Direct Enolate Alkylation

Treatment of an aldehyde or ketone with base and an alkyl halide (RX) results in alkylation— the substitution of R for H on the a carbon atom. Alkylation forms a new carbon-carbon bond on the a carbon. 

We will begin with the most direct method of alkylation, and then (in Sections 23.9 and 23.10) examine two older, multistep methods that are still used today. Direct alkylation is carried out by 

Because Step [2] is an Sn2 reaction, it works best with unhindered methyl and 1 alkyl halides. Hindered alkyl halides and those with halogens bonded to sp hybridized carbons do not undergo substitution. 

CH2=CHX, and CsHgX do not undergo alkylation reactions with enolates, because they are unreactive in Sn2 reactions. 

Ester enolates and carbanions derived from nitriles are also alkylated under these conditions. 

Intramoiecular Sn2 reaction of a nitrogen nucieophile with an a-haio ketone affords a compound that can be converted to quinine in a singie step. The new C-N bond on the a carbon is iabeled in red. 

L1] Deprotonation Base removes a proton from the a carbon to generate an enolate. The reaction works best with a strong nonnucleophilic base like LDA in THF solution at low temperature (—78 °C). 

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The acetoacetic ester synthesis and direct enolate alkylation are two different methods that prepare similar ketones. 2-Butanone, for example, can be synthesized from acetone by direct enolate alkylation with CH3I (Method [1]), or by alkylation of ethyl acetoacetate followed by hydrolysis and decarboxylation (Method [2]). 

In the chemical industry, moreover, cost is an important issue. Any reaction needed to make a large quantity of a useful drug or other consumer product must use cheap starting materials. Direct enolate alkylation usually requires a very strong base like LDA to be successful, whereas the acetoacetic ester synthesis utilizes NaOEt. NaOEt can be prepared from cheaper starting materials, and this makes the acetoacetic ester synthesis an attractive method, even though it involves more steps. 

Direct enolate alkylation using LDA and an alkyl halide... 

In the context of total synthesis, the reduction in the level of functionalization implicit in these processes is not always at variance with synthetic objectives, a simple example being the aldol condensation-deoxygenation sequence of Scheme 1, which could replace a (frequently more difficult) direct enolate alkylation. The conversion of readily available, polyfunctionalized materials such as carbohydrates into specifically deoxygenated or deaminated derivatives provides a variety of chiral synthons for the assembly of more complex substances. 

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... 

Enantioselectivity can also be based on structural features present in the reactants. A silyl substituent has been used to control stereochemistry in both cyclic and acyclic systems. The silyl substituent can then be removed by TBAF.326 As with enolate alkylation (see p. 32), the steric effect of the silyl substituent directs the approach of the acceptor to the opposite face. 

The stereochemistry of the C(3) hydroxy was established in Step D. The Baeyer-Villiger oxidation proceeds with retention of configuration of the migrating group (see Section 12.5.2), so the correct stereochemistry is established for the C—O bond. The final stereocenter for which configuration must be established is the methyl group at C(6) that was introduced by an enolate alkylation in Step E, but this reaction was not very stereoselective. However, since this center is adjacent to the lactone carbonyl, it can be epimerized through the enolate. The enolate was formed and quenched with acid. The kinetically preferred protonation from the axial direction provides the correct stereochemistry at C(6). 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

The relationship between the structure of the tertiary amine and the intrinsic rate of racemization was clear. This effect has been studied before by Williams,[32 among others. Two families of bases were compared trialkylamines and 4-alkylmorpholines. The trends were most clearly expressed in the experiments using Boc-Ser(OBzl)-NCA. The rate was decreased within each family as the steric bulk of the amine was increased. This result was consistent with the direct enolization mechanism that requires a close approach of the tertiary amine for the abstraction of the a-proton. The rate was much lower with 4-alkyl-morpholines than with trialkylamines because of the decreased basicity of the former (triethylamine and 4-ethylmorpholine have similar structures TEA is actually more hindered). The most favorable results with respect to racemization were obtained when a weak base was combined with a sterically hindered substituent, as with 4-cyclohexylmorpholine. In the case of Boc-Phe-NCA, the same trends were seen, except that racemization by the 4-alkylmorpholines was so slow that the differences within that family were not significant. 

One of the factors directing the alkylation of an enolate is the Jt-facial selectivity. The differences in reactivity of the two diastereotopic faces of the enolate, due to steric and electronic features, contribute to the steric control of the alkylation (for extensive reviews, see refs 1, 4, and 30). Likewise, stereoelectronic features are important control elements for C- versus O-alkylation, as illustrated by the cyclization of enolates 1 and 3 via intramolecular nucleophilic substitution 39. 

The formation of aldehyde enolates is complicated by the disposition of aldehydes to undergo aldol condensation. Therefore, there are very few examples of direct asymmetric alkylations of aldehydes. 

Steric effects on direction of enolate alkylation are quite obvious ... 

This protecting group can direct enolate formation of an ester as well as the site of alkylation. Thus the enolate of 2 is alkylated at the benzylic position rather... 

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). 

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