A-arylacetic acid

Phthalic anhydride, when used as the carbonyl component in the Peikin reaction, affords, on treatment with acetic anhydride and potassium acetate, phthalylacetic acid (15 equation 12) a-Arylacetic acids also react with aromatic aldehydes to afford a-arylcinnamic acids (Ogliaro modirication of the Pericin condensation, equation 7) this type of reaction presumably involves the formation of the mixed anhydride of phenylacetic acid and acetic acid and/or phenylacetic anhydride. This modirication is also illustrative of the equilibrium that is established between acid, acid salt and acid anhydrides under the conditions of the reaction. 

So far we have referred to the decarboxylative enzymes that work on the naturally occurring intermediates of biochemical pathways. Due to the high affinity for the native substrates by these enzymes, however, the applicability to nonnatural synthetic substrates was somewhat limited. Thus we intended to develop a new biocatalysis, such as an enzyme which can decarboxylate a-aryl-a-methylmalonic acids to yield enantiomerically enriched a-substituted a-arylacetic acids because those products are useful compounds as antiinflammatory agents [8-10] and the chiral derivatizing agents [11]. 

Ogura and colleagues have also shown that 135 can be further converted to various products such as arylacetic acids, their esters181,182 and a-bromoarylacetic acid183. The condensation product of 94 with ketones can also be converted to the corresponding methyl ester by treatment with hydrogen chloride in methanol184. 

In another nonelectrolytic process, arylacetic acids are converted to vi c-diaryl compounds 2A1CR2COOH —> ArCR2CR2Ar by treatment with sodium persulfate (Na2S20g) and a catalytic amount of AgNOs." Both of these reactions involve dimerization of free radicals. In still another process, electron-deficient aromatic acyl chlorides are dimerized to biaryls (2 ArCOCl —> ArAr) by treatment with a disilane RsSiSiRs and a palladium catalyst." " ... 

Quite recently, a series of arylacetic acid derivatives has come into clinical use as potent antiinflammatory agents. In general, these compounds show profiles of activity quite similar to aspirin, and though as a rule they are more active and are less likely to cause or exacerbate gastric ulcers. 

As noted previously, a wide variety of aromatic systems serve as nuclei for arylacetic acid antiinflammatory agents. It is thus to be expected that fused heterocycles can also serve the same function. Synthesis of one such agent (64) begins with condensation of indole-3-ethanol (60) with ethyl 3-oxo-caproate (61) in the presence of tosic acid, leading directly to the pyranoindole 63. The reaction may be rationalized by assuming formation of hemiketal 62, as the first step. Cyclization of the carbonium ion... 

Landwehr, M., Hochrein, L., Otey, C.R. et al. (2006) Enantioselective a-hydroxylation of 2-arylacetic acid derivatives and buspirone catalyzed by engineered cytochrome P450 BM-3. Journal of the American Chemical Society, 128, 6058-6059. 

Preparation of arylacetic acids using a cobalt carbonyl complex... 

Method A The benzyl halide (0.13 mol) is added slowly with stirring at 55 °C over 1 h to NaCo(CO)4 (0.5 g, 2.6 mmol) and TEBA-C1 or TBA-C1 (4 mmol) in aqueous NaOH (40%, 50 ml) and Ph20 (50 ml) under CO (1 atmos.). Stirring is continued for a further 2 h at 55°C and the aqueous phase is then separated, washed with Et20 (2 x 25 ml) and acidified. The acidified aqueous phase is extracted with CH2C12 (3 x 25 ml) and the extracts washed with H20 (25 ml), dried (MgS04), and evaporated to produce the arylacetic acid. 

Method B Co2(CO)8 (0.17 g, 0.5 mmol) and TEBA-C1 (0.23 g, 1.0 mmol) in aqueous NaOH (5M, 25 ml) and PhH (25 ml) are stirred at room temperature for 30 min under CO (1 atmos.). The benzyl halide (25 mmol) is added and the reaction mixture is stirred at room temperature for ca. 12 h. The aqueous phase is separated, washed with PhH (2 x 25 ml) and acidified to produce the arylacetic acid (with arylpyruvic acid), which is isolated using the procedure described in 8.2.2.A. The PhH solutions contain the neutral products which are formed. 

The phase-transfer catalysed reaction of nickel tetracarbonyl with sodium hydroxide under carbon monoxide produces the nickel carbonyl dianions, Ni,(CO) 2- and Ni6(CO)162, which convert allyl chloride into a mixture of but-3-enoic and but-2-enoic acids [18]. However, in view of the high toxicity of the volatile nickel tetracarbonyl, the use of the nickel cyanide as a precursor for the carbonyl complexes is preferred. Pretreatment of the cyanide with carbon monoxide under basic conditions is thought to produce the tricarbonylnickel cyanide anion [19], as the active metal catalyst. Reaction with allyl halides, in a manner analogous to that outlined for the preparation of the arylacetic acids, produces the butenoic acids (Table 8.7). 

The toxic potential of metabolic intermediates, of the carrier moiety, or of a fragment thereof, should never be neglected. For example, some problems may be associated with formaldehyde-releasing prodrugs such as N- and 0-[(acyloxy)methy 1] derivatives or Mannich bases. Similarly, arylacetylenes assayed as potential bioprecursors of anti-inflammatory arylacetic acids proved many years ago to be highly toxic due to the formation of an intermediate ketene. 

Br a-Hydroxy-arylacetic acid esters were oxidized with bromide ion as a mediator to give a-oxo-arylacetic acid esters [37]. 

The methylation of arylacetic acid derivatives is chosen as a model reaction for the mechanistic discussion. Experimental evidence of DMC-mediated alkylation of A1CH2X (X = CN, C02Me) with DMC supports the hypothesis that the reaction does not proceed through a 8 2 displacement of the ArCH X nucleophile on DMC (Bai2 mechanism).Rather, the selectivity arises from consecutive... 

In order to confirm the radical character of 51 and to extend its utility, oxidations of ary-lacetic acids to the corresponding ketones, aldehydes or alcohols have been conducted. Competitive decarboxylation reactions of phenylacetic acid and p-substituted phenylacetic acids were carried out. The ratio of the rate constants for the decarboxylation of various substituted phenylacetic acids relative to that of phenylacetic acid was found to decrease on decreasing the electron density at the benzylic carbon. Consequently, compound 51 shows an electrophilic oxidation ability towards arylacetic acids, giving a Hammett p value of —0.408. 

The Staudinger reaction of imines 481 derived from 7-oxanorbornenone with arylacetic acid chlorides 482 furnished a 0-40 60-100 mixture of C-2-epimeric, spiro-condensed l,3-oxazin+-one derivatives 483 and 484, the ratio of which proved to depend on the substituents on the aromatic rings and on the nitrogen atom (Equation 54) <2002TL6405>. 

Yet a further increase in potency is observed when the para-isobutyl group is replaced by a benzene ring. One published synthesis for that compound is quite analogous to the malonate route to the parent drug. The acetyl biphenyl (50-1) is thus converted to the corresponding arylacetic acid by reaction with sulfur and morpholine, followed by hydrolysis of the first-obtained thiomorpholide. This is then esterified and converted to malonate anion (50-2) with sodium ethoxide and ethyl formate. The anion is quenched with methyl iodide hydrolysis of the esters followed by decarboxylation yields the NSAID flubiprofen (50-3) [51]. 

Several authors cited previously (Section II,B,1) have found that, besides the direct cyclization of o-acyl-arylacetic acid derivatives, a suitable method of synthesizing the title compounds involves the reaction of iso-chromanones with amines. This reaction has been investigated in detail (73JHC317). 

A modification of the WiUgcrodt reaction that simplifies the procedure by obviating the necessity of a sealed tube 01 autoclave consists in refluxing the ketone with a high-boiling amine and sulfur (Schwenk, 1942). Morpholine, so named because of a relationship to an early erroneous partial formula suggested for morphine, is suitable and is made technically by dehydration of diethanolamine. The reaction is conducted in the absence of water, and the reaction product is not the amide but the thioamide this, however, undergoes hydrolysis in the same manner to the arylacetic acid. 

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