Ester enolates from .alpha.-acetoxy esters. synthesis of arylmalonic and .alpha.-arylalkanoic esters from aryl nucleophiles and .alpha.-keto esters

Abstract

Eater enolates are generated by reductive α-deacetoxylation of α-acetoxy-α-arylmalonic esters or a-acetoxy-α-arylalkanoic esters with lithium in liquid ammonia or sodium α-(dimethylamino)naphthalenide in hexa- methylphosphoramide-benzene. Since the requisite α-acetoxy esters are available from aryl nucleophiles. the reductions provide effective new synthetic routes to arylmalonic esters and α-arylalkanoic esters. For example, 2-(p-isobutylphenyl)propionic acid (ibuprofen. a commercially important nonsteroidal antiinflammatory agent) is obtained in 73% yield overall from isobutylbenzene. Arenes, aryllithiums, or aryhrtagnesium halides react with α-keto esters, e.g., diethyl oromalonate, ethyl pyruvate, methyl phenylglyouxalate, or alkyl glyoxylates, to afford α-hydroxy esters. These are acetylated with acetic anhydride-triethylamine and p-(dimethylamino)pyridine as a catalyst. Reductive α-deoxygenation then allows replacement of the acetoxy group by hydrogen or an alkyl group.