Acetonedicarboxylate

As an e.xtension of the oxidative carbonylation with alkyl nitrites, malonate can be prepared by the oxidative carbonylation of ketene (583)[524], Also, the acetonedicarboxylate 585 is prepared by the Pd-catalyzed, alkyl nitrite-mediated oxidative carbonylation of diketene (584)[525],... 

Batchwise operated multipurpose plants are per defmitionem the vehicle for the production of fine chemicals. There are, however, a few examples of fine chemicals produced ia dedicated, coatiauous plants. These can be advantageous if the raw materials or products are gaseous or Hquid rather than soHd, if the reaction is strongly exothermic or endothermic or otherwise hazardous, and if the requirement for the product warrants a continued capacity utilization. Some fine chemicals produced by continuous processes are methyl 4-chloroacetoacetate [32807-28-6] C H CIO [32807-28-6], and malononittile [109-77-3] C2H2N2, made by Lonza dimethyl acetonedicarboxylate [1830-54-2] made by Ube and L-2-chloropropionic acid [107-94-8] C2H C102, produced by Zeneca. 

Fig. 1. Thermal decomposition of citric acid (1) to aconitric acid (2), citraconic acid (3), itaconic acid (4), and oxidation to acetonedicarboxylic acid (5).

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). 

Acetonedicarboxylic acid [542-05-2] M 146.1, m 138" (dec), pK 3.10. Crystd from ethyl acetate and stored over P2O5. Decarboxylates in hot water. 

The following synthesis of p ewdopelletierine is of special interest, since it involves only materials and conditions which could occur in plants and is therefore a possible bio-synthesis. Menzies and Robinson showed that when calcium acetonedicarboxylate, glutardialdehyde and methyl-amine are mixed in aqueous solution under specified conditions and the mixture is kept for twenty-four hours, a produet (XX) is formed, which can be decarboxylated to -pelletierine (XXI) and the latter isolated as the picrate, whieh after recrystallisation yields the pure base (m.p. 48-5°), the identity of which can be established by eonversion to the characteristic dipiperonylidene derivative. The course of the synthesis is represented as follows — ... 

Blount and Robinson have extended this mode of synthesis to the preparation of iV-methyl/iomogranatonine (XXII) by the use of adipaldehyde, CHO. [CH2]4. CHO. The base, on reduetion with sodium in butyl aleohol, yields A -methyl/mmogranatoline (XXII CO — CHOH), the benzoyl derivative of which possesses marked local anaesthetic aetion. Similarly Blount, by eondensing /3-(o-formylphenyl)propaldehyde, CHO. CgH4. CHj. CHj. CHO, with methylamine and calcium acetonedicarboxylate, has prepared 8 9-benz-d - -feomogranatene-3-one (XXIII), which was reduced to the -alcohol (cf. reduction of tropinone to -tropine) and the latter converted to the benzoyl-derivative (m.p. 98°),... 

Sehdpf and Lehmann have effeeted syntheses on this prineiple under varying conditions. Thus, using buffered solutions of glutardialdehyde, raethylamine hydrochloride and acetonedicarboxylic acid, they have obtained yields of 60-72 per cent, of A-pelletierine working at pH 3-7, with smaller, but still important, yields at pH 9-0-13 0. 

A better yield was obtained when, in place of acetone, calcium acetonedicarboxylate was used, the initial product in this case being calcium tropinonedicarboxylate, from which the free dibasic acid is readily isolated and can be decarboxylated by heating in acid solution, yielding tropinone. This idea was taken up in Germany, and a number of processes for the production of tropinone derivatives have been described, mostly in patent literature. According to Willstatter and Pfannenstiel, a yield of... 

Using maleic aldehyde, acetonedicarboxylic acid and methylamine hydrochloride in aqueous solution, in presence of sodium acetate, Iheobrazhenskii, Rubtsov, Dankova and Pavlov have prepared troperume. 

Though the dialdehyde-tropinone synthesis does not succeed when the dialdehyde is replaced by a diketone, Blount and Robinson have shown that 1-methyltropinone (XXXV) can be obtained by the interaction of the keto-aldehyde, laevulinaldehyde. Me. CO. CH. CH. CHO, with methylamine and calcium acetonedicarboxylate, and from this by reduction to 1-methyl- -tropine and benzoylation, 1-methyl tropacocaine (b.p. 210°/15 mm. picrate, m.p. 163-4°) has been prepared. 

Anet et al. ( 04) obtained in 1947 the alkaloids hygrine (191) and kusk-hygrine (192) in a very good yield by treatment of y-methylaminobutyralde-hyde with acetoacetic or acetonedicarboxylic acids at pH 7. The same reaction was later accomplished by Galinovsky et al. (305-307), who prepared the starting aldehyde by partial reduction of 1-methyl-2-pyrroli-done with lithium aluminum hydride. He used acetonedicarboxylic acid for the synthesis of both alkaloids and showed that a mixture of both alkaloids is formed, the composition of which depends on the ratio of components. 

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. 

Cocaine has been prepared by a sequence beginning w ith a Mannich reaclion (Problem 23.63) between dimethyl acetonedicarboxylate, an amine, and a dialdehyde. Show the structures of the amine and dialdehyde. 

Although the most recent modifications of the Prelog condensation of 1,3-dike-tones and 1,3,5-triketones, for example that of acetylacetone with dimethyl 1,3-acetonedicarboxylate in the presence of NaOH in H2O, afford substituted benzenes such as 1486 in up to 94% yield (Scheme 9.22) and coumarins [40], these condensations of highly substituted polyketones with the corresponding aromatic systems might also be effected in the presence of HMDS 2/TCS 14 or TMSOTf... 

The original Robinson synthesis (66) of tropinone (124), which consists of a reaction between succinaldehyde (140), methylamine (141), and the calcium salt of acetonedicarboxylic acid (142), proceeds in low yield (Scheme 2). However, it has the great merit of being the pioneering achievement in the field of biomimetic syntheses of natural products. 

The domino approach is also used by Nature for the synthesis of several alkaloids, the most prominent example being the biosynthesis of tropinone (0-16). In this case, a biomimetic synthesis was developed before the biosynthesis had been disclosed. Shortly after the publication of a more than 20-step synthesis of tropinone by Willstatter [14], Robinson [15] described a domino process (which was later improved by Schopf [16]) using succinaldehyde (0-13), methylamine (0-14) and acetonedicarboxylic acid (0-15) to give tropinone (0-16) in excellent yield without isolating any intermediates (Scheme 0.5). 

Even fully substituted aromatic compounds can be prepared utilizing the Mi-chael/Dieckmann strategy. As reported by Covarrubias-Zuniga and coworkers (Scheme 2.32) [67], reaction of the anion of l-allyl-l,3-acetonedicarboxylate (2-138) and the ynal 2-139 afforded the intermediate 2-140 which led to the resorcinol 2-142 with spontaneous aromatization under acidic conditions via 2-141 in an overall yield of 32 %. 2-142 was transformed into mycophenolic acid (2-143) in only a few additional steps [68]. 

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