Mechanistic Studies and Data Science-Guided Exploration of Bromotetrazine Cross-Coupling

A thorough mechanistic investigation of the Pd- catalyzed and Ag-mediated cross-coupling of the monosubstituted tetrazine 3-bromo-1,2,4,5-tetrazine with boronic acids is reported. The study combines kinetic analyses, isolation of catalytic intermediates, and computational methods to gain insights into the mechanism. On the basis of these experimentally validated hypotheses, a highly electron-deficient ligand was predicted to overcome the challenge of coupling previously unfeasible substrates, which in turn was confirmed experimentally. In addition, a data-driven workflow was applied to study how the mechanistic understanding impacts the generality of the scope.