Malonate ester anions alkylation

Less basic malonic ester anions may be employed for the twofold alkylation of dibro-... 

Less basic malonic ester anions may be employed for the twofold alkylation of dibromides. Cyclic 1,1-dicarboxylic esters are formed, if the reaction is executed in an appropriate manner. In the synthesis of cyclobutane diester A the undesired open-chain tetraester B was always a side product (J.A. Cason, 1949), the malonic ester and its monoalkylation product were always only partially ionized. Alkylation was therefore slow and intermolecular reactions of mono-alkyl intermediates with excess malonic ester prevailed. If the malonic ester was dissolved in ethanol containing sodium ethoxide, and 1,3-dibromopropane as well as more sodium ethoxide were added slowly to the solution, 63% of A and only 7% of B were isolated. The latter operations kept the malonic ester and its monoalkylated product in the ionic form, and the dibromide concentration low, so that the intramolecular reaction was favored against intermolecular reactions. The continuous addition of base during the reaction kept the ethoxide concentration low, which helped to prevent decomposition of the bromide by this nucleophile. 

When adding malonic ester anion to an allenic sulfoxide, rearrangement of the derived addition product leads to an allylic alcohol which cyclizes to (18) and isomerizes to the isolated product (19). If one alkylates the intermediate carbanion one gets an entry to a -methylenelactone system (18 Scheme 23). ... 

The same careful studies that led Begtrup and Pedersen to an understanding of alkylation in hydroxy-1,2,3-triazoles have produced important esterification methods. An especially interesting early examples involves the preparation of the internal salt 8.1>7 and its reaction with benzoyl chloride (Eq. 12). The direct reaction with benzoyl chloride often leads to both N-and O-benzoylation (Eq. 13), but the ester can be obtained in excellent yield by selective hydrolysis. A new method developed in this work starts from the malonic ester anion (Eq. 14) although the yields are not great, the method is potentially important. ... 

The sodiocompound may be written [CHtCOOCjHjij] Na, and it must always be home in mind that the anion is mesomeric. The system reacts smoothly with an alkyl halide to give a C-substituted malonic ester, evidently through the carbanion (I) ... 

The monosubstituted malonic ester still possesses an activated hydrogen atom in its CH group it can be converted into a sodio derivative (the anion is likewise mesomeric) and this caused to react with an alkyl halide to give a C-disubstituted malonic ester. The procedure may accordingly be employed for the synthesis of dialkyImalonic and dialkylacetic acids ... 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

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 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. 

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 ... 

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. 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

Nucleophilic attack on ( -alkene)Fp+ cations may be effected by heteroatom nucleophiles including amines, azide ion, cyanate ion (through N), alcohols, and thiols (Scheme 39). Carbon-based nucleophiles, such as the anions of active methylene compounds (malonic esters, /3-keto esters, cyanoac-etate), enamines, cyanide, cuprates, Grignard reagents, and ( l -allyl)Fe(Cp)(CO)2 complexes react similarly. In addition, several hydride sources, most notably NaBHsCN, deliver hydride ion to Fp(jj -alkene)+ complexes. Subjecting complexes of type (79) to Nal or NaBr in acetone, however, does not give nncleophilic attack, but instead results rehably in the displacement of the alkene from the iron residue. Cyclohexanone enolates or silyl enol ethers also may be added, and the iron alkyl complexes thus produced can give Robinson annulation-type products (Scheme 40). Vinyl ether-cationic Fp complexes as the electrophiles are nseful as vinyl cation equivalents. ... 

In this sequence, malonic ester was used as a synthetic equivalent of the enolate anion derived from acetic acid. The presence of an additional carboxyl substituent served as an auxiliary tool to stabilize the enolate species. This approach was extended to the alkylation of enolates of more complicated structure, but here it was mandatory to create first the required )8-dicarbonyl system by supplementing the initial structure with an additional carbonyl substituent. This auxiliary operation, while being generally viable, noticeably... 

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. 

Mono- and dialkylations of malonic acid esters generally are performed in an alcoholic solution of a metal alkoxide. Alkylation of a monoalkylated malonic ester requires the presence of another equivalent of alkoxide and the appropriate alkyl halide. The alkylation works well with RCH2X (X=l, Br, OTs), PhCH2X (X=C1, Br) and even with unhindered sec alkyl bromides." Subsequent hydrolysis of the diester under acidic or basic conditions followed by heat-induced decarboxylation yields the a-alkylated carboxylic acid. Thus, dialkyl malonates are the synthetic equivalents (SE) of acetate enolate anions and can be used to obtain mono- or disubstituted carboxylic acids. 

---