Pinacolone lithium

On the other hand, with heterosubstituted chiral aldehydes, the product distribution for the reaction with methyl ketone enolates is strongly influenced by the nature of the metal, the nature of the heteroatom and its position within the molecule. A chair-like transition state explained the formation of the Felkin adduct, while a boat-like transition state was invoked for the formation of the anti-Felkin adduct. However, this assumption was recently challenged by Roush and coworkers using deuterated pinacolone lithium enolate565. Performing a set of aldolizations with chiral and non chiral aldehydes led these authors to show that the isomeric purity of the enolate correlates almost perfectly with the ratio and pattern of deuterium labeling in the 2,3-an/t-aldol formed consistent with a highly favoured chair-like transition state (Scheme 115). 

SCHEME 115. Chair-like transition states and product distribution for the aldol reaction of deuterium-labeled pinacolone lithium enolate with a 3-hetero-substituted chiral aldehyde565... 

The pinacolone lithium enolate condensation product with pivaldehyde (147) has been characterized as the tetrameric aggregate (148).However, an attempted condensation reaction of pinacolone with itself as shown in Scheme 8 led to crystallization of a product derived from subsequent dehydration and reenolization, i.e. (149). This dienolate (149) was characterized as the dimer (150) solvated by ditnethyl-propyleneurea (DMPU). ... 

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

Modest induced stereoselectivity is observed when 2-phenylpropanal reacts with the lithium enolates derived from acetone, pinacolone, methyl acetate or V.jV-dimethylacetamidc the typical ratio of the syn-janti-adducts is about 3 128-31. 

Similar stereochemical results were obtained from the addition of the potassium and lithium ions of ethyl acetate, /V,V-dimethylacetamide, acetonitrile, acetophenone and pinacolone to 3-(/erf-butyldimethylsilyloxy)-T-phenylsulfonyl-1-cyclohexene followed by protonation or methylation of the resulting sulfonyl carbanion intermediates7. 

Potassium or lithium derivatives of ethyl acetate, dimethyl acetamide, acetonitrile, acetophenone, pinacolone and (trimethylsilyl)acetylene are known to undergo conjugate addition to 3-(t-butyldimethylsiloxy)-1 -cyclohexenyl t-butyl sulfone 328. The resulting a-sulfonyl carbanions 329 can be trapped stereospecifically by electrophiles such as water and methyl iodide417. When the nucleophile was an sp3-hybridized primary anion (Nu = CH2Y), the resulting product was mainly 330, while in the reaction with (trimethylsilyl)acetylide anion the main product was 331. 

A study of the lithium enolate of pinacolone with several a-phenyl aldehydes gave results generally consistent with the Felkin model. Steric, rather than electronic, effects determine the conformational equilibria.77 If the alkyl group is branched, it occupies the large position. Thus, the f-butyl group occupies the large position, not the phenyl. 

In this study, benzaldehyde and benzaldehyde-methyllithium adduct were fully optimized at HF/6-31G and their vibrational frequencies were calculated. The authors used MeLi instead of lithium pinacolone enolate, since it was assumed that the equilibrium IBs are not much different for the MeLi addition and lithium enolate addition. Dehalogena-tion and enone-isomerization probe experiments detected no evidence of a single electron transfer to occur during the course of the reaction. The primary carbonyl carbon kinetic isotope effects and chemical probe experiments led them to conclude that the reaction of lithium pinacolone enolate with benzaldehyde proceeds via a polar mechanism. 

FIGURE 27. The polar addition mechanism and electron transfer-radical coupling sequence in the addition of lithium pinacolone enolate to benzaldehyde. Reprinted with permission from Reference 28. Copyright 1997 American Chemical Society... 

Reactivities of lithium pinacolone enolate with various ketones were determined by competition experiments in diethyl ether at —78 °C. For a series of substrates, MeCOCH2X and PhCOCH2X, pi(X) = 6.62 and 7.61, indicating a large electronic field effect. ... 

Arnett and coworkers later examined the reaction of lithium pinacolone enoiate with substituted benzaldehydes in THE at 25 °C. The determination of the heat of reaction indicated that the Hammett p value for the process is 331. Although the aldol reaction was instantaneous in THF at 25 °C, the reaction with o- or p-methylbenzaldehyde could be followed using a rapid injection NMR method in methylcyclohexane solvent at —80 °C. Application of Eberson s criterion based on the Marcus equation, which relates the free energy of ET determined electrochemically and the free energy of activation determined by kinetics, revealed that the barriers for the ET mechanism should be unacceptably high. They concluded that the reaction proceeds via the polar mechanism . Consistent with the polar mechanism, cyclizable probe experiments were negative . The mechanistic discrepancy between the reactions of benzaldehyde and benzophenone was later solved by carbon kinetic isotope effect study vide infraf. ... 

Tetrahydrofuran (THF) and ether were distilled from sodium benzophenone ketyl. Pentane was distilled from lithium aluminum hydride and stored in bottles under a positive pressure of nitrogen. Pinacolone was distilled from potassium carbonate prior to use, bp 106°C (760 mm). 

Aldol reactions have continued to attract attention.28-39 hi order to determine the mechanism of addition of lithium pinacolone enolate [CH2=C(OLi)C(Me)3] to benzaldehyde the carbonyl-carbon KIE (xlk/nk = 1.019) and the substituent effects (p = 1.16 0.31) have been compared with those for other lithium reagents.28,29 The small positive KIE, which is larger than the equilibrium IE (nK/nK = 1.006) determined by ab initio MO calculations (HF/6—31 + G ), is in contrast with nk/l4k = 1.000 for MeLi addition which proceeds by the rate-determining ET mechanism, characterized by a much smaller p value. Since probe experiments showed no evidence of single electron transfer, it has been concluded that the significant isotope effect for reaction of lithium pinacolone enolate is indicative of rate-determining polar attack (PL) rather than radical coupling (RC) (Scheme 2). 

The mechanism of addition of lithium pinacolone enolate, H2C=C(OLi)Bff, to benzaldehyde has been investigated by the determination of kinetic isotope effects69 (phenyl-t/s and carbonyl-13C) C—C bond formation occurs in the rate-determining step (a result supported by MO calculations), in contrast to addition of MeLi or PhLi, which proceed via electron transfer. Further carbonyl-13 C isotopic studies on substituted benzaldehydes (including equilibrium effects) by the same authors confirmed these conclusions.70... 

D. Seebach, Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures, Angew. Chem. Int. Ed. Engl 1988, 27, 1624-1654. 

There is one important class of exchange which is unique to tellurium telluroesters such as 181 undergo tellurium-lithium exchange to generate the highly unstable acyllithiums such as 183.147 These must be formed in the presence of an electrophile - typically pinacolone (t-butyl methyl ketone 182) or they decompose. 

D. Seebach, Structure and reactivity of lithium enolates From pinacolone to selective C-alkyla-tions of peptides. Difficulties and opportunities afforded by complex structures, Angew. Chem., Int. Ed. Engl. 1988, 27,1624. 

The enantioselective reduction of unsymmetrical ketones to produce optically active secondary alcohols has been one of the most vibrant topics in organic synthesis.8 Perhaps Tatchell et al. were first (in 1964) to employ lithium aluminum hydride to achieve the asymmetric reduction of ketones9 (Scheme 4.IV). When pinacolone and acetophenone were treated with the chiral lithium alkoxyaluminum hydride reagent 3, generated from 1.2 equivalents of 1,2-0-cyclohexylidene-D-glucofuranose and 1 equivalent of LiAlHzt, the alcohol 4 was obtained in 5 and 14% ee, respectively. Tatchell improved the enantios-electivity in the reduction of acetophenone to 70% ee with an ethanol-modified lithium aluminum hydride-sugar complex.10... 

Not much is currently known concerning diastereoselective addition of metal enolates to ketones 48,108), but selectivities are expected to be lower. In case of titanium enolates, several examples have been studied 77). The reaction shown in Equation 67 involves an ester-enolate21 and proceeds strictly in a 1,2 manner with 90% diastereoselectivity. The observation is significant because similar reactions with aldehydes are essentially stereo-random77). Also, the lithium analog of 203 affords a 1 1 mixture of diastereomers. Diastereoface-selectivity in Equation 67 is not an exception, because 203 adds to acetophenone and pinacolone to afford 85 15 and >76 24 diastereomer mixtures, respectively 77). Although stereochemical assignments have not been made in all cases, the acetophenone adduct was converted stereospecifically into the p-lactone which was decarboxylated to yield an 85 15 mixture of Z- and E-2-phenyi-2-butene 77). 

Another access to alkyl and aryl acyllithiums is based on a tellurium-lithium exchange58. Thus, telluroesters 44 reacted with n-BuLi at —105 or —78 °C in the presence of pinacolone or chlorotrimethylsilane to afford products 45 or 46, respectively (Scheme 11). However, selenoesters and acylstannanes did not give the corresponding adducts under similar reaction conditions. 

Seebach, Dunitz and coworkers reported, in 1981226, the first crystal structures of lithium enolates of simple ketones, obtained in THF from pinacolone (3,3-dimethyl-2-butanone) and cyclopentanone. Both were arranged as tetrasolvated cubic tetramers, one THF molecule capping each lithium cation (Scheme 58A). Note that pinacolone enolate can also be crystallized, from heptane at — 20 °C, as a prismatic unsolvated hexamer exhibiting an approximate S6 symmetry and six slight it-cation interactions227,228 (Scheme 58B) or as a dimer in the presence of 2 molecules of TriMEDA29. Similarly,... 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

Mixed-metal enolate has also been found. The core of the lithium sodium enolate of pinacolone forms an open stack structure in which two edges of the face-sharing cubes are absent. 

The carbonyl-carbon kinetic isotope effect (KIE) and the substituent effects for the reaction of lithium pinacolone enolate (112) with benzaldehyde (equation 31) were analyzed by Yamataka, Mishima and coworkers ° and the results were compared with those for other lithium reagents such as MeLi, PhLi and AllLi. Ab initio (HF/6-31-I-G ) calculations were carried out to estimate the equilibrium isotope effect (EIE) on the addition to benzaldehyde. In general, a carbonyl addition reaction (equation 32) proceeds by way of either a direct one-step polar nucleophilic attack (PL) or a two-step process involving electron transfer (ET) and a radical ion intermediate. The carbonyl-carbon KIE was of primary nature for the PL or the radical coupling (RC) rate-determining ET mechanism, while it was considered to be less important for the ET rate-determining mechanism. The reaction of 112 with benzaldehyde gave a small positive KIE = 1.019),... 

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