Difluoromethyl Nitrile Oxide (CF₂HCNO): A Neglected Chemical Reagent

Abstract

A novel chemical reagent – difluoromethyl nitrile oxide, CF2HCNO – was generated in situ for the first time. The synthesis commenced with ethyl difluoroacetate and included only two chemical steps. The difluoromethyl nitrile oxide smoothly participated in [3+2]‐cycloaddition reactions with alkynes and enamines to give CF2H‐isoxazoles; these products are promising cores for agrochemistry. A representative CHF2‐isoxazole was incorporated into the known fungicide Fluxapyroxad (BASF), and the synthesized analogue showed higher antifungal activity than the parent fungicide.

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

“…The starting chloroximes 5 – 9 [both ( R )‐ and ( S )‐isomers were used in the case of chiral compounds] and enamines 10 – 18 were prepared according to the known procedures. Existing literature protocols for the [3+2] cycloaddition of halogenoximes and “push‐pull“ enamines varied in the reaction conditions, including AcOH in dioxane–H 2 O, neat Et 3 N, NaHCO 3 in EtOAc,, , and no promoter in dioxane , . In this work, we have used the conditions described in our previous works for similar transformations of the chloroximes 5 – 9 , , .…”

“…Existing literature protocols for the [3+2] cycloaddition of halogenoximes and “push‐pull“ enamines varied in the reaction conditions, including AcOH in dioxane–H 2 O, neat Et 3 N, NaHCO 3 in EtOAc,, , and no promoter in dioxane , . In this work, we have used the conditions described in our previous works for similar transformations of the chloroximes 5 – 9 , , . Thus, treatment of 5 – 9 with NaHCO 3 in EtOAc at room temp., followed by addition of 10 – 18 and subsequent stirring at room temp.…”

“…The known methods for the synthesis of 4‐(het)arylisoxazoles include palladium‐catalyzed C–C couplings,, , various heterocyclizations and recyclizations, diazotative deamination of the corresponding 5‐aminoisoxazoles, and formal [3+2] cycloaddition of alkynes, electron‐deficient enamines or their synthetic equivalents with halogenoximes , . The latter approach can be considered as the most convenient since generally, the target products are obtained in good yields with high regioselectivity.…”

“…formal [3+2] cycloaddition of alkynes, electron-deficient enamines or their synthetic equivalents with halogenoximes. [21,[33][34][35][36][37][38][39][40][41] The latter approach can be considered as the most convenient since generally, the target products are obtained in good yields with high regioselectivity. In most cases, however, the above-mentioned reactions were performed with aryl-substituted halogenoximes (Scheme 1).…”

“…[34,36] In this work, we have used the conditions described in our previous works for similar transformations of the chloroximes 5-9. [37,44,46] Thus, treatment of 5-9 with NaHCO 3 in EtOAc at room temp., fol-Eur. J. Org.…”