Methyl hydrogen malonate

The diastereoselectivity and the stereochemical outcome of the addition of 2,3,4,6-tetrahydro-3, 4-dimethyl-2-phenyl-1,4-oxazepine-5,7-dione, derived from ephedrine and methyl hydrogen malonate, to 1 -nitrocyclohexene was found to be dependent on the nature of the base and the solvent. The highest diastereoselectivity was obtained when potassium /tr/-butoxide in the presence of dicyclohcxyl-18-crown-6 was employed. In the absence of crown ether the diastereoselection was poor and the sense of the stereochemical outcome was reversed26. 

Methyl hydrogen malonate, HOOCCH2COOCH3 (1). Methyl potassium malonate is available from Fluka. 

An auxiliary that has proven to function remarkably well, though, is the use of ephedrine to form a cyclic acceptor68. The cyclic dicarbonyl substrate is prepared from methyl hydrogen malonate and /-ephedrine hydrochloride using 2-chloro-l-methylpyridinium tosylate as coupling reagent. Knoevenagel condensation with an appropriate aldehyde affords, with few exceptions, the Z-isonier preferentially. 

Ethyl / -(dimethylamino)cinnamate 922 /7-(Dimethylamino)benzaldehyde (3 g, 0.02 mole), methyl hydrogen malonate (4.8 ml, ca. 0.04 mole), piperidine (0.25 ml), and dry pyridine (10 ml) are heated on a steam-bath for 4 h under reflux. The pyridine is then distilled off in a vacuum and the crystalline residue is taken up in hot acetone (10-15 ml). Water is added gradually to this solution until precipitation is complete. The crystals are collected, washed with acetone, and dried at 90-100°. The yield is 95 % (3.9 g). 

Several procedures required for the preparation of porphyrins with labile side chains have already been referred to above or in the earlier article, for example, the conversion of acetoxyethyl or aminoethyl groups (introduced at the pyrrole stage) into vinyl groups. The preparation of porphyrin 3-keto esters has now been improved by the use of imidazolides (rather than acid chlorides) in condensations with magnesium methyl hydrogen malonate. The porphyrin acyl imidazolides have also been converted into acrylic esters by the sequence porCo-imidazole - -CH2OH — CHO - CH = CHC02Me. Alternatively the porphyrin ketoesters may be reduced with borohydride to hydroxyesters and dehydrated to acrylic esters. ... 

Acylacrylic acids afford a-aryl-y keto-acids under Friedel-Crafts conditions, The enolate of the (2i ,3S)-oxazepinedione (18), simply prepared from methyl hydrogen malonate and /-ephedrine hydrochloride, undergoes smooth Michael additions to enones to give, after hydrolysis and decarboxylation, 5-oxocarboxylic acids of high optical purity.Thus, cyclopent-2-en-l-one is converted into the keto-acid (19), while addition of (18) to l-phenylbut-2-en-l-one leads to (20) (cf. 2, 11 3, 4, 5). 

Olefinic esters may be obtained directly by the Knoevenagel reaction. Alkyl hydrogen malonates are used in place of malonic acid. Decarboxylation then gives the ester directly as in the preparation of ethyl 2-heptenoate (78%) and methyl m-nitrocinnamate (87%). Alkyl hydrogen malonates are readily available by partial hydrolysis of dialkyl malonates. The use of malonic ester in the condensation leads to olefinic diesters, namely, alkylidenemalonates such as ethyl heptylidenemalonate (68%). A small amount of organic acid is added to the amine catalyst since the salts rather than the free amines have been shown to be the catalysts in condensations of this type. Various catalysts have been studied in the preparation of diethyl methylenemalonate. Increased yields are obtained in the presence of copper salts. Trimethylacetalde-hyde and malonic ester are condensed by acetic anhydride and zinc chloride. Acetic anhydride is also used for the condensation of furfural and malonic ester to furfurylidenemalonic ester (82%). ... 

Among other studies of the decarboxylation of malonic acids is the interesting discovery that racemic methyl propionate is obtained from methyl hydrogen ethylmalonate this racemization is most simply interpreted as arising through formation of an enol or enolate as intermediate. 

In the first step the diethyl ester of malonic acid is treated with ethyl bromide in the presence of sodium ethoxide when one of the active hydrogen atoms in the former gets eliminated with bromine atom in the later as a molecule of hydrobromic acid resulting into the formation of the corresponding diethyl ester of ethyl malonic acid. This on subsequent addition of 2-monobromopentane and in the presence of sodium ethoxide gives rise to diethyl ether of ethyl-(l-methyl butyl) malonate with the elimination of one molecule of hydrobromic acid. Urea is made to condense with the product obtained from the previous step when pentobarbital is formed with the elimination of two moles of ethanol. Finally, the pentobarbital is treated with a calculated amoimt of sodium hydroxide when the required official compoimd is formed. 

Substituted tetronic acids (89) can be obtained by condensation between the magnesium complex of ethyl hydrogen malonate and a-acetoxy-acid chlorides, followed by acid-catalysed lactonization in the presence of an alcohol (Scheme 15).The fungal metabolite derivative methyl (if)-O-methylmulticolanate (90)... 

The carbopalladation is extended to homoallylic amines and sulfides[466. Treatment of 4-dimethylamino-l-butene (518) with diethyl malonate and Li2PdCl4 in THF at room temperature leads to the oily carbopalladated complex 519, hydrogenation of which affords diethyl 4-(dimethylamino) butylmalonate (520) in an overall yield of 91%. Similarly, isopropyl 3-butenyl sulfide (521) is carbopalladated with methyl cyclopentanonecarboxylate and Li2PdCl4. Reduction of the complex affords the alkylated keto ester 522 in 96% yield. Thus functionalization of alkenes is possible by this method. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Ethyl hydrogen sebacate, 21, 48 electrolysis of, 21, 48 Ethyl isothiocyanate, 21, 82 Ethyl lactate, 21, 71 Ethyl laurate, 20, 69 Ethyl linoleate, 22, 77 Ethyl linolenate, 22, 83 Ethyl malonate, 23, 16 Ethyl mercaptan, 22, 59 Ethyl 1V-methyl-/3-aminopropionate, 20, 37... 

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