Synthesis of Phenylacetic Acids with 2-Oxoalkyl Substituents in theortho-Position fromo-Phenylenediacetic Acid

Abstract

A one-step procedure for the synthesis of 2-(2-oxoalkyl)-substituted phenylacetic acids is described. Very slow addition of organolithium compounds to o-phenylenediacetic acid is the crucial feature to obtain the desired e-oxo acids in good yields. The selective formation of the e-oxo acids from the diacid is explained on the basis of hemiketal anion formation.The g-, d-, and e-oxo acids constitute valuable building blocks for the asymmetric synthesis of several carbo-and heterocycles including substituted naphthalenones, 1 pyrrolidines, 2 piperidones, 3 azepines, and 3-benzazepines. 4 These carbo-and heterocycles are of particular interest in medicinal chemistry. However, the methods described for the synthesis of oxo acids involve several steps and are, thus, rather circumstantial and time-consuming. 1,5,6 Although the synthesis of ketones by the reaction of carboxylic acids with organolithium reagents is well known, the formation of undesired tertiary alcohols is a problem associated with this transformation. 7-9 Only a few reports in the literature describe the reaction of diacids with organolithium reagents. 10In this paper we wish to report on a general method for the synthesis of phenylacetic acid derivatives with various 2-oxoalkyl residues in position 2 of the phenyl ring starting from the diacid o-phenylenediacetic acid (1). We postulate that the selective formation of e-oxo acids as the main product is based on the intermediate formation of a hemiketal anion.At first we concentrated on the production of the phenylacetic acid 2 with a 2-oxopropyl residue in position 2. However, all attempts to transform the dimethyl ester of 1 with methyllithium 8 or Tebbe reagent 11,12 into the corresponding methyl ester of 2 failed. In a further approach we tried to prepare the e-oxo acid 2 by reaction of o-bromophenylacetic acid and active methylene compounds using several palladium/copper catalysts and different bases; 13 this reaction did not result in the formation of the desired phenylacetic acid derivatives.Then we focused our attention on the direct reaction of ophenylenediacetic acid with methyllithium (Scheme 1). Indeed the reaction of diacid 1 with eight equivalents of methyllithium provided the desired oxo acid 2, albeit in low isolated yield (10%) along with large amounts of unreacted diacid 1.Next, the yield of 2 was improved by varying the reaction conditions (Table 1). In order to obtain a rapid result, the 1 H NMR spectrum (CD 3 OD) of the crude reaction mixture was recorded. Usually the signals for only two compounds (diacid 1 and oxo acid 2) were observed in the 1 H NMR spectrum indicating a clean transformation. The ratio of oxo acid 2 to diacid 1 was calculated by integration of characteristic signals (CH 2 CO 2 H singlets of 1 and CH 2 COR singlets of 2-5, see Figure 1).At first the solvent diethyl ether was employed instead of tetrahydrofuran. However, due to the low solubility of the anionic intermediates only a very low conversion was observed. Scheme 1 R O CO 2 H CO 2 H CO 2 H RLi, THF 1 2 R =...