Halides esters, synthesis

The acetoacetic ester synthesis brings about the overall transformation of an alkyl halide to an alkyl derivative of acetone... 

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... 

This reaction sequence is called the acetoacetic ester synthesis. It is a standard procedure for the preparation of ketones from alkyl halides, as the conversion of 1-bromobutane to 2-heptanone illustrates. 

One of the oldest and best known carbonyl alkylation reactions is the malonic ester synthesis, a method for preparing a carboxylic add from an alkyl halide while lengthening the carbon chain by two atoms. 

Strategy The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane. 

Strategy The acetoacetic ester synthesis yields a methyl ketone by adding three carbons to an alkyl halide. 

What alkyl halides would you use to prepare the following ketones by an acetoacetic ester synthesis ... 

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. 

Which, If any, of the following compounds can be prepared by a malonic ester synthesis Show the alkyl halide you would use in each case. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

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 (Section 22.7) The synthesis of a methyl ketone by alkylation of an alkyl halide, followed by hydrolysis and decarboxylation. 

This selectivity for preferred reaction displacing the halide is found withboth P(III) and P(V) mixed halide/ester systems (Equation4.15)38 and has been noted in several patents to be of value for phosphonite synthesis (Equation 4.16).39 40... 

Nucleophile substitution of the T1 resin synthesis of phenols, biaryls, alkyl arenes, azides, aromatic hydrazines, halides, ester, azo compounds cinnolines, benzotriazoles [129-137, 140, 141]... 

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. 

Three-component reactions between organic electrophile (halide, ester, etc.), carbon monooxide, and organic nucleophile (organometallic compound) (Equation (1)) catalyzed by transition metal complexes afford a powerful method for the synthesis of various ketones. The pioneering works in this area appeared in the early 1980s. 

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... 

Cyclization of diallylic halides 0-90 Cyclization of 1,3-diols 0-94 Internal malonic ester synthesis 0-102 Carbonylation of 1,4-dihalides 0-108 Internal condensation of diesters (Dieckmann)... 

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]. 

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

Therefore carry out the acetoacetic ester synthesis using a benzyl halide as the alkylating... 

Like the acetoacetic ester reaction, the malonie ester synthesis also proceeds via a carbanion and thus the alkyl halide should be either primary or secondary. Tertiary and aromatic halides will not work. 

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 ... 

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