Halides, alkyl, reaction with malonate enolates

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... 

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

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 ... 

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. 

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. 

Chiral malonate esters have been used successfully in asymmetric cyclopropanations, as shown by the example in Scheme 6.39, part of a total synthesis of steroids such as estrone [143,144]. The key step in this sequence is an intramolecular Sn2 alkylation of the monosubstituted malonate. The rationale for the diastereoselec-tivity is shown in the illustrated transition structure. Note that the enolate has C2 symmetry, so it doesn t matter which face of the enolate is considered. The illustrated conformation has the ester residues syn to the enolate oxygens to relieve Al>3 strain, with the enolate oxygens and the carbinol methines eclipsed. The allyl halide moiety is oriented away from the dimethylphenyl substituent, exposing the alkene Re face to the enolate. The crude selectivity is about 90% as determined by conversion to the dimethyl ester and comparison of optical rotations [143], but a single diastereomer may be isolated in 67% yield by preparative HPLC [144], This reaction deserves special note because it was conducted on a reasonably large scale ... 

Reaction of the enolate of diethyl malonate with alkyl halides leads to alkylation at C-2. 

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. 

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. 

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. 

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]. 

The most general method of preparation for a amino acids is the amido-malonate synthesis, a straightforward extension of the malonic ester synthesis (Section 22.8). The reaction begins with conversion of diethyl acetamidomalonate into an enolate ion by treatment with base, followed by Sf 2 alkylation with a primary alkyl halide. Hydrolysis of both the amidel protecting group and the esters occurs when the alkylated product is warmed 1 with aqueous acid, and decarboxylation then takes place to yield an a-amiaOj acid. For example, aspartic acid can be prepared from ethyl bromoacetate ... 

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. ... 

Therefore, diethyl malonate is deprotonated but not ethyl acetate. Moreover, the ethoxide ion is strong enough to deprotonate the diethyl malonate quantitatively such that all the diethyl malonate is converted to the enolate ion. This avoids the possibility of any competing Claisen reaction since that reaction needs the presence of unaltered ester. Diethyl malonate can be converted quantitatively to its enolate with ethoxide ion, alkylated with an alkyl halide, treated with another equivalent of base, then alkylated with a second different alkyl halide (Fig.R). Subsequent hydrolysis and decarboxylation of the diethyl ester yields the carboxylic acid. The decarboxylation mechanism (Fig.S) is dependent on the presence of the other carbonyl group at the P-position. 

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