Acetoacetic ester synthesis methyl ketones

In addition, methyl ketones can be synthesized by the acetoacetic ester synthesis, aromatic ketones can be synthesized by a Friedel-Crafts acylation, and a cyclic ketone, when treated with diazomethane, forms the next-size-larger cyclic ketone. Unless you have an exceptional memory, recalling all the methods you have learned to synthesize a particular functional group might be challenging. Therefore, they are listed for you in Appendix III. 

Just as the malonic ester synthesis converts an alkyl halide into a carboxylic acid, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone having three more carbons. 

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

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. 

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

Fig. 13.26. Acetoacetic ester synthesis of methyl ketones I preparation of an alkylated acetoacetic ester.

The butylated /J-ketoester C of Figure 13.26 is not the final synthetic target of the acetoacetic ester synthesis of methyl ketones. In that context, the /J-ketoester C is converted into the corresponding /J-ketocarhoxylic acid via acid-catalyzed hydrolysis (Figure 13.27 for the mechanism, see Figure 6.22). This /i-ketocarboxylic acid is then heated either in the same pot or after isolation to effect decarboxylation. The /f-ketocarboxylic acid decarboxylates via a cyclic six-membered transition state in which three valence electron pairs are shifted at the same time. The reaction product is an enol, which isomerizes immediately to a ketone (to phenyl methyl ketone in the specific example shown). 

Fig. 13.29. Synthesis of complicated ketones in analogy to the acetoacetic ester synthesis II generation of a cyclic ketone. In the first step, the /3-ketoester is alkylated at its activated position. In the second step, the /3-ketoester is treated with Li I . SN2 reaction of the iodide at the methyl group generates the /3-ketocar-boxylate ion as the leaving group. The /3-ketocarboxylate decarboxylates immediately under the reaction conditions (temperature above 100 °C) and yields the enolate of a ketone.

Alkylation of the enolate anion derived from ethyl acetoacetate followed by removal of the ester group is known as the acetoacetic ester synthesis and is an excellent method for the preparation of methyl ketones. The product of an acetoacetic ester synthesis is the same as the product that would be produced by the addition of the same... 

In the malonic ester synthesis this enolate ion is alkylated in the same manner as in the acetoacetic ester synthesis. Saponification of the alkylated diester produces a diacid. The carbonyl group of either of the acid groups is at the /3-position relative to the other acid group. Therefore, when the diacid is heated, carbon dioxide is lost in the same manner as in the acetoacetic ester synthesis. The difference is that the product is a carboxylic acid in the malonic ester synthesis rather than the methyl ketone that is produced in the acetoacetic ester synthesis. The loss of carbon dioxide from a substituted malonic acid to produce a monoacid is illustrated in the following equation ... 

Decide which synthesis to use. The acetoacetic ester synthesis is used to prepare methyl ketones, and the malonic ester synthesis is used to prepare carboxylic acids. Both syntheses provide a method to add alkyl groups to the a-carbon. Therefore, next identify the group or groups that must be added to the a-carbon. Remember that the a-carbon is the nucleophile, so the groups to be attached must be the electrophile in the Sn2 reaction they must have a leaving group bonded to the carbon to which the new bond is to be formed. 

The acetoacetic ester synthesis is used to prepare methyl ketones such as this. In this example, a butyl group must be attached to the enolate nucleophile. 

The acetoacetic ester synthesis produces a methyl ketone with an alkyl group(s) substituted on the a-carbon, whereas the malonic ester synthesis produces a... 

Monoalkylation of ethyl acetoacetate and subsequent ketonic hydrolysis gives methyl ketones of the type CHjCOCHjR (acetoacetic ester synthesis). 

The acetoacetic ester synthesis prepares methyl ketones having two general structures ... 

An interesting synthesis of citral reported by a Russian group starts with 6-methyl-A -heptene-2-one (4) prepared by Cope rearrangement of the acetoacetate ester (3). The ketone (4) was converted in very high yield into the diethyl ketal (.5) by... 

The Acetoacetic Ester Synthesis Synthesis of Methyl Ketones... 

The only difference between the acetoacetic ester synthesis and the malonic ester synthesis is the use of acetoacetic ester rather than malonic ester as the starting material. The difference in starting material causes the product of the acetoacetic ester synthesis to be a methyl ketone rather than a carboxylic acid. The carbonyl group of the methyl ketone and the carbon atoms on either side of it come from acetoacetic ester, and the rest of the ketone comes from the alkyl halide used in the second step of the reaction. 

What alkyl bromide should be used in the acetoacetic ester synthesis of each of the following methyl ketones ... 

Acetoacetic ester synthesis preparation of methyl ketones (Section 19.19). 

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