Halides esters, synthesis with

Sodium hydride a-Bromocarboxylic acid esters from halides via / -ketocarboxylic acid esters Synthesis with addition of 2 C-atoms... 

Section 21 6 The acetoacetic ester synthesis is a procedure in which ethyl acetoac etate is alkylated with an alkyl halide as the first step in the preparation... 

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... 

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. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

Acetoacetic ester synthesis is the preparation of substituted acetones, and it s an important method for creating a variety of products. It begins with the reaction of acetoacetic ester (a dicarbonyl) or a similar compound with a strong base to produce a carbanion, which then reacts with alkyl halide, RX. The structure of acetoacetic ester is in Figure 15-10. Figure 15-11 illustrates an example of an acetoacetic ester synthesis and two possible outcomes. Figure 15-12 shows the preparation of 2-heptanone with a 65 percent yield via the acetoacetic ester synthesis. Figure 15-13 presents the preparation of 2-benzylcyclohexanone with a 77 percent yield. 

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... 

With respect to the synthesis from amines, C02 and alkyl halides, the synthesis of carbamates from amines, C02 and alcohols (Equation 6.10) is not only a phosgene-free, but also a halogen-free process. Moreover, water forms as the only reaction coproduct. Whilst these features make the route very attractive from the point of view of environmental sustainability, unfortunately the reaction suffers from both thermodynamic and kinetics limitations. Kinetic impediments make necessary the use of a suitable catalyst which, moreover, must be water-tolerant in order to avoid deactivation by cogenerated H20. Several strategies have been explored to overcome these restraints, based mainly on the use of alcohols in a dehydrated form (for instance, as ortho esters or ortho carbonates) [63], or on the use of dehydrating agents [64, 65]. 

Amino acid synthesis (8, 389). Alkylation of the aldimine (1) from glycine ethyl ester and /j-chlorobenzaldehyde under phase-transfer conditions offers a general route to amino acids. Either liquid-liquid phase-transfer or solid-liquid phase-transfer catalytic conditions are satisfactory with active halides, but alkylation with allylic halides and less active alkyl halides is best effected under ion-pair extraction conditions (6,41), with 1 equiv. of tetra-n-butylammonium hydrogen sulfate (76-95% yields).1... 

The first stage of the malonic ester synthesis is the alkylation of diethyl malonate with an alkyl halide. 

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 ... 

The malonic ester synthesis converts a primary or secondary alkyl halide into a carboxylic acid with two more carbons (a substituted acetic acid). Identify the component that originates from malonic ester (the acid component). The rest of the molecule comes from the alkyl halide, which should be primary or methyl. 

Malonic ester synthesis (Section 22.7) a multistep sequence for converting an alkyl halide into a carboxylic acid with the addition of two carbon atoms to the chain. 

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. 

An alternative ester synthesis, the reaction of a carboxylate anion with an alkyl halide, was used by Madejewski [62] for the preparation of ( , )-l,9-dioxacy-clohexadeca-3,1 l-dien-2,10-dione (76) under dilution conditions. This 16-membe-red dilactone represents a precursor for the synthetic norpyrenophorin 77 a, the physiological activity of which corresponds to the one of the natural products pyrenophorin 77b and vermiculin 77c. The lactone 76 can be obtained in 77% yield by dimerization of ( )-7-bromo-2-heptenic acid (75) in DMF in the presence of potassium carbonate. 

Enolates derived from 2-phenylselanyl esters react with various electrophiles such as alkyl halides and benzeneselenenyl halides [45]. The Michael addition of the enolate, formed from ferf-butyl 2-phenylselanyl propanoate, to (R)-5-n-octyl(5ff)furan-2-one and subsequent iodination afforded a key intermediate for the total synthesis of (-)-Avenaciolide [46] (Scheme 37). 

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