Halides, alkyl reaction with malonate anions

This method is useful for aryl-substituted malonates 27 where the normal alkylation of the malonate anion 26 is impossible as Sn2 reactions fail on unactivated aryl halides. For Ar = Ph reaction of 28 with NaH and diethyl carbonate gives3 27 Ar = Ph in 86% yield. 

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 ... 

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

Diethyl malonate can be converted into its enolate anion, which may then be used to participate in an Sn2 reaction with an alkyl halide (see Section 10.7). Ester hydrolysis and mild heating leads to production... 

When treated with one equivalent of sodium ethoxide, diethyl malonate is converted into the mono-sodio derivative, as a result of removal by base of one of the a-methylene protons to yield a mesomeric anion (12). This nucleophilic anion undergoes an S 2 reaction with an alkyl halide to give a C-substituted malonic ester. A second, different, alkyl group can be similarly introduced on to the a-carbon atom, or alternatively two identical alkyl groups may be introduced in a one-step operation by using appropriate proportions of reactants. 

In both the acetoacetic ester synthesis and the malonic ester synthesis, it is possible to add two different alkyl groups to the a-carbon in sequential steps. First the enolate ion is generated by reaction with sodium ethoxide and alkylated. Then the enolate ion of the alkylated product is generated by reaction with a second equivalent of sodium ethoxide, and that anion is alkylated with another alkyl halide. An example is provided by the following equation ... 

Allylation of Stabilized Anions. Electrophilic 7r-allyl Pd(0) complexes can be generated from Pd(dba)2 and functionalized allylic acetates, carbonates, halides, etc. These complexes are susceptible to reaction with a range of stabilized nucleophiles, such as malonate anions. Alkylation usually occurs at the less-substituted allylic terminus. Silyl-substituted r-allyl complexes undergo re-gioselective alkylation at the allyl terminus farthest removed from the silyl group (eq 14). ... 

Microwaves Alkylation of ethylphenyl sulfonyl acetate, diethyl malonate, anions derived from active methylene Dihalocyclopropanation of substituted olefins under LLPTC and SLPTC conditions Ethoxylation of o,p-nitrochlorobenzene Reactions of carboxylic acids with halides Wang and Jiang (1992), Wang et al. (1995) Villemin and Labiad (1992) Yuan et al. (1992a) Yuan et al. (1992b)... 

In Chapter 22 (Section 22.7.4), malonate derivatives were easily converted to the corresponding enolate anion, and reaction with alkyl halides or other electrophilic species gave the C3-alkylated product. Indeed, if 102 is treated with sodium metal (or NaH, LDA, etc.), enolate anion 103 is formed it reacts with an alkyl halide such as benzyl bromide (PhCH2Br) to give 104. If 104 is heated with aqueous sodium hydroxide and then treated with aqueous HCI, phthalic acid (35) and the amino acid phenylalanine (57) are formed as the final products. 

Dearomatization of r -benzylpalladium complexes represents an electronically reversed variation on the reactions described earlier. Initial examples utilized allyl and allenyl stan-nanes as nucleophilic components in combination with benzyl halides and invoked mechanisms involving aryl-alkyl Pd(II) intermediates [84]. Subsequently, direct addition of stabilized nucleophiles (e.g., malonate anions) to q -naphthylpalladium complexes has been achieved [85]. 

The malonic ester required for synthesis of cyclopal (107) can be obtained by alkylation of diethyl allylmalonate (115) with 1,2-dibromocyclopentane in the presence of excess base. It is probable that the reaction proceeds by elimination of hydrogen bromide from the dihalide as the first step. The resulting allilic halide (116) would be the most reactive electrophile in the reaction mixture and thus would quickly alkylate the anion of the malonate to afford 117. 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which have resonance contributors RCH=C(0 )2 ] by treatment with a strong base, such as LDA. ° The use of Li" " as the counterion increases the solubility of the dianionic salt. The reaction has been applied to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCH2COOH and RR CHCOOH. ° Allkylation occurs at carbon, the more nucleophilic site relative to the carboxylate oxygen anion (see p. 513). this procedure is an alternative to the malonic ester synthesis (10-67) as a means of preparing carboxylic acids and has the advantage that acids of the form RR R CCOOH can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure. 

There are two classical reaction sequences in organic chemistry that rely on enolate alkylation. One is the malonic ester synthesis.61 jjj synthetic example taken from the Clive and Hisaindee synthesis of brevioxime,62 diethyl malonate was treated with a base such as sodium ethoxide, under thermodynamic control conditions. The resulting enolate anion is treated with the indicated alkyl halide to give the alkylated product 81 (in 72% yield).Saponification of 81 to the dicarboxylic acid (82, in 99% yield), was followed by decarboxylation (sec. 2.9.D) and formation of the substituted acid 83, in 94% yield. ... 

A p-keto ester can be hydrolyzed to a P-keto acid, and heating leads to decarboxylation. Malonic acid derivatives, as well as P-ketone acids decarboxylate upon heating 63,109, 111, 135. Enolate anions react with alkyl halides by an S]v2 reaction to give alkylated carbonyl compounds 65, 67, 70, 84, 108, 116, 127,... 

In (alkene)iron complexes, either neutral or cationic, the electron density at the alkene is reduced. This allows for nucleophilic addition to such complexes. For example, malonates are added to give ethyl malonate derivatives after aqueous workup. Reaction of the intermediate anionic T -alkyl-Fp complexes with alkyl halides leads to migratory insertion of a carbonyl ligand and provides acylated products (Scheme 4-73). ... 

We have already met this reaction in its simplest form at the end of Chapter 9 when we studied the nucleophilic substitution of alkyl halides by the anions of dicarbonyl compounds (Figure 17.37). Ethoxide is used as the base in the reaction of diethyl malonate, to avoid any problems with ester interchange. Dialkylation requires a stronger base for the second step—the alkyl group already introduced is electron-donating and destabilizes the carbanion. 

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