Acetoacetic ester synthesis acylation

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

The method is especially valuable for the preparation of certain substituted acetophenones, namely, o- and p-nitroacetophenone and o-chloro-acetophenone. Methods involving Grignard, Friedel-Crafts, or nitration reactions are apparently not applicable for the preparation of these nitro compounds, and the Friedel-Crafts reaction is not applicable to the preparation of o-chloroacetophenone. Although the acetoacetic ester synthesis has been used for the preparation of these and other substituted acetophenones, it may be complicated by O-acylation and also by cleavage at either acyl group (cf. method 212). 

Acetoacetic ester synthesis, 839—841, 850. See also Ethyl acetoacetate Acetoacetyl acyl carrier protein, 1021 Acetoacetyl coenzyme A, 1021, 1032 Acetone... 

Aldehyde, Ketone, and Ester Enolates 867 Enolate Regiochemistry 872 The Aldol Condensation 873 Mixed Aldol Condensations 878 Chalcones From the Mulberry Tree to Cancer Chemotherapy 880 The Claisen Condensation 882 Intramolecular Claisen Condensation The Dieckmann Cyclization 884 Mixed Claisen Condensations 885 Acylation of Ketones with Esters 886 Alkylation of Enolates 887 The Acetoacetic Ester Synthesis 889 The Malonic Ester Synthesis 891 Alkylation of Chiral Enolates 893 Enolization and Enol Content 895 a Halogenation of Aldehydes and Ketones 900... 

We have described what is commonly known as the acetoacetic ester synthesis and have illustrated the use of ethyl acetoacetate as the starting reagent. This same synthetic strategy is applicable to any j8-ketoester, as, for example, those that are available by the Claisen (Section 19.3A) and Dieckmann (Section 19.3B) condensations. For example, following are structural formulas for two jS-ketoesters available from Dieckmann and Claisen condensations that can be made to tmdergo (1) formation of an enolate anion, (2) alkylation or acylation, (3) hydrolysis followed by (4) acidification, and finally (5) decarboxylation just as we have shown for ethyl acetoacetate. 

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. 

In contrast, /3-dicarbonyl compounds such as malonic ester and acetoacetic ester are more acidic than alcohols. They are completely deprotonated by alkoxides, and the resulting enolates are easily alkylated and acylated. At the end of the synthesis, one of the carbonyl groups can be removed by decarboxylation, leaving a compound that is difficult or impossible to make by direct alkylation or acylation of a simple ester. 

The second route to ipalbidine also provides the first synthesis of its /5-d-glucoside ipalbine.3 2-Methoxypyrroline (4) was condensed with methyl acetoacetate at 85 °C in the absence of solvent to give the keto-ester (5). Acylation of the sodium salt of (5) was achieved with p-methoxyphenylacetyl chloride, but the expected acyl derivative could not be isolated. However, after the addition of a further equivalent of sodium hydride and heating at 80 °C the cyclization product (6) was obtained in moderately good yield. Some of the corresponding carboxylic acid was also isolated. Demethylation and decarboxylation of (6) by means of 48 % hydrobromic acid then gave the tetrasubstituted pyridone (7), which was... 

Acyl chlorides, as well as alkyl halides, react with the sodium derivative of acetoacetic ester as a consequence, ketones and acids which contain acyl radicals can be prepared by means of this synthesis. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

The Claisen condensation is a carbon-carbon bond-forming reaction that is useful for synthesizing j8-keto esters. In Chapter 18 we saw how j8-keto esters are useful in synthesis. In a Qaisai condensation, the enolate of one ester molecule adds to the carbonyl group of another, resulting in an acyl substitution reaction that forms a j8-keto ester and an alcohol molecule. The alcohol molecule that is formed derives from the alkoxyl group of the ester. A classic example is the Claisen condensation by which ethyl acetoacetate (acetoacetic ester) can be synthesized. 

While the preceding provides perfectly good solutions, the problem requires us to employ methodology from the current chapter. Having ruled out acetoacetic ester chemistry, we have an alternative in the use of acyl anion equivalents, for which we saw examples applied to the synthesis of a-hydroxyketones (Section 23-4). Can simple aldehydes and ketones be prepared with these equivalents as well The answer is yes, by simple alkylation with RX, followed by hydrolysis. Thus,... 

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

Acylation of the dianion of ethyl acetoacetate by an ester is a useful addition to this area of pyranone synthesis. In this reaction and in the formation of the trianions of 2,4,6-triketones the use of lithium diisopropylamide as the base is valuable (76JA7733). The triketo acid from the trianion cyclizes in mineral acids to the pyran-4-one, but in acetic anhydride the pyran-2-one is formed (Scheme 101) (71JA2506). 

---