Acetoacetic acid, activation decarboxylation

Gas-phase decarboxylation of /i-ketocarboxylic acids XCOCH2COOH (X = H, OH, and CH3) has also been the subject of theoretical studies.42 Ah initio calculations reveal that decarboxylation via a six-membered (rather than four-membered) ring transition state is favoured. Activation barriers of 23.8, 23.3 and 28.5 kcal mol-1 have been calculated for decarboxylation of 3-oxopropanoic acid, acetoacetic acid, and malonic acid, respectively. Only marginal effects of solvent on the energy barriers and on the geometries of the reactants and transition structures are predicted. The activation energy predicted for reaction of malonic acid agrees well with the experimental value and rate constants have been predicted for decarboxylation of 3-oxopropanoic acid and acetoacetic acid in the gas phase. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Acetoacetic acid, CHgCOCHgCOOH, is an aliphatic -keto acid. Derivatives are formed by reduction, activation of the carboxylic group, and decarboxylation. 

Foods frequently contain saturated and unsaturated aliphatic ketones with between 3 and 17 carbon atoms in the molecule. These ketones are formed by several different mechanisms. Frequently occurring aliphatic ketones are methylketones. The most common methylketone is acetone (propanone, 8-46, = 0). Acetone is present, usually in small quantities, in all biological substrates, where it arises by decarboxylation of acetoacetic (3-oxobutanoic) acid. Acetoacetic acid is formed as an intermediate during degradation of fatty acids by -oxidation. Acetone in the skins of apples, for example, is produced from pyruvic acid via citramalic acid (Figure 8.16). The relatively large amount of acetone is generated by acetone-butanol fermentation (see Section 8.2.2.1.1). Many other saturated and unsaturated methylketones occur as odour-active components of essential oils. For example, a component of cinnamon and star anise essential oils is heptane-2-one, also known as methyl pentyl ketone (8-46, = 4). 

The roots of iminium activation can be traced back to the pioneering works of Knoevenagel [4]. The Knoevenagel condensation became the first reaction that might proceed via iminium catalysis. Next, Pollack reported that several proteins and amino acids catalyzed the decarboxylation of acetoacetic acid. The mechanism suggested by Petersen involves an imine intermediate [5]. 

Cyclization of the two pendant alkyl side chains on barbiturates to form a spiran is consistent with sedative-hypnotic activity. The synthesis of this most complex barbiturate starts by alkylation of ethyl acetoacetate with 2-chloropentan-3-one to give 152. Hydrolysis and decarboxylation under acidic conditions gives the diketone, 153. This intermediate is then reduced to the diol (154), and that is converted to the dibromide (155) by means of hydrogen bromide. Double Internal alkylation of ethyl... 

Biotin is a growth factor for many bacteria, protozoa, plants, and probably all higher animals. In the absence of biotin, oxalacetate decarboxylation, oxalosuccinate carboxylation, a-ketoglutarate decarboxylation, malate decarboxylation, acetoacetate synthesis, citrulline synthesis, and purine and pyrimidine syntheses, are greatly depressed or absent in cells (Mil, Tl). All of these reactions require either the removal or fixation of carbon dioxide. Together with coenzyme A, biotin participates in carboxylations such as those in fatty acid and sterol syntheses. Active C02 is thought to be a carbonic acid derivative of biotin involved in these carboxylations (L10, W10). Biotin has also been involved in... 

Aldolases such as fructose-1,6-bisphosphate aldolase (FBP-aldolase), a crucial enzyme in glycolysis, catalyze the formation of carbon-carbon bonds, a critical process for the synthesis of complex biological molecules. FBP-aldolase catalyzes the reversible condensation of dihydroxyacetone phosphate (DHAP) and glyceralde-hyde-3-phosphate (G3P) to form fructose-1,6-bisphosphate. There are two classes of aldolases the first, such as the mammalian FBP-aldolase, uses an active-site lysine to form a Schiff base, whereas the second class features an active-site zinc ion to perform the same reaction. Acetoacetate decarboxylase, an example of the second class, catalyzes the decarboxylation of /3-keto acids. A lysine residue is required for good activity of the enzyme the -amine of lysine activates the substrate carbonyl group by forming a Schiff base. 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

The alkylation of p-keto ester enolates followed by decarboxylation affords substituted ketones (acetoacetic ester synthesis). The ester group acts as a temporary activating group. Retro-Claisen condensation can be a serious problem during hydrolysis of the ester, particularly in basic solution if the product has no protons between the carbonyl groups. In these cases, the hydrolysis should be carried out under acidic conditions or using one of the methods of decarbalkoxylation described in the next section. 

There has been considerable activity in the synthesis of orsellinic acids in the past decade. On account of their ready decarboxylation all these procedures also give access to 5-alkylresorcinols. These routes are summarised in the scheme shown. Homologous alkyl acetoacetates (R = R = alkyl) with thallium ethoxide or sodium hydride followed by reaction with diketene (route a) afford the corresponding homologous alkyl orsellinates (ref.23). In a related method (route b) methyl orsellinate (R = Me) results from the interaction of the monoanion with the dianion of methyl acetoacetate (ref.24). 

Protection as an ester overcomes this problem, but the resulting ester enolate is not particularly stable and its reactions can be low yielding. Addition of a second ester to the alpha carbon serves as an activating group and allows the formation of a stabilized enolate. As seen with the acetoacetic ester synthesis, this ester group can be eventually removed by a decarboxylation reaction. The malonic ester synthesis starts with commercially available diethyl malonate. Deprotonation, alkylation of the resulting enolate with an alkyl haUde, and hydrolysis followed by decarboxylation furnishes a carboxylic acid product. 

Similar reactions are also possible with ethyl acetoacetate. The electrophiles that work well are primary and secondary alkyl halides and sulfonates. Tertiary halides do not react well— elimination is the main reaction. Acyl halides and unhindered epoxides also react well. An important aspect of these processes is that carboxylic acids with a carbonyl group at the p-position are readily decarboxylated (Figure 17.38). We will see in later chapters that we are using the ester as an activating group so that we can make the enolate more easily, but we can eliminate it later. Some examples of the use of this process in synthesis are given in Figure 17.39. 

Just like the aryl azides 2, the vinyl azides 11 are more reactive in their cycloadditions with active methylene compounds than are alkyl azides. In 1970, Alfred Hassner et al. developed a general synthetic approach to 1-vinyl-1,2,3-triazoles 12 and 14, (Scheme 4.4) [6] by the cycloaddition of active methylene compounds 10 or 13 with vinyl azides 11 (or their precursors, the P-haloalkyl azides), in the presence of 1 equiv. of an alkoxide (NaOMe). Decarboxylation of the l- dnyl-5-substituted l,2,3-triazole-4-carboxylic acids 14 synthesized from the reaction of ethyl acetoacetate or ethyl benzoylacetate with vinyl and P-haloalkyl azides led to 1-vinyl-5-substituted 1,2,3-triazoles in almost quantitative yield [6]. 

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