Decarboxylation of the free acid

Some evidence for this mode of decarboxylation of the free acid has been obtained by trapping the enol intermediate (48). (3y-Unsaturated acids (49) probably also decarboxylate by an analogous pathway ... 

Over this variation in solvent polarity, an appreciable change in rate for the decarboxylation of the free acid was not observed. This observation led these... 

ACTIVATION PARAMETERS FOR DECARBOXYLATION OF THE FREE ACID AND ANION ... 

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

This intermediate will exist as a stable enolate under the reaction conditions. Now aqueous KOH g is added to the reaction mixture, which is refluxed to hydrolyse the remaining ester. On acidification Decarboxylation of the free acid is faster with HCl decarboxylation occurs and dimedone is released. than that of the anion (Chapter 26). 

The isomeric mixture of EDOT-CH2OH (Figure 12.1a) and ProDOT-OFl (Figure 12.1b) is difficult to separate. More easily than in the end product stage, the two isomeric ester intermediates can be separated by flash chromatography on silica gel. Further hydrolysis and decarboxylation of the free acids by copper catalysts allow the isolation of pure EDOT-CH20F1 and ProDOT-OH. Chevrot and coworkers later found that a specific solvent mixture of diethylether/cyclohexane (95 5) facilitates separation of EDOT-CH2OH... 

Amino-2-hydroxybenZOiC acid. This derivative (18) more commonly known as 4-aminosa1icy1ic acid, forms white crystals from ethanol, melts with effervescence and darkens on exposure to light and air. A reddish-brown crystalline powder is obtained on recrystallization from ethanol —diethyl ether. The compound is soluble ia dilute solutioas of nitric acid and sodium hydroxide, ethanol, and acetone slightly soluble in water and diethyl ether and virtually insoluble in benzene, chloroform or carbon tetrachloride. It is unstable in aqueous solution and decarboxylates to form 3-amiaophenol. Because of the instabihty of the free acid, it is usually prepared as the hydrochloride salt, mp 224 °C (dec), dissociation constant p 3.25. 

Completion of the total synthesis afforded only six further steps, including the installation of the second 2-aminopyrimidine ring via a second domino sequence. This process presumably involves a conjugate addition of guanidine (2-293) to the enone system of2-292, followed by a cyclizing condensation and subsequent aromatization. Under the basic conditions, the ethyl ester moiety is also cleaved and 2-294 is isolated in form of the free acid, in 89 % yield. Finally, decarboxylation and deprotection of the amino functionality yielded the desired natural product 2-295. 

The observed poor conversion of 24 under more basic conditions suggested that the neutral protonated form of 24 may be the more reactive form of this intermediate in the reaction. Evidence for the participation of the free acid form of 24 in the reaction was obtained with a react-IR study of the decarboxylation process, which allowed us to differentiate between the neutral (HA) and anionic (A") forms of 24 (Figure 5.1).The reaction profile (combination of the anion and free acid of 24 vs... 

Cyclization of the free acids in acetic anhydride may lead to the decarboxylated 3-acetoxy derivative (Section 3.15.2.2.3). Several 3-hydroxybenzo[6]thiophenes were obtained in excellent yield by the interaction of phenylsulfonylbenzisothiazolone with substances containing a reactive methylene group in the presence of pyridine (equation... 

The published synthesis uses a cadmium reagent but we should rather use copper nowadays.4 Double alkylation of malonate, again adding the benzyl group last, gives 33. Hydrolysis and decarboxylation releases the free acid 34 which is easily converted into its acid chloride and then with Pr2Cd, or perhaps better P CuLi, into the target molecule 28. 

In polar solvents the first process is more efficient and leads to the decarboxylation, and this yields a radical centered on the ot-carbon with respect to the carboxylic acid group. In less polar and viscous solvents there is no separation of the radical ions and an addition-type secondary reaction is more likely for example, proton transfer to produce a free radical centered on a-carbon with respect to the carboxylate group takes place. In this case, no decarboxylation of the amino acid is observed. Based on this and the properties of A-phenylglycine [166-169], Scheme 20 describes the photochemical properties of dye NPG photoinitiator systems. 

RELATIVE IMPORTANCE OF THE FREE ACID AND THE ANION TO THE RATE OF DECARBOXYLATION... 

The intimate details of the decarboxylation mechanism of the free acid are not completely clear. Westheimer and Jones studied the effect of changing solvent polarity on the rate of decarboxylation of a,a-dimethylacetoacetic acid (Table 44). 

Preliminary studies showed that 3 was unstable in acidic media at ambient temperature but was stable in basic solution or as a crystalline solid, hi order to overcome the instability of the free acid of 3 which would occur upon attempted isolation, a through process to prepare 5 was required. However, when 3 was formed in the presence of 3 equiv of i-Pr2NEt in 95% yield, and treated directly with 1.0 equiv of triazole HCl salt 4, the decarboxylation/aminolysis reaction was slow and resulted in incomplete reaction (even at 90°C for 24 h). The reaction stalled at about 80% conversion. 

The decarboxylation involves the simultaneous decomposition of the free acid and die anion and the rate expression is given by... 

It was found that E. coli adapted to growth on glucuronic acid or galactu-ronic acid as sole carbon sources were unable to oxidize or ferment D-xylose or L-arabinose before an additional adaptation to these pentoses. If the metabolism had led through a decarboxylation of the free uronie acid, adaptation and utilization of the uronie acid as sole carbon source should have resulted in simultaneous adaptation to the homologous pentose. A pathway leading through the phosphates (Fig. 28), however, was not excluded by these experiments. 

The most convenient laboratory method for the preparation of 2,4-dimethyl-5-carbethoxypyrrole is that given above. A cheaper method of obtaining large quantities consists in the partial hydrolysis of 2,4-dimethyl-3,5-dicarbethoxypyrrole with sulfuric acid, followed by decarboxylation. The ester has been obtained also by the alcoholysis of 5-trichloroaceto-2,4-dimethyl-pyrrole in the presence of sodium ethylate. The free acid has been obtained fronii-[2,4-dimethylpyrrole-5]-2,4-dimethylpyrrole-5-carboxylic acid and from 2,4-dimethylpyrrole-5-aldehyde. ... 

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