Synthetic methods: Soft enolization

24 july 2008 - Organic chemistry

Soft enolization is a modification of C-alkylation by an enolate with a Lewis acid. The metal forms a coordination complex with the carbonyl group, increasing the acidity of the alpha protons. The enolate is thus formed with milder bases.

The origin of this reaction can possibly be traced back to nitromethane carboxylation or cyclohexanone methylation using magnesium methyl carbonate by Stiles & Finkbeiner in 1959 ( DOI DOI OS:439)

Lehnert in 1970 was the first to employ lewis acids in Aldol-type reaction (DOI) in a titanium chloride modification of the Knoevenagel condensation extending its scope to simple aliphatic aldehydes.

Masamune et al. in 1984 developed a mild Horner-Wadsworth-Emmons reaction based on a combination of lithium chloride and an amine for use with base-sensitive substrates (DOI)

Rathke and Cowan in 1985 (DOI) reacted diethyl malonate, acetyl chloride and two equivalents of triethylamine in presence of one equivalent of magnesium chloride

They then pushed on with a novel alpha ketone carboxylation DOI.

Most recently Lim et al. in 2008 adapted a Claisen condenation to soft enolization with magnesium bromide (DOI) citing an important advantage in that the reaction can be carried with wet solvents and open to air.