Ketones, enolate anions reaction with alkyl halides

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

Similar information is available for other bases. Lithium phenoxide (LiOPh) is a tetramer in THF. Lithium 3,5-dimethylphenoxide is a tetramer in ether, but addition of HMPA leads to dissociation to a monomer. Enolate anions are nucleophiles in reactions with alkyl halides (reaction 10-68), with aldehydes and ketones (reactions 16-34, 16-36) and with acid derivatives (reaction 16-85). Enolate anions are also bases, reacting with water, alcohols and other protic solvents, and even the carbonyl precursor to the enolate anion. Enolate anions exist as aggregates, and the effect of solvent on aggregation and reactivity of lithium enolate anions has been studied. The influence of alkyl substitution on the energetics of enolate anions has been studied. ... 

This chapter will discuss carbanion-like reactions that utilize enolate anions. The acid-base reactions used to form enolate anions will be discussed. Formation of enolate anions from aldehyde, ketones, and esters will lead to substitution reactions, acyl addition reactions, and acyl substitution reactions. Several classical named reactions that arise from these three fundamental reactions of enolate anions are presented. In addition, phosphonium salts wiU be prepared from alkyl halides and converted to ylids, which react with aldehydes or ketones to form alkenes. These ylids are treated as phosphorus-stabilized car-banions in terms of their reactivity. 

Because enolate anions ffle sources of nucleophilic car bon, one potential use in organic synthesis is their- reaction with alkyl halides to give a-alkyl derivatives of aldehydes and ketones ... 

In the example shown, alkylation of the ketone is readily accomplished using such a two-stage process with 1 mol of alkyl halide. Note that the specificity of this reaction relies on one of the a-carbons having no acidic hydrogens, so that only one enolate anion can be formed. 

The anions of esters such as ethyl 3-oxobutanoate and diethyl propanedioate can be alkylated with alkyl halides. These reactions are important for the synthesis of carboxylic acids and ketones and are similar in character to the alkylation of ketones discussed previously (Section 17-4A). The ester is converted by a strong base to the enolate anion, Equation 18-18, which then is alkylated in an SN2 reaction with the alkyl halide, Equation 18-19. Usually, C-alkylation predominates ... 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

The copper-mediated 1,4-addition of alkyl groups to a,P-unsaturated ketones affords regiochemically pure enolate anions (see also Section 7.5) which may be trapped at oxygen with silyl halides, acyl halides, or dialkylcarbonates to provide silyl enol ethers, enol acetates, or enol carbonates, respectively. These can be unmasked at a later stage by reaction with MeLi to regenerate the enolate for further elaboration. ... 

Until about 30 years ago, hydrazones derived from carbonyl compounds were not used in organic synthesis. They were used only for analytical purposes , and as protecting groups of aldehydes and ketones ". Corey investigated dimethylhydrazones of ketones and aldehydes with a-hydrogens, and found that they undergo deprotonation with LDA or BuLi in THF at the a-carbons to the hydrazonic moiety in 90-100% yield. The formed lithium compounds, used as enolate anion equivalents, create new carbon-carbon bonds in their reaction with different electrophiles such as alkyl halides or oxiranes, ketones and aldehydes (equation 21). 

On the other hand, enolates almost always form trialkyl enol ethers on reaction with the hard chlorosilanes (144). Ethylation of 4-/er/-butylcyclo-hexanone lithium enolate (145) with iodoethane leads solely to a-ethylated ketones. However, up to 17% enol ether is obtained when the Meerwein reagent is used. Acetophenone anion is alkylated at oxygen and carbon in the following ratios—0.1, 3.5, and 4.9—depending on whether the reagent is EtI, Me2S04, or EtjO BF respectively (146). Amylation of butyrophenone enolate in dimethyl sulfoxide (DMSO) with reference to halide variation has also been studied (147). The lesser amount of enol ether formed corresponds to the softer halide. 

A p-keto ester can be hydrolyzed to a P-keto acid, and heating leads to decarboxylation. Malonic acid derivatives, as well as P-ketone acids decarboxylate upon heating 63,109, 111, 135. Enolate anions react with alkyl halides by an S]v2 reaction to give alkylated carbonyl compounds 65, 67, 70, 84, 108, 116, 127,... 

Compound 58 clearly offers more possibilities for disconnection. Disconnections are available at or near the carbon atom bearing the OH group, but also at or near both carbonyl carbons. The larger number of functional groups leads to more choices. Does the chemistry of the alcohol, the aldehyde, or the ketone offer the best choice for a disconnection The chemistry of alcohols is associated with oxidation and reduction (Chapter 17, Section 17.2 Chapter 19, Sections 19.2,19.3.4,19.4.1), formation and reactions of alkoxides as nucleophiles (Chapter 11, Section 11.3.2) and as bases (Chapter 12, Section 12.1), and formation of esters (Chapter 20, Section 20.5). Alcohols are converted to alkyl halides (Chapter 11, Section 11.7). Aldehydes and ketones are formed by the oxidation of alcohols (Chapter 17, Section 17.2), are reduced to alcohols (Chapter 19, Sections 19.2, 19.3.4, 19.4.1), undergo acyl addition (Chapter 18, Sections 18.1-18.7), and participate in enolate anion reactions (Chapter 22, Sections 22.2, 22.4, 22.6). Based on these reactions, several disconnections are shown, but several more are possible. 

The most common representatives of alkenyliron complexes are iron-substituted enones and enals. They are prepared from Fp-anions and P-halovinyl ketones and aldehydes (Scheme 4-30), ° and they can be further functionalized via their enolates and reaction with alkyl halides or mesylates. ... 

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