Alkylation of arylacetic acids

Diastereoselective a-alkylation of arylacetic acids.1 The binaphthyl ester (1) of phenylacetic acid undergoes highly diastereoselective methylation on treatment of... 

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. 

Chiral lithium diphenylbinaphtholate (2) has been found to be an effective catalyst for the enantioselective aldol-Tishchenko reaction, affording 1,3-diol derivatives with three contiguous chiral centres and high stereoselectivities (up to 99% ee) ° A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide (3) as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. 

As an alternative to the use of auxiliaries for the asymmetric alkylation of carboxylic acid derivatives, in 2011, Zakarian and Stivala reported on the direct stereoselective alkylation of arylacetic acids with chiral lithium amide bases.This method offers an alternative to traditional auxiliary-based methods and operates through the formation of enediolates also, it builds on earlier work by Shioiri and Ando and by Koga and Matsuo . Zakarian and Stivala examined several C2-symmetric tetramines for their enan-tiodirecting power. After significant experimentation, conditions were established that used 4 equivalents of -BuLi and a slight excess of the tetramine that provided clean formation of the desired product. The enantioselectivity was found to be dependent on the quality of the -butyllithium. The reaction scope was examined with a variety of... 

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... 

The dianions of arylacetic acids 997 undergo alkylation reactions with l-bromo-3-chloropropane, with the resulting 5-chloropentanoic acids 998 cyclizing upon treatment with DBU providing a one-pot preparation of 3-aryltetrahy-dropyran-2-ones 999 (Scheme 259) <2003TL365>. 

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). 

Tetracarbonylcobaltate anion, generated under PTC conditions, catalyzes the reaction of aryl halides with excess methyl iodide under a CO atmosphere [122]. The reaction produces aryl methyl ketones and carboxylic acids as the main products. Stoichiometric or catalytic iron pentacarbonyl can also be used for the carbonylation of organohalides under PTC conditions [123-128]. For example, reactions of alkyl and arylalkyl halides with CO in aqueous-organic systems using catalytic amounts of Fe(CO)5 and a PT agent afford alkyl- and arylacetic acids as the main products [127]. 

Alkyl aryl ketones can be converted to arylacetic acid derivatives in an entirely different manner. The reaction consists of treatment of the substrate with silver nitrate and I2 or Br2, ° or with thallium nitrate, MeOH, and trimethyl orthoformate adsorbed on Montmorillonite K-10 clay, an acidic clay. ... 

H. Weber, H. Spahn, E. Mutschler, and W. Moehrke, Activated-alkyl-arylacetic acid enantiomers for stereoselective thin-layer chromatographic and high-performance liquid chromatographic determination of chiral amines, J. Chromatogr., 307 145 (1984). 

The PTC carbonylation of substituted benzyl chlorides with Co2(CO)g gives a mixture of products [111, 115]. In all cases, arylacetic acids prevail. These are the sole products when R = H, CF3. Double carbonylation with subsequent alkylation producing ketoacids is observed in the case of methyl-substituted benzyl chlorides. 2,4,6-Trimethylbenzyl chloride yields mesitylacetic and mesitylpyruvic acid in equal amounts [115]. 

Arylthallium bis(trifluoroacetate)s are converted by successive treatment with KF and BF3 into aryl fluorides.Thallium(iii) nitrate (TTN) readily oxidizes dialkyl sulphides and selenides to the corresponding sulphoxides or selenoxides, and 2-(alkylthio)-l-arylethanones (37) into compounds (38) in methanolic solution.In a modification of the TTN oxidative conversion of aryl alkyl ketones into arylacetic acids, enol ethers derived from the ketones are used instead of the ketones themselves. This reduces the formation of side products. Cyclic aralkyl ketones (39) may be ring-expanded and alkylated to give compounds (40) via treatment of their Wittig-derived alkenes with TTN/ an extrapolation of the basic reaction discovered previously. 

Alkylation of arylacetonitriles and their derivatives in the presence of 50% NaOH aq and benzyltriethylammonium chloride (TEBA) as a catalyst was thoroughly studied, because many pharmaceuticals contain the arylacetic acid framework. High yields of monoalkylated products are as a rule obtained in alkylation with primary alkyl bromides. For dialkylation or introduction of secondary alkyl group, the use of 60% (or even more concentrated) KOH aq and tetrabutylammo-nium bromide (TBAB) as a catalyst is often recommended (23) (eqs. 38 and 39). 

The Suzuki reaction is a powerful carbon-carbon bond-forming reaction method for the rapid introduction of diverse substituent onto an aromatic ring. Substituted arylacetic acids represent an important class of cyclooxygenase inhibitors. These inhibitors that are built on the phenylacetic acid core, typically incorporating three elements of variability an a-alkyl group, R alkyl, aryl or heteroaryl substitution on the phenyl ring, R and acid or amide functionality (Scheme 31.5). To synthesize this variety of molecules requires successful construction of a combinatorial library of a class of compounds and that depends... 

These agents are considered to be 7/-aryl-substituted derivatives of anthranilic acid, which itself is a bioisostere of salicylic acid. These agents retain the acidic properties that are characteristic of this class of agents though mefenamic acid and meclofenamic acid are derivatives of anthranilic acid, diclofenac is derived from 2-arylacetic acid (Figure 13.10). The most active fenamates have small alkyl or halogen substituents at the 2, 3, or 6 position of the iV-aryl moiety... 

Methyla-arylacetates. These esters have been obtained by oxidative rearrangement of alkyl aryl ketones with thallium(III) nitrate in acidic methanol or trimethyl orthoformate (4,496 5, 656 7, 362). A new method, which avoids the toxic TTN, is based on the Woodward version of the Prevost reaction. Thus, treatment of the ketone with iodine (or bromine) and silver nitrate (2 equiv.) in refluxing methanol containing trimethyl orthoformate results in methyl a-arylacetates in 90% yield from simple substrates. Yields are lowered by electron-withdrawing substituents on the aromatic group and by a-branching in the alkyl group.2... 

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