Synthesis of mono- and dimethoxylated polychlorinated biphenyl derivatives starting from fluoroarene derivatives

Polychlorinated biphenyls (PCBs) are environmental pollutants implicated in a variety of adverse health effects, including cancer and noncancer diseases in animals and humans. PCBs are metabolized to hydroxylated compounds, and some of these PCB metabolites are more toxic than the parent PCBs. Unfortunately, most PCB metabolites needed for toxicological studies are not available from commercial sources. Moreover, it is challenging to synthesize PCB metabolites because starting materials with suitable substitution patterns are not readily available. Here, we report the novel synthesis of a variety of mono- and dimethoxyarene derivatives from commercially available fluoroarenes via nucleophilic aromatic substitution with sodium methoxide. This reaction provided good to excellent yields of the desired methoxylated products. Suzuki coupling of selected mono- and dimethoxy haloarenes with chlorinated phenylboronic acids yielded methoxylated derivatives of PCB 11, 12, 25, 35, and 36 in low to good yields. Crystal structures of 3,3'-dichloro-2,5-dimethoxy-1,1'-biphenyl and 3',5-dichloro-2,3-dimethoxy-1,1'-biphenyl confirmed the substitution pattern of both compounds. This synthesis strategy provides straightforward access to a range of mono- and dimethoxylated PCB derivatives that were not readily accessible previously.