Late-Stage Phenylation From [13C6] and [2H5]Benzene: A Versatile Tool for Stable Isotope Labeled MS Standards.

We explored aryl thianthrenation as a tool for directly incorporating multiple isotopes into molecular scaffolds starting from full isotopically labeled benzene. Stable isotope-labeled (SIL) molecules are indispensable tools for investigating chemical and biological mechanisms and quantifying metabolites. However, the late-stage incorporation of isotopically labeled benzene remains challenging and under-investigated. This challenge stems from the direct functionalization of non-substituted benzene, which remains a difficult task. The approach described in this work is based on sulfonium salts used as a source of [13C6] and [2H5]benzene under palladium catalysis conditions. This approach demonstrates its efficiency in C─C and C─S bond formation with different substrates. Additionally, this methodology was employed for the synthesis of poly-substituted [13C6]benzene derivatives.