Carbonyl compounds lithium enolates

Highly stereoselective aldol reactions of lithium ester enolates (LiCR1 R2CC>2R3) with (/0-2-(/ -tolylsulfiny I (cyclohexanone have been attributed to intermediacy of tricoordinate lithium species which involve the enolate and the sulfinyl and carbonyl oxygens of the substrates.43 The O-metallated /<-hydroxyalkanoatcs formed by aldol-type reaction of carbonyl compounds with enolates derived from esters of alkanoic acids undergo spontaneous intramolecular cyclization to /1-lactones if phenyl rather than alkyl esters are used the reaction has also been found to occur with other activated derivatives of carboxylic acids.44... 

On the other hand, if a very strong base is employed, the equilibrium hes far to the right. One very useful strong base for converting carbonyl compounds to enolates is lithium diisopropylamide (LD. or LiN(i-Pr)2 ... 

Scheme 2.19 Proposed transition-state models for enolate formation starting from heterotrimers of carbonyl compound, lithium amide base, and lithium halide.

Although ethereal solutions of methyl lithium may be prepared by the reaction of lithium wire with either methyl iodide or methyl bromide in ether solution, the molar equivalent of lithium iodide or lithium bromide formed in these reactions remains in solution and forms, in part, a complex with the methyllithium. Certain of the ethereal solutions of methyl 1ithium currently marketed by several suppliers including Alfa Products, Morton/Thiokol, Inc., Aldrich Chemical Company, and Lithium Corporation of America, Inc., have been prepared from methyl bromide and contain a full molar equivalent of lithium bromide. In several applications such as the use of methyllithium to prepare lithium dimethyl cuprate or the use of methyllithium in 1,2-dimethyoxyethane to prepare lithium enolates from enol acetates or triraethyl silyl enol ethers, the presence of this lithium salt interferes with the titration and use of methyllithium. There is also evidence which indicates that the stereochemistry observed during addition of methyllithium to carbonyl compounds may be influenced significantly by the presence of a lithium salt in the reaction solution. For these reasons it is often desirable to have ethereal solutions... 

Structural effects on the rates of deprotonation of ketones have also been studied using veiy strong bases under conditions where complete conversion to the enolate occurs. In solvents such as THF or DME, bases such as lithium di-/-propylamide (LDA) and potassium hexamethyldisilylamide (KHMDS) give solutions of the enolates in relative proportions that reflect the relative rates of removal of the different protons in the carbonyl compound (kinetic control). The least hindered proton is removed most rapidly under these... 

Common reagents such as lithium diisopropylamide (LDA see Chapter 11, Problem 5) react with carbonyl compounds to yield lithium enolate salts and diisopropylamine, e.g., for reaction with cyclohexanone. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

There is no simple answer to this question, but the exact experimental conditions usually have much to do with the result. Alpha-substitution reactions require a full equivalent of strong base and are normally carried out so that the carbonyl compound is rapidly and completely converted into its enolate ion at a low temperature. An electrophile is then added rapidly to ensure that the reactive enolate ion is quenched quickly. In a ketone alkylation reaction, for instance, we might use 1 equivalent of lithium diisopropylamide (LDA) in lelrahydrofuran solution at -78 °C. Rapid and complete generation of the ketone enolate ion would occur, and no unreacled ketone would be left so that no condensation reaction could take place. We would then immediately add an alkyl halide to complete the alkylation reaction. 

Another example of a [2s+2sh-1c+1co] cycloaddition reaction was observed by Barluenga et al. in the sequential coupling reaction of a Fischer carbene complex, a ketone enolate and allylmagnesium bromide [120]. This reaction produces cyclopentanol derivatives in a [2S+2SH-1C] cycloaddition process when -substituted lithium enolates are used (see Sect. 3.1). However, the analogous reaction with /J-unsubstituted lithium enolates leads to the diastereoselective synthesis of 1,3,3,5-tetrasubstituted cyclohexane- 1,4-diols. The ring skeleton of these compounds combines the carbene ligand, the enolate framework, two carbons of the allyl unit and a carbonyl ligand. Overall, the process can be considered as a for-... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

Finally, the addition of the carbanion of 1-chloroalkyl p-tolyl sulfoxides 154 to carbonyl compounds gave the adducts 155, which were treated with alkyllithium such as f-C4H9Li to afford the one-carbon homologated carbonyls compounds 158, from their lithium enolate forms 157, having an alkyl group at the a-position, via the carbenoid /S-alkoxides 156 (equation 53) °. 

The present preparation illustrates a general and convenient method for a two-step deoxygenation of carbonyl compounds to olefins. Related procedures comprise the basic decomposition of p-toluenesulfonylhydrazones, the hydride reduction of enol ethers, enol acetates, enamines, the reduction of enol phosphates (and/or enol phosphorodiamidates) by lithium metal in ethylamine (or liquid ammonia),the reduction of enol phosphates by titanium metal... 

Lithium Enolates. The control of mixed aldol additions between aldehydes and ketones that present several possible sites for enolization is a challenging problem. Such reactions are normally carried out by complete conversion of the carbonyl compound that is to serve as the nucleophile to an enolate, silyl enol ether, or imine anion. The reactive nucleophile is then allowed to react with the second reaction component. As long as the addition step is faster than proton transfer, or other mechanisms of interconversion of the nucleophilic and electrophilic components, the adduct will have the desired... 

In general, LiBr and NEt3 are employed in 1.5 and 1.2 equiv, respectively. Although the reaction becomes rather slower, catalytic amounts of LiBr/NEt3 (0.1 equiv each) are also sufficient. In reactions with the highly reactive dipolarophile N-methylmaleimide, the catalytic reaction results in a better yield. A similar lithiation is possible with a-substituted (alkylideneamino)acetates and (alkylideneamino)-acetamides to generate lithium enolates (86). Cycloadditions with a variety of a,(3-unsaturated carbonyl compounds leads to endo cycloadducts. However, the reaction with acrylonitrile is again nonstereoselective. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

Iron-acyl enolates, such as 2, prepared by x-deprotonation of the corresponding acyl complexes with lithium amides or alkyllithiums, are nearly always generated as fs-enolates which suffer stereoselective alkylation while existing as the crmt-conformer which places the carbon monoxide oxygen anti to the enolate oxygen (see Section 1.1.1.3.4.1.). These enolates react readily with strong electrophiles, such as primary iodoalkanes, primary alkyl sulfonates, 3-bromopropenes, (bromomethyl)benzenes and 3-bromopropynes, a-halo ethers and a-halo carbonyl compounds (Houben-Weyl, Volume 13/9 a, p 413) (see Table 6 for examples). 

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