Acetonedicarboxylic esters

While mechanistically this reaction is related to the Robinson-Schopf reaction for the generation of the tropinone skeleton, it also has similarities to the Hantzsch reaction. Here the heterocyclic ring 75 is assembled by the condensation of an equivalent of acetonedicarboxylic ester 72 with 2 equivalents of aldehyde 73 in the presence of ammonia or primary amine 74. 

Decarbomethoxylation. A recent stereoselective synthesis of coccinelline (4), an alkaloid used by the ladybug for defense, has been achieved by use of a variant of the classical Robinson-Schopf synthesis of tropinone. The reaction of 1 with acetonedicarboxylic ester at pH 5.5 yields a single product in 75 % yield, even though five chiral centers are produced. The next step, conversion of 2 to 3, requires neutral conditions in order to avoid retro-Mannich or retro-Michael reactions. This decar-bomethoxylation was accomplished most satisfactorily by NaCl in refluxing wet... 

Pentadienedioic esters. Acetonedicarboxylic esters are dehydrated with this salt in the presence of EtjN. 

A lactam carbonyl is annulated to its neighbouring methylene by heating with either the enamine (41.3) or the acetonedicarboxylic ester (41.4)... 

An interesting approach to the substituted 6,8-bisdehydro[13]annulenone (238) includes a double Knoevenagel reaction of the mixed acetonedicarboxylic ester (235) with aldehyde (236) in the presence of piperidine to give (237). Oxidative coupling of the acetylene moieties in (237) with Cu(OAc)2 in pyridine affords (238) in 10% yield (Scheme 47).2 a,p-Unsaturated malonodinitriles are suitable intermediates for the synthesis of a variety of carbocyclic systems. Cyclization of the benzylidene malonodinitrile (239) to form a five-membered carbocyclic ring (240) can be achieved upon treatment with acid and subsequent hydrolysis (Scheme 48). A similar cyclization of (241) affords six-mem-bered carbocyclic ring systems. ... 

A method of esterification introduced by Meyer807 is to dissolve the carboxylic acid in an excess of concentrated sulfuric acid (if necessary with warming) and to treat the solution cautiously with a small excess of the requisite alcohol when the reaction, which is often violent, ceases—if the mixture does not become warm, it must be heated—the solution is poured on solid sodium carbonate and worked up. This method has been used for esterification of sterically hindered acids and for carboxy derivatives of nitrogenous heterocycles, also for preparation of acetonedicarboxylic esters from citric acid and alcohols.808... 

This reaction was first reported by Petrenko-Kritschenko in 1906. It is the preparation of piperidone via a double Mannich Reaction from acetonedicarboxylic ester, two equivalents of aldehyde, and ammonia (or a primary amine), and is known as the Petrenko-Kritschenko piperidone synthesis. In this reaction, the mixture of reaction components is usually refluxed in an aqueous or alcoholic solution, and the resulting product is difficult to purify. It has been found that the addition of acid to the reaction medium is useful for this reaction.2... 

Formation of piperidones via cyclization of two moles of aldehyde and one mole each of acetonedicarboxylic ester and ammonia or a primary amine ... 

Substitutedisoxazole-3,5-dicarboxylic acids have been prepared from ethyl nitroacetate and an aldehyde (63BCJii50). A related reaction leads to diethyl 4-hydroxyisoxazole-3,5-dicarboxylate (334) and involves the reaction of acetonedicarboxylic acid ester (333) with nitrosyl chloride (78JHC1519). 

The first in this series to be reported was 4-oxoisoxazoline-3,5-dicarboxylic acid diethyl ester, which was formed by the reaction of nitrous acid on diethyl acetonedicarboxylate in 1891. Quilico described a number of syntheses in his 1962 review and the most general include the reaction of hydroxylamine and a-hydroxy-(or acetoxy)- 3-diketones and the conversion of 4-isoxazolediazonium salts to the hydroxy moiety (62HC(17)1, p. 3). Additional syntheses reported were the oxygenation of a 4-boric acid derivative (67JOM(9)l9) and peroxide oxidation of a 4-nitro-2-isoxazoline (Scheme 151) (79ZOR2436). 

Phenylethyl Alcohol Pyruvic Acid Oxalylacetic Acid Dihydroxytartaric Acid Dihydroxymaleio Add Acetonedicarboxylic Acid (ethyl ester) Muoonio Acid... 

Highest yields are obtained when the reaction is carried out in boiling toluene until all water and ethanol are eliminated by azeotropic distillation. Other /S-ketocarboxylic esters such as ethyl benzoyl acetate, o-methoxybenzoyl acetate and ethyl acetonedicarboxylate react similarly with aromatic amidoximes (50). 

The reaction of the isatins 7 and 40 with P-keto acids and their esters 68 under analogous conditions led to the corresponding dicarboxylic acids 69 [21, 50-52], The tricarboxylic acid 71 was synthesized from acetonedicarboxylic acid 70 and the isatin 7 [21],... 

Ketohendecanedioic acid has been prepared by the reactions described,3 4 by the dialkylation of diethyl acetonedicarboxylate with ethyl 7-iodobutyrate in the presence of sodium ethoxide followed by hydrolysis and decarboxylation,2 5 and by the permanganate oxidation of 6-(l -cyclohexenyl)-l-hexene.6 The present method is a simplification of the procedure originally described by Sauer.3 This method is practical for the preparation of symmetrical keto dibasic acids and esters.7... 

This disconnection led to the C3 synthon 48 (and hence to its already familiar synthetic equivalent 44) and C9 amino dialdehyde 47. The Michael addition of malonic ester to acrolein was employed for the synthesis of the key starting material 49. The Claisen ester condensation of the latter followed by decarboxylation and reductive aminolysis led to the preparation of amino-bis-acetal 47a. The respective amino dialdehyde 47, generated in situ by a controlled hydrolysis of the acetal groups of 47a, reacted smoothly with acetonedicarboxylic diester and gave the required adduct 46 in a good yield and nearly complete stereoselectivity. 

The mycotoxin patulin was synthesized via the oxidation of a disubstituted furan in the laboratory of M. Tada. The required 2,3-disubstituted furan was conveniently prepared via the Feist-Benary reaction of acetonedicarboxylic acid dimethyl ester and chloroacetaldehyde in the presence of pyridine. Subsequent functional group modification and oxidation of this furan finally gave the natural product. 

Displacement of an ethoxy attached to a vinylic side-chain occurs in mineral acid at ambient temperature with concurrent formation of a C—C bond [2042]. Ethereal hydrogen chloride annulates nitro and side-chain epoxide groups intramolecular reduction-oxidation leads to the 4-quinolinone in high yields [2314]. A C—N bond is formed when a methylthiovinylpyrrole is treated with a strong base and a malonic ester. Lactim ethers such as 5-methoxy-2 -pyrrole condense with acetonedicarboxylate in a base-induced cyclization at room temperature [3258]. 

The pool of C H acidic components is restricted to compounds that allow a double Mannich reaction. Most common are esters of acetonedicarbonic acid, especially dimethyl acetonedicarboxylate, which is the general substrate for the... 

The synthesis of pyridazine derivatives from hydrazones includes the thermal cyclization of 2-arylhydrazono-3-oxo-5-phenyl-4-pentenenitriles (readily obtained from ethyl cinnamate by condensation with acetonitrile followed by Japp-Klingemann type reactions) to l-aryl-3-cyano-6-phenyl-5,6-dihydro-4(l//)-pyridazinones (Scheme 85) <86JHC93>, and base-induced cyclization of a hydrazone of a 4-chloro-l-arylbutan-l-one to prepare a 2,3,4,5-tetrahydropyridazine (Scheme 85) <88JHC1543>. An earlier route to 6-carboxy-5-hydroxy-2-phenyl-3(2//)-pyridazinone via condensation of benzenediazonium chloride and dimethyl acetonedicarboxylate has been adapted to give a series of aryl derivatives either as esters (by thermal cyclization) or as acids (by cyclization with hydroxide). Both cyclizations proceed in high overall yield (Scheme 86) and decarboxylation of the acids also proceeds in high yield <89JHC169>. 

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