Steric limits to ester alkylation; synthesis of highly hindered esters via hexamethylphosphoramide-favoured enolization

Abstract

The steric limits to the alkylation of carboxylic esters by alkyl iodides with lithium di-isopropylamide as base in the presence of hexamethylphosphoramide have been investigated by using, with modifications, a method originally proposed by Schlessinger et al. The influence of hexamethylphosphoramide in promoting ester enolization, as opposed to its influence on the alkylation step, as previously reported, has been examined. The formation of αα-disubstituted from α-monosubstituted esters takes place in high yields and appears to be only slightly influenced by the nature of the alkylating agent (Mel, Etl, or Prⁱl). In contrast, the formation of ααα-trisubstituted for αα-disubstituted esters appears to be sensitive to the steric nature of the ester to be alkylated. Thus in the synthesis of tri-from mono-substituted esters the order of introduction of alkyl groups is critical. The failure of certain esters to react is interpreted as due to an inability to undergo enolization.