Dimethyl 1,3-acetonedicarboxylate

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. 

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. 

Optically pure 1,3-allenedicarboxylate 110c possessing central and axial chirality was prepared from dimethyl acetonedicarboxylate by incorporation of menthol as a chiral auxiliary [98]. The [4+2]-cycloaddition reaction of 110c with cyclopentadiene in the presence of A1C13 proceeded with high diastereoselectivity to afford adduct 115. 

The first member of the diazaphenalene system (which could be considered to be a benzonaphthyridine) to be synthesized was the 1,6-diazaphenalene (353). This was obtained in six steps starting from the reaction of dimethyl acetonedicarboxylate with cyclohexane-1, 3-dione. The intermediate steps are shown (78H(9)1561, 79H(12)903>. Compound (353) has similar chemical and physical properties to those of imidazole. For a full account of the syntheses and reactions of this ring system the review <83H(20>87) should be consulted. 

A simpler and more versatile route to comparably functionalized bicyclooctanes has been developed more recently by Weiss and his co-workers.174-176 Specifically, the reaction of 1,2-dicarbonyl compounds with dimethyl 3-ketoglutarate (dimethyl acetonedicarboxylate) in aqueous solution at pH 5, or preferably in a citrate-phosphate buffer, followed by hydrolytic decarboxylation, affords 117 in good... 

Condensation of dimethyl acetonedicarboxylate with acetaldehyde and methylamine led to dimethyl L, 2,6-trimethyl-4-piperidone- 3,5-dicarboxylate, further reactions of which yielded a 2,6-dimethyl analog of arecaidine (36)29,30 (see also Section V,A.)... 

Several 4-piperidone syntheses are based on the addition of a primary amine to a divinyl ketone and methods for the preparation of l,2,5-trimethyl-4-piperidone (the precursor of the promedols) and the 2,3-dimethyl analog by this means are shown (Schemes 7.2 and 7.3). 3,5-Dimethyl-4-piperidone is prepared on a similar basis/41 while the 2,6-dimethyl ketone is made either by a Mannich procedure from dimethyl acetonedicarboxylate and acetaldehyde (leading to c-t mixtures)(26) or by catalytic reduction of l,2,6-trimethyl-4(lH)-pyridone (37) and oxidation of the resultant 4-piperidinols, giving a cis product.(58)... 

Cyclizations. Cyclization of hydroxylated propargyl sulfones may involve isomerization to the corresponding allenyl sulfones which should behave as Michael acceptors. Access to the indolizidine skeleton by an intramolecular Michael reaction of 5-tosyl-4-pentenamide and subsequent alkylation at nitrogen and carbon is quite efficient. A synthesis of resorcinols from dimethyl acetonedicarboxylate and alkyl alkynoates involves a Michael reaction-Dieckmann cyclization sequence. 

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... 

Control of the pH is also of importance for the Mannich-based bispidine synthesis. Formation of an aldol product competes with the Mannich condensation in the basic pH region. It is for this reason that, in some cases, the reaction is sensitive to the order in which the reactants are added to the reaction mixture. It is possible to add the aldehyde and amine components one after another to a solution of the CH-acidic compound, but sometimes the aldol reaction can be disfavored by changing the order. This allows the imminium ion to be formed in advance. The precursors of 45 and 46 have been prepared by this method. In some cases, it has been useful to use a protonated amine component as the acetate salt (e.g., 49 or precursors for 44, 47, and 48), as the chloride salt (e.g., 11) or to carry out the reaction in acetic acid. Aromatic amines (e.g., aniline) give rise to para-substituted aromatic amines if the solution is not approximately neutral. In a very elegant procedure, a condensate of formaldehyde and aniline, which is the trimeric methyleneaniline, was prepared separately, and treated in the Mannich reaction with dimethyl acetonedicarboxylate and formaldehyde to yield the 3,7-diphenylbispidone... 

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>. 

To a 1 mmol solution of dimethyl acetonedicarboxylate in 15 mL dry THF was added 2.5 mmol powdered K2CO3. The mixture was stirred under nitrogen for 15 min at room temperature. Then 1 mmol ran -l,4-dibromo-2-butene in 10 mL dry THF was added through a syringe, and the resulting reaction mixture was refluxed until the completion of... 

Dimethyl acetonedicarboxylate or ethyl acetoacetate can provide the 3-, 4-, and 5-carbons to give 3,5-disubstituted-4-pyridones (XI-177, Rs = CH3CO, CO2CH3). s-Triazine has been used to provide the 2- and 6-carbons. A compound, previously described as 4-hydroxy-3-pyridinecai o lic acid (XII-177, R = Rj = H) ° was shown to be nicotinic acid-l-oxide(XII-I78). ° ... 

Methoxy-l,4,4-triphenylbut-2-yn-l-one and dimethyl acetonedicarboxylate dissolved in tetrahydrofuran, K-t rt-butoxide added portionwise under anhydrous conditions, and stirred 12 hrs. at room temp. dimethyl 2-hydroxy-4-phenyl-6-(a methoxy-a-phenylbenzyl)isophthalate. Y 84%. F. e. s. W. Ried and E. Konig, A. 757,153 (1972) reactions of a,/ -acetyleneketones, review, cf. R. L. Bol shedvors-kaya and L. I. Vereshdiagin, Russ. Chem. Rev. 42, 225 (1973) (Eng. transl.). 

While enamines react with chromones 230 mainly at the R CO group to produce pyridine derivatives, reactions of dimethyl acetonedicarboxylate with 230 took an entirely different course and gave a series of 6//-benzo[c]chromenes 260 in good yields. This heterocyclic system certainly is the product of the primary 1,4-addition... 

Scheme 84 Reaction of chromones 230 with dimethyl acetonedicarboxylate...

A soln. of 4-methyl-4-dichloromethyl-2,5-cyclohexadien-l-one in abs. methanol and dimethyl acetonedicarboxylate added to a soln. of Na in abs. methanol, and refluxed 2 hrs. dimethyl 9-methy 1-9-dichloromethylbicydo [3.3.1 ]nona-3,7-dione-2,4-dicarboxylate (Y 63.2%) dissolved in glacial acetic acid, treated with coned. H2SO4, and refluxed 10 hrs. 9-methyl-9-dichloromethylbicyclo-[3.3.1]nona-3,7-dione (Y 84.0%). H. Stetter and J. Mayer, B. 92, 2664 (1959). 

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