The Regiospecific C-3 Lithiation of 5-Ethyl-2-furoic acid: An Approach to Key Natural Product Intermediates

Treatment of 5-ethyl-2-furoic acid with n -butyl-lithium in tetrahydrofuran gave regiospecific C-3 lithiation, whereas treatment of the same acid with lithium di-isopropylamide (LDA) afforded only starting material. The synthetic utility of dilithiated 5-ethyl-2-furoic acid has been demonstrated with the synthesis of two substituted 3-benzyl-5-ethyl-2-furoic acid derivatives which are key intermediates for the preparation of naturally occurring cytotoxic 2-ethylfuronaphthoquinones. Reaction of the C-3 lithiated species with two equivalents of benzaldehyde and subsequent reduction affored the corresponding 3-benzyl-5-ethyl-2-furoic acids. An alternative route to 5-ethyl-2-furoic acid has been described allowing for a more convenient preparation of longer-chain 5-alkyl-2-furoic acids.