O-alkylation, of enolates

Exercise 18-31 Arguing from the factors that appear to regulate the ratio of C- to O-alkylation of enolate anions (Section 17-4), show how you could decide whether the reaction of the sodium enolate salt of ethyl 3-oxobutanoate with a strong acid would give, as the initial product, mostly the enol form, mostly the keto form, or the equilibrium mixture. 

O-Alkylation of enolate ions by the reagent occurs to some extent in aprotic, polar solvents (1,2-dimethoxyethane), but may become the major reaction in DMSO orDMF.10... 

Reaction of most enolates with MeOTf or Me0S02F is always likely to be kinetically controlled. There does not appear to have been a definitive study, but 0-alkylation is the normal outcome. O-Alkylation of a bicyclodecatrienone by Me0S02p is enhanced by the use of polar solvents like HMPA. O-Alkylation of enolates of appropriate cyclohexadienones by MeOTf has been used to generate various 3ai/-indenes. A ketene acetal is formed by exclusive 0-alkylation of the sodium enolate of isopropyl bis(pentachlorophenyl)acetate by MeOTf. ... 

Indeed, even attempts at the formation of enol ethers by O-alkylation of enols (or enolate anions) is generally frustrated by the intrusion of C-alkylation (Scheme 8.93 see Chapter 9), although some adjustment of the ratio of C- to O-alkylation can be effected by choice of metal-base (e.g., t-butyllithium [(CHsjsC LC] rather... 

The heats of reaction for O-alkylation and C-alkylation of enolate anions clearly show that the latter reactions lead to the thermodynamically more stable products 12). 

Some representative Claisen rearrangements are shown in Scheme 6.14. Entry 1 illustrates the application of the Claisen rearrangement in the introduction of a substituent at the junction of two six-membered rings. Introduction of a substituent at this type of position is frequently necessary in the synthesis of steroids and terpenes. In Entry 2, formation and rearrangement of a 2-propenyl ether leads to formation of a methyl ketone. Entry 3 illustrates the use of 3-methoxyisoprene to form the allylic ether. The rearrangement of this type of ether leads to introduction of isoprene structural units into the reaction product. Entry 4 involves an allylic ether prepared by O-alkylation of a (3-keto enolate. Entry 5 was used in the course of synthesis of a diterpene lactone. Entry 6 is a case in which PdCl2 catalyzes both the formation and rearrangement of the reactant. 

The final ring coupling reaction is usually an O-alkylation of the sodium enolate with a methyl sulfonate-, bromo-, or chloro-butenolide in acetonitrile or an ether solvent (8.22-24). Use of the methyl sulfonate derivative is least preferred because of its poor stability (9,24). The isolated hydroxymethylene lactone can be allowed to react with the bromobutenolide using potassium carbonate in hexamethylphosphoric triamide (caution a potential carcinogen). 

Treatment of aldehydes or ketones with acceptor-substituted carbene complexes leads to formation of enol ethers [1271-1274], oxiranes [1048], or 1,3-dioxolanes [989,1275] by O-alkylation of the carbonyl compound. Carboxylic acid derivatives... 

Intramolecular alkylation of enolates leads to formation of cyclic products. In addition to the other factors that govern C/O-alkylation ratios, the element of stereo elec -tronic control comes into play in such cases. The following reactions illustrate this point.51... 

In the aliphatic series, the C-alkylation of enolates 17 is achieved through their O-silylated derivatives 66. In the presence of a catalytic amount of ZnBr2, the silyl enol ether 66 reacted with CICH2OCH3 to give only the C-alkylated a-ketoester 67. The alkylation is regiospecific but the ketoesters (67a, c) are obtained with modest yields (about 50% yield). 

Although O-alkyl-substituted enol ethers react smoothly with zinc carbenoids (eqna-tion 18) , higher yields are usually obtained with the Fnrnkawa reagent nsing a slight excess of diethylzinc to scavenge zinc iodide (and convert it into the less Lewis acidic ethylzinc iodide as it is formed) (see equation 18 vs 19). ... 

Enol Ethers and Esters 0-15 O-Alkylation of carbonyl compounds with diazo alkanes 0-17 Transetherification 0-20 Reaction between acyl halides and active hydrogen compounds 0-23 Transesterification 0-24 Acylation of vinylic halides 0-94 Alkylation with ortho esters 0-107 O-Acylation of 1,3-dicarbonyl compounds... 

There is another correlation that seems to have validity in many situations, at least where kinetic control is dominant namely, the.freer (less associated) the ambident anion is from its cation, the more likely is the electrophile to attack the atom of the anion with the highest negative charge. Thus O-alkylation of the sodium enolate of 2-propanone is favored in aprotic solvents that are good at solvating cations [such as (CH3)2SO, Section 8-7F],... 

N-Acetyl-L-phenylalanylsarcosine amide, 348 O-Acetylserine, 148 N-0 Acyl migrations, 157 Acyl-enzyme, 342-350 Z-0-Acylisoamide, 295 1,4-Addition, 221-242 1,6-Addition, 231 L-Ala-L-Ala-pNA,350 f-Ala-T-Pro-pNA, 350 AicohoT dehydrogenase, 340-341 Aldehydes, 209-211 Aldol condensation, 304-306 2-Alkoxytetrahydrofuran, 86 2-Alkoxytetrahydropyran, 18, 85-90 Alkylation of enamine, 282 Alkylation of enolate, 280 C and 0-Alkylation, 240 O-Alkylbenzohydroximoyl chloride, 155... 

Whilst simple alkylations of enolates and Michael additions have been successfully catalyzed by phase-transfer catalysts, aldol-type processes have proved more problematic. This difficulty is due largely o the reversible nature of the aldol reaction, resulting in the formation of a thermodynamically more stable aldol product rather than the kinetically favored product. However, by trapping the initial aldol product as soon as it is formed, asymmetric aldol-type reactions can be carried out under phase-transfer catalysis. This is the basis of the Darzens condensation (Scheme 8.2), in which the phase-transfer catalyst first induces the deprotonation of an a-halo... 

As mentioned on p. 99, gas-phase reactions are under charge control and, therefore, almost by definition, FO theory is inappropriate for their study. Such a conclusion would be precipitous. Note to begin with that only the anion behaves in an unusual manner, the comportment of its partner being normal. An FO study of gas-phase SN2 reactions (X- + RY —> XR + Y ) is therefore perfectly possible. We can also study the competition of electrophilic sites. On the other hand, FO theory will give questionable conclusions for the regioselectivity of anions (e.g. O-alkylation versus C-alkylation of enolates). For these problems, a more thorough study, requiring in particular transition states determination, is necessary. 

The selective C-silylation of some zinc enolates on treatment with chloro-trimethylsilane deserves mentioning because it is in clear contrast to the preponderant O-alkylation of other metal enolate reagents. Although this transformation is essentially confined to alkyl bromozincacetate and halozinc-... 

This chapter will provide coverage of the scope and limitations of alkylations of metal enolates of saturated and unsaturated ketones, aldehydes and carboxylic acid derivatives, together with a discussion of alkylations of various enols and enolate equivalents. Where applicable, the utility of these reactions for the diastereoselective and enantioselective synthesis of a-substituted carbonyl compounds will be described. Inevitably, the coverage of a vast research area such as this will be incomplete and in part will reflect the author s interests. However, it is hoped that most of the useful methods of carbon-carbon o-bond formation by alkylations of enolates and enols will be included. 

O-Alkylation of the enolate may compete with C-alkylation. The Iwnzoselenophene (76) gives a 3 1 mixture of C-alkylation (77) and 0-alkylation (78) with methyl iodide in methanol but a 1 3 mixture with dimethyl sulfate in water (equation 23). ... 

Alkylation of enolate anions usually gives C-alkylation and is therefore not suitable for the preparation of enol ethers. The exception is when triethyloxonium tetrafluoroborate is used as the alkylating agent in a dipolar aprotic solvent.11 O-Alkylation can be regioselectively achieved if the enolate anion is derived from acetoacetate or a similar compound. On the other hand, O-acylation of enols or enolate anions is quite common. Enol esters can therefore be prepared readily from the parent carbonyl compounds. For... 

Fig. 3.37. Differential reaction energy profiles for O versus C alkylation of enolates. (a) O-Alkylation is characterized by an early transition state, weak O-solvation, high anion reactivity, and relatively large electrostatic effects, (b) C-Alkylation is characterized by a later transition state with more C—C bond formation and more diffuse charge distribution.

Alkylation of heterofunctionalities. Etherification of alcohols can be conducted in the absence of solvent using a polyether." The O-alkylation of 1-perfluoro-alkyl-2-fluoroethanols is accompanied by dehydrofluorination thus the products are enol ethers. Selective (9-alkylation of o-aminophenols is observed, and an efficient method for the synthesis of triaryl phosphates from sodium phenolates and... 

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