Enolate alkylation reaction

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... 

Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents for enolate alkylation reactions because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding. The solvated enolate is relatively less reactive because the hydrogen-bonded enolate must be disrupted during alkylation. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive than the same enolate in a polar aprotic solvent such as DMSO. 

One of the most important factors for successful diastereoselection in chiral amide enolate alkylation reactions is the presence of strongly chelated ionic intermediates1 3. The chelation serves the purpose of locking the chiral auxiliary in a fixed position relative to the enolate. The metal counterion is chelated between the enolate oxygen and an additional polar group, anionic, carbonyl or ether oxygen attached to the chiral auxiliary. 

In most cases98 conjugate addition-enolate alkylation reaction sequences do not exhibit particular sensitivity with respect to the identity of the alkyl group present in the alkyl alkenoate substrate. When a Michael donor has been chosen that reacts in both the 1,4- and 1,2-addition modes, it may be possible to choose an alkyl group for the ester substrate that forces the Michael donor to undergo exclusive 1,4-addition by sterically shielding the carbonyl carbon from attack by the nucleophile (equation 23)."... 

A short review describes recent developments in the transfer of chirality within enolate alkylation reactions.290... 

In modern organic chemistry, silyl enol ethers, as well as the corresponding titanium, tin, boron, or zirconium derivatives, are widely employed as nucleophilic components in enolate alkylation reactions. Their usefulness prompted the elaboration of numerous methods for the selective production of isomeri-cally pure enol ethers from almost any type of carbonyl compounds. 

Coixjugate Addition Reactions. a,3-Unsaturated N-acyloxazolidinones have been implemented as Michael acceptors, inducing chirality in the same sense as in enolate alkylation reactions. Chiral a,3-unsaturated imides undergo 1,4-addition when treated with diethylaluminum chloride (eq 55). Photochemical initiation is required for the analogous reaction with Dimethylaluminum Chloride. ... 

Epoxides can also be used as substrates in pseudoephedrine amide enolate alkylation reactions, but react with opposite di-astereofacial selectivity (suggesting a change in mechanism, proposed to involve delivery of the epoxide electrophile by coordina-... 

Aldol Reactions. Pseudoephedrine amide enolates have been shown to undergo highly diastereoselective aldol addition reactions, providing enantiomerically enriched p-hydroxy acids, esters, ketones, and their derivatives (Table 11). The optimized procedure for the reaction requires enolization of the pseudoephedrine amide substrate with LDA followed by transmeta-lation with 2 equiv of ZrCp2Cl2 at —78°C and addition of the aldehyde electrophile at — 105°C. It is noteworthy that the reaction did not require the addition of lithium chloride to favor product formation as is necessary in many other pseudoephedrine amide enolate alkylation reactions. The stereochemistry of the alkylation is the same as that observed with alkyl halides and the formation of the 2, i-syn aldol adduct is favored. The tendency of zirconium enolates to form syn aldol products has been previously reported. The p-hydroxy amide products obtained can be readily transformed into the corresponding acids, esters, and ketones as reported with other alkylated pseudoephedrine amides. An asymmetric aldol reaction between an (S,S)-(+)-pseudoephe-drine-based arylacetamide and paraformaldehyde has been used to prepare enantiomerically pure isoflavanones. ... 

The enolate alkylation process with simple aldehydes and ketones does not generally lend itself to enan-tioselective control, due to the planar nature of the enolate Jt system.206 inspection of 331 shows that the si-re face (face a) has no more steric hindrance than the re-si face (face b). When this enolate reacts with iodo-methane, therefore, no facial selectivity is anticipated and the product will be racemic. In general, enolate alkylation reactions produce chiral, racemic products. The reaction can be diastereoselective, however, when substituents attached to the molecule provide facial bias. In general, enolate alkylation proceeds by approach... 

Certain aprotic polar solvents, including dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoramide, have been found to markedly accelerate enolate alkylation reactions. The relative rates of alkylation of the sodium enolate of diethyl n-butylmalonate by butyl bromide are shown in Table 1.3. The greatly enhanced rates in dimethylformamide and dimethyl sulfoxide illustrate the rate enhancement by polar aprotic solvents. 

One of the general features of the reactivity of enolate anions is the sensitivity of both the reaction rate and the ratio of C- versus O-alkylation to the degree of aggregation of the enolate. For example, addition of HMPA frequently increases the rate of enolate alkylation reactions. Use of dipolar aprotic solvents such as DMF and DMSO in place of the THF also leads to rate acceleration. These effects can be attributed, at least in part, to dissociation of the lithium enolate aggregates. Similar effects are observed when crown ethers or similar cation-complexing agents are added to reaction mixtures. 

When 5,5-dimethyl-2-hexanone (107) is treated with LDA in THF at -78°C, the product is the kinetic enolate anion 108. In a subsequent alkylation reaction, 108 reacts with 2iS-bromobutane to give 109. Because this is an Sn2 reaction, there is inversion of configuration at the C-Br bond (see Chapter 11, Section 11.2), as shown in 109. Other factors play a role in the stereoselectivity of the alkylation, but assume that enolate alkylation reactions proceed with 100% inversion of configuration. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

When an ester enolate reacts with an aldehyde or a ketone, the product is a hydroxy-ester. This disconnection is shown for both partners. If the reaction is turned around, the reaction of an enolate derived from an aldehyde or a ketone and then with an ester gives a keto-aldehyde or a diketone. Both disconnections are shown. The enolate alkylation reaction involves disconnection of an alkyl halide fragment from an aldehyde, ketone, or ester. In addition, the malonic acid and acetoacetic acid syntheses have unique disconnections. 

An enolate alkylation reaction with 2-butanone and benzyl bromide gave a mixture of the kinetic and thermodynamic alkylation products. Draw both of them and describe differences in the IR spectrum and proton NMR spectrum that will allow you to distinguish them. 

Three examples of Sn2 (substitution, nucleophilic, bimolecular) reactions are shown in Scheme 11.5. These are simple reactions from a mechanistic standpoint. They are concerted, and there is very little that can go wrong when considering the proper electron-pushing notation. These reactions fit our paradigm for predicting reactivity, because they are combinations of nucleophiles and electrophiles, whose reactivity can be predicted solely based upon electrostatic considerations. The specific reaction shown in Scheme 11.5 B is an example of the Menschutkin reaction, defined as the reaction between an amine nucleophile and an alkyl halide. Scheme 11.5 C shows the second step of the enolate alkylation reaction we described in Section 11.3. 

It was thought that a new type of analog that does not contain the endocyclic double bond could be synthesized in almost exactly the same manner. Instead of the mono-esterified pimelic acid undergoing the aldol reaction with acrolein, an allyl group could be installed via a simple enolate alkylation reaction. Subsequent methylation, elimination, decarboxylation, cycloaddition, and cross-metathesis steps could be performed in the same manner as before with the result being a more saturated analog (76 Scheme 15). The synthesis to generate diester 73 proceeded as planned however, numerous decarboxylation conditions failed. 

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