Synthesis of 5‑(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

A comprehensive study on the synthesis of 5-fluoroalkyl-substituted isoxazoles starting from functionalized halogenoximes is reported. One-pot metal-free [3 + 2] cycloaddition of CF3-substituted alkenes and halogenoximes bearing ester, bromo, chloromethyl, and protected amino groups was developed for the preparation of 5-trifluoromethylisoxazoles. The target 3,5-disubstituted derivatives were obtained in a regioselective manner in good to excellent yield on up to 130 g scale. 5-Fluoromethyl- and 5-difluoromethylisoxazoles were synthesized by late-stage deoxofluorination of the corresponding 5-hydroxymethyl or 5-formyl derivatives, respectively, in turn prepared via metal-free cycloaddition of halogenoximes and propargylic alcohol. An alternative approach based on nucleophilic substitution in 5-bromomethyl derivatives was found to be more convenient for the preparation of 5-fluoromethylisoxazoles. Reaction of isoxazole-5-carbaldehydes with the Ruppert–Prakash reagent was used for the preparation of (β,β,β-trifluoro-α-hydroxyethyl)­isoxazoles. Utility of described approaches was shown by multigram preparation of side-chain functionalized mono-, di-, and trifluoromethylisoxazoles, for example, fluorinated analogues of ABT-418 and ESI-09.本文报道了一项以官能化卤代肟为起始原料合成5-氟烷基取代异恶唑的系统性研究。开发了一种无需金属的一锅法[3+2]环加成反应，以含酯基、溴原子、氯甲基及保护氨基的卤代肟与三氟甲基取代烯烃为底物，用于制备5-三氟甲基异恶唑。目标3,5-二取代衍生物以区域选择性方式获得，产率良好至优异，放大规模可达130克。5-氟甲基异恶唑与5-二氟甲基异恶唑则分别通过对应5-羟甲基或5-甲酰基衍生物的后期脱氧氟化反应合成，而前述中间体可通过卤代肟与炔丙醇的无金属环加成反应制备。针对5-氟甲基异恶唑的合成，另一种基于5-溴甲基衍生物亲核取代的策略被证明更为便捷。异恶唑-5-甲醛与鲁普特-普拉卡什（Ruppert–Prakash）试剂的反应可用于制备(β,β,β-三氟-α-羟乙基)异恶唑。通过多克级规模制备侧链官能化的一氟、二氟及三氟甲基异恶唑（例如ABT-418与ESI-09的氟化类似物），验证了所报道方法的实用性。