Regioselective preparation of 2,4-, 3,4-, and 2,3,4-substituted furan rings .2. Regioselective lithiation of 2-silylated-3-substituted furan rings

A new method for the preparation of 3,4- and 2,5-disubstituted furan rings is described. A variety of 2-silylated-3-(hydroxymethyl)furans and 2-silylated-3-furoic acids lithiate exclusively at C-4 when treated with 2.2 equivs of BuLi. The resulting dianions were quenched with a variety of electrophiles to provide 2-silylated-3-(hydroxymethyl)-substituted furans and 2-silylated-4-substituted 3-furoic acids in good to excellent yields. Removal of the silyl group (n-Bu4NF) provided a variety of 4-substituted-3-(hydroxymethyl)furans and methyl 4-substituted-3-furoates, respectively. The latter esters were prepared due to difficulties encountered in isolating 4-substituted-3-furoic acids. The site of lithiation was altered by protecting the 3-hydroxyl group with a triethylsilane. Lithiation of 2-silylated-3-(((triethylsilyl)oxy)methyl)furan with 1.2 equivs of BuLi followed by the addition of electrophiles provided 2-silylated-3-(((triethylsilyl)oxy)methyl)-5-substituted furan rings. Subsequent removal of both silyl groups provided 2,4-disubstituted furan rings in moderate to good yields. A rationale is provided to explain why protection of the hydroxyl group at C-3 leads to a change in lithiation from the C-4 to the C-5 position of the furan ring. In addition, an explanation for the observed effect of adding HMPA or LiCl to the solution during the lithiation of 2-(tert-butyldimethylsilyl)-3-(hydroxymethyl)furan is provided.