2-arylacrylic acid

Asymmetric catalytic hydrogenation is one of the most efficient and convenient methods for preparing a wide range of enantiomerically pure compounds, and Ru-BINAP-catalyzed asymmetric hydrogenation of 2-arylacrylic acids has attracted a great deal of attention,11 as the chiral 2-arylpropionic acid products constitute an important class of nonsteroidal antiinflammatory drugs. 

Treatment of benzaldehydes with ethyl diazoacetate and a catalytic quantity of the iron Lewis acid [ -CpFe(CO)2(THF)]+BF4 yields the expected homologated ketone (80). However, the major product in most cases is the aryl-shifted structure (81a), predominantly as its enol tautomer, 3-hydroxy-2-arylacrylic acid (81b). This novel reaction occurs via a 1,2-aryl shift. Although the mechanism has not been fully characterized, there is evidence for loss of THF to give a vacancy for the aldehyde to bind to the iron, followed by diazoacetate attachment. The product balance is then determined by the ratio of 1,2-aryl to -hydride shift, with the former favoured by electron-donating substituents on the aryl ring. An alternative mechanism involving epoxide intermediates was ruled out by a control experiment. 

It has been shown that the lead tetraacetate-mediated 1,2-aryl shift of various meta-substituted / -cyclohexyl aryl ketones, e.g. (10), results in excellent yields of the corresponding rearranged esters (11). A unique reaction, providing 3-hydroxy-2-arylacrylic acid ethyl esters (14), has been observed between aryl aldehydes and ethyl diazoacetate in the presence of the iron Lewis acid [rj — (C5H5)Fe(CO)2(THF)BF4], It appears that the enol esters are formed by an unusual 1,2-aryl shift from a possible intermediate (13), which in turn is formed from the reaction of the iron aldehyde complex (12) with ethyl diazoacetate (see Scheme 4). 

Asymmetric Catalytic Hydrogenation of 2-Arylacrylic Acids as a Low-Cost Route to Pharmaceutical Products... 

The homogeneous catalytic asymmetric hydrogenations of 2-arylacrylic acids have been studied. Both rhodium and ruthenium catalysts have been examined. The reaction temperatures and hydrogen pressures have profound effects on the optical yields of the the products. The presence of a tertiary amine such as triethylamine also significantly increases the product enantiomer excess. Commercially feasible processes for the production of naproxen and S-ibuprofen have been developed based on these reactions. 

Although the Rh-catalyzed asymmetric hydrogenations of prochiral enamides have been extensively studied and excellent results have been frequently achieved, the catalytic asymmetric hydrogenations of 2-arylacrylic acids have been less successful. Until recently most catalyst systems gave only moderate optical yields for the 2-arylpropionic acid products (77). An important breakthrough in the study of these reactions was reported by Noyori et al. By using Ru(BINAP)(OAc)2 as a catalyst precursor, these researchers obtained excellent optical yields in the asymmetric hydrogenation of 2-(6 -methoxy-2 -naphthyl)acrylic acid (72). 

The ultimate goal in most industrial research is to develop economically attractive processes or products. The technology of asymmetric hydrogenation of 2-arylacrylic acids is probably most useful for the production of naproxen and S-ibuprofen. Naproxen is currently one of the top ten prescription drugs in the world S-ibuprofen is the active isomer in the popular anti-inflammatory drug ibuprofen. Figures 5 and 6 summarize two commercially feasible processes for the manufacturing of these products. 

C4C im][BF4] [RuC12(BINAP)]2 2-Arylacrylic acids 25-100 bar, 20 °C iPrOH as co-solvent catalyst active [30] for at least four cycles product isolated by decantation. 

J. Asymmetric Hydrogenation of 2-Arylacrylic Acids Catalyzed by Immobilized Ru-BINAP Complex in 1 -n-Butyl-3-Methylimidazolium Tetrafluoroborate Molten Salt, Tetrahed. Asymm. 1977, 8, 177-179. 

Scheme 5.3-9 Hydrogenation of 2-arylacrylic acid to (S)-2-phenylpropionic acid with the chiral [RuCl2(S)-BINAP]2NEt3 complex as catalyst in [BMIM][BF4].

Hossain et al have already found that the cyclopentadienyl dicarbonyl iron Lewis acid, [CpFe(CO)2(THF)] BF4 (108), catalyzes a variety of reactions including cy-clopropanation [34a], aziridination [34b], and Diels-Alder reactions [34c]. Recently, they have reported that the iron Lewis acid [CpFe(CO)2(THF)]+BF4 (108) catalyzed synthesis of 3-hydroxy-2- arylacrylic acid ethyl ester (106) [34d]. The product distribution of (108) is not affected in the presence of proton sponge, but is dependent on temperature and the nature of the substrate aldehyde. 

Chauvin et al. reported the asymmetric hydrogenation of acetamidocinnamic acid to (S)-phenylalanine with a cationic chiral rhodium catalyst in [C4-mIm][SbFg] ionic liquid, more recently the 2-arylacrylic acid has been produced with a reasonable 64% yield using a chiral ruthenium catalysts in [C4-mIm][BF4] ionic liquids. Palladium catalysts " immobilized in an ionic liquid-polymer gel membrane containing either [C2-mIm][CF3S03] or [C2-mIm][BF4] have also been reported as catalysts for heterogeneous hydrogenation reactions. 

---