Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions

Using a mechanically guided ligand
design approach, a new ligand
(SEGFAST) for the CuH-catalyzed hydroamination reaction of unactivated
terminal olefins has been developed, providing a 62-fold rate increase
over reactions compared to DTBM-SEGPHOS, the previous optimal ligand.
Combining the respective strengths of computational chemistry and
experimental kinetic measurements, we were able to quickly identify
potential modifications that lead to more effective ligands, thus
avoiding synthesizing and testing a large library of ligands. By optimizing
the combination of attractive, noncovalent ligand–substrate
interactions and the stability of the catalyst under the reaction
conditions, we were able to identify a finely tuned hybrid ligand
that greatly enables accelerated hydrocupration rates with unactivated
alkenes. Moreover, a modular and robust synthetic sequence was devised,
which allowed for the practical, gram-scale synthesis of these novel
hybrid ligand structures.