The Darzen's condensation of 4-iodoacetophenone (I) with methyl chloroacetate (II) in the presence of NaOMe afforded the glycidic ester (III), which was further hydrolyzed to the corresponding glycidic acid (IV) with NaOH in aqueous ethanol. Subsequent decarboxylation of (IV) under acidic conditions furnished 2-(4-iodophenyl)propionaldehyde (V). After oxidation of aldehyde (V) with sodium chlorite, the resultant carboxylic acid was converted to the corresponding zinc salt (VI) upon treatment with ZnCl2 and NaOH. Coupling of aryl iodide (VI) with the Grignard reagent (VIII) (prepared from 2-bromo-3-methylthiophene (VII)) in the presence of PdCl2 gave rise to the racemic biarylpropionic acid (IX)). The title (R)-enantiomer was then resolved via formation of the diastereoisomeric salts with D-phenylglycine methyl ester (X)
Preparation of the racemic arylpropionic acid (IX) has been reported through a number of different procedures. 4-Aminoacetophenone (XI) was diazotized to (XII) employing isoamyl nitrite and either acetic or fluoboric acid. Then, the Gomberg-Bachmann coupling of diazonium salt (XII) with 3-methylthiophene (XIII) furnished 4-(3-methyl-2-thienyl)acetophenone (XIV). Subsequent Darzen's condensation of acetophenone (XIV) with methyl chloroacetate (II) afforded the glycidic ester (XV), which was further hydrolyzed to acid (XVI), and then decarboxylated to aldehyde (XVII). Oxidation of (XVII) to the key carboxylic acid was performed by treatment with potassium permanganate
Alternatively, Darzen's condensation of acetophenone (XIV) with methyl 2-chloropropionate (XVIII) produced glycidic ester (XIX), which was hydrolyzed and decarboxylated to the 3-arylbutanone (XX). The haloform reaction of ketone (XX) with sodium hypobromite generated acid (IX)
Acetophenone (XIV) was converted to oxirane (XXI) by treatment with the in situ-generated dimethylsulfonium methylide. Rearrangement of epoxide (XVII) in the presence of molecular sieves furnished aldehyde (XVII), which was converted to acid (IX) by oxidation with sodium chlorite.
In an alternative procedure, acetophenone (XIV) was condensed with KCN in the presence of ammonium carbonate to produce hydantoin (XXII). Basic hydrolysis of (XXII) led to amino acid (XXIII), which was converted to the dimethylamino analogue (XXIV) by reductive alkylation under Eschweiler-Clarke conditions. The desired arylpropionic acid (IX) was obtained from (XXIV) by hydrogenolysis in the presence of Pd/C
In a different approach, the precursor aldehyde (XVII) was obtained by addition of the Grignard reagent prepared from chloromethyl ethyl ether (XXV) to acetophenone (XIV), and then rearrangement of the resultant ethoxy alcohol (XXVI) in refluxing AcOH
The thienyl bromobenzene (XXVII) was converted to the corresponding Grignard reagent and subsequently treated with ZnCl2 to afford the organozinc derivative (XXVIII). Condensation of (XXVIII) with ethyl bromopropionate (XXIX) led to the arylpropionic ester (XXX), which was further hydrolyzed to acid (IX) under basic conditions.
Glycidonitrile (XXXII) was prepared by condensation of ketone (XIV) with chloroacetonitrile (XXXI) under Darzens conditions. Epoxide ring opening in (XXXII) by HCl in toluene provided the chlorohydrin (XXXIII). Acetylation of (XXXIII), followed by dehydrohalogenation led to the acetoxy acrylonitrile (XXXIV). Hydrolysis and decarbonylation of (XXXIV) provided an alternative access to the arylpropionic acid (IX)
The glycidic ester (XV), obtained as in Scheme 2, was alternatively rearranged to the alpha-keto ester enol form (XXXV) under acidic conditions. Hydrolysis and decarbonylation of (XXXV) employing NaOMe furnished acid (XI)
The chlorohydrin (XXXIII), obtained as in Scheme 8, was converted to enol ether (XXXVI) via O-alkylation with bromoethane and sodium amide, followed by basic dehydrohalogenation. Acid hydrolysis of enol ether (XXXVI) produced the keto nitrile (XXXVII), which was then hydrolyzed and decarbonylated to acid (IX)
A different strategy was based on the Knoevenagel condensation of ketone (XIV) with methyl cyanoacetate (XXXVIII) to produce the alkylidene cyanoacetate (XXXIX). Double-bond epoxidation by means of H2O2 led to (XL), which was further rearranged to keto amide (XLI). Decarboxylation of (XLI) under Hofmann rearrangement conditions furnished the arylpropionic acid (IX)
Methylation of arylacetic ester (XLII) was accomplished via Claisen condensation with diethyl carbonate and alkylation of the resultant arylmalonate (XLIII) with iodomethane and NaOMe. The methylated compound (XLIV) was further subjected to hydrolysis and decarboxylation to give (IX)
2-(4-Iodophenyl)-2-methyloxirane (XLV) was obtained by addition of dimethylsulfonium methylide to 4-iodoacetophenone (I). Rearrangement of epoxide (XLV) in the presence of molecular sieves led to aldehyde (V), which was protected as the dimethyl acetal (XLVI) upon treatment with trimethyl orthoformate. Palladium-catalyzed condensation of the Grignard reagent (VIII) with aryl iodide (XLVI) furnished the biaryl adduct (XLVII). This was subsequently hydrolyzed to the key aldehyde (XVII) employing AcOH
The iodophenyl propionic acid (XLVIII) was protected as the oxazoline (LII) via activation as the corresponding acid chloride (XLIX), which was condensed with 2-amino-2-methylpropanol (L) to yield amide (LI). Subsequent cyclization of hydroxy amide (LI) by treatment with phosphorus oxychloride led to oxazoline (LII). Palladium coupling between aryl iodide (LII) and the Grignard reagent (VIII) provided the biaryl adduct (LIII). The oxazoline (LIII) was then hydrolyzed to (IX) with sulfuric acid and AcOH
In an asymmetric synthesis of the title compound, aldehyde (V) was oxidized with sodium chlorite to afford the corresponding racemic acid, which was resolved via formation of the diastereoisomeric salts with cinchonidine. The target (R)-2-(4-iodophenyl)propionic acid (LIV) was then converted to the zinc salt and subsequently coupled to 3-methyl-2-thienylmagnesium bromide (VIII) in the presence of palladium catalyst to provide the desired chiral arylpropionic acid