Polysubstituted Pyridazinones from Sequential Nucleophilic SubstitutionReactions of Tetrafluoropyridazine

摘要

4,5,6-Trifluoropyridazin-3(2H)-one can be used as a scaffold for the synthesis of various 4,5- and 4,6-disubstituted and ring-fused pyridazinone systems by sequential nucleophilic aromatic substitutionprocesses. Although the regioselectivity of nucleophilic substitution can be affected by the nature ofthe nucleophile and the substituent attached to the pyridazinone ring, a variety of polyfunctionalsystems can be readily accessed by sequential nucleophilic substitution methodology which may haveapplications in the drug discovery arena. For example, reaction of 4,5,6-trifluoropyridazin-3(2H)-one with nitrogen nucleophiles leads to a mixture of aminated products arising from substitution offluorine located at the 4- and 5-positions. The ratio of isomers obtained depends on the nucleophilewhere the 4-isomer is the major product for reaction with primary and secondary amines such asbutylamine, morpholine, and aniline derivatives. Subsequent reaction of representative 4-aminatedproducts gave 4,5-disubstituted systems and ring fused derivatives may be formed by reaction of4,5,6-trifluoropyridazin-3(2H)-one or 4-substituted systems with N,N'-dimethylethylenediamine.