Sodium ethoxide, as a base

Thiopental Thiopental, 5-ethyl-5-(l-methylbutyl)2-thiobarbituric acid (1.2.10), is synthesized by the alkylation of ethyhnalonic ester with 2-bromopentane in the presence of sodium ethoxide. The product ethyl-(l-methylbutyl)malonic ester (1.2.9) undergoes hete-rocyclization with thiourea, using sodium ethoxide as a base [16,17]. 

Stobbe condensations. W. S. Johnson and Daub, having found potassium f-butoxide superior to sodium ethoxide as a base for carrying out the Stobbe condensation, found an even better base in sodium hydride. When a mixture of benzo-phenone, diethyl succinate, and sodium hydride was stirred at room temperature,... 

Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.3. Entries 1 to 4 are typical examples using sodium ethoxide as the base. Entry 5 is similar, but employs sodium hydride as the base. The synthesis of diethyl cyclobutanedicarboxylate in Entry 6 illustrates ring formation by intramolecular alkylation reactions. Additional examples of intramolecular alkylation are considered in Section 1.2.5. Note also the stereoselectivity in Entry 7, where the existing branched substituent leads to a trans orientation of the methyl group. 

Polystyrene-bound benzaldehydes can be smoothly olefinated with benzyl- or cin-namylphosphonium salts in DMF or THF using sodium methoxide as a base (Entry 1, Table 5.5 [64-67]). Alkylphosphonium salts, however, only react with resin-bound aldehydes upon deprotonation with stronger bases, such as butyllithium [30,68-70]. The more acidic acceptor-substituted phosphonium salts, on the other hand, even react with resin-bound aldehydes and ketones upon treatment with tertiary amines, DBU, sodium ethoxide, or lithium hydroxide [71-75], but stronger bases are also used occasionally [76]. 

In fact, even with an ester that gives an acceptable yield of the condensation product with sodium ethoxide as the base, a better yield is often obtained when a stronger base is employed. 

In the case of a strong base, such as sodium ethoxide, as a homogeneous catalyst, the selectivity was as low as 1-7% during the whole course of the reaction due to further conversion of the product toward an undesired cycUzation product (entry 11) [17]. The cooperative activation by the surface acid and amine group, which is a weaker base compared to sodium ethoxide, realizes selective catalysis compared to when using only a strong base. 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

Using sodium ethoxide as base, the reaction does not proceed. This can be ascribed to the nature of the P-ketoester product, which contains no protons sandwiched between two carbonyls and, therefore, no protons that are sufficiently acidic for the hnal equilibrium-disturbing step. The reaction can be made to proceed, however, and the solution is simple use a stronger base. In this way, the base used is sufficiently powerful to remove a less acidic proton from the product, removing it from the reaction mixture and... 

The Claisen condensation is one method of synthesizing (3-dicarbonyl compounds, specifically a (3-keto ester. This reaction begins with an ester and occurs in two steps. In the first step, a strong base, such as sodium ethoxide, removes a hydrogen ion from the carbon atom adjacent to the carbonyl group in the ester. (Resonance stabilizes the anion formed from the ester.) The anion can then attack a second molecule of the ester, which begins a series of mechanistic steps until the anion of the (3-dicarbonyl compound forms, which, in the second reaction step (acidification), gives the product. 

The general mechanism of the Claisen condensation, with ethoxide as the base, is shown in Figure 15-2. Sodium ethoxide is necessary because the starting material is an ethyl ester. If the starting material were a methyl ester, then the base would be sodium methoxide. Choosing a base that matches the type of ester minimizes the formation of other products. 

The synthesis may thus be seen to be an intramolecular Claisen ester condensation, which is known as the Dieckmann reaction. The procedure is an important method for the synthesis of five- and six-membered ring systems, and the cyclic /2-keto ester product may be converted into the corresponding cyclic ketone by hydrolysis followed by decarboxylation (ketonic hydrolysis, see Section 5.8.5, p. 619). The base catalyst used in Expt 7.8 is sodium ethoxide, but sodium hydride as a 50 per cent dispersion in oil is a recommended alternative. 

The concentration of acidic groups can be determined by neutralization with a base, using solutions of sodium bicarbonate, sodium carbonate, sodium hydroxide or sodium ethoxide as titrants. Only those acidic groups which are much more strongly dissociated than the conjugate acids of the bases are completely neutralized. Thus, the differences in the amount of base required may be used to characterize the acidity of surface groups. Boehm (12) identified four different type of surface groups by this technique. 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

Anhydro bases resulting from the proton abstraction by a base at an activated a -methyl group of a quaternary salt (see Section 4.19.2.3.3(iv)(a)) are active C-nucleophiles. These attack the C-2 position of a thiazolium salt affording adducts whose further reaction may lead to thiacyanines. Scheme 28 summarizes the successive steps in the reaction resulting from the addition of sodium ethoxide to a fairly concentrated ethanolic solution of 2,3-dimethylbenzothiazolylium salt (45) (c =0.1 moll-1). The initially formed anhydro base (46) cannot be isolated, it reacts as a nucleophile with a second molecule of benzothiazoly-lium salt yielding an adduct (47) which is deprotonated by ethoxide anion affording the dimeric anhydro base (48) whose reactivity will be discussed later (see Section 4.19.2.3.3.i). Monocyclic thiazolylium salts react similarly. 

These two diastereoisomeric cyclohexyl chlorides derived from menthol react very differently under the same conditions with sodium ethoxide as base. Both eliminate HC1 but diastereoisomer A reacts rapidly to give a mixture of products, while diastereoisomer B (which differs only in the configuration of the carbon atom bearing chlorine) gives a single alkene product but very much more slowly. We can safely exclude El as a mechanism because the same cation would be formed from both diastereoisomers, and this would mean the ratio of products (though not necssarily the rate) would be the same for both. 

Recently, the bis(methylthio)methylene imine of pseudoephedrine glycinamide was shown to undergo diastereoselective alkylation at 23 °C with lithium terf-butoxide or sodium ethoxide as base and various alkyl halides as electrophiles (eq 21 ). This procedure was used to prepare enantiomerically enriched a-amino acids. 

Acylation of ketones. Noting that on alkylation of malononitrile in ethanol or benzene with sodium ethoxide as base the yield is only 70% and formation of imide esters is an important side reaction, Bloomfleld was led to try the non-nucleophilic base sodium hydride in dimethyl sulfoxide, a relatively non-nucleophilic solvent capable of dissolving intermediate salts. With this combination he obtained dimethyl-malononitrile in 60% yield. He then studied the acylation of the ketone (1) with the... 

Use as a base. For the conversion of dibenzoyl peroxide into sodium perbenzoate, sodium methoxide is preferred to sodium ethoxide because it is more soluble in methanol and does not precipitate provided that the temperature does not fall below... 

The reaction of diethyl oxalate with ketones in the presence of sodium ethoxide, or other bases, has been used extensively examples are given in Scheme 66. Reaction may occur with esterketone ratios of 1 1, 2 1, or 1 2, but only the 1 1 case finds substantial use in modem synthetic practice. Frequently the a-oxalyl ketone is thermally decarbonylated to give the 3-heto ester.An early example of this was provided by Bachmann s synthesis of equilenin. The mechanism of this reaction has teen examined labeling studies showed that it was the ester carbonyl that was eliminated. The intact oxalyl group has teen used as a directing group in steroid methylation while, more recently, 2-oxalylcyclohexanone has provided a route to (R)-(-)-hexahydromandelic acid (Scheme 67). The products of acylation of suitable acyclic ketones can cyclize to form (enolic) cyclopentane-1,2,4-triones (equation 39). ... 

For secondary halides in aqueous solvents, unimolecular and bimolecular processes compete, and the result is usually a mixture of products. With strong bases and protic solvents other than water, bimolecular elimination is usually faster than substitution, although this is only an assumption and accurate predictions can be difficult with secondary substrates. In polar aprotic solvents, bimolecular processes are usually faster. If a strong base is present and a protic solvent is used, bimolecular elimination is usually preferred to bimolecular substitution, but this is another assumption. If ethanol is used as a solvent and sodium ethoxide is a nucleophilic base. Table 2.9 shows the competition between bimolecular substitution (Sn2) and bimolecular elimination (E2) for a series of alkyl bromides. The preference for E2 reactions of secondary and tertiary halides in this protic solvent is clearly shown. 

B.iv. Nitrile Enolates. Nitrile enolates are formed by reaction of a nitrile with LDA or another suitable base. Both alkylation 30 and condensation reactions with aldehydes 3 or ketones are known. 32 in addition to alkyl halides and carbonyl derivatives, condensation can occur with another nitrile. The base-catalyzed condensation of two nitriles to give a cyano-ketone, via an intermediate cyano enolate, is known as the Thorpe reaction. 33.109e Reaction of butanenitrile with sodium ethoxide gave a nitrile enolate, which reacted with a second molecule of butanenitrile at the electrophilic cyano carbon to give 206. Hydrolysis gave an intermediate imine-nitrile (207), which is in equilibrium with the enamine form (208, sec. 9.6.A). Hydrolysis led to the final product of the Thorpe reaction, an a-cyano ketone, 209. 33 Mixed condensations are possible when LDA and kinetic conditions are used to generate the a-lithionitrile (a mixed Thorpe reaction). When pentanenitrile was treated with LDA and condensed with benzonitrile, 2-cyano-l-phenyl-1-pentanone was the isolated product after acid hydrolysis. Nitrile enolates can also be alkylated with a variety of alkyl halides. 34... 

The simplest preparation of the C3o-ester 1 is by Horner-Emmons olefination of 507 with the Cs-ester 67 [75]. Similar results are obtained by Wittig olefination of 507 with the triphenyl-phosphonium bromide corresponding to 67 [76]. Sodium ethoxide has proved suitable as a base in the ethanol/heptane solvent system. The desired product crystallizes out during the reaction. Thermal isomerization yields a second crystal fraction from the mother liquor. 

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