Diester malonates

You may not want a product with both ester groups present, and we discussed in Chapter 26 how one of two 1,3-related ester groups may be removed by hydrolysis and decarboxylation. There is a simpler route with the aldol reaction. If, instead of the malonate diester, malonic add is used, the... 

Diesters (malonates and substituted derivatives) combine three useful features in conjugate addition reactions they form stable enolate anions that undergo clean conjugate addition if required, one of the ester groups can be removed by hydrolysis and decarboxylation and, finally, the remaining acid or ester is ideal for conversion into other functional groups,... 

P-Diesters (malonates and substituted derivatives, see p. 595) combine three useful features in conjugate addition reactions ... 

Enolate anions derived from aldehydes and ketones (aldol reactions), esters (Claisen and Dieckmann condensations), j8-diesters (malonic ester syntheses), and )8-ketoesters (acetoacetic ester syntheses). 

When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced even more. Table 22.1 thus shows that 1,3-diketones (/3-diketones), 3-0X0 esters (/3-keto esters), and 1,3-diesters (malonic esters) are even more acidic than water. The enoiate ions derived from these /3-dicarbonyl compounds are stabilized by sharing of the negative charge by both neighboring carbonyl oxygens. The enoiate ion of 2,4-pentanedione, for instance, has three... 

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

Hydrochloric acid [7647-01-0], which is formed as by-product from unreacted chloroacetic acid, is fed into an absorption column. After the addition of acid and alcohol is complete, the mixture is heated at reflux for 6—8 h, whereby the intermediate malonic acid ester monoamide is hydroly2ed to a dialkyl malonate. The pure ester is obtained from the mixture of cmde esters by extraction with ben2ene [71-43-2], toluene [108-88-3], or xylene [1330-20-7]. The organic phase is washed with dilute sodium hydroxide [1310-73-2] to remove small amounts of the monoester. The diester is then separated from solvent by distillation at atmospheric pressure, and the malonic ester obtained by redistillation under vacuum as a colorless Hquid with a minimum assay of 99%. The aqueous phase contains considerable amounts of mineral acid and salts and must be treated before being fed to the waste treatment plant. The process is suitable for both the dimethyl and diethyl esters. The yield based on sodium chloroacetate is 75—85%. Various low molecular mass hydrocarbons, some of them partially chlorinated, are formed as by-products. Although a relatively simple plant is sufficient for the reaction itself, a si2eable investment is required for treatment of the wastewater and exhaust gas. 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

A number of examples of enantioselective hydrolysis of diesters (I and 2) of malonic and glutaric acids are given in Table I. 

Porcine liver esterase (PLE) gives excellent enantioselectivity with both dimethyl 3-methylglutarate [19013-37-7] (lb) and malonate (2b) diester. It is apparent from Table 1 that the enzyme s selectivity strongly depends on the size of the alkyl group in the 2-position. The hydrolysis of ethyl derivative (2c) gives the S-enantiomer with 75% ee whereas the hydrolysis of heptyl derivative (2d) results in the R-monoester with 90% ee. Chymotrypsin [9004-07-3] (CT) does not discriminate glutarates that have small substituents in the 3-position well. However, when hydroxyl is replaced by the much bulkier benzyl derivative (Ic), enantioselectivity improves significantly. 

In the alkylation of l-phenylpyrazole-3,5-diones both carbon and oxygen compete successfully with nitrogen (B-76MI40402). Phenylbutazone (Section 4.04.4.1.1) can be prepared by reaction of l,2-diphenylpyrazole-3,5-dione with -butyl halides and alkali, even if the industrial procedure uses -butyl malonic diesters and hydrazobenzene (Section 4.04.3.1.2(h)). 

If a Knoevenagel condensation with malonic acid is conducted in refluxing pyridine, a subsequent decarboxylation often occurs. It has been shown that the decarboxylation of a ,/3-unsaturated diesters 3 under these conditions is slow the decarboxylation of the corresponding free dicarboxylic acid is formulated as follows ... 

Molecular ion The molecular ion is generally not observed for diesters larger than diethyl malonate. 

Diesters dimethyl malonate, dimethyl succinate, dimethyl glu-tarate, and dimethyl adipate... 

The application of 3-aminopropyl phosphine (3) [41,46] as a building block for incorporation into -COOH functionalized frameworks provides an excellent example of the utility of preformed primary phosphine frameworks (Scheme 8) [46]. The reactions involved Michael addition of ferf-butyl acrylate to malonic acid dimethyl ester to produce the intermediate adduct, 2-methoxycarbonyl-pentanedioc acid 5-ferf-butyl ester 1-methyl ester, which upon treatment with trifluro-acetic acid (TFA) produced the corresponding diester acid,2-methoxy-carbonyl-pentanedioic acid 1-methyl ester, in near quantitative yield. It is remarkable to note that the reaction of NH2(CH2)3PH2 (3) with the diester acid is highly selective as the -COOH group remained unattacked whereas the reaction occurred smoothly and selectively at the -COOMe groups to pro-... 

Diester (20) could be made by the usual 1,5-dicarbonyl route involving Michael addition to (21), but we can use its symmetry to devise an alternative route from malonate adduct (22). 

Diesters are malonates, and are often used for the synthesis of barbiturates. Malonyl dichlorides can be used in place of a malonyl diesters, in which case the reaction can be performed at room temperature, as demonstrated by the synthesis of A-phenyl and A -pyridyl 2-thiobarbituric acids 666 from malonyl dichloride 664 and A, iV -diarylureas 665 <2002AJC287>. 

---