Synthesis of nordihydroguaiaretic acid derivatives via suzuki and stille cross-coupling reactions and subsequent raney nickel desulfurization and reduction

Abstract

The predictability of selectivity in organopalladium chemistry employed to generate carbon-carbon bonds between polyhalogenated heteroaromatic compounds and their cross-coupling partners allow for efficient production of NDGA derivatives. Suzuki couplings between tetrabromo thiophene and arylboronic acids reliably generate substrates for Stille carbon-carbon bond forming reactions. Several methods for desulfurization and reduction of tetra-substituted thiophenes have been published, and a number of these methods were evaluated toward producing the desired end products. Raney

nickel under an atmosphere of hydrogen gas in a Parr hydrogenator, highly activated Raney nickel in alcohol, and nickel boride generated in-situ from nickel chloride and sodium borohydride in a number

of solvent systems were each tested en route to manufacturing substituted NDGA. The primary focus of this research is the synthesis of NDGA derivatives from tetrabromo thiophene.

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