PdII-Catalyzed Conjugate Addition of Boronic Acids to Ketoglutaconic Esters toward the Synthesis of Functionalized Pyridazin-3(2H)-ones with Neuroprotective Activity



The development of the regioselective conjugate addition of boronic acids to ketoglutaconic esters under transition metal catalysis is reported. Among the different catalysts tested for this transformation, the dicationic PdII catalysts generated with Pd(OCOCF3)2, dppben, and HBF4 performed best in terms of yields, regioselectivities and avoidance of Heck-type by-products. The resulting 4-aryl-2-oxopentadienoates were transformed into pyridazin-3(2H)-ones, potentially useful for the therapy of neurodegenerative diseases. These compounds simultaneously exhibited β-secretase activity, inhibition of β-amyloid (βA) aggregation, and disaggregation of pre-formed βA fibrils, and also had a good scavenging profile for intracellular reactive oxygen species (ROS).