Kinetics and Mechanism of the (−)-Sparteine-Mediated Deprotonation of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine

• Published in: Journal of the American Chemical Society 2001-05, Vol.123 (21), p.4919-4927
• Main Authors: Pippel, Daniel J, Weisenburger, Gerald A, Faibish, Neil C, Beak, Peter
• Format: Article
• Language: English
• Subjects: Allylamine - analogs & derivatives; Allylamine - chemistry; Cyclohexanes - chemistry; Deuterium; Kinetics; Lithium - chemistry; Magnetic Resonance Spectroscopy; Protons; Sparteine - chemistry; Spectrophotometry, Infrared
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja001955k

The (−)-sparteine-mediated asymmetric lithiation−substitution of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine ((E)-5) to afford γ-substituted enantiomerically enriched products 6 is reported. The solution structure for the lithiated intermediate 8·1 in these reactions was determined by heteronuclear NMR to be a configurationally stable, α-lithio, η1-coordinated monomer. This intermediate is proposed to exist as two rotamers that are rapidly equilibrating on the NMR time scale; competitive electrophilic substitution of each conformation results in the formation of Z or E products. Kinetic measurements of the lithiation by in situ infrared spectroscopy provide pseudo-first-order rate constants for reactions with a variety of concentrations of amine, (−)-sparteine, and n-BuLi. The reaction is first order in amine and zero order in 1:1 base−ligand complex. When the concentration 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 °C, a result consistent with C−H bond breaking in the rate-determining step and indicative of tunneling. A reaction pathway involving a prelithiation complex is supported by kinetic simulations.