Methyl ethyl malonic acid

The first successful attempt in asymmetric synthesis was made by Marckwald in 1904 who prepared an active (-) -valeric acid by heating the half brucine salt of ethyl methyl malonic acid at 170°C. 

As early as 1904, Marckwald et al. [4] reported the thermal decarboxylation of ethyl(methyl)malonic acid 1 at 170°C in the presence of brucine affording (S)-2-methylbutyric acid 2 in 10% ee (Scheme 3.2). While this report might probably be considered as the first asymmetric transformation, this result could not be successfully reproduced several decades later [6]. In 1975, Verbit et al. [7] reported the decarboxylation of ethylphenylmalonic acid 3 in cholesteryl benzoate at 160°C giving rise to (/ )-phenylbutanoic acid 4 in 18% ee (Scheme 3.2). However, Kagan et al. [8] failed to obtain any enantioenriched phenylbutanoic acid 4 under the same reaction conditions. 

A less familiar ring system, but one that was part of a molecule selected for advanced testing, was the 5-methyl-6-oxo-4-(trifluoromethyl)-l-(6H)-pyridazinyl ring system of flufenpyr-ethyl (43). The pyridazinyl heterocycle can be prepared from the reaction of 4-chloro-2-fluoro-5-hydroxyphenyl hydrazine (48) and 1,1-dibromo-3,3,3-trifluoroacetone (49) to give the corresponding hydrazone 50, which when reacted with methyl malonic acid (51), in the presence of a base, provides the intermediate 52. Acid-catalyzed ring closure of 52, followed by 0-alkylation of 53 with ethyl chloroacetate, results in the synthesis of flufenpyr-ethyl (43) [73] (Scheme 3.2). 

The first discussions concerning the conditions for aeating optically active compounds in the laboratory may be traced to Pasteur and Le Bel. The first mention of the expression "asymmetric synthesis" can be found in the work of E. Fischer in 1894 concerning his stereochemical studies on sugars. He observed the formation of unequal amounts of cyanohydrins in the Kiliani reaction applied to aldehydic sugars. In 1904, Marckwald reported an asymmetric synthesis of 2-methyl-butanoic acid by decarboxylation of 2-ethyl 2-methyl-malonic acid in the presence of an alkaloid. The importance and the mechanism of this reaction were later the subject of much debate. However, this paper remains significant because Marckwald defined asymmetric synthesis, as follows "It is a reaction giving optically active products from symmetrical... 

C17H17NO3S 13623-32-0) see Protizinic acid 7-methoxy-10-methylphenothiazine-2-malonic acid ethyl methyl ester... 

The preparation of malonic acid monoesters has been demonstrated using the microbial nitrilase activity of Corynebacterium nitrilophilus ATCC 21 419, Gordona terrae MA-1, or Rhodococcus rhodochrous ATCC 33 025 to hydrolyze methyl cyanoacetate, ethyl cyanoace-tate, M-propyl cyanoacetate, isopropyl cyanoacetate, M-butyl cyanoacetate, tertbutyl cyanoacetate, 2-ethylhexyl cyanoacetate, allyl cyanoacetate, and benzyl cyanoacetate [96]. By maintaining the concentration of nitrile in a reaction mixture at <5 wt%, significant inactivation of the nitrilase activity was avoided for example, a total of 25 g of M-propyl cyanoacetate was added in sequential 5g portions to a lOOmL suspension of Rhodococcus rhodochrous ATCC 33 025 cells (OD630 = 5.6) in 50 mM phosphate buffer (pH 7.0) over 30h at 25 °C to produce mono-M-propyl malonate in 100% yield (Figure 8.17). 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

Synthesis (Mayer and Testa, 1997 Cleij et al., 1999 Kleemann et al., 1999) a) Treatment of ethyl 4-isobutylphenylacetate and diethyl carbonate with sodium ethoxide gives diethyl 4-isobutylphenylmalonate, which is methylated using methyl iodide and sodium ethoxide. Saponification followed by decarboxylation of the resulting malonic acid derivative affords ibuprofen. 

Methyl 3-ethoxy-3,3-difluoro-2-(trifluoromethyl)propanoate is hydrolyzed by sulfuric acid to give ethyl methyl (trifluoromethyl)malonate (29).151... 

The ethyl sec,-butylmalonate was prepared from sec-butyl bromide and malonic ester according to the general method described in Org. Syn. 4, n. The yield of ester boiling at i24-i32°/28 mm. was 80-81 per cent of the theoretical amount. The yields of 3-methyl pentanoic acid given in this procedure were obtained with this grade of ester. 

Different cyclic products are formed in the double Michael addition of malonic acid ethyl methyl ester to ( vE)-l,5-diphenylpenta-l,4-dien-3-one under basic conditions. Label the stereogenic units in the reaction products with the appropriate stereodescriptors. 

Methyl ethyl acetic acid may be prepared from methyl ethyl malonic ester by hydrolysis and subsequent heating of the methyl ethyl malonic acid.1 The yield by this method, in the preparation of large quantities, is about 61 per cent of the theoretical amount based on the malonic ester used. The acid was first prepared by Saur2 from methyl ethyl acetoacetic ester. It has also been made by oxidation of the corresponding aldehyde with chromic acid.3... 

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