Acetone dicarboxylic acid

The standard laboratory method for the synthesis of acetone dicarboxylic acid is decarbonylation of citric acid with oleum :

The reaction is carried out in the cold (0 - 10 ° C) and under traction, since toxic carbon monoxide is released during the reaction; the yield of crude acid suitable for further esterification is 85-90%, if necessary, the product can be purified by recrystallization from ethyl acetate ^[1] .

Acetone dicarboxylic acid can also be synthesized from acetone - by direct carboxylation with carbon dioxide or in three stages through 1,3-dichloroacetone with further chlorine substitution with cyanide and hydrolysis of the resulting 1,3-dicyanoacetone under mild conditions, however, due to their complexity, these methods are not used in practice ^[2] .

According to its chemical properties, acetone dicarboxylic acid is a typical representative of β-keto acids: its reactivity is determined, firstly, by the presence of two electron-withdrawing substituents — carbonyl and carboxyl — in methylene groups, which determines their nucleophilicity and acidity and, secondly, the possibility of the formation of a six-membered ring in which the proton of the carboxyl group forms a hydrogen bond with the oxygen of the keto group.

The combination of these properties determines the ease of decarboxylation of acetone dicarboxylic acid, which occurs already at room temperature, this reaction, as in the case of other β-keto acids (e.g. acetoacetic acid), proceeds through the formation of a cyclic transition state, while acetone dicarboxylic acid is decarboxylated first to acetoacetic acid which, by splitting off carbon dioxide, forms acetone:

Reactions involving methylene groups

For acetone dicarboxylic acid, as well as for other β-dicarbonyl compounds, reactions caused by the nucleophilicity of methylene groups are also characteristic.

Thus, acetone dicarboxylic acid enters into an azo coupling reaction with diazonium salts (2) with the formation of bis- hydrazone of mesoxalic aldehyde (3), and decarboxylation also occurs:

Acetone dicarboxylic acid undergoes Mannich’s double condensation with dialdehydes and aromatic amines to form bicyclic products ( Robinson – Schöpf reaction ), this reaction is used as a method for the synthesis of tropanes (in the case of succinic dialdehyde) ^[3] , ^[4] and pseudopeltierin (when using glutaraldehyde ) ^[5] and is also accompanied by decarboxylation:

The cyclocondensation of acetone dicarboxylic acid esters with aromatic aldehydes and ammonia or primary amines, similar in mechanism, leads to the formation of piperidones ^[6] , ^[7] , ^[8] :  

Esters of acetone dicarboxylic acid enter into condensation of Knevenagel with aldehydes, and bis-products of condensation are formed ^[9] ; the interaction of acetone dicarboxylic acid esters with α-dicarbonyl compounds (Weiss-Cook reaction) leads to the formation of bicyclo [3.3.0] octane-3,7-diones ^[10] :

Esters of acetone dicarboxylic acid, like acetoacetic ester and other 1,3-dicarbonyl compounds, are easily alkylated with alkyl halides in the presence of bases, and the ratio of the products of C-alkylation and O-alkylation of the enolate depends on the reaction conditions ^[11] .

Such alkylation of acetone dicarboxylic acid esters with α-halogenocarbonyl compounds involving the ester carbonyl group in the reaction is used in the synthesis of heterocyclic compounds.

So, under the conditions of the Feist-Berari reaction, acetone dicarboxylic acid esters are used to synthesize furans, the reaction of dimethyl acetone dicarboxylate with chloroacetaldehyde leading to 2,3-disubstituted furan was used as the first stage of the synthesis of patulin mycotoxin ^[12] :

In combination with amines or ammonia, acetone dicarboxylic acid esters are used in the Ganch pyrrole synthesis; interaction with diethylacetone dicarboxylate with chloroacetone and methylamine is the first step in the synthesis of the anti-inflammatory drug zomepirac ^{[13] [14]} :

Reactions involving a carbonyl group

Acetonicarboxylic acid condenses with phenols and their esters (2) to form β-substituted derivatives of glutaconic acids (3), which serve as initial reagents for the synthesis of 2,5-dihydroxypyridines (4) ^[15] :

Under the reaction conditions, the resulting glutaconic acids with a hydroxyl substituent in the ortho position of the aromatic ring (3) can be closed to form coumarins (4) ^[16] ; in modern synthesis methods, acetone dicarboxylic acid is used, which is formed in situ from citric acid during condensation in concentrated sulfuric acid acid ^[17] , ^[18] :

Reactions involving carboxyl groups

Acetone dicarboxylic acid is esterified with alcohols under the influence of dry hydrogen chloride, forming diesters ^[19] , acetone dicarboxylic acid monoesters are obtained by acylation of alcohols with acetone dicarboxylic acid anhydride.

Upon dehydration of acetone dicarboxylic acid in acetic anhydride, its cyclic anhydride (1,2H-pyran-2,4,6 (3H, 5H) -trion) is formed, however, the reaction is complicated by ongoing acetylation with the formation of its mono- and diacetyl derivatives ^[20] :

Under severe conditions, dehydroacetic acid becomes the predominant product ^[21] , ^[22] .

During the interaction of acetone dicarboxylic acid esters with ammonia, ammonolysis occurs with the formation of a cyclic imide and the oxygen of the carbonyl group is replaced by an imino group, which leads to the formation of 4-amino-2,6-dihydroxypyridine (glutazine) ^[15] :

• α-ketoglutaric acid
• Lemon acid