Complex-Induced Proximity Effects in Directed Lithiations:  Analysis of Intra- and Intermolecular Kinetic Isotope Effects in Directed Aryl and Benzylic Lithiations

The mechanism of proton transfers in directed lithiations has been investigated by measuring the intra- and intermolecular kinetic isotope effects for the benzylic lithiation of N-benzyl-N,N‘-dimethyl urea (6) and the ortho lithiations of the tertiary amide N,N-diisopropylbenzamide (7) and the secondary amide N-isopropylbenzamide (8) by sec-BuLi/TMEDA in THF. For the lithiation of 6, a large primary kinetic isotope effect is observed for intramolecular competition of monodeuterated substrate, and a much smaller apparent isotope effect is seen for the intermolecular competition between diprotiated and dideuterated substrates. These results support a two-step mechanism of largely irreversible initial complexation between the substrate and the organolithium reagent, which is followed by hydrogen transfer to the organolithium reagent for the directed lithiation of urea 6. Indistinguishable limits for large intermolecular and intramolecular isotope effects are measured for the lithiations of 7 and 8. The directed lithiations of amides 7 and 8 are suggested to proceed by a two-step mechanism in which initial complexation is largely reversible.