Copper-Catalyzed Ring-Opening Defluorinative Alkylation of Siloxydifluorocyclopropanes: Synthesis of γ‑Fluoro-δ-Ketoesters and γ,δ-Diketonitriles

In
view of the importance of both fluorinated synthons and homoenolate
equivalents, synthetic application of difluorocyclopropanols is desired
but remains challenging due to their thermodynamic instability. Herein,
we use siloxydifluorocyclopropanes as difluorocyclopropanol precursors
to carry out new Cu-catalyzed ring-opening defluorinative alkylation.
With α-bromo carboxylic esters as coupling partners, the reaction
affords γ-fluoro-δ-ketoesters via a CuI/CuII catalytic cycle. Interestingly, by the use
of α-bromoamides, the ring-opening defluorinative alkylation
is followed by an additional intramolecular C–N oxidative coupling
to deliver a lactam intermediate, which further undergoes defluorination,
hydrolysis, ring opening, and dehydration cascade via a CuI/CuII/CuIII catalytic pathway,
leading to γ,δ-diketonitriles as the final products.

鉴于氟化合成子与同烯醇等价物均具有重要应用价值，二氟环丙醇的合成应用虽备受期待，但因其热力学不稳定性，相关研究仍存在诸多挑战。本文以硅氧基二氟环丙烷作为二氟环丙醇前体，开发了一种新型铜催化开环脱氟烷基化反应。当以α-溴代羧酸酯作为偶联底物时，该反应可通过一价铜/二价铜催化循环，生成γ-氟代-δ-酮酸酯类产物。值得注意的是，当采用α-溴代酰胺作为底物时，开环脱氟烷基化反应完成后，会进一步发生分子内C-N氧化偶联，得到内酰胺中间体；该中间体随后通过一价铜/二价铜/三价铜催化路径，依次经历脱氟、水解、开环与脱水级联反应，最终得到γ,δ-二酮腈类目标产物。