Malonate, enolates, reaction with halides

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, or malonic ester, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C=0, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the -NH2 groups of urea (Figure 22.7). Amobarbi-tal (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate or ace tome tic ester, is much like malonic ester in that its ct hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic a hydrogens. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

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... 

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 ... 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

Diethyl propanedioate, commonly called diethyl malonate or malonic ester, is more acidic than monocarbonyl compounds pK =13) because its a hydrogens are flanked by two carbonyl groups. Thus, malonic ester is easih converted into its enolate ion by reaction with sodium ethoxide in ethanol. The enolate ion, in turn, is a good nucleophile that reacts rapidh with an alkyl halide to give an a-substituted malonic ester. Note in the following examples that the abbreviation "Et" is used for an ethyl group, CH2CH3. 

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. ... 

When an ester enolate reacts with an aldehyde or a ketone, the product is a hydroxy-ester. This disconnection is shown for both partners. If the reaction is turned around, the reaction of an enolate derived from an aldehyde or a ketone and then with an ester gives a keto-aldehyde or a diketone. Both disconnections are shown. The enolate alkylation reaction involves disconnection of an alkyl halide fragment from an aldehyde, ketone, or ester. In addition, the malonic acid and acetoacetic acid syntheses have unique disconnections. 

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. 

Malonate anions are convenient sources of ester enolates. They react with halides and a variety of other electrophiles. Acid hydrolysis of the ester followed by decarboxylation gives the mono-acid. An example of this approach used phthalic anhydride 1.178) as a starting material in a reaction with 2-aminoethanol to give 1.179. Conversion of the alcohol moiety in 1.179 to its 0-benzenesulfonate ester... 

Alkyl halides are converted to carboxylic acids by reaction with the enolate derived from diethyl malonate, followed by saponification and decarboxylation. 

Allenes also react with aryl and alkenyl halides, or triflates, and the 7r-allyl-palladium intermediates are trapped with carbon nucleophiles. The formation of 283 with malonate is an example[186]. The steroid skeleton 287 has been constructed by two-step reactions of allene with the enol trillate 284, followed by trapping with 2-methyl-l,3-cyclopentanedione (285) to give 286[187]. The inter- and intramolecular reactions of dimethyl 2,3-butenylmalonate (288) with iodobenzene afford the 3-cyclopentenedicarboxylate 289 as a main product) 188]. 

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 rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

As the last example of C-C bond-formation reactions catalyzed by alkaline earth hydroxides, we mention the recently reported a-arylation of diethyl malonate in the presence of a palladium catalyst and a base in a separate phase 299). The arylation of carbonyl compounds is a carbon-carbon coupling reaction between an aryl halide and an enolate, which is usually catalyzed by palladium salts in the presence of an appropriate base (300,301). The arylation of diethyl malonate with bromobenzene (Scheme 48) was performed with tetrachloropalladate as the... 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0 )21497] by treatment with a strong base such as lithium diisopropylamide.1498 The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied1499 to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCHjCOOH and RR"CHCOOH.1454 This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 368), is an alternative to the malonic ester synthesis (0-94) 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.1500... 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

Among the nucleophiles that add exo to coordinated dienes are aUcoxides, amines, azide, acetates, halides, and stabilized carbon enolates, such as malonates and /3-diketones. The alkoxide addition is reversible if the product is treated with HCl. With a few nucleophiles, double addition reactions are observed. Acetate will react with 1,5-cod in the presence of Pb(OAc)4 and palladium salts to give a bicyclic product from addition of two acetate groups, both exo (equation 43). 

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