The results of a combination of 6Li and 13C NMR spectroscopic

The results of a combination of 6Li and 13C NMR spectroscopic and computational studies of oxazolidinone-based lithium enolates-Evans enolates-in tetrahydrofuran (THF) solution revealed an assortment of dimers tetramers and oligomers (possibly ladders). uncovered their importance in selective alkylations highly.2 What followed is Kdr currently background: oxazolidinone-based chiral enolates-so-called Evans enolates-have appeared in a BMS-345541 lot more than 1600 patents and countless academics and industrial syntheses.3 Variations from the extensions and auxiliaries4 of oxazolidinones beyond the chemistry of enolates5 verify their importance. (1) Despite speedy and broad advancements of Evans enolates in synthesis structural and mechanistic research of these substances remain conspicuously uncommon.6 7 Presumably the lack of crystal buildings is due to limiting physical properties rather than lack of curiosity; the BMS-345541 ranks have already been BMS-345541 joined by us of these who possess didn’t develop diffractable crystals. Spectroscopic determination from the buildings of enolates in option is inherently hard owing to the absence of usable O-M scalar coupling and we have found only a single spectroscopic study of a boron-based Evans enolate.6a 6 The paucity of computational studies is most vexing 6 but computations of the lithium enolates unsupported by experimental data would be of limited value regardless.8 9 We describe herein NMR spectroscopic and computational studies of a number of oxazolidinone-derived lithium enolates. The general structural types are illustrated in Plan 1. The auxiliary- and solvent-dependent structural assignments are summarized in Table 1 and limited data on an additional 28 enolates are archived in the supporting information. We focus on the propionate enolate 5 (observe Table 1) derived from phenylalanine owing to its importance in synthesis3 4 and structural tractability. In a subsequent paper we will offer insights into why aldol additions based on lithiated Evans enolates are so challenging1 10 11 12 while possibly nudging them out of relative obscurity. Plan 1 Table 1 Structures of oxazolidine-derived enolates (0.10 M) in tetrahydrofuran (THF)/toluene and THF solutions at ?80 °C corresponding to tetramers (1) and dimers (2 and 3). Results Structure Determinations General Strategies BMS-345541 Our structural studies required a variety of techniques and analytical methods which centered on the method of continuous variations (MCV) delineated in a series of previous papers.13 14 In short the high symmetry of lithium enolate aggregates is usually broken by mixing two enolates generically denoted as Aand Bin eq 2 to afford an ensemble containing heteroaggregates whose figures spectral symmetries and concentration dependencies reveal the aggregation number the same however. Enolization at ?78 °C affords exclusively dimer as the product which is stable for hours. Warming to ?40 °C equilibrates the homoaggregates affording distributions of dimers and tetramers that are sensitive to enolate and THF concentrations. We focus exclusively on equilibrated mixtures in this statement and reserve conversation of unequilibrated mixtures21 for any subsequent treatise around the BMS-345541 aldol addition. Plan 2 Solvated Dimers Neat THF solutions of hindered enolates 7 and 18 at ?80 °C each display a single 6Li resonance. Both also show marked (>0.6 ppm) downfield shifts with the addition of pyridine which attests to the importance of solvation analyzed quantitatively below.17 22 The 6Li resonances of 7 and 18 are sufficiently well-resolved for the use of MCV (Determine 1). Thus varying the proportions in mixtures of 7 and 18 at a constant total enolate titer revealed a single heteroaggregate consistent with enolate dimers. Plotting the relative integration versus the measured mole portion of enolate subunit 18 (mixtures of 7 (Physique 3) was a bit unusual in showing only two curves because the homochiral dimers [(axis) and = 0.50 (axis). between ?80 and ?95 °C were consistent with isomer exchanges. In general however dimer isomerism eluded detailed experimental scrutiny; all we realize for several is that unsymmetric and symmetric variations are observable in a few examples.23 24 Body 4 6 NMR spectral range of 5 (0.10 M total concentration) in neat THF at ?80 °C teaching equilibrium populations of tetramer 1 and isomeric dimers 2 and 3. Computational research on the B3LYP degree of theory using the 6-31G(d) basis established and MP2.