Malonic acids, decarboxylation formation

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]. 

Decarboxylation is not a general reaction of carboxylic acids. Rather, it is unique to compounds that have a second carbonyl group two atoms away from the —COoH. That is, only substituted malonic acids and /3-keto acids undergo loss of CC>2 on heating. The decarboxylation reaction occurs by a cyclic mechanism and involves initial formation of an enol, thereby accounting for the need to have a second carbonyl group appropriately positioned. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

The enzymatic reaction was performed at 30 °C for 2 hours in a volume of 1 ml of 250 mM phosphate buffer (pH 6.5) containing 50 mM of KOH, 32 U/ml of the enzyme, and [1- C]-substrate. The product was isolated as the methyl ester. When the (S)-enantiomer was employed as the substrate, C remained completely in the product, as confirmed by C NMR and HRMS. In addition, spin-spin coupling between and was observed in the product, and the frequency of the C-O bond-stretching vibration was down-shifted to 1690 cm" (cf. 1740 cm for C-O). On the contrary, reaction of the (R)-enantiomer resulted in the formation of (R)-monoacid containing C only within natural abundance. These results clearly indicate that the pro-R carboxyl group of malonic acid is ehminated to form (R)-phenylpropionate with inversion of configuration [28]. This is in sharp contrast to the known decarboxylation reaction by malonyl CoA decarboxylase [1] and serine hydroxymethyl transferase [2], which proceeds with retention of configuration. 

A typical chemical system is the oxidative decarboxylation of malonic acid catalyzed by cerium ions and bromine, the so-called Zhabotinsky reaction this reaction in a given domain leads to the evolution of sustained oscillations and chemical waves. Furthermore, these states have been observed in a number of enzyme systems. The simplest case is the reaction catalyzed by the enzyme peroxidase. The reaction kinetics display either steady states, bistability, or oscillations. A more complex system is the ubiquitous process of glycolysis catalyzed by a sequence of coordinated enzyme reactions. In a given domain the process readily exhibits continuous oscillations of chemical concentrations and fluxes, which can be recorded by spectroscopic and electrometric techniques. The source of the periodicity is the enzyme phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate by ATP, resulting in the formation of fructose-1,6 biphosphate and ADP. The overall activity of the octameric enzyme is described by an allosteric model with fructose-6-phosphate, ATP, and AMP as controlling ligands. 

An example of the formation of 1,2-dithiolium salts by protonation of an alkylidene-l,2-dithiole is the decarboxylation of 1,2-dithiol-3-ylidene malonic acids (14) in the presence of perchloric acid. In this particular case, a strongly acidic reaction medium is necessary for obtaining satisfactory yields because the corresponding 3-aryl-5-methylene-l,2-dithiole is unstable and undergoes an autocondensation reaction leading to an a-(thiopyran-2-ylidene)thioketone (cf. Ref. 1 p. 83). 

Photochemical decomposition of malonic acid by irradiation in solution has been reported. Some of the radical species produced by this treatment are identical to those formed by the Ce decomposition of malonic acid in the Belousov-Zhabotinsky reaction. The (2 + 2)-cycloadducts (172) can be readily prepared by irradiation of mixtures of the corresponding enone and alkene, and these adducts can conveniently be converted into the hydroperoxide (173) by irradiation at 366 nm in the presence of air and acridine in toluene.The decarboxylation occurs by a free radical pathway and treatment of the hydroperoxide with dimethyl sulfide brings about formation of the ring-expanded ketones or lactones (174),... 

Bronsted LFERs also apply to reactions of metal ions (Lewis acids). Dissociation rates of Ni(II) complexes are correlated with corresponding dissociation equilibrium constants. This suggests that the reactions occur by dissociative interchange, in which breakage of the Ni(II)-ligand bond predominates over formation of the Ni(II)-water bond in the rate-determining step (Hoffmann, 1981). In addition, rates of metal-catalyzed decarboxylation of malonic acid are correlated with the stability constants for the metal-malonate complexes (Prue, 1952). 

Now we must put the molecule together again. 2-Bromothiazole is available so lithiation and carbonylation with DMF gives 213 and an aldol (Knoevenagel) reaction with malonic acid gives 214 without a separate decarboxylation step. The best one-carbon electrophile is ethyl formate (HC02Et) and thiourea makes a suitable derivative of 209 for displacement. 

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. 

The mechanism for decarboxylation of malonic acids is similar to what we have just studied for the decarboxylation of S-ketoacids. The formation of a cyclic, six-membered transition state involving a redistribution of three electron pairs gives the enol form of a carboxylic acid, which, in turn, isomerizes to the carboxylic acid. 

Ester enolates undergo alkylation reactions. When ethyl 3-methylpentanoate (110) reacts with sodium ethoxide in ethanol and then with bromoethane, the product is 111. Alkylation of malonate derivatives leads to an interesting sequence of reactions that are useful in synthesis. The reaction of diethyl malonate (90) and NaOEt in ethanol, followed by reaction with benzyl bromide, gives 112. In a second reaction, 112 reacts with NaOEt in ethanol and then with iodomethane to give 113. Saponification of 113 (see Chapter 20, Section 20.2) gives the dicarboxylic acid, 114, and heating leads to decarboxylation (Section 22.8) and formation of acid 115. This overall sequence converted malonic acid via the diester to a substituted carboxylic acid, and it is known as the malonic ester synthesis. 

Triphenylplumbyl half-esters of malonic acid can be decarboxylated, as mentioned in Section C, with the formation of a new Pb—C bond. Willemsens and van der Kerk (274) and Davies et al, (45) have extended this procedure to other triphenylplumbyl esters of carboxylic acids, an example being phenylpropiolic acid. 

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... 

It is interesting to note that dicarboxylic acids were observed initially during hydrous pyrolysis of kerogen (MacGowan and Surdam 1988). However, as heating continued the formation of monocarboxylic acids mirrored decreases in dicarboxylic acid concentrations - suggesting that a portion of the monocarboxylic acids found in basin brines may be the product of decarboxylation of less stable dicarboxylic acid precursors. Of the three dicarboxylic acids found in basin brines, the decarboxylation of malonic acid has been studied most extensively in hydrous systems and in various other solvent systems. 

Inherently, the decarboxylation of p-keto acids and malonic acids (1) proceeds very smoothly, as the resulting product bearing anion adjacent to carbonyl group stabilizes as its enolate form (2) [Eq. (1)]. Enzyme-mediated reaction sometimes utilizes this facilitated decarboxylation. Indeed, isocitric acid (3) was oxidized to the corresponding keto acid, which subsequently decarboxylated to a-ketoglutaiic acid (4) by means of isocitrate dehydrogenase (EC 1.1.1.41) [Eq. (2)]. Another example is observed in the formation of acetoacetyl-CoA (5), which occupies the first step of fatty acid biosynthesis. A p-keto carboxylate 6, derived from the acetylation of malonyl-CoA with acetyl-CoA, decarbox-ylates to 5 by the action of 3-ketoacyl synthase [Eq. (3)]. 

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