O-Heterocycle Synthesis Via Intramolecular C-H Alkoxylation Catalyzed By Iron Acetylacetonate

Intramolecular alkoxylation of C-H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of Spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C-H alkoxylation to furnish oxacycles from easily prepared alpha-diazo-beta-ketoesters using commercially available iron acetylacetonate (Fe(acac)(2)) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N-2 extrusion, which mediates a proximal H-atom abstraction followed by a rapid C-O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C-D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C-H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C-H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic 0-heterocycles from readily available precursors.