Organic Chemistry

Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions



The selective functionalization of saturated oxygen heterocycles at positions remote to the embedded heteroatoms remains an outstanding challenge in organic synthesis. Although many methods exist for the undirected replacement of C–H bonds with heteroatomic subunits the number of site selective C–H functionalization reactions for the introduction of carbon-carbon bonds pales in comparison. This paper describes the initial stages of a long-term program aimed at elucidating how organolithium reagents can be re-engineered to selectively deprotonate and functionalize saturated heterocycles at new locations. Through rigorous NMR spectroscopic investigations, it was determined for the first time that the addition of Lewis basic phosphoramides can shift the equilibrium of strong organolithium bases, such as t-BuLi, to include the triple ion pair (t-Bu–Li–t-Bu) / L4Li which serves as a reservoir for the highly reactive separated ion pair t-Bu / L4Li . Because the Li-atom’s valences are saturated the Lewis acidity is significantly decreased and the basicity is maximized which allowed for the typical directing effects within oxygen heterocycles to be overridden and for remote sp3-CH bonds to be deprotonated. In certain cases, this enabled the removal of stronger C–H bonds in the presence of weaker C–H bonds. Furthermore, these newly accessed lithium aggregation states were leveraged to develop a simple γ-lithiation and capture protocol (lithium nucleophilic coupling – “LiNC”) of chromane heterocycles with a variety of alkyl halide electrophiles in good yields.


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Supplementary material

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Supplementary Information
Full experimental procedures, characterization, and kinetic data.