Enolate anions, malonic acid, reaction with

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,... 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

There are two classical reaction sequences in organic chemistry that rely on enolate alkylation. One is the malonic ester synthesis.61 jjj synthetic example taken from the Clive and Hisaindee synthesis of brevioxime,62 diethyl malonate was treated with a base such as sodium ethoxide, under thermodynamic control conditions. The resulting enolate anion is treated with the indicated alkyl halide to give the alkylated product 81 (in 72% yield).Saponification of 81 to the dicarboxylic acid (82, in 99% yield), was followed by decarboxylation (sec. 2.9.D) and formation of the substituted acid 83, in 94% yield. ... 

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 reaction of diethyl malonate (90) with sodium hydride generates enolate anion 91 as the conjugate base, and hydrogen gas is the conjugate acid. It has the three resonance contributors shown in the illustration, although 91A has the highest concentration of electron density, and 91 will react as a carbanion nucleophile. There is one extra resonance form in the malonate enolate anion relative to a simple ester due to the second carbonyl unit, and it means that 91 is more stable than the enolate derived from a monoester. In part, this accounts for the enhanced acidity and easier formation of the enolate anion using a weaker base. Once formed, 91 is a carbon nucleophile and it will react with both aldehydes and ketones, as well as with other esters. 

Aqueous acid workup of 92 gives the alcohol, 93. With malonic ester derivatives, loss of water to form 94 occurs very easily, with dilute acid or with gentle heating because the C=C unit is conjugated to two carbonyl groups, facilitating dehydration. Although it is possible to isolate 83, it is more usually difficult. The enolate anion of malonate esters also reacts with ketones and may be condensed with other esters in acyl substitution reactions. When 90 is treated with NaOEt in ethanol and then with ethyl butanoate, the final product after mild hydrolysis is a keto-diester, 95. 

A variation of the malonic ester synthetic uses a P-keto ester such as 116. In Section 22.7.1, the Claisen condensation generated P-keto esters via acyl substitution that employed ester enolate anions. When 116 is converted to the enolate anion with NaOEt in ethanol, reaction with benzyl bromide gives the alkylation product 117. When 117 is saponified, the product is P-keto acid 118, and decarboxylation via heating leads to 4-phenyl-2-butanone, 119. This reaction sequence converts a P-keto ester, available from the ester precursors, to a substituted ketone in what is known as the acetoacetic acid synthesis. Both the malonic ester synthesis and the acetoacetic acid synthesis employ enolate alkylation reactions to build larger molecules from smaller ones, and they are quite useful in synthesis. 

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 p-keto ester can be hydrolyzed to a P-keto acid, and heating leads to decarboxylation. Malonic acid derivatives, as well as P-ketone acids decarboxylate upon heating 63,109, 111, 135. Enolate anions react with alkyl halides by an S]v2 reaction to give alkylated carbonyl compounds 65, 67, 70, 84, 108, 116, 127,... 

In the late nineteenth century, Michael found that the enolate anion (46) derived from diethyl malonate reacts with ethyl acrylate at the P-carbon (as shown in the illustration) to give an enolate anion, 47, as the product. Remember from Chapter 22 (Section 22.7.4) that the a-proton of a 1,3-dicarbonyl compound such as diethyl malonate is rather acidic (pK of about 11), and even a relatively weak base will deprotonate to form the enolate anion. Michael addition of 46 with ethyl acrylate will give enolate anion 47, and aqueous acid workup leads to the isolated product, 48. Attack at the -carbon is possible because that carbon is less hindered than the acyl carbon, so reaction at the C=C unit is somewhat faster than attack at the acyl carbon. Michael addition occurs with relatively stable carbanion nucleophiles, such as malonate derivative 46 and some other common nucleophiles. Other conjugated carbonyl derivatives react similarly. 

In Chapter 22 (Section 22.7.4), malonate derivatives were easily converted to the corresponding enolate anion, and reaction with alkyl halides or other electrophilic species gave the C3-alkylated product. Indeed, if 102 is treated with sodium metal (or NaH, LDA, etc.), enolate anion 103 is formed it reacts with an alkyl halide such as benzyl bromide (PhCH2Br) to give 104. If 104 is heated with aqueous sodium hydroxide and then treated with aqueous HCI, phthalic acid (35) and the amino acid phenylalanine (57) are formed as the final products. 

Malonate anions are convenient sources of ester enolates. They react with halides and a variety of other electrophiles. Acid hydrolysis of the ester followed by decarboxylation gives the mono-acid. An example of this approach used phthalic anhydride 1.178) as a starting material in a reaction with 2-aminoethanol to give 1.179. Conversion of the alcohol moiety in 1.179 to its 0-benzenesulfonate ester... 

The reactions discussed in section 4.1 obviously describe enolate anion reactions. The reactions in this section involve malonate derivatives that react with bases such as sodium hydride or lithium dialkylamides to generate the malonate anion, a highly stabilized enolate. This section also includes reactions of enolate anions derived from mono-esters and other acid derivatives. 

Rather than pyridine or ammonia, bases such as sodium hydride or sodium ethoxide can be used to generate a malonate enolate anion. Such enolates are easier to control, from a synthetic viewpoint, and allow a wider range of reactions. For this reason, they are collected into this section. An example is the reaction of the sodium enolate of diethyl 2-methylmalonate with the bromine moiety in phthalimide derivative 4.42. This displacement reaction was followed by removal of the phthalimidoyl group, hydrolysis of the esters and decarboxylation to give 2-methyl-6-aminohexanoic acid (4.4J),23 Phthalimide 4.42 was prepared by reaction of 1,4-dibromobutane with potassium phthalimide.23 The length of the carbon chain in the... 

Active Methylene Compounds. Triethyl orthoformate can formylate diethyl malonate under slightly acidic conditions. With less activated compounds it can be induced to undergo a Mannich reaction, and can also formylate a cyclohexanone enolate anion (eq 9). ... 

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)]. 

When a catalytic amount of base is used, the reaction proceeds with thermodynamic control of enolate formation. The most effective nucleophiles under these conditions are carbanions derived from relatively acidic compounds such as /i-kctocstcrs or malonate esters. The adduct anions are more basic and are protonated under the reaction conditions. Scheme 1.11 provides some examples. 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

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