Enolate ions, preparation alkylation

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

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. 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

Many of the reactions assembled in Scheme 5.4are of undiminished interest in modern allene chemistry when relatively simple alkyl derivatives are the preparative goal. For example, /3-eliminations of enolphosphates prepared from saturated ketones constitute a simple route to 1,3-dialkylated allenes. Thus 3-octanone (49), on LDA treatment followed by quenching the generated enolate ions with diethyl chlor-ophosphate, affords a mixture of the enolphosphates 50. When these are treated with further LDA in THF at low temperatures, 2,3-octadiene (51) is produced in 50% yield (Scheme 5.5) [15]. 

Furans can be prepared by acid catalyzed cyclization of masked 1,4-diketones. /3-Chloroallyl ketones which are obtained by alkylation of enamines or enolate ions behave as masked 1,4-diketones and afford furans on treatment with acid (67JA4557). 2,4-Dialkyl-furans (40) have been prepared by cyclization of the 3-chloroallyl ketone (39), which may be obtained by acylation of allyl chlorides (73KGS1434). 

Enolate ions, which are usually strong nucleophiles, are more important in preparative applications than are the enols. In additions to carbonyl groups, the carbon end, rather than the oxygen end, attacks but in SA,2 substitutions on alkyl halides, significant amounts of O-alkylation occur. The more acidic compounds, such as those with the j3-dicarbonyl structure, yield enolates with the greater tendency toward O-alkylation. Protic solvents and small cations favor C-alkylation, because the harder oxygen base of the enolate coordinates more strongly than does the carbon with these hard Lewis acids.147... 

The a-protons of a ketone like propanone are only weakly acidic and so a powerful base (e.g. lithium diisopropylamide) is required to generate the enolate ion needed for the alkylation. An alternative method of preparing the same product by using a milder base is to start with ethyl acetoacetate (a [3-keto ester) (Fig.G). The a-protons in this structure are more acidic because they are flanked by two carbonyl groups. Thus, the enolate can be formed using a weaker base like sodium ethoxide. Once the... 

In a formal sense, the reaction of ascorbic acid (11) with various electrophiles may also be regarded as an intramolecular conjugate addition with subsequent alkylation of the intermediate enolate ion. For example, the reaction of 11 with ( )-2-methyl-2-butenenitrile afforded the natural product piptosidin (12), together with its di-epimer 1351. In a quite similar fashion, leucodrin (14) and delesserin (15) were prepared from the corresponding benzyl alcohols52. 

Many highly branched ketones have been prepared by the alkylation of simpler ketones, sodium amide or sodium alkoxides generally being used to form the enolate ion. For example, ketones of the type RCOR j where R and R represent many combinations of methyl (Me), ethyl (Et), n-propyl (Pr), isopropyl, w-butyl, s-butyl, t-butyl, isoamyl, EtjCH—,... 

Alkylation of disubstituted acetic esters has become an important new route to trisubstituted acetic acids and their derivatives. Sodium tri-phenylmethide or potassium triphenylmethide is used to convert the ester to its enolate ion, which, in turn, is allowed to react with an alkyl iodide to form the trialkylated ester. The yields are in the range of 42-61%. Potassium hydroxide in acetal solvents serves as basic reagent in the alkylation of certain esters by reactive halides. An interesting preparation of diethyl tetramethylsuccinate involves alkylation of ethyl isobutyrate with ethyl a-bromoisobutyrate. The yield is 30%. ... 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full equivalent of base per equivalent of ketone is used, the enolate ion (18) is formed and can be isolated (see, e.g., the alkylation reaction in 10-68). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an stereogenic carbon a to a carbonyl group (as in 19) is treated with acid or base, racemization results. 

The most general method of preparation for a amino acids is the amido-malonate synthesis, a straightforward extension of the malonic ester synthesis (Section 22.8). The reaction begins with conversion of diethyl acetamidomalonate into an enolate ion by treatment with base, followed by Sf 2 alkylation with a primary alkyl halide. Hydrolysis of both the amidel protecting group and the esters occurs when the alkylated product is warmed 1 with aqueous acid, and decarboxylation then takes place to yield an a-amiaOj acid. For example, aspartic acid can be prepared from ethyl bromoacetate ... 

Alkylation of Enolate Ions 855 Problem 22.12 How could you use a malonic ester synthesis to prepare the following compound ... 

The nitrogen analogs of enolate ions can be prepared from imines and strong bases. The resulting anions are alkylated by alkyl halides ... 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

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