posted on 2021-05-05, 14:35authored byYuyang Dong, Alexandra T. Wrobel, Gerard J. Porter, Jessica J. Kim, Jake Z. Essman, Shao-Liang Zheng, Theodore A. Betley
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 α-diazo-β-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 N2 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 O-heterocycles from readily available precursors.