Reactions of Malonic Acid Derivatives

This reaction involves 1 equiv of chalcone and pyrrolidine and two molecules of malononitrile. The structure of compound 112 was unambiguously established only with help of X-ray analysis [119]. 

The reaction of oc,(3-unsaturated carbonyls with other derivatives of malonic acid, for example, with malonoamide 121 [129, 130] and malonothioamide 124 [131, 132], were also described. 

A lot of publications are devoted to the reactions of a,(3-unsaturated carbonyls with derivatives of cyanoacetic acid cyanoacetamide 128, cyanothioacetamide 

There are publications devoted to a study of the mechanism of the treatment of unsaturated carbonyls with cyanoacetic acid derivatives [134, 153]. According to these communications, the sequences of such reactions are similar to those of urea-like binucleophiles. Using piperidine as the catalyst, Al-Hajjar and Jarrar [134] and Otto [153] isolated a series of known intermediates. 

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Most of the publications on the reactions of malonic acid derivatives are devoted to the reaction of a,(3-unsaturated carbonyls with malononitrile 107. In this book we do not describe the results of all known publications but only the most characteristic or interesting ones in our opinion. The reactions of unsaturated ketones with malononitrile are usually carried out in methanol or ethanol in the presence of ammonium acetate [102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117]. Treatment of malononitrile 107 with chalcone 5 [115] and its heterocyclic analogue 109 [104] yielded 3-cyanopyri-dines 108 and 110 (Scheme 3.33). 

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

Both CO2 activation and enolate formation are combined in the preparation of malonic acid derivatives. The reaction of CO2 with methacrylic esters or methacry-lonitrile and under visible light irradiation produced the corresponding aluminum porphyrin malonate complex. When diethylzinc was added to this system, Al(TPP)Et could be regenerated by axial ligand exchange reactions, and the malonic acid derivatives were formed catalytically with respect to the aluminum porphyrins in a one-pot photosynthetic route (Scheme 1). The first step in this... 

III C) 1967 Degn, H. Effect of Bromine Derivatives of Malonic Acid on the Oscillating Reaction of Malonic Acid, Cerium Ions and Bromate, Nature, vol. 213, 589-590... 

The reaction of halogen-substituted 1,3,5-triazines and salts of malonic acid derivatives also affords C-C bonded compounds128-130 (see also Houben-Weyl, Vol. E16a, Parti, p 761 ff). 

Isomeric amino alcohols (83 X = O, Y = NH X = NH, Y = O) react with carbon suboxide to form positional isomers (65) and (66), each in ca. 50% yield, together with lower yields of malonic acid derivatives (Equation (29)) <92G485>. Similarly, carbon suboxide is reported to react with hydroxyimines to afford mesoionic derivatives 67) in 9-14% yield <84H(22)2587>, although, as discussed above, others have questioned the outcome of these reactions <82CC1328,85JHC157>. 

Degn, H. (1967). "Effect of bromine derivatives of malonic acid on the oscillating reaction of malonic acid, cerium ions and bromate." Nature 213, 589-590. 

Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or acid derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation. 

The key feature in the decarboxylation of malonic acid derivatives is that they are 1,3-dicarbonyl compounds with the acidic proton of the acid in close proximity to a carbonyl oxygen that is two carbon atoms away from the carboxyl unit. The proximity of these units is essential, which is why decarboxylation occurs with 1,3-dicarbonyl compormds and 7 o with 1,4-dicarbonyl compounds. This is a form of an elimination reaction (see Chapter 12). Going back to the expected product, 97 from 96, it is clear that this is a 1,3-dicarbonyl compound capable of decarboxylation upon heating. That is precisely what occurs, so the product is 98 rather than 97. Decarboxylation of malonic acid derivatives gives functionalized carboxylic acids. 

The intra-molecular Claisen condensation is called a Dieckmann condensation, and it generates a cyclic compound 58,99,101,118. Malonic esters can be converted to the enolate anion and condensed with aldehydes, ketones, or add derivatives. The reaction of malonic acid with an aldehyde using pyridine as a base is called the Knoevenagel condensation 59, 60, 61, 62, 69, 99,108,110,112, 113,119,124. 

A kinetic study of the isotope-exchange reactions of malonic acid and several of its monoalkyl derivatives in various acidic D2O media using H NMR spectroscopy has revealed the order of reactivity of RCH(C02H)2 to be R = Ph > H > Me > Et, Bu." ... 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

C2S2, is a red Hquid (mp —0.5° C, bp 60—70°C at 1.6 kPa (12 mm Hg)) produced by the action of an electric arc on carbon disulfide (1 4). The stmcture has been shown to be S=C=C=C=S on the basis of its reactions to form malonic acid derivatives and on the basis of physical measurements. It is unstable and decomposes ia a few weeks at room temperature it decomposes explosively when heated rapidly at 100—120°C with formation of a black polymeric substance (C2S2) (5,6). Dilute solutions ia CS2 are fairly stable, but photochemical polymerisation to (C2S2) occurs. 

A related reaction has been described for the synthesis of 2-quinolones, reacting substituted secondary anilines with malonic acid derivatives. The reaction was carried out neat under microwave irradiation at 290 °C for 15 min. These harsh conditions were reqiured for the elimination of two... 

The monocyclic 1,4-diazepine, l,4-diaza-S,7-cycloheptanedione, has in the past been reported to have been formed by the reaction of 1,2-diaminoethane with various malonic acid derivatives. It is now claimed that this derivative has never been formed, and may never be formed <96JPR121>. Oligomers and polymers are the sole products. However, reaction of... 

In this chapter, decarboxylation of disubstituted malonic acid derivatives and application of the transketolases in organic syntheses are summarized. Although decarboxylation may be seen as a simple C-C bond breaking reaction, it can be regarded as a carbaniongenerating reaction. As the future directions of this field, expansion of some unique decarboxylation reactions is proposed. In relation of carbanion chemistry, promiscuity of enolase superfamily is discussed. 

Although the reaction mechanism of this type of reactions is not fully elucidated, it is easily anticipated that no intramolecular special stabilization effect for the carbanion generated from decarboxylation is expected, different from the case of malonic acid-type compounds. Moreover, cinnamic acid derivatives that have both the electron-donating and withdrawing substituents have been reported to undergo this reaction. This fact suggests that the enzyme itself stabilizes the transition state without the aid of mesomeric and inductive effects of the other part of the substrate molecule itself. If such unknown mechanism also works for other... 

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,... 

Chloro-l,2,3-thiadiazole-4-carboxamides 38 react with the sodium salt of diethyl malonate to give the corresponding malonic acid derivatives 39. The yield in these reactions falls as the electron-releasing properties of the 4-substituents in the aromatic ring increase (Equation 8) <1997JCM396>. 

Table 20 Ring closures to [1,2,4]triazolo[1,5-a]pyrimidines by reaction of 3-amino[1,2,4]triazoles with /3-oxo ketones, esters, nitriles, or malonic acid derivatives...

Saalfrank, Hoffmann and co-workers performed a number of reactions with tetra-alkoxyallenes such as 196 (Scheme 8.47) [1, 41, 105, 114—116] and demonstrated that this class of donor-substituted allenes can serve as a 1,3-dianion equivalent of malonic acid. Treatment of 196 with cyclopropyldicarboxylic acid dichloride 197 produces 2,4-dioxo-3,4-dihydro-2H-pyran 198 through release of two molecules of ethyl chloride [115]. Similarily, the reaction of this allene 196 with oxalyl chloride gives 3-chloromalonic acid anhydride derivative 199. This intermediate is a reactive dieno-phile which accepts 2,3-dimethyl-l,3-butadiene in a subsequent [4+2] cycloaddition to afford cycloadduct 200 in good yield [116]. 

Quinolylaminomethylenemalonates (267) were prepared in the reactions of 2-aminoquinoline, ethyl orthoformate, and malonic acid derivatives (266) in the presence of A1C13 at 135-140°C for 30 min (74MIP1). 

RhClCO(dppp) 2] for the sequential construction of an enyne precursor, starting from a malonic acid derivative and allylic acetate, which was converted in situ to the cycloaddition product with excellent yields. Obviously, the Pd complex catalyzes the allylic substitution reaction, while the rhodium catalyst is responsible for the PKR (Eq. 6). 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

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