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.