Pinacolone lithium enolates

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). ... 

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. 

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. 

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. 

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. 

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... 

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). 

Exactly 10 years after the previous statement appeared, the first lithium enolate crystal structures were published as (5) and (6). Thus, structural information derived from X-ray diffraction analysis proved the tetrameric, cubic geometry for the THF-solvated, lithium enolates derived from r-butyl methyl ketone (pinacolone) and from cyclopentanone. Hence, the tetrameric aggregate characterized previously by NMR as (7) was now defined unambiguously. Moreover, the general tetrameric aggregate (7) now became embellished in (5) and (6) by the inclusion of coordinating solvent molecules, i.e. THE. A representative quotation from this 1981 crystal structure analysis is given below. 

Seebach, Dunitz and cowoikers fust described the THF-solvated tetrameric aggregates obtained from THF solutions of 3,3-dimethyl-2-butanone (pinacolone) and cyclopentanone lithium enolates. These are represented as (137). The pinacolone enolate also crystallizes as the unsolvated hexamer (138) from hydrocarbon solution, but this hexamer rearranges instantaneously to the tetramer (137) in the presence of THF. Williard and Carpenter completed the characterization of both the Na+ and the K+ pinacolone enolates.Quite unexpectedly the Na pinacolone enolate is obtained from hydrocarbon/THF solutions as the tetramer (139) with solvation of the Na atoms by unenolized ketone instead of by THF. Hie potassium pinacolone enolate is a hexameric THF solvate depicted as (140) and described as a hexagonal prism. A molecular model of (140) reveals slight chair-like distortions of the hexagonal faces in (140) so that the solvating THF molecules nicely fit into the holes between the pinacolone residues. 

Ashby, E. C., Park, W. S. Evidence for single electron transfer in Claisen condensation. The reaction of ethyl p-nitrobenzoate with the lithium enolate of pinacolone. Tetrahedron Lett. 1983, 24,1667-1670. 

After this chapter had been completed, there appeared a paper describing the first determination of the thermochemistry of an aldol reaction of a preformed enolate (E. M. Arnett, F. J. Fisher, M. A. Nichols and A. A. Ribeiro, J. Am. Chem. Soc., 1989, 111, 748). The enthalpy of reaction of the hexameric lithium enolate of pinacolone with pivalaldehyde in hexane at 25 C is -30.19 0.76 kcal mol. With one equivalent of various added ligands, enthalpies of reaction are -17.94 0.36 kcal mol in tetrahydrofu-ran (THF) -20.85 0.72 kcal mol in tetramethylethylenediamine (TMEDA) and -19.05 0.44 kcal mol in dimethoxyethane (DME). The product is believed to be a tetrameric lithium aldolate in each case. In view of the discussion given in this section, these reactions are surprisingly exothermic. Note, however, that one equivalent of THF makes the reaction about 10 kcal mol less exothermic. The enthalpy of reaction in pure THF has yet to be determined experimentally. 

The two faces of a chiral aldehyde are diastereotopic, and reaction with an achiral enolate can therefore give two diastereomeric products. Qualitatively, the major and minor products of such a reaction are determined by the intrinsic diastereofacial preference of the chiral aldehyde, which may be evaluated by the use of Cram s rule or one of its more modem derivatives. Quantitatively, the diastereomeric ratio in such a reaction is a function of the enolate. An example is seen in Scheme 8. 2-Phenylpropanal reacts with the lithium enolates of acetone, pinacolone, methyl acetate and N,N-dimethylacetamide to give 3,4-syn and 3,4-ant diastereomers in ratios of 3 1 to 4 1. With ethyl ketones and propionate esters, the diastereofacial ratio is approximately 6 1 and with methyl isobutyrate only a single isomeric product is produced. This tendency of more bulky nucleophiles to give higher diastereofacial ratios in reactions... 

Data for the addition of the lithium enolate of pinacolone to a variety of a-chiral aldehydes are presented in equation (105) and Table 17. The results in the table show that the diastereofacial preference of a chiral aldehyde is a function of the steric bulk and the electronic nature of the groups attached to the stereocenter. In a purely empirical manner, the major isomer may be correctly predicted by the... 

Work by Ashby et al. has established the intermediacy of radicals in a variety of processes previously thought to be purely ionic. The Claisen condensation of ethyl p-nitrobenzoate with the lithium enolate of pinacolone gave an EPR-active species whose rate of formation and decay indicated that it was on the pathway to the product. The postulated mechanism is shown in Scheme 3. However, this was the only example of SET observed by this group for this reaction and the intermediacy of the radical anion of the ester in this case is plausible but not proved."... 

Diketones. Saegusa et al have reported the synthesis of 1,4-diketones by treatment of lithium enolates of methyl ketones with cupric chloride (1 eq.) in DMF at -78°, Yields of coupled products are high in the case of ketones with only one enohzable hydrogen (pinacolone and acetophenone) ... 

Lithium enolates of ketones exist as aggregates in solution.29-3l,34d,35 Mixed aggregates between the enolate anion and the amide base are also possible. In 1981, Seebach and co-workers confirmed by X-ray crystallography that the lithium enolates of pinacolone and cyclopentanone form a tetrameric aggregate in the solid state, and it was assumed that a similar species exited in solution. A THF solvated tetramer of lithium pinacolonate is shown (see 33), as it was reported by Seebach. Williard et al. reported the X-ray structure of... 

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