Sodium Diisopropylamide in Tetrahydrofuran: Selectivities, Rates, and Mechanisms of Arene Metalations.

Sodium diisopropylamide (NaDA)-mediated metalations of arenes in tetrahydrofuran (THF)/hexane or THF/MeNEt solutions are described. A survey of >40 benzenoid- and pyridine-based arenes with a range of substituents demonstrates the efficacy and regioselectivity of metalation. Metalations of activated disubstituted arenes and selected monosubstituted arenes are rapid at -78 °C. Rate studies of 1,3-dimethoxybenzene and related methoxylated arenes show exclusively monomer-based orthometalations with two or three coordinated THF ligands. Rate studies of the isotopic exchange of benzene and monosubstituted arenes with weakly activating groups reveal analogous di- and trisolvated monomer-based metalations. Cooperative inductive, mesomeric, steric, and chelate effects are discussed.