Arylpropanoic acids

Asymmetric Hydroformylation of Vinylarenes a-Arylpropanals, the products of asymmetric hydroformylation of vinylarenes, serve as useful intermediates for pharmaceutical drugs. For example, (5)-2-arylpropanals can be oxidized to the corresponding (5)-2-arylpropanoic acids, such as (5)-ibuprofen (Ar = 4-isobutylphe-nyl), (5)-naproxen (Ar = 6-methoxynaphthalen-2-yl), and (5)-suprofen (Ar = 4-(2-thienylcarbonyl)phenyl) (see later in chapter. Scheme 4.4). Styrene is thus one of the most popular substrates used to test new catalyst systems. Representative ligands and their use as Pt or Rh complexes in the asymmetric hydroformylation are summarized in Figure 4.1 and Table 4.1. (See also Scheme 4.3.)... 

Arylpropanoic acid derivative with one chiral center... 

This conversion of a 1,2-diol to an epoxide has been used as an approach to 2-arylpropanoic acids, members of the nonsteroidal antiinflammatory drugs (NSAIDS) family of drugs.163 However, the sequence can be shortened by a selective hydrogenolysis, as illustrated for naproxen (20) (Scheme 9.24).164... 

Isse, A.A., Ferlin, M.G. and Gennaro, A. (2005a) Electrocatalytic reduction of arylethyl chlorides at silver cathodes in the presence of carbon dioxide Synthesis of 2-arylpropanoic acids. J. Electroanal. Chem. 581, 38 15. 

Arylpropanoic acids. The ethylene kctals (2) of aryl a-phenylselenoethyl ketones, prepared by reaction of aryl a-bromo ketals (1) with diphenyl diselenide and sodium wire, are converted into the hydroxycthyl esters (3) of 2-arylpropanoic acids (4) on oxidation with excess w-chloroperbenzoic acid. The reaction probably involves a selenone intermediate, in which the rearrangement of the aryl group occurs. The acetal group of 2 is essential for this rearrangement. 

In the case of 2-arylpropanoic acids, although the (5)-enantiomer (9) is available by a terminal oxidation, the alternative (/ )-enantiomer (11) can be prepared by the more extensive oxidative degradation of the alkylbenzene (10 equation 3) by Rhodococcus spp. (BPM 1613). In this case the optical induction is due to oxidative kinetic resolution of intermediates the recovered substrate is racemic. 

Combination of the processes of the C-O bond cleavage in 1-naphthylethyl esters with CO insertion catalyzed by palladium complexes in the presence of a formate salt affords a new route to 2-arylpropanoic acids [67]. 

Keywords Asymmetric hydrocyanation. Hydrogen cyanide, Vinylarenes, 2-Arylpropanoic acids, Naproxen, Arylphosphinites, Carbohydrate ligands. Electronic effects. Electronic asymmetry... 

Hydrovinylation reactions of vinylarenes, Eq. (1), have been investigated most extensively because of the importance of 3-aryl-1-butenes as potential intermediates for widely used anti-inflammatory 2-arylpropanoic acids [4]. Since the first report of a high pressure (1000 atm) ethylene/styrene codimerization in the presence of RhClj [5] various metals such as Ru [6], Co [7],Pd [8],andNi [9,... 

Thus, considerable effort is necessary to achieve a wide and synthetically useful application of this method. Nevertheless, the first examples of interesting target molecules obtainable via asymmetric hydroformylation have appeared (amino acids, arylpropionic acids)180. Thus, if appropriate catalytic systems and reaction conditions can be found, even industrial applications might be realized within the near future. Thus, asymmetric hydroformylation is considered to be a powerful tool for the preparation of a large number of different chiral products to be used as precursors of several organic compounds endowed with therapeutical activity180. Examples are the essential and non-essential amino acids, 2-arylpropanoic acids, aryloxypropyl-and /1-phenylpropylamines. modified /1-phenylethylamines, pheniramines and others180. 

Determination of enantiomeric purity. Three mL of the solution was diluted in 50 mL of acetone and treated with 0.3 g of potassium permanganate and 0.32 g magnesium sulfate to effect oxidation of the product aldehydes to their respective acids. The mixture was stirred at room temperature for 30 minutes after which time the solvent was removed under reduced pressure. The residue was extracted three times with 50 mL of hot water. The three aqueous solutions were then combined, filtered, and washed with 50 mL of chloroform. The aqueous layer was acidified with hydrochloric acid to a pH of 2 and then extracted with 50 mL of chloroform. The chloroform was removed in vacuo and the resulting residue dissolved in 0,5 mL of toluene. This solution was analyzed by GC on a chiral /3-cyclodextrin column which separated the two enantiomers of the resulting 2-arylpropanoic acid. This analysis indicated a 91 9 ratio of the S and R enantiomers for an ee of 82%. 

Addition to multiple bonds. A water-soluble Pd catalyst (picolinic acid as one of the ligands) is applicable to the synthesis of 2-arylpropanoic acids from styrenes by carbonylation. ... 

The anti-inflammatory activities of 2-arylpropanoic acids (54) continue to stimulate new methods for their preparation. Hydrocyanation of styrenes and other vinylarenes can be catalysed... 

Lee reported that selected chiral ester 21 (Scheme 15) could be carbonylated direclly to optically active 2-arylpropanoic acid 22 with net inversion of its configuration at carbon. ... 

Electrochemical Fixation of Carbon Dioxide (Cathodic Reduction in the Presence of Carbon Dioxide), Scheme 4 Synthetic Routes to NSAIDs having 2-Arylpropanoic Acid Skeletons by Electrochemical Carboxylation... 

One of great synthetic applications of electrochemical fixation of carbon dioxide is synthesis of 2-arylpropanoic acids, nonsteroidal anti-inflammatory drugs (NSAlDs), and their derivatives. Electrochemical carboxylations of benzyl halides [1, 3, 8-13], aryl methyl ketones [14, 15], and a-bromostyrenes [16] are reported to be successfully applied to the synthesis of several NSAIDs, such as ibuprofen and naproxen, and their precursors and derivatives (Scheme 4). 

Fauvarque JF, Jutand A, Francois M (1988) Nickel catalysed electrosynthesis of anti-inflammatory agents part I - synthesis of 2-arylpropanoic acids, under galvanostatic conditions. J Appl Electrochem... 

Griesbach RC, Hamon DPG, Kennedy RJ. Asymmetric dihydroxylation in an approach to the enantioselective synthesis of 2-arylpropanoic acid non-steroidal anti-inflammatory drugs. Tetrahedron Asymm. 1997 8 (4) 507-510. 

A model for prediction of enantiopreference in the resolution of chiral acids is only published for C. rugosa lipase [16,17] (Fig. 1). This lipase shows high enantioselectivity toward many carboxylic acids, such as the commercial targets 2-arylpropanoic acids and 2-aryloxypropanoic acids, which fit the model. It appears, however, that when the large substituent is extensively branched the substrate no longer fits the model. 

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