Polysubstituted Pyridazinones from Sequential Nucleophilic Substitution Reactions of Tetrafluoropyridazine

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 substitution processes. Although the regioselectivity of nucleophilic substitution can be affected by the nature of the nucleophile and the substituent attached to the pyridazinone ring, a variety of polyfunctional systems can be readily accessed by sequential nucleophilic substitution methodology which may have applications 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 of fluorine located at the 4- and 5-positions. The ratio of isomers obtained depends on the nucleophile where the 4-isomer is the major product for reaction with primary and secondary amines such as butylamine, morpholine, and aniline derivatives. Subsequent reaction of representative 4-aminated products gave 4,5-disubstituted systems and ring fused derivatives may be formed by reaction of 4,5,6-trifluoropyridazin-3(2H)-one or 4-substituted systems with N,N′-dimethylethylenediamine.

4,5,6-三氟哒嗪-3(2H)-酮 (4,5,6-Trifluoropyridazin-3(2H)-one)可作为合成骨架，通过连续亲核芳香取代反应，用于制备各类4,5-及4,6-二取代并环稠合哒嗪酮体系。尽管亲核取代的区域选择性会受亲核试剂性质与哒嗪酮环上取代基的影响，但借助连续亲核取代策略，可便捷获取多种多官能团体系，这类体系在药物研发领域具备潜在应用价值。例如，4,5,6-三氟哒嗪-3(2H)-酮与氮亲核试剂反应时，会因4位和5位氟原子被取代而生成胺化产物混合物。所得异构体的比例由亲核试剂种类决定：对于正丁胺、吗啉及苯胺衍生物等伯、仲胺类亲核试剂，4位取代异构体为主要产物。对代表性的4位胺化产物进行后续反应，可得到4,5-二取代体系；而4,5,6-三氟哒嗪-3(2H)-酮或4位取代体系与N,N'-二甲基乙二胺反应时，可生成环稠合衍生物。