Arylacetic acids, synthesis

Arylacetic acids, synthesis of, 1, 2 22, 4 3-Arylacrylic acids, synthesis of, 1, 8... 

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... 

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]. 

Many of the foregoing acids have been shown to inhibit prostaglandin synthesis. This involves several enzymic reactions and it is the first step, mediated by cyclooxygenase, that is usually stopped (Scheme 5). Aspirin has been shown to acetylate the enzyme, destroying its activity, but indomethacin and the arylacetic acids appear to compete with arachidonic acid for the active site on the enzyme. 

The reaction of nitroarenes with silyl end ethers and ketene silyl acetals in MeCNATiF with 1 equiv. of TASF, followed by in situ oxidation with Br2 or DDQ, provides an easy route to a-nitroaryl carbonyl compounds (Scheme l).12 The use of these compounds as reagents for the synthesis of arylacetic acids, propionic acids, indoles, 2-indolinones and other heterocyclic compounds has recently been described.88... 

Arylacetic acids. A new synthesis of phenylacetic acids from aromatic ketones is illustrated for conversion of 6-methoxy-l-tetralone (1) into 6-methoxy-l,2,3,4-tetrahydronaphthalene-1-carboxylic acid (3). 

In an industrial asymmetric synthesis en route to the antiinflammatory agent naproxen, the dimethyl L-tartrate acetals of ethyl aryl ketones are brominated in high yield and selectivity to give the corresponding a-bromo derivatives. Subsequent stereospecific Ag -promoted 1,2-aryl migration provides the 2-alkyl-2-arylacetic acid after hydrolysis of the tartrate auxiliary, which is recovered (e.g. eq 4). 

The reaction of ceric acetate with aromatic hydrocarbons can be used for synthesis of arylacetic acids. Thus the reaction of ceric acetate with toluene in acetic anhydridc-... 

Canicio, J. A. Ginebreda, A. Canela, R., A New Direct a-Alkylation of Arylacetic Acids by Solid-Liquid Phase-Transfer Catalysis Synthesis of 2-Arylalkanoic Acids. An. Quint. 1985, 81, 181. 

Gilard, J. W, Belanger, R Metabolic synthesis of arylacetic acid antiinflammatory drugs from arylhexenoic acids. 2. Indomethacin. J. Med. Chem. 1987, 30, 2051-2058. 

Malone. G.R.. and Meyers. A.I., The chemistry of 2-chloromethyl-5,6-dihydro-l,3-oxazines. Grignard coupling metalation studies. A synthesis of a-chloro aldehydes and arylacetic acids, J. Org. Chem., 39. 618. 1974. 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

The condensation of rhodanine (42) with aldehydes is an important reaction closely related to the Er-lenmeyer azalactone synthesis (equation 22) the resulting condensation products are particularly useful intermediates for the preparation of various functionalized arylacetic acids and derivatives via standard manipulations of the nitrile (43), which is available as illustrated in Scheme 11. Similarly, aldehydes... 

Miscellaneous Reactions. In addition to the key reactions above, DDQ has been used for the oxidative removal of chromium, iron, and manganese from their complexes with arenes and for the oxidative formation of imidazoles and thiadia-zoles from acyclic precursors. Catal)ftic amounts of DDQ also offer a mild method for the oxidative regeneration of carbonyl compounds from acetals, which contrasts with their formation from diazo compounds on treatment with DDQ and methanol in nonpolar solvents. DDQ also provides effective catalysis for the tetrahydropyranylation of alcohols. Furthermore, the oxidation of chiral esters or amides of arylacetic acid by DDQ in acetic acid provides a mild procedure for the synthesis of chiral a-acetoxy derivatives, although the diastereoselectivity achieved so far is only 65-67%. ... 

The synthesis of 69 substituted arylacetic acids has been described by SzARVASi and Neuvy [257]. Among these compounds the most active hypo-cholesterolemic agent was the acid LS-53 (LXXXIX). Another acid in this series was compound XC, which possessed hypolipidemic but not hypocholesterolemic... 

---