Alkylations of relatively acidic carbon acids

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON ENOLATES AND ENAMINES 

The reason for using ethyl acetoacetate as the source of a carbon nucleophile rather than using acetone itself is based on several considerations. 

The stereochemistry of enolate alkylations has been studied by determining the stereochemistry of products from alkylation of cyclic ketones. The stereochemistry of alkylation of the enolates 1 and 2 has been determined. While 

1 (generated by cleavage of the enol acetate with methyllithium) shows no preference for the two possible approaches by alkylating agent, 2 undergoes alkylation 

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Scheme 1.5. Alkylations of Relatively Acidic Carbon Acids...

Alkylation of enolate is an important synthetic method.27 The alkylation of relatively acidic compounds such as /i-dikctoncs, /i-ketoesters, and esters of malonic acid can be carried out in alcohols as solvents using metal alkoxides as bases. The presence of two electron-withdrawing substituents facilitates formation of the enolate resulting from removal of a proton from the carbon situated between them. Alkylation then occurs by an Sn2 process. Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.5. These reactions are all mechanistically similar in that a... 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

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. 

Mono-A-alkylation of the amides occurs under relatively mild liquiddiquid two-phase conditions (Table 5.10), using concentrated aqueous sodium or potassium hydroxide. Under soliddiquid conditions with sodium hydroxide-potassium carbonate or potassium hydroxide, or by using super-saturated aqueous potassium or sodium hydroxide, it is possible to control the reaction to obtain either the mono-or dialkylated derivatives f2-4]. Soliddiquid two-phase conditions also provide the most effective route to mono-AI-alkylalion of weakly acidic aliphatic amides, but it has been suggested that the procedure is not sufficiently selective for the monoalkylation of the more acidic amides [4],... 

Relatively acidic carbon acids such as malonic esters and jS-keto esters were the first class of carbanions for which reliable conditions for alkylation were developed. The reason being that these carbanions are formed using easily accessible alkoxide ions. The preparation of 2-substiuted /i-kcto esters (entries 1, 4, and 8) and 2-substituted derivatives of malonic ester (entries 2 and 7) by the methods illustrated in Scheme 1.5 are useful for the synthesis of ketones and carboxylic acids, since both /1-ketoacids and malonic acids undergo facile decarboxylation ... 

Esters are formed in nucleophilic substitution reactions in which the nucleophile is a carboxylate anion. The anions of carboxylic acids are relatively weak nucleophiles towards sp3-hybridized carbon. Swain s nucleophilic constant, n, for acetate ion is 2.7183, slightly smaller than that for chloride. Thus acetate is selectively alkylated by alkyl halides in aqueous solution, e.g. 

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