Enolates alkyl halides

Reaction of stabilized carbanions (enolates) with alkyl halides (enolate alkylation)... 

A nickel-catalyzed ene cyclization (sec. 11.13) has been reported that uses Ni(cod)2- The reaction proceeds by initial formation of a ac-allylnickel complex, which facilitates the intramolecular ene reaction with an allylic amine unit. l jt-Allylnickel complexes can be used in coupling reactions with both aryl and alkyl halides. Enolate anions react with nickel(O) reagents to form a complex that subsequently couples to aryl iodides. Semmelhack s final step in the synthesis of cephalotaxinone (446) treated 445 with Ni(cod)2 to... 

Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents in enolate alkylation reactions because they can coordinate to both the metal cation and the enolate ion. Coordination to the enolate occurs through hydrogen bonding. The solvated enolate will be relatively less reactive because the solvation lowers its energy. The hydrogen-bonded enolate must shed some of its solvent molecules in order to react with an alkyl halide. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are less reactive than the same enolate in a polar aprotic solvent such as DMSO. 

Substitution Derivatives of Ethyl Malonate, Ethyl malonate resembles ethyl acetoacetate in that it gives rise to mono- and di-substituted derivatives in precisely similar circumstances. Thus when ethanolic solutions of ethyl malonate and of sodium ethoxide are mixed, the sodium derivative (A) of the enol form is produced in solution. On boiling this solution with an alkyl halide, e.g, methyl iodide, the methyl derivative (B) of the keto form is obtained. When this is treated again in ethanolic solution with sodium ethoxide, the... 

The preparation of the sodium derivative of the phenol may be avoided by heating the enol and alkyl halide in the presence of potassium carbonate and acetone, for example ... 

Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides) Comprehensive Organic Synthesis 1991, vol. 3, 1. 

Alkylation occurs by an 8 2 mechanism m which the enolate ion acts as a nucleophile toward the alkyl halide... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Direct alkylation of esters can be carried out by forming the enolate with LDA fol lowed by addition of an alkyl halide Tetrahydrofuran (THF) is the solvent most often used m these reactions... 

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... 

The critical carbon-carbon bond forming step requires nucleophilic substitution on an alkyl halide by an ester enolate Methyl halides are more reactive than... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Alkyl halides by reaction with the enolate anion derived from diethyl acetamidomalonate... 

Soft electrophiles will prefer carbon, and it is found experimentally that most alkyl halides react to give C-alkylation. Because of the n character of the HOMO of the anion, there is a stereoelectronic preference for attack of the electrophile approximately perpendicular to the plane of the enolate. The frontier orbital is ip2, with electron density mainly at O and C-2. The tpi orbital is transformed into the C=0 bond. The transition state for an 8 2 alkylation of an enolate can be represented as below. 

On catalytic hydrogenation it furnishes mainly dihydroquinidine. Benzoyl chloride converts it into the enol benzoate, m.p. 114-5°, and on interaction with magnesium alkyl halides it forms alkylquinidines, e.g., methylquinidine, 2H2O, m.p, 105-12°, [a] ° -(- 168° (EtOH),... 

Mazur " obtained 2a-alkyl-5a-H (3) or 4 -alkyl-5 -H products (6) by direct alkylation of either 5a-H (1) or 5 -H-3-keto steroids (4) with alkyl halides under basic conditions. In general, formation and alkylation of the more stable enolate ion is observed in this procedure. 

The equatorial orientation of the newly introduced alkyl group may be controlled in both (3) and (6) by stereoelectronic and steric factors. The attack of the enolate anions (2) and (5) by the alkyl halide proceeds in a plane that is perpendicular to the plane of the enolate system. Products result from attack at the less hindered a- or -face, respectively... 

Weiss ° treated 16-dehydro- (6), 17a-acetoxy- (8), 17a-hydroxy- (9) and 17a-bromopregnan-20-one (11) with a solution of lithium, barium, calcium or sodium in liquid ammonia and reacted the intermediate enolate anion (7) with the appropriate alkyl halide. 

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 ... 

OL Alkylation of aldehydes and ketones (Section 18.15) Alkylation of simple aldehydes and ketones via their enolates is difficult. p-Diketones can be converted quantitatively to their enolate anions, which react efficiently with primary alkyl halides. 

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 problem of nitrogen alkylation of enamines, which one encounters with alkyl halides, is of no consequence in alkylations with positively activated olefins, since the generation of amonium salts can be expected to be reversible in these cases. Thus such enamine alkylations are obviously attractive to the synthetic chemist. Their particular importance, however, arises from avoidance of the serious obstacles often found with parallel enolate anion reactions. 

Enolates react with alkyl halides to form a new CC bond. A mixture of stereoisomers may result. For example, each of the reactions shown below gives two products, with the major product constituting > 90% of the mixture. 

Treatment of 1,3-dicarbonyl eompounds with two equivalents of strong base ean give a dianion that will react selectively with alkyl halides. For example, ethyl acetoacetate reacts first with NaH to form an enolate, and then with n-BuLi to form a dianion. This then adds t-PrI. 

The reactive species is the corresponding enolate-anion 4 of malonic ester 1. The anion can be obtained by deprotonation with a base it is stabilized by resonance. The alkylation step with an alkyl halide 2 proceeds by a Sn2 reaction ... 

The rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

With highly reactive alkyl halides, like allylic, benzylic or phenacyl halides, the ZjA-alkylation can be a serious side-reaction. Because of a SNl-like mechanism in those cases, the effect of enolate concentration on the reaction rate is low, and the resulting monoalkylester 5 may be more acidic than the unsubstituted starting material ... 

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

Because they re negatively charged, enolate ions act as nucleophiles and undergo many of the reactions we ve already studied. For example, enolates react with primary alkyl halides in the SK2 reaction. The nucleophilic enolate ion displaces halide ion, and a new C-C bond forms ... 

The Sn2 alkylation reaction between an enolate ion and an alkyl halide is a powerful method for making C-C bonds, thereby building up larger molecules from smaller precursors. We ll study the alkylation of many kinds of carbonyl compounds in Chapter 22. 

Perhaps the single most important reaction of enolate ions is their alkylation by treatment with an alkyl halide or tosylate, thereby forming a new C-C bond and joining two smaller pieces into one larger molecule. Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic alkyl halide in an SN2 reaction and displaces the leaving group by backside attack. 

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