Insight into the Behaviour of a Lithium Enolate in Solution

(2S,4S)-2-(tert-Butyl)-5-oxo-1,3-dioxolan-4-acetic acid ( 1 ) was dilithiated to the enolate 2 in toluene and THF with lithium diisopropylamide (LiN(i-Pr)₂) under various conditions. Deuteration experiments with 2 showed that two different stable forms of the enolate could be produced, depending on whether the deprotonation of 1 had been carried out in toluene or THF. The generated (i-Pr)₂NH was coordinated to the enolate and, hence, served as a strong lipophilic solvating agent. LiN(i-Pr)₂ could substitute the amine ligands of the two species to a different extent. THF was partially able to displace (i-Pr)₂NH that solvated the species produced in toluene, but the coordination of the amine to the one produced in THF was quantitive. Correlations with given explanations are made.     

Influence de la solvatation par le tert-butanol sur la structure et la reactivite de l'enolate de potassium de l'acetylacetate d'ethyle en presence de couronne ou de cryptand. etude par spectrometrie infra-rouge et cinetique

The structure and the nucleophilic reactivity of crowned (18-crown-6) or cryptated {cryptand (2.2.2)} potassium ethyl acetoacetate enolate have been compared in tert-butanol and in DME (or THF). In the protic solvent tert-butanol, the crowned and the cryptated potassium enolate species both exist as loose ion pairs in which the enolate anion, strongly hydrogen-bonded to the solvent, is in a “transoid” (non chelating) conformation. Both species show similar reactivities towards alkylating agents but completely different reactivities are observed in aprotic weakly dissociating media (THF, DME). In contrast to what is observed in tert-butanol, the cryptated species and the crowned species have very different nucleophilic reactivities in THF or DME; in those solvents only the cryptated species retains a loose ion pair structure; the crowned species is a contact ion pair in which the enolate anion chelates the potassium cation. The solvation of this crowned chelate species by tert-butanol has been demonstrated in binary mixtures of solvents (C₆D₆-t-BuOH, THF-t-BuOH). The oxygen basicity of the enolate anion is very different in the crowned chelated ion pair compared with the cryptand separated ion pair.     

Convergent regiodirected assembly of 2,3-disubstituted furans

The conjugate addition of organocopper reagents to alpha, beta-unsaturated enones results in the regiospecific generation of enolate anions, which can be made to undergo the aldol reaction with (tetrahydropyranyloxy)acetaldehyde under zinc chloride catalysis. Treatment of the resulting product with p-toluenesulfonic acid in THF affords the targeted 2,3-disubstituted furan.     

Why is alkylation of an enolate accompanied by so much polyalkylation?

[reaction: see text] The lithium enolate 1-Li of 6-phenyl-alpha-tetralone forms a monomer-tetramer equilibrium in THF at 25 degrees C with K(1,4) = 4.7E+10 M(-3). The lithium enolate 2-Li, however, forms a monomer-dimer equilibrium with K(1,2) = 3800 M(-1). In both cases reaction with benzyl bromide is dominantly with the monomer. The results support an earlier conjecture of House that alkylation of an enolate is frequently accompanied by extensive polyalkylation because the less substituted enolates are more aggregated.     

二(2,6-二叔丁基-4-个甲基苯氧基)钐催化丙交酯开环聚合

聚丙交酯（PLA）可以生物降解，产物无毒，可用于外科手术的缝合线、人造器官以及药物缓释等方面，因此引起了人们的广泛注意．丙交酯的开环聚合是合成聚丙交酯的一种方便方法，所用的催化剂主要是主族及副族金属的配合物，如双金属氧桥配合物［‘j，烷基金属有机化合物［‘j，异丙氧基铝［’‘以及叶琳铝「“等．最近，关于三价烷氧基稀土化合物作为单组份催化剂催化丙交酯开环聚会已有报道［’·’‘．我们发现两价芳氧基稀土化合物（ArO）。Sin（THF）。（ArO一2，已二叔丁基一个甲基苯氧基）也可以有效地催化丙文酯的开环聚合．本…     

Mechanistic studies of the lithium enolate of 4-fluoroacetophenone: rapid-injection NMR study of enolate formation, dynamics, and aldol reactivity

Lithium enolates are widely used nucleophiles with a complicated and only partially understood solution chemistry. Deprotonation of 4-fluoroacetophenone in THF with lithium diisopropylamide occurs through direct reaction of the amide dimer to yield a mixed enolate-amide dimer (3), then an enolate homodimer (1-Li)(2), and finally an enolate tetramer (1-Li)(4), the equilibrium structure. Aldol reactions of both the metastable dimer and the stable tetramer of the enolate were investigated. Each reacted directly with the aldehyde to give a mixed enolate-aldolate aggregate, with the dimer only about 20 times as reactive as the tetramer at -120 °C.     

Lithium and Cesium Ion-Pair Acidities of Dibenzyl Ketone. Aggregation of Lithium and Cesium Ion Pairs of the Enolate Ion and Dianion(1)(,)

Spectral study of the cesium and lithium enolates of dibenzyl ketone (DBK) showed that both salts exist as contact ion pairs in THF solutions. The spectral data for the dicesium salt of DBK indicate that it exists as triple ions in which both cations are in contact with the dianion. The dilithium salt of DBK forms triple ions of two types in THF: in one, both cations are in contact with the DBK dianion, in the other, one of the lithium cations is solvent-separated. Evidence for dimerization of the ion pairs was obtained for both lithium and cesium enolates of DBK from UV-vis spectral (blue shift of the absorbance band at higher concentrations) and acidity (the decrease of pK at higher concentrations) studies. The dimerization constant for the cesium enolate of DBK obtained from the acidity data (3.5 x 10(3) M(-)(1)) is considered to be more accurate than that from the spectral analysis (1.7 x 10(3) M(-)(1)). The lithium enolate is much less dimerized than its cesium counterpart with a dimerization constant from acidity data of 4.2 x 10(2) M(-)(1). The first and second cesium pK values of DBK are 18.07 and 33.70, respectively, compared to the first lithium pK of 11.62.     

Cascade approach toward the core structure of neosarpagine

[reaction: see text] A palladium-catalyzed domino sequence was developed to rapidly construct the core structure of neosarpagine and other quinuclidine-related alkaloids. The cyclization of ketone 11 to ethylidene 4 with Pd(dba)2, DPEphos, LiHMDS, and ZnCl2 in THF represents a new domino process wherein a nonstabilized enolate served as a nucleophile.     

Diastereoselective alkylation of beta-amino esters: structural and rate studies reveal alkylations of hexameric lithium enolates

Alkylation of beta-amino ester enolates proceeds with high diastereoselectivity. Single crystal, powder, and solution X-ray diffraction studies of the enolate show that the racemic enolate forms prismatic hexamers. 6Li NMR spectroscopic studies on partially racemic enolates reveal complex mixtures of homo- and heterochiral hexamers. An implicit fit of the aggregate populations to the Boltzmann distribution provides the free energy differences and equilibrium constants for the ensemble. Rate studies show that enolate alkylation occurs directly from the hexamer with participation by THF. A mechanism based on the alkylation of a ladder-like aggregate is proposed.     

DFT and ONIOM study on the alkylation of the lithium enolate in solution: microsolvation cluster models for CH2=CHOLi?+?CH3Cl?+?(THF)0�C6

DFT computational study on the alkylation of the lithium enolate derived from acetaldehyde with MeCl was performed. The reaction of the free enolate CH₂=CHO^? with MeCl has an early transition state with low barrier, and the reaction of its lithium enolate gave a cyclic transition structure with high activation energy; neither of them is a good model for reaction in solution. In the presence of 1?C6 THF molecule(s), a typical S_N2 transition structures were obtained with reasonable activation energies after the PCM correction. Especially, the reaction in the presence of three THF molecules completed the tetra-coordination of the lithium cation, and structurally and energetically, this is an optimal model for the reaction in the solution. The transition structures were also located at the ONIOM level (high?=?B3LYP/6?C31(+)G*: low?=?RHF/3?C21 G*). The results are favorably compared with the full DFT results.     

DFT study of the effect of sigma-ligands on the structure of ester enolates in THF, as models of the active center in the anionic polymerization of methyl methacrylate.

A Density Functional Theory (DFT) study was carried out on structures of the lithium ester enolate of methyl isobutyrate (MIB-Li) in THF solution, in the presence of TMEDA, dimethoxyethane (DME), crown ether 12-crown-4, and cryptand-2,1,1, as electron donor ligands (sigma-ligands). Both specific solvation with THF and/or ligand molecules and nonspecific solvation by the solvent continuum were taken into account. The possibility of ligand-separated ion pair formation was analyzed for each of the ligands, including THF alone. In most cases peripherally solvated dimers are the most stable species. Only in the presence of cryptand-2,1,1 was a ligand-separated triple ion pair, (MIB-Li-MIB)(-)(THF)(2),Li(2,1,1)(1)(+), shown to be comparable in stability to the THF-solvated dimer, (MIB-Li)(2)(THF)(4). These results are in agreement with experimental NMR data on the structure of MIB-Li in the presence of DME, 12-crown-4, and cryptand-2,1,1. An upfield shift of the (13)C NMR signal of the alpha-carbon of MIB-Li observed in the presence of cryptand-2,1,1, originally attributed to a ligand-separated monomer, MIB(-),Li(2,1,1)(+), was well reproduced by Hartree--Fock calculated NMR shifts for the predicted ligand-separated triple ion pair.     

Effet de solvant sur support solide:régiosélectivité de l'alkylation des énolates de l'acétylacétate d'éthyle par le sulfate d'éthyle en présence de “hmpt solide”

The reaction of Li, Na, K enolates of ethylaceto acetate with diethylsulfate in THF at room temperature gives 60–70% O-alkylation when performed in the presence of one molar equivalent of solid HMPA. Without HMPA, in the same conditions, Li enolate docs not react, Na enolate only gives C-alkylation while K enolate leads to 90% C-alkylation, the reactions being quite slower in the two latter cases. The effects of one molar equivalent of solid and liquid HMPA are compared: for the K enolate the reaction is faster and the degree of O-alkylation higher with solid HMPA; practically no difference is seen for Na enolate, while the reverse is observed with the Li enolate. The cooperative effect of the polymer should thus only work for a sufficiently large cation, as the Li enolate is fixed on the solid HMPA in a larger amount than the K enolate. The study of this reaction is proposed to test the efficiency of other “solid solvents” interacting strongly with cations.     

Practically useful Reformatsky Type Reactions of Chlorodifluoroacetate and Bromodifluoroacetate Induced by Samarium(II) Diiodide

Treatment of XCF₂COOEt (X = Cl and Br) with SmI₂ in THF gave efficiently β,β-difluorinated enolate equivalent, which was used for Reformatsky type reaction with aldehydes and ketones to give 2,2-difluoro-3-hydroxy ester.     

Reversible enolization of beta-amino carboxamides by lithium hexamethyldisilazide

The enolization of beta-amino carboxamides by lithium hexamethyldisilazide (LiHMDS) in THF/toluene and subsequent diastereoselective alkylation with CH(3)I are reported. In situ IR spectroscopic studies reveal that beta-amino carboxamides coordinate to LiHMDS at -78 degrees C before enolization. Comparison with structurally similar carboxamides suggests that the beta-amino group promotes the enolization. IR spectroscopic studies also show that the enolization is reversible. Efficient trapping of the enolate by CH(3)I affords full conversion to products. (6)Li and (15)N NMR spectroscopic studies reveal that lithium enolate-LiHMDS mixed dimers and trimers as well as a homoaggregated enolate are formed during the reaction. At ambient temperature, racemization of the beta-position through a putative reversible Michael addition was observed.     

Hydrogenation of carbon monoxide by tetranuclear rare earth metal polyhydrido complexes. Selective formation of ethylene and isolation of well-defined polyoxo rare earth metal clusters

The reaction of the tetranuclear rare earth metal polyhydrido complexes {Cp'Ln(mu-H)2}4(THF) (Cp' = C5Me4SiMe3, Ln = Y (1a), Lu (1b)) with carbon monoxide (1 atm) yielded ethylene and the corresponding tetraoxo cubane complexes (Cp'Ln)4(mu3-O)4 (Ln = Y (5a), Lu (5b)). Stepwise formation of some key reaction intermediates, such as oxymethylene complexes (Cp'Ln)4(mu-OCH2)(mu-H)6(THF) (Ln = Y (2a), Lu (2b)), enolate species (Cp'Y)4(OCH=CH2)(mu-O)(mu-H)5(THF) (3), and dioxo complex (Cp'Y)4(mu3-O)2(mu-H)4(THF) (4), was confirmed. The molecular structures of 2a, 4, and 5b were determined by X-ray diffraction studies.     

α-alkylation of serine with self-reproduction of the center of chirality

The lithium enolate 6 of methyl (2R,4S)-2-$\text{t}$-butyl-3-formyl-oxazolidine-4-carboxylate (4b) derived from (s)-(+)-serine can be generated with LDA in THF solution at ?75°C. Alkylations (→ 9) and hydroxyalkylations (→ 10, 11) occur preferentially (>95:5) from the Re-face of the donor center (relative topicity lk). This stereochemical course is derived from the absolute configuration of 2-deuterio- and 2-methyl-serine (12, 13) obtained through the enolate 6.     

A New Synthesis and the 13C-NMR OF β-Cyperone 1,3-Dibromo-2-Pentene,A New Ethyl Vinyl Ketone Equivalent

In connection with another study underway i n this lab we have been investigating the use of vinylogous thioester 1 as a synthon f o r sesquiterpene synthesis. We have found that 1 is useful for ring annelations and introduction of multiple substituents when pursuing carbocyclic synthesis. In recent studies with thioesters we have found that the lithium enolate of 1 (LDA/THF) will undergo 1,4-addition to Michael acceptors such as ethyl vinyl ketone (2, - EVK) in moderate yields (～60).     

The formation of bicyclo[n.2.0]alkan-1-ols from the reaction of the lithium enolates of simple ketones and phenyl vinyl sulfoxide

The enolates generated from cyclopentanone, cycloheptanone or cyclooctanone and LDA at -78 degrees C in THF react with (+/-)-phenyl vinyl sulfoxide under controlled conditions of temperature, reaction time, and concentration. Upon oxidation with MCPBA of the product mixtures, the novel sulfonylbicyclo[3.2.0]heptan-1-ols10-12,sulfonylbicyclo[5.2.0]-nonan-1-ols 16-18, and sulfonylbicyclo[6.2.0]decan-1-ols 21 and 22 in conjunction with alkylated ketones 8, 9, 15, 19 and 20 were obtained from the respective ketones. The enolate generated from cyclobutanone and LDA at -78 degrees C in THF reacts with (+/-)-phenyl vinyl sulfoxide and upon oxidation with MCPBA, the cyclohexanone 4 and monoalkylated cyclobutanone 5 were obtained. The ratio of bicyclo[n.2.0]alkan-1-ol to alkylated products varied with the ketone enolate, conversion of phenyl vinyl sulfoxide, time, temperature and concentration of reaction and the stability and steric strain of the final bicyclo[n.2.0]alkan-1-ol product.     

Generation and aldol reaction of enolate anion adjacent to a η-alln-mo(co)2 Cp moiety. Anew approach to the to the stereoselective synthesis of 1,3,5-triol and 2-vinyl-3-hydroxyl-tetrahydrofuran.

The enolate of CpMo(CO)₂(syn-η³-1-C₃H₄COCH₃) generated with lithium diisopropylamide in THF undergoes diastereoselective aldol reaction with benzaldehyde; the alcohol thus formed has been utilized for stereoselective synthesis of 1.5-diphenyl-2-vinyl-pentan-1,3,5-triol and 2-vinyl-3-hydroxyl-5-phenyl-tetrahydrofuran.     

Aggregation and reactivity of the cesium enolate of 6-phenyl-alpha-tetralone: comparison with the lithium enolate

The cesium enolate of 6-phenyl-alpha-tetralone (CsPAT) has a lambda(max) in THF at about 387 nm, but the variation with concentration is too small for application of singular value decomposition. Proton-transfer studies with several indicators show that CsPAT forms monomer-tetramer mixtures with a tetramerization equilibrium constant, K(1,4) = 2.3 x 10(11) M(-3). The pK of the monomer is 23.39 on a scale where fluorene is assigned 22.9 (per hydrogen). For comparison, the lithium enolate, LiPAT, is also a monomer-tetramer with K(1,4) = 4.7 x 10(10) M(-3) and a monomer pK = 14.22. HMPA in large amounts promotes dissociation to monomer with both enolates. Ion-pair S(N)2 initial rates were measured for CsPAT with several alkyl halides and with methyl tosylate and compared with other rates with LiPAT. In all cases, the enolate monomers are much more reactive than the aggregates. Reaction of CsPAT with alkyl halides is generally C-alkylation but HMPA promotes increasing amounts of O-alkylation. A new indicator, 11-methyl-11H-benzo[b]fluorene, has a pK on the cesium scale of 23.39.