Decarboxylation of malonic acid derivatives

The thermal decarboxylation of malonic acid derivatives is the last step m a multistep synthesis of carboxylic acids known as the malonic ester synthesis This synthetic method will be described m Section 21 7... 

SAMPLE SOLUTION (a) Thermal decarboxylation of malonic acid derivatives leads to the replacement of one of the carboxyl groups by a hydrogen. 

Lynn Zara, C., Jin, T., Giguere, R. J. Microwave heating in organic synthesis decarboxylation of malonic acid derivatives in water. Synth. Commun. 2000, 30, 2099-2104. 

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. 

Decarboxylation of malonic acid derivatives is a well studied process in the biosynthesis of biomolecules such as long-chain fatty acids and polyketides. A decarboxylase that exhibits enantioselectivity for substituted malonates would be useful for producing ophcally active carboxylic acids, hi fact, malonyl-CoA decarboxylase does catalyze an enantioselective decarboxylation (Figure 3.2) [5], but malonyl-CoA is an unsuitable precursor for optically active substances. Instead, we focused on the prochiral-activated compoimd arylmalonate, an intermediate of malonic ester synthesis, to develop a method for enantioselective decarboxylation. Malonates are stable at room temperature but readily decompose to arylacetate and CO2 at high temperatures. This suggests that the decarboxylation of arylmalonate may occur naturally if arylmalonate acts as a substrate for a decarboxylase. 

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 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 ... 

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. 

Converting the C-2 alkylated derivative to the conesponding malonic acid derivative by ester hydrolysis gives a compound susceptible to thermal decarboxylation. Temperatures of approximately 180°C are normally required. 

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... 

A frequently employed route comprises preparation of 3-alkoxycar-bonyltetramic acids from malonic acid derivatives and a-aminocarboxylic esters (77MI1 84CPB3724) or, alternatively, a-aminonitriles (86UP1) followed by hydrolysis and decarboxylation [72JCS(P1)2121 85AJC1847 86ZN(B)219]. 

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. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

The conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. 

The hydrolysis product is a substituted derivative of malonic acid and undergoes decarboxylation on being heated. The product of this decarboxylation is aspartic acid (in its protonated form under conditions of acid hydrolysis). 

The treatment of alkenes with iodine(III) reagents usually results in functionalization of the carbon-carbon double bond. However, 1,1-diphenylethylene affords a low yield of (l,l-diphenylethenyl)phenyliodonium tosylate with HTIB (equation 181)11,138. The cyclic dithiolylidene derivative of malonic acid, shown in equation 182, undergoes decarboxylation with [bis(trifiuoroacetoxy)iodo]benzene in methanol and gives an unusual vinyliodo-nium trifluoroacetate139. Finally, when the allenylphosphonate shown in equation 183 is added to a mixture of (difluoroiodo)benzene and BF3-etherate in dichloromethane, a... 

The Mannich bases investigated are acctoacetic and malonic acid derivatives, Y-carboxyglutamic acid included. - Compounds having the lactone structure give preferably decarboxylation of the ester groups not involved in the lactone ring. - ... 

The decarboxylation of amino acids is facilitated by copper Lewis acids. Treatment of tryptophan with copper(II) acetate in HMPA afforded tryptamine 117 in 45 % yield (Sch. 26) [58]. Chelation is thought to activate the carboxylate for elimination. The stable chelate can be isolated and undergoes decarboxylation when heated. An asymmetric version of a similar decarboxylation of malonate derivatives has been reported poor selectivity resulted from addition of chiral alkaloids [59]. 

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