Lithium Enolates Derived from Weinreb Amides: Insights into Five-Membered Chelate Rings

Abstract

Enolization of O-methyl hydroxamic acids (Weinreb amides) in tetrahydrofuran solution with lithium diisopropylamide affords predominantly tetrameric enolates. Aryl substituents on the enolates promote deaggregation. The aggregation states are assigned by using the method of continuous variation in conjunction with 6Li NMR spectroscopy. Decoalescence of the tetramer resonance below −100 °C shows considerable spectral complexity attributed to isomerism of the methoxy-based chelates. Density functional theory calculations were used to examine the consequences of the bite angle of five-membered chelates in cubic tetramers and resulting solvation numbers that were higher than anticipated.

Lithium Amino Alkoxide–Evans Enolate Mixed Aggregates: Aldol Addition with Matched and Mismatched Stereocontrol

“…However, at –105 °C, four resonances corresponding to the pyridine solvate were observed in the slow-exchange limit. 22 In a second experiment, the addition of 2.0 equiv hexamethylphosphoramide (HMPA) per lithium to a THF solution afforded ( S )- 25a for which the most upfield resonance appeared as a doublet (0.26 ppm, J Li–P = 4.3 Hz) owing to 6 Li – 31 P coupling, but no change in the four 6 Li chemical shifts was observed. 32 …”

“…A glimmer of hope was found in contemporaneous studies of Weinreb enolates in which fully chelated tetramers showed evidence of coordinating external ligands to afford five-coordinate lithium owing to the geometric constraints of five-membered chelates. 22 We hoped the aldehyde might find its way into the mixed tetramer core.…”

“…Job plot showing relative integration of the 6 Li resonances ( Cy OLi) 4 22 (gray), 14 (black), 17 (green), and 18 (red) versus the measured mole fraction of Cy OLi (χ Cy OLi ) monitored with 6 Li NMR spectroscopy in 0.11 M THF/toluene at −80 °C. The total lithium alkoxide titer (enolate and alkoxide) is constant (0.10 M).…”

Recent Developments in Weinreb Synthesis and Their Applications

“…It is noteworthy to indicated that this method has some benefits like the isolation of the diastereomers products88 and 89 is totally easy though flash column chromatography and the reaction conditions are compatible at room temperature without using metal catalysts or presence of an inert gases safeguard. Later, Collum and co-workers reported a soft and efficient synthesis of Weinreb enolates91 through coordination between Weinreb amides 90 and LDA base in dry THF/benzene mixture solvents 37 (Scheme 24). Routinely, enolates form tetramers and dimers represented normally as 93 and 94, respectively.…”

Z-Enolate Geometry in the Thioamide Aldol Reaction Illuminated by the 7-Azaindoline Auxiliary

“…Although there has been substantial progress in amide and thioamide aldol reactions from a synthetic standpoint, the geometry of in situ-generated enolate species under catalytic conditions is underexplored. Direct observation of the amide enolate in solution by spectroscopic means remains elusive, and determination of the enolate geometry under specific conditions with a chiral catalyst is a formidable task. Herein we report that combining thioamide chemistry with the 7-azaindoline auxiliary provided explicit evidence of the involvement of the Z -configured thioamide enolate in delivering syn -aldols (Scheme b).…”