Acetoacetate and its Derivatives

Acetoacetic acid, CHgCOCHgCOOH, is an aliphatic -keto acid. Derivatives are formed by reduction, activation of the carboxylic group, and decarboxylation. 

Derivatives of acetoacetic acid occur in microorganisms, plants, and animals. 

I 3-Ketothiolase 2 acetoacetyl CoA reductase 3 3-hydroxybutyryl CoA polymerase 4 polyhydroxy butyrate depolymerase 5 hydrolase 6 3-hydroxybutyrate dehydrogenase 7 CoA-trans-ferase 

1 Enoyl CoA hydratase (crotonase) 2 butyryl CoA dehydrogenase 3 Co A-transferase 4 butyraldehyde dehydrogenase 5 butanol dehydrogenase 

Acetoacetyl Co A is built from two acetyl Co A molecules. Free acetoacetic acid is either formed from acetoacetyl CoA or from /5-hydroxybutyric acid (Fig. 50). Acetoacetic acid decarboxylates spontaneously to acetone. Reduction of acetoacetyl CoA yields j8-hydroxybutyryl CoA which may be transformed to a polymeric derivative (Fig. 50), to butyric acid, or to butanol (Fig. 51). 

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Recognize too that the reaction sequence is one that is characteristic of p keto esters in general and not limited to just ethyl acetoacetate and its derivatives Thus... 

Chancel [80a] described another general method of preparing 1,1-dinitroparaf-fins and in particular 1,1-dinitroethane, starting from ethyl acetoacetate and its derivatives ... 

Random incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. For example, treatment of ethyl acetoacetate with ammonia gives the corresponding P-aminocrotonate 32. The aldehyde (34) required for preparation of such an unsymmetrical compound is prepared by reaction of the product from direct metallation of 33 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate and the p-aminocrotonate from isopropyl acetoacetate leads to isradipine (35) [9]. The same aldehyde with ethyl acetoacetate and the P-aminocrotonate from ethyl acetoacetate gives darodipine (36) [10]. In much the same vein, condensation of the ben-zaldehyde 37 with methyl acetoacetate and its P-aminocrotonate derivative affords riodipine (38) [11]. 

Other common intermediates for azo pigment production are 2,4-dinitro-aniline, acetoacet-o-chloroanilide, acetoacet-o-toluidide, phenyl- and p-tolyl-methylpyrazolone, 2-hydroxy-3-naphthoic acid, Naphtol AS and its derivatives, and 2-chloro-4-aminotoluene-5-sulfonic acid. 

Compounds such as aceto-succinic ester and its derivatives which contain the acetoacetic ester grouping also undergo this hydrolysis. 

Malonic ester syntheses are the classical analog of acetoacetic ester syntheses of methyl ketones. Neither case requires the use of an amide base for the enolate formation, and in both cases alkoxides suffice to deprotonate the substrate completely. Malonic esters are active-methylene compounds just like acetoacetic ester and its derivatives. 

Methyl-5-nitrobenzimidazole is formed on heating 4-nitro-l,2-phenylendi-amine and its derivatives with the ester of acetoacetic acid (Scheme 2.50) [396,397], Depending on the experimental conditions, isomeric 8-nitro-4-methyl-2,5-dihydro-IH-1,5-bcnzodiazepinone-2 and 8-nitro-4-methyl-2,3-dihydro-1//-1,5-benzodiaze-pinone-2 easily transform into each other, and 5-nitro-l-isopropenylbenzimidazolone can be obtained (in this case). 

A new carbon-carbon bond is formed during the reaction of lactim ethers with compounds containing active methylene groups, such as malonic ester and its derivatives, acetylacetone, barbituric acid, rhodanine, nitromethane, and oxindole.8 9 33 100-102 Examples are the condensation of the lactim ether of tetrahydro-/S-carbolinone with acetoacetic ester103 [Eq. (5)] and the condensation of the bislactim ether of 2,2 -dipyrrolidine-5,5 -dione (48) with butyl cyanoacetate20 [Eq. (6)]. Another instance is the reaction of 2 (R = Me) with 2-phenyloxazolin-5-one, to give 3,4-pentamethyleneimidazoles (49) via the intermediate 4-(homopiperid-2-ylene)oxazolin-5-one (50)104 (Scheme 16). 

Amino-l-alkyl-s-triazolium salts, on condensation with acetoacetic ester and its derivatives, give mesoionic triazolopyridazines 364 (73JPR97). The reaction needs a base for the generation of ylid 363. 

Diaminoimidazoles (78JHC937) and 1,2-diaminobenzimidazoles (84 KGS700 88T7185) react with acetoacetic ester and its derivatives with complications. 

Although acid and alkali may frequently be used interchangeably on the same materials to give essentially the same products, tl is not in-variab true. The action of acid on acetoacetic ester and its derivatives leads to acetone, carbonic acid, and alcohol and its related products, while alkali on the same ester produces acetic acid and alcohol. 

Acetoacetic Ester Synthesis.—The hydrolysis of acetoacetic ester and its derivatives presents many points of interest, on account of the fact that the acid and its substitution-products, which are formed by the hydrolysis, are unstable and yield important decomposition-products. When the saponification of acetoacetic ester is effected by boiling it with a dilute aqueous solution of an acid or a base, it is probable that alcohol and acetoacetic acid are first formed —... 

The reaction was extensively stndied for cinnamyl esters (acetate and carbonate) as allylic snbstrates, with some examples given for allyl acetate and its homologues, and a wide range of nncleophiles inclnding N-nucleophiles (primary and secondary amines, hydroxylamine and its derivatives, and sodium azide), C-nucleophiles (malonates, ethyl acetoacetate, acetylacetone, sodium tetraphenylborate), and S-nucleophile sodium p-toluenesuhinate. 

Coumarin can also be formed by the reaction of phenol with diketene (40). Similarly, diphenols can react with hydroxycarboxyUc acids or beta-ketoesters to give hydroxycoumaria derivatives. The reaction of resorciaol with malic acid produces umbeUiferone (7-hydroxycoumaria) and its reaction with ethyl acetoacetate gives beta-methylumbeUiferone (7-hydroxy-4-methylcoumaria). 

The synthetic capabilities of this compound arc not yet exhausted. Acetoacetic ester and its alk d derivatives undergo decomposition in two wajs, accoidiiig to whether dilute alkalis and acids or, on the other hand, strong alkalis are employed. 

Although bromo derivatives have been used, the two most common ot-halocarbonyl compounds for this reaction are chloroacetaldehyde and chloroacetone. The dicarbonyl component is typically ethyl acetoacetate or one of its derivatives. A variety of bases including triethylamine and potassium hydroxide can promote the reaction however, the most popular base is pyridine. Conversion to the furan takes place either at room temperature or upon heating to 50°C with reaction times varying from four hours to five days and yields ranging from 30-86%. 

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