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

Abstract

As part of a program to prepare new antithrombotic agents, we discovered that unprotected -amino esters can be exclusively C-alkylated. We sought to optimize this process by studying the structures and reactivities of -amino ester enolates. 1 Determining the aggregation state of an enolate, however, is especially difficult due to the high symmetry of the possible aggregatessmonomers, dimers, tetramers, and hexamerssand the spectroscopically opaque Li-O linkage. 2 Herein we describe a spectroscopic method used to assign -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 organolithium aggregates but may seem surprising to the nonspecialist. 3 At the lowest attainable NMR probe temperatures (<-100°C), fast processes including solvent exchange, 4 conformational equilibria, 5 and chelate isomerizations 6 can become observable on NMR spectroscopic time scales, with concomitant spectral complexity. The spectra typically simplify on warming above -100°C due to time averaging. Further warming of the probe often leads to a particularly odd effect in which intra-aggregate exchanges of 6 Li nuclei become fast, whereas inter-aggregate exchanges are still slow. 7 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 6 Li NMR spectroscopy, but each aggregate manifests a single 6 Li resonance. This combination of rapid intra-aggregate exchange in conjunction with slow inter-aggregate exchange proves critical to the structural assignments.The 6 Li NMR spectrum recorded on [ 6 Li](R)-1 in 9.0 M THF/ toluene at -100°C shows a single resonance, consistent with almost any aggregation state of high symmetry. The 6 Li NMR spectrum recorded on [ 6 Li]rac-1 affords a single resonance at a markedly different chemical shift than ( Figure 1A) show both resonances along with considerable "noise" in the baseline. Additionally, 6 Li spectra recorded on [ 6 -Li, 15 N](S)-1 and [ 6 Li, 15 N]rac-1 show 6 Li-15 N coupling (d, J Li-N ) 3.4 and 3.6 Hz, respectively), confirming chelation as drawn. 8 Varying the probe temperature from -100 to -50°C afforded a single sharp resonance for Figure 1B). The data are consistent with deep-seated structural complexities that simplify by rapid intra-aggregate exchange at elevated temperatures. Furthermore, the relative intensities are independent of the enolate concentration (0.04-0.40 M) and the THF concentration (2.0-9.0 M), indicating that the four species are at the same aggregation and solvation state.We considered models based on homochiral aggregates (R N or S N ) and heterochiral aggregates (R n S N-n ). R n S N-n /R N-n S n and R N / S N refer to pairs of spectroscopically indistinguishable enantiomers. Dimers (R 1 S 1 and R 2 /S 2 ) and tetramers (R 4 /S 4 , R 1 S 3 /R 3 S 1 , and R 2 S 2 ) afford only two and three 6 Li resonances, respectively. ...

Lithium Phenolates Solvated by Tetrahydrofuran and 1,2-Dimethoxyethane: Structure Determination Using the Method of Continuous Variation

“…An ensemble of homo- and heteroaggregated phenolates (eq 1) was monitored as a function of the mole fractions of phenolate subunits (denoted generically as A and B ) using 6 Li NMR spectroscopy 6,7. The number of aggregates and their symmetries reflect the aggregation state, n (Table 2; Chart 2).…”

“…The parametric fits show that all are nearly statistical distributions; non-statistical ensembles usually attest to deep-seated structural anomalies (vide infra). The math underlying the parametric fits has been discussed previously 6,7…”

“…Characterizing O-lithiated species in solution is particularly important because of their role in organic chemistry,1 but it is a daunting task 2,3,4,5,6,7. Problems stem from a combination of both the high inherent symmetry of the possible aggregates and the absence of measurable Li-X scalar couplings that have in other studies proven indispensable for characterizing alkyllithiums8 and lithium amides 9.…”

“…We have recently found the method of continuous variation10,11 to be a powerful and widely applicable method for characterizing lithium enolates 6,7. The strategy finds its origins in studies by Chabanel,12 Gagne,13 Günther,14 and others 15.…”

A convenient method for the synthesis of α-silylacetic acids

“…Recently, it has been shown that the C-alkylation of b-amino esters proceeds via hexameric enolates, which exist as such both in the solid state and in THF solution. 23 Based on the above observations, the existence of a C-lithiated ester enolate has been ruled out. Therefore, it is likely that O-versus C-silylation depends on the equilibrium between the two OLi structures, monomeric 'A' and aggregated 'B', as depicted in Scheme 1.…”