Selective Metalation and Solid Phase Organometallic Chemistry

Abstract

Recently, solid-phase synthesis has been recognized as an important methodology for combinatorial chemistry or automated synthesis directed at drug discovery. Various synthetic methodologies have been applied to solid-phase synthesis, although it appears that organometallic chemistry in this area is still being explored. In solution-phase chemistry, organometallic reagents have been utilized for various molecular transformations, especially selective carbon-carbon bond formation. Metallation chemistry is considered to be an important area of organometallic chemistry. Lithiation has been most widely used for metallation, although the reaction conditions must be strictly controlled to avoid various side reactions. Chemoselective transformation was carried out using the newly developed halogen-zinc exchange reaction of aromatic halides using lithium trialkylzincate. This reaction shows high chemoselectivity and compatibility with alkoxycarbonyl or nitro groups. A highly selective hydrogen-zinc exchange reaction was also developed. In solid-phase organometallic chemistry, an immobilized iodobenzoate was used as a substrate and the halogen-zinc exchange reaction was investigated. The exchange reaction was found to proceed smoothly. As an application of the reaction, various transformations on polymer support were investigated using transmetallation and cyclization. The palladium-catalyzed coupling reaction on polymer support was also investigated, and new cyclization for condensed heteroaromatic compounds was developed. The methodology described here is considered to contribute to expanding the application spectrum of solid-phase organometallic chemistry.