Enolate from carbonyl compounds

Dialkylboron trifluoromethanesulfonates (Inflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazoiidinones. Recentiy, the combination of dicylohexyiboron trifluoromethanesulfonate and triethyiamine was found to effect the enolization of carboxyiic esters. The boron-mediated asymmetric aldoi reaction of carboxyiic esters is particuiariy usefui for the construction of anti p-hydroxy-a-melhyl carbonyl units. The present procedure is a siight modification of that reported by Brown, et ai. ... 

Similarly, the production of enolates from carbonyl compounds involves base removal of a proton from the a position. The enolate is negatively charged and has delocalized electrons. 

Thus the polarization in the carbonyl group, = secures the opportunity to generate enolates from carbonyl compounds and to employ them as nucleophiles in organic syntheses. This very polarization also accounts for the property of carbonyl compounds r R C = 0 to serve as electrophilic reagents, synthetic equivalents to the cation r r C -OH. 

Forming enolates from carbonyl compounds was first discussed in Section 21.7. 

This may look like a new reaction, but think back to the Reformatsky reaction (Chapter 27). Both form zinc enolates from carbonyl compounds with adjacent leaving groups. 

The lithium salt of diisopropylamine. A strong base used to form lithium enolates from carbonyl compounds. 

The most useful pseudo-halides are aryl triflates (trifluoromethylsulfonates) of phenols and enol triflates derived from carbonyl compounds[4,5,6]. 

Diene carboxylates can be prepared by the reaction of alkenyl halides with acrylates[34]. For example, pellitorine (30) is prepared by the reaction of I-heptenyl iodide (29) with an acrylate[35]. Enol triflates are reactive pseudo-halides derived from carbonyl compounds, and are utilized extensively for novel transformations. The 3,5-dien-3-ol triflate 31 derived from a 4,5-unsaturated 3-keto steroid is converted into the triene 32 by the reaction of methyl acrylate[36]. 

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. 

Hydroxy-substituted iron-acyl complexes 1, which are derived from aldol reactions of iron-acyl enolates with carbonyl compounds, are readily converted to the corresponding /i-methoxy or /1-acetoxy complexes 2 on deprotonation and reaction of the resulting alkoxide with iodomethane or acetic anhydride (Tabic 1). Further exposure of these materials to base promotes elimination of methoxide or acetate to provide the a,/ -unsaturated complexes (E)-3 and (Z)-3 (Table 2). 

The prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

These compounds ionize and act as sources of hydride and amide ions respectively, which are able to remove a-protons from carbonyl compounds. These ions are actually the conjugate bases of hydrogen and ammonia respectively, compounds that are very weak acids indeed. What becomes important here is that enolate anion formation becomes essentially irreversible the enolate anion formed is insufficiently basic to be able to remove... 

We now have examples of the generation of enolate anions from carbonyl compounds, and their potential as nucleophiles in simple Sn2 reactions. However, we must not lose sight of the potential of a carbonyl compound to act as an electrophile. This section, the aldol reaction, is concerned with enolate anion... 

The formation of diastereomers is also possible when two new chiral centers are produced from achiral starting materials. A pertinent example is found in aldol-type reactions between enolates and carbonyl compounds. The achiral enolate and the achiral aldehyde or ketone gives a product with two new... 

By way of Mannich reaction (step 1) and /1-elimination (step 2), the transformations shown in Figures 12.14 and 12.15 demonstrate how an aldol condensation (for the term see Section 13.4.1) can be conducted under acidic conditions as well. Both the enamine reaction in Figure 12.18 and the enol ether reaction in Figure 12.23 illustrate the same thing differently. Many aldol condensations, however, start from carbonyl compounds only and proceed under basic conditions. They follow a totally different mechanism (Section 13.4.1). 

Obviously, only nonucleophilic bases can be employed for the formation of enolates from carbonyl and carboxyl compounds. A base is nonnucleophilic if it is very bulky. The only non-nucleophilic organolithium compounds that deprotonate carbonyl and carboxyl compounds are mesityllithium (2,4,6-trimethylphenyllithium) and trityllithium (triphenylmethyllithium). However, these bases do not have any significance for the generation of enolates because of the difficulties associated with their preparation and with the separation of their conjugate acid hydrocarbons. 

In contrast, the related silyl enol ethers are available by mild selective transformations from carbonyl compounds or other precursors 55). Their stability and that of products derived from these alkenes can easily be regulated by choosing suitable substituents at silicon. Selective cleavage of a Si—O-bond is possible with fluoride reagents under very mild conditions, and this is why cyclopropane ring opening can now be performed with high chemoselectivity. 

The hydrogen on the carbon attached to the two sulfur atoms is weakly acidic (pAf, = 31) and can be removed by reaction with a strong base, such as butyllithium. (Butyl-lithium is also a nucleophile, and therefore it is not used to generate enolate anions from carbonyl compounds. However, the dithiane is not electrophilic, so butyllithium can be used as the base in this reaction.)... 

Ab initio Hartree-Fock calculations of the stabilities of enols and carbonyl compounds (Table 5) have been performed in recent years by Hehre and Lathan (1972), Bouma et al. (1977, 1980 see also Bouma and Radom, 1978a,b) and Noack (1979). The order or magnitude of the differences in energies (AE) is the same as that estimated for acetone in the gas phase (AG = 13.9 + 2 kcal mol-1 at 25 °C) by Pollack and Hehre (1977) from an ion cyclotron resonance spectroscopy study of the proton and deuteron transfers from CD3C(OH)CD to aniline. This gave relative values for the O—H and... 

In this section, the hydrogen atom lost in the enolization is shown in green. First let us summarize the various kinds of enol and enolate we can have from carbonyl compounds. We have seen such... 

The overall process, from carbonyl compound to carbonyl compound, amounts to an enolate alkylation, but no strong base or enolates are involved so there is no danger of self-condensation. The example below shows two specific examples of cyclohexanone alkylation using enamines. Note the relatively high temperatures and long reaction times enamines are among the most reactive of neutral nucleophiles, but they are still a lot less nucleophilic than enolates. 

The other side of the coin is that the S 2 reaction at carbon is not much affected by partial positive [ charge (5+) on the carbon a tom. The Sn2 reaction at silicon is affected by the charge on silicon. The r most electrophilic silicon compounds are the silyl triflates and it is estimated that they react some 108-109 times faster with oxygen nucleophiles than do silyl chlorides. Trimethylsilyl triflate is, in fact, an excellent Lewis acid and can be used to form acetals or silyl enol ethers from carbonyl compounds, and to react these two together in aldol-style reactions. In all three reactions the triflate attacks an oxygen atom. 

The kinetically controlled nucleophilic addition of preformed lithium enolates onto carbonyl compounds is reversible with a low activation barrier, and the thermal conditions are likely to have a major impact on the stereoisomeric ratio of the final aldols through the retroaldolization and the thermodynamic equilibration of lithium enolates76. The tendency of aldolates to undergo retroaldolization increases with the stability of enolates, and when going from lithium to potassium. On the other hand, boron enolates usually undergo completely irreversible aldol reaction511,512. 

Tetrahydropyranyl (THP) protection of the hydroxy group of 48 yields a useful reagent for the Horner-Wadsworth-Emmons synthesis of enol ethers from carbonyl compounds.103 104... 

Dtalkylamine anions like 1J)A are extremely powerftil bases that are much used in organic chemistr> v particularly for the generation od enolate ions from carbonyl compounds (Section 22.tt). 

The classical example of a stabilized carbanion is the enolate anion, formed from carbonyl compounds upon treatment with a base. Such an ion can be represented as a resonance hybrid of two canonical structures, namely 29, with the charge on carbon, and 30, with the charge on oxygen (Scheme 2.15). The structure is perhaps more properly described by the hybrid structure 31, where the dashed line and the charge sign indicate that the electron pair is spread over... 

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