Autocatalysis in Lithium Diisopropylamide-Mediated Ortholithiations

Ortholithiation of 3-fluorophenyl-N,N-diisopropyl carbamate by lithium diisopropylamide (LDA) in THF at -78 degrees C affords unusual rate behavior including linear decays of the carbamate, delayed formation of LDA-aryllithium mixed dimers, and evidence of autocatalysis. A mechanistic model in conjunction with numeric integration methods accounts for the time-dependent changes in concentration. The two critical rate-limiting steps in the model entail (1) an LDA dimer-based metalation of arylcarbamate, and (2) a rate-limiting condensation of the resulting aryllithium with the LDA dimer to form two isomeric LDA-ArLi mixed dimers. One isomer elicits a highly efficient (post-rate-limiting) metalation of aryl carbamate, in turn, regenerating aryllithium. The prevalence and implications of such autocatalysis are discussed.