Malonic esters, condensation with

An effective antiserum for dehydroepiandrosterone 3-sulphate has been obtained by use of the 17-hydrazone as hapten, coupled to BSA. 3a,5p Tetrahydroaldosterone (22), the main urinary metabolite of aldosterone, is efficiently bound by an antiserum induced by the conjugate of BSA with the 3-carboxymethyloxime of aldosterone 18,21-diacetate. Haptens for RIA of cortisone and cortisol have been prepared by the introduction of 7a- and 7/3-carboxymethyl substituents (23) through a malonic ester condensation with the 7-bromo-derivative (24). ... 

This process represents a Knoevencigel condensation,3 a reaction in which a compound with an acidic methylene group, such as dimethyl malonate (8). condenses with a carbonyl compound like citronellal (9) to give an alkene. Reaction occurs in a weakly basic or neutral medium. Catalytic amounts of piperidinium acetate suffice to deprotonate malonic ester 8. The resulting anion 15 adds to the aldehyde citronellal (9) to give alkoxide 16. 

A condensation occurs between 5-hydroxymethylfurfural and malonic ester20 and in a similar way, two molecules of malonic ester react with furan 2,5-dialdehyde.88 A condensation product, XXXV, has also been obtained with hydantoin.89 5-Hydroxymethylfurfural and its acetyl derivative undergo the Perkin reaction with sodium acetate and acetic anhydride giving 5-acetoxymethylfuran 2-acrylic acid (XXXVI).70 Similar products of the same reaction are obtained from 5-methyl-furfural71 and 5,5 -diformyl-l,l -furylmethyl ether (XXVII).61,72... 

Required are ioo g. of carefully dried and freshly distilled malonic ester, prepared according to the directions in the elementary text books, 28 8 g. of sodium (2 molecular equivalents), 380 cc of absolute alcohol (dried by adding to ordinary absolute alcohol enough sodium to combine with 1 per cent of water and distilling), and 195 g of carefully dried and freshly distilled ethyl iodide (2 molecular equivalents). One-half of the sodium is dissolved in one-half of the alcohol under a reflux condenser surmounted by a calcium chloride tube, the malonic ester added with stirring, and then... 

Problem 26.5 In an example of the Michael condensation, malonic ester reacts. with ethyl 2-butenoate in the presence of sodium ethoxide to yield A, of formula C13H22O6. The sequence of hydrolysis, acidification, and heating converts A into 3-methylpentanedioic acid. What is A, and how is it formed Hint See Sec. 8.20. Check your answer in Sec. 27.7.)... 

Diesters of malonic acid, as well as other active methylene compounds such as ace-toacetic esters and cyanoacetic esters, condense with aldehydes and ketones in the presence of catalytic amounts of primary or secondary amines or ammonium salts. 

Russell, R. R., VanderWerf, C. A. Malonic ester synthesis with styrene oxide and with butadiene oxide. J. Am. Chem. Soc. 1947, 69,11-13. Mizuno, Y., Adachi, K., Ikeda, K. Condensed systems of aromatic nitrogenous series. XIII. Extension of malonic ester synthesis to the heterocyclic series. Pharmaceutical Bulletin 1954, 2, 225-234. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Malonic Ester Derivatives (Knoevenagel reaction). Malonic acid esters can be condensed with aldehydes through the use of a basic catalyst. The very labile a-H atom of the malonic ester reacts with the catalyst as follows ... 

An example of an intermolecular aldol type condensation, which works only under acidic catalysis is the Knoevenagel condensation of a sterically hindered aldehyde group in a formyl-porphyrin with a malonic ester (J.-H. Fuhrhop, 1976). Self-condensations of the components do not occur, because the ester groups of malonic esters are not electrophilic enough, and because the porphyrin-carboxaldehyde cannot form enolates. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

Reactions. The chemical properties of cyanoacetates ate quite similar to those of the malonates. The carbonyl activity of the ester function is increased by the cyano group s tendency to withdraw electrons. Therefore, amidation with ammonia [7664-41-7] to cyanoacetamide [107-91-5] (55) or with urea to cyanoacetylurea [448-98-2] (56) proceeds very easily. An interesting reaction of cyanoacetic acid is the Knoevenagel condensation with aldehydes followed by decarboxylation which leads to substituted acrylonitriles (57) such as (29), or with ketones followed by decarboxylation with a shift of the double bond to give P,y-unsaturated nitriles (58) such as (30) when cyclohexanone [108-94-1] is used. 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

Z-Furan. 3-(5-Nitro-2-furanyl)-2-propenamide, is prepared by condensation of 5-nitro-2-furancarboxaldehyde diacetate with malonic ester followed by PCl chlorination and amination (29). The product was marketed in Japan as a food preservative. 

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

KNOEVENAGEL OOEBNER STOBBE Condensation Base catalyzed aldol condensation of aldehydes or ketones with an activated methylene group of a malonic ester (Knoevenagel Doebner) or a succinic ester (Stobbe)... 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

The Gould-Jacobs reaction is a sequence of the following reactions (1) condensation of an arylamine 1 with either alkoxy methylenemalonic ester or acyl malonic ester 2 providing the anilidomethylenemalonic ester 3 (2) cyclization of 3 to the 4-hydroxy-3-carboalkoxyquinoline 4 (3) saponification to form acid 5, and (4) decarboxylation to give the 4-hydroxyquinoline 6. All steps of this process will be described herein with emphasis on the formation of intermediates like 3 and 4. 

In 1939, Gould and Jacobs reported the condensation of aniline with acetyl malonic ester (AME) and ethoxymethylenemalonate (EMME), respectively, followed by cyclization of anilinomethylenemalonic ester 13 and 14 in mineral oil to afford the esters 15 and 16. Saponification of the esters gave the known acids 17 and 18, respectively. 

In order to expand the utility of the reaction, modification of the route to anilidomethylene malonic ester equivalents was developed. Simple condensation of triethyl orthoformate with cyanoacetic ester, acetoacetic ester, or malonic ester in the... 

Condensation of Af-aryliminochlorides with malonic ester followed by thermal cyclization, as initially reported by Just, was found to be a general method for the preparation of 2, 3, 4-substituted quinolines. Various substituents on the aryl ring of the iminochloride proved uneventful, even though the conditions required to generate the iminochloride utilized PCI5. 

In the 1880s, Pinner found that the amidine derivative 2 reacted with acetoacetic ester (4) to furnish 2-substituted-6-hydroxy-4-methylpyrimidine 5. The condensation of amidine derivative 2 with other (l-keto esters, malonic esters, and (l-diketones proceeded similarly (see the following pages for examples). ... 

The prototype of a Knoevenagel reaction shown in the scheme above is the condensation of an aldehyde or ketone 1 with a malonic ester 2, to yield an a ,/3-unsaturated carboxylic ester 4. 

Catalytic reduction of the nitrile 79 in the presence of semicarbazide affords initially the semicarbazone of 80. Hydrolysis-interchange, for example in the presence of pyruvic acid, gives the aldehyde 80. Condensation with the half ester of malonic acid leads to the acrylic ester 81 the double bond is then removed by means of catalytic reduction (82). Base catalyzed reaction of the... 

One such compound, bropirimine (112), is described as an agent which has both antineo-plastic and antiviral activity. The first step in the preparation involves formation of the dianion 108 from the half ester of malonic acid by treatment with butyllithium. Acylation of the anion with benzoyl chloride proceeds at the more nucleophilic carbon anion to give 109. This tricarbonyl compound decarboxylates on acidification to give the beta ketoester 110. Condensation with guanidine leads to the pyrimidone 111. Bromination with N-bromosuccinimide gives bropirimine (112) [24]. 

MalONIC ACID, ETHYLHYDROXY, DIETHYL ESTER, BENZOATE, 45, 37 Mfsitaidehydf, 47, 1 Mesitylcne, condensation with dichloro methyl methyl ether, 47, 1 Methalljl chloride in alkylation of 2,4-pentanedione with potassium carbonate, 47, 87... 

Malonic acid, amino-, diethyl ester, HYDROCHLORIDE, 40, 24 Malonic acid, bts(hydroxymethyl)-, DIETHYL ETHER, 40, 27 Malonitrile, condensation with tetra-cyanoethylene, 41, 99 2-Mercaptopyrimidine, 43, 6S hydrochloride of, 43, 68 Mercuric oxide in preparation of bromo-cyclopropane, 43, 9 Mesityl isocyanide, 41,103 5-Methallyl-l,2,3,4,5-pentachlorocyclo-pentadiene, 43, 92 Methane, dimesityl-, 43, 57 Methanesiileinyl chloride, 40, 62 Methanesulfonic acid, solvent for making peroxybenzoic acid from benzoic acid, 43, 93... 

Condensation of aminopyrazole 116 with ethoxy-methylene malonic ester gives the product of addition-elimination (117), which is then cyclized to the piperidone by heating in diphenyl ether. The product tautomerizes spontaneously to the hydroxypyridine 118. The hydroxyl group is then converted to the chloro derivative by means of phosphorus oxychloride (119). Displacement of halogen by n-butylamine gives... 

The Knoevenagel-type condensation of salicylaldehydes with malonic acid [14, 27], malonic ester [28], cyanoacetic ester [29], or Meldrum s acid [30], is... 

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