2-Arylpropanoic acids synthesis

Hydrocarbonylation. The hydrocarbonylation reaction can be applied to the synthesis of a-arylpropanoic acids of the NSAIDS type.239 For this synthesis to be effective, selective carbonylation of the more-substituted sp2 carbon is required. Although many carbonylation conditions are unselective, PdCl2(PPh3)2 with /2-toluenesulfonic acid and LiCl achieves excellent selectivity. The selectivity is thought to involve the formation of a benzylic chloride intermediate. 

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

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. 

As the previous chapters have demonstrated, chiral auxiliaries have found a widespread application in the asymmetric synthesis of lignans. Among them, chiral oxazolidinones have been used extensively due to their ability to produce excellent diastereoselectivities in aldol as well as in numerous other reactions. For example, Kise et al. reported the use of (5)-4-isopropyl-3-(phenylacetyl)-2-oxazolidinone (141) in oxidative homocoupling reactions and its application in the asymmetric synthesis of dibenzylbutyrolactones and dibenzylbutandiols, Scheme (26) [86,87]. Treatment of 3-arylpropanoic acid derivative 142 with LDA in the presence of TiCU yielded a mixture of the dimeric compounds 143 in a ratio of 85 15 to 87 13. The major product having (R,R) configuration was converted into dibenzylbutyrolactones 145 in a three step sequence... 

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. ... 

An enantioselective route to 1,3-dithiane 1-oxide (33) (R = R = H) was subsequently developed [69]. It involves asymmetric oxidation of (32) (R = pivaloyl, R = H) by cumene hydroperoxide in presence of the chiral titanium complex. The syn/anti mixture (around 90% ee for each diastereoisomer) is recrystallized and then deacylated, giving the desired product in 80% yield. A recent application of this chemistry is the asymmetric synthesis of enantiopure (R)-(-)-2,6-dimethylheptanoic acid in two steps from (33) (R = C(0)Et, R = Et) [70]. The reaction involves a fully stereoselective methylation in the a-position of the keto group, followed by basic deacylation, which also regenerates enantiopure 2-ethyl-l,3-dithiane 1-oxide (33) (Ri = H, R = Et). A range of a-arylpropanoic acids have since been prepared by similar routes in high ee s. [162]... 

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... 

Z. Xiao, M. Lei, L. Hu, Tetrahedron Lett. 2011, 52, 7099-7102. An unexpected multi-component reaction to synthesis of 3-(5-amino-3-methyl-l//-pyrazol-4-yl)-3-arylpropanoic acids in ionic liquid. 

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. 

The formation of the isocoumarin skeleton in the total synthesis of achlisocoumarins I and II involved the cyclocondensation in neat conditions of a homophthalic acid with methyl 3-arylpropanoate or methyl ( )-... 

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