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.