Ketone enolates alkylations

The F-alkyl ketone enolates were readily prepared by dephosphorylation of the corresponding 1-substituted F-l-aUcenyl phosphates with DIBAL at 0°C for a few minutes (Scheme 6.29) [50]. The resulting diisobutylaluminum enolate undergoes aldol reaction with benzaldehyde to give fhe -hydroxycarbonyl compound in a reasonable yield. 

Robinson Annulation Sequential Michael addition/aldol condensation between a ketone enolate and an alkyl vinyl ketone (i.e. MVK) to give a cyclohex-2-en-l-one... 

Lithium dialkylamides are excellent bases for making ketone enolates as well Ketone enolates generated m this way can be alkylated with alkyl halides or as illus trated m the following equation treated with an aldehyde or a ketone... 

Acetylenedimagnesium bromide, 66, 84, 137 Acyl-alkyl diradical disproportionations, 299 Acyl-alkyl diradical recombination, 296 Alkaline hydrogen peroxide, 10, 12, 20 Alkylation of formyl ketones, 93 Alkylation via enolate anions, 86 17a-Alkynyl steroids from 17-ketones, 67 2a-Al]yl-17jS-hydroxy-5a-androstan-3 -one, 9 5 Allylic acetoxylation, 242 Allylmagnesium bromide, 64 17 -Aminoandrost-5-en-3 -ol, 145 17 a-Aminomethy 1-5 a-androstane-3, 1718-diol, 387... 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

The familiar alkylation of -ketoesters followed by decarboxylation is still a useful route to a-alkyl ketones, although the alkylation of enamines is frequently the preferred route. Given below are two examples of alkylation of 2-carbethoxycycloalkanones (prepared in Chapter 10, Section I). In the first case, sodium ethoxide is the base employed to generate the enolate ion of 2-carbethoxycyclohexanone. In the second case, the less acidic 2-carbethoxycyclooctanone requires sodium hydride for the generation of the enolate ion. 

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. 

Unless a proton donor is added, the lithium-ammonia reduction of an cnone leads to the lithium enolate and lithium amide. The latter is a sufficiently strong base to rapidly convert the mono-alkylated ketone into its enolate, which can be further alkylated. The function of the... 

NHC-promoted enolate formation from an enal, followed by a desymmetrising aldol event to generate P-lactones and loss of CO, has been exploited by Scheidt and co-workers to generate functionalised cyclopentenes 240 in high ee from enal substrates 238 (Scheme 12.52) [94]. Interestingly, the use of alkyl ketones in this reaction manifold allows the isolation of the p-lactone intermediates with acyclic diketones, P-lactones 239 are formed with the R group anti- to the tertiary alkox-ide, while with cyclic diketones the P-lactone products have the R group with a syn relationship to the alkoxide [95]. 

The equilibrium ratios of enolates for several ketone-enolate systems are also shown in Scheme 1.1. Equilibrium among the various enolates of a ketone can be established by the presence of an excess of ketone, which permits reversible proton transfer. Equilibration is also favored by the presence of dissociating additives such as HMPA. The composition of the equilibrium enolate mixture is usually more closely balanced than for kinetically controlled conditions. In general, the more highly substituted enolate is the preferred isomer, but if the alkyl groups are sufficiently branched as to interfere with solvation, there can be exceptions. This factor, along with CH3/CH3 steric repulsion, presumably accounts for the stability of the less-substituted enolate from 3-methyl-2-butanone (Entry 3). 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Scheme 1.5 gives some examples of alkylation of ketone enolates. Entries 1 and 2 involve formation of the enolates by deprotonation with LDA. In Entry 2, equilibration... 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

Scheme 1.8 shows some intramolecular enolate alkylations. The reactions in Section A involve alkylation of ketone enolates. Entry 1 is a case of a-alkylation of a conjugated dienolate. In this case, the a-alkylation is also favored by ring strain effects because y-alkylation would lead to a four-membered ring. The intramolecular alkylation in Entry 2 was used in the synthesis of the terpene seychellene. 

Ketone imine anions can also be alkylated. The prediction of the regioselectivity of lithioenamine formation is somewhat more complex than for the case of kinetic ketone enolate formation. One of the complicating factors is that there are two imine stereoisomers, each of which can give rise to two regioisomeric imine anions. The isomers in which the nitrogen substituent R is syn to the double bond are the more stable.114... 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are [Tdicarbonyl compounds, which are rather acidic and can be alkylated by the procedures described in Section 1.2. Reaction of ketone enolates with formate esters gives a P-ketoaldehyde. As these compounds exist in the enol form, they are referred to as hydroxymethylene derivatives. Entries 1 and 2 in Scheme 2.16 are examples. Product formation is under thermodynamic control so the structure of the product can be predicted on the basis of the stability of the various possible product anions. 

Ketones are converted to (3-ketoesters by acylation with diethyl carbonate or diethyl oxalate, as illustrated by Entries 4 and 5 in Scheme 2.16. Alkyl cyanoformate can be used as the acylating reagent under conditions where a ketone enolate has been formed under kinetic control.227... 

In the general context of donor/acceptor formulation, the carbonyl derivatives (especially ketones) are utilized as electron acceptors in a wide variety of reactions such as additions with Grignard reagents, alkyl metals, enolates (aldol condensation), hydroxide (Cannizzaro reaction), alkoxides (Meerwein-Pondorff-Verley reduction), thiolates, phenolates, etc. reduction to alcohols with lithium aluminum hydride, sodium borohydride, trialkyltin hydrides, etc. and cyloadditions with electron-rich olefins (Paterno-Buchi reaction), acetylenes, and dienes.46... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

In the late 1960s, methods were developed for the synthesis of alkylated ketones, esters, and amides via the reaction of trialkyl-boranes with a-diazocarbonyl compounds (50,51), halogen-substituted enolates (52), and sulfur ylids (53) (eqs. [33]-[35]). Only one study has addressed the stereochemical aspects of these reactions in detail. Masamune (54) reported that diazoketones 56 (Ri = CH3, CH2Ph, Ph), upon reaction with tributylborane, afford almost exclusively the ( )-enolate, in qualitative agreement with an earlier report by Pasto (55). It was also found that E) - (Z)-enolate isomerization could be accomplished with a catalytic amount of lithium phenoxide (CgHg, 16 hr, 22°C) (54). 

The concept of memory of chirality —in which the chirality of the starting material is preserved in a reactive intermediate for a limited time—is discussed with particular reference to the C-alkylation of enolates of chiral ketones. ... 

Scheme 9.15 Alkylations with ketone enolates derived from silyl enol ethers as nucleophiles.

The a-alkylation of enolates derived from ketones with alkyl halides is a very important and frequently used method for forming new carbon-carbon bonds in organic synthesis [40]. Yet, if the a-alkylation of enolates derived from ketones with alkyl halides can be replaced by the direct reaction of ketones with alcohols, this method would provide a very useful waste-free, green route to a-alkylation, producing no side products other than water. 

Several examples of alkylation of ketone enolates are given in Scheme 1.7. 

To summarize, the amount of O-alkylation is maximized by use of an alkyl sulfate or alkyl sulfonate in a polar aprotic solvent. The amount of C-alkylation is maximized by use of an alkyl hahde in a less polar or protic solvent. The majority of synthetic operations involving ketone enolates are carried out in THF or DME using an alkyl bromide or alkyl iodide, and C-alkylation is favored. 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. For these reactions to be useful as a method for synthesis, there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

The enolates of ketones can be acylated by esters and other acylating agents. The products of these reactions are all /5-dicarbonyl compounds. They are all rather acidic and can be alkylated by the procedures described in Section 1.4. Reaction of ketone enolates... 

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