Kinetics and mechanism of the (-)-sparteine-mediated deprotonation of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine

The (-)-sparteine-mediated asymmetric lithiation-substitution of (E)-N-Boc- N-(p-methoxyphenyl)3-cyclohexylallylamine ((E)-5) to afford gamma -substitu ted enantiomerically enriched products: 6 is reported. The solution structu re for the lithiated intermediate 8.1 in these reactions was determined by heteronuclear NMR to be a configurationally stable, alpha -lithio.,eta (1)- coordinated monomer. This intermediate is proposed to exist as two rotamers that are rapidly equilibrating on the NMR time scale: competitive electrop hilic substitution of each conformation results in the formation of Z or E products. Kinetic measurements of the lithiation by in situ infrared spectr oscopy provide pseudo-first-order rate constants for reactions with a varie ty of concentrations of amine, (-)-sparteine. and n-BuLi. The reaction is f irst order in amine and zero order in 1:1 babe-ligand complex. When the con centration of n-BuLi is varied independently of (-)-sparteine concentration , the reaction rate exhibits an inverse dependence on n-BuLi concentration. The deuterium isotope effect for the reaction was determined to be 86 at - 75 degreesC, a result consistent with C-H bond breaking in the: rate-determ ining step and indicative of tunneling. A reaction pathway involving a prel ithiation complex is supported by kinetic simulations.