Solid-phase directed ortho-lithiation and the preparation of a phthalide library

An efficient solid-phase synthesis of phthalides is described in which aromatic carboxylic acids or acid chlorides and ketones are used as building blocks. The carboxylic acid or acid chloride is tethered to aminomethylated polystyrene resin, forming a secondary amide, which functions as both the linker and the directing metalation group. This allows the resin-bound benzamides to be ortho-lithiated at 0 degrees C. The ortho-lithiated species can be quenched with benzaldehydes, benzophenones, and even acetophenones, affording resin-bound alcohols. A cyclative cleavage is induced by simply warming the resin in toluene or dioxane, yielding the desired phthalide compounds in exceptionally high purity.