Synthesis of Functionalized 3‑Cyanoisoxazoles Using a Dianionic Reagent

A series of 5-acylated 3-cyanoisoxazoles were efficiently synthesized by the Michael addition of dianionic cyano-aci-nitroacetate to α-chloro-α,β-unsaturated ketones followed by intramolecular nucleophilic substitution of the nitronate ion intermediate. In this process, the dianionic reagent serves as the safe synthetic equivalent of the explosive nitroacetonitrile. The 3-cyano group is sufficiently reactive toward ethanolysis and 1,3-dipolar cycloaddition with an azide to afford ethyl ester and tetrazole, respectively. A pyridine ring between the 5-acyl and the 4-aryl group was also constructed. This led to the formation of the isoxazolo­[5,4-c]­quinoline derivative.通过双阴离子氰基-aci-硝基乙酸酯（dianionic cyano-aci-nitroacetate）与α-氯代α,β-不饱和酮的迈克尔加成（Michael addition）反应，再经硝酮离子中间体（nitronate ion intermediate）的分子内亲核取代，我们高效合成了一系列5-酰基取代3-氰基异恶唑（3-cyanoisoxazoles）。在该合成过程中，该双阴离子试剂可作为易爆硝基乙腈（nitroacetonitrile）的安全合成等价体。该产物的3-氰基具有足够反应活性，可分别发生醇解（ethanolysis）以及与叠氮化物（azide）的1,3-偶极环加成（1,3-dipolar cycloaddition）反应，分别得到乙酯（ethyl ester）与四唑（tetrazole）。我们还在5-酰基与4-芳基之间构建了吡啶环（pyridine ring），最终得到异恶唑并[5,4-c]喹啉（isoxazolo[5,4-c]quinoline）衍生物。