Deoxygenative Route to Alkynylation of Heterocyclic N-Oxides under Ball Milling

Herein, we disclose the first example of stainless-steel-induced deoxygenative C-2 alkynylation of heterocyclic N-oxides under ball milling via a radical-mediated pathway. The current approach afforded the corresponding alkynylated quinolines/pyridines through alkynylation and deoxygenation in one step. Significant tolerance of structural variations with various electron-donating (-Me, -OMe, -Et, -ⁿBu, -OEt) and electron-withdrawing substituents (-I, -Br, -Cl, -F, -CF₃, -NO₂), both in the quinoline/pyridine N-oxides and in phenylacetylene derivatives, has been observed, affording 34 products in 61-94% yields. The method was successfully applied to the synthesis of two mGluR5 antagonists. Detailed mechanistic investigations based on extensive control experiments and XPS analysis corroborated the significant role of Fe(III) species present in the milling equipment (stainless steel) as well as the mechanical impact of the milling equipment (Fe/Zr-jar/balls) in facilitating the reaction via a radical pathway.