Characterization of β-Amino Ester Enolates as Hexamers via ~6Li NMR Spectroscopy

摘要

As part of a program to prepare new antithrombotic agents, we discovered that unprotected β-amino esters can be exclusively C-alkylated. We sought to optimize this process by studying the structures and reactivities of β-amino ester enolates. Determining the aggregation state of an enolate, however, is especially difficult due to the high symmetry of the possible aggregates—monomers, dimers, tetramers, and hexamers—and the spectroscopically opaque Li—O linkage. Herein we describe a spectroscopic method used to assign β-amino ester enolates (1) as hexamers in solution. To understand these studies we must briefly digress by describing the dynamic phenomena that are commonly observed for organo-lithium aggregates but may seem surprising to the nonspecialist.3 At the lowest attainable NMR probe temperatures (< —100 ℃), fast processes including solvent exchange, conformational equilibria, and chelate isomerizations can become observable on NMR spectroscopic time scales, with concomitant spectral complexity. The spectra typically simplify on warming above —100℃ due to time averaging. Further warming of the probe often leads to a particularly odd effect in which intra-aggregate exchanges of ~6Li nuclei become fast, whereas inter-aggregate exchanges are still slow. Consequently, aggregates that differ by virtue of their aggregation numbers (dimers versus hexamers) or subunit composition (4:2 versus 3:3 mixed hexamers) appear as separate species by ~6Li NMR spectroscopy, but each aggregate manifests a single ~6Li resonance. This combination of rapid intra-aggregate exchange in conjunction with slow inter-aggregate exchange proves critical to the structural assignments.