ABSTRACT: Axially chiral biaryls featuring a C−N axis areimportant functional molecules in diverse fields. The asymmetric Buchwald−Hartwig reaction represents a powerful strategy for thesetargets. Previous studies, however, have been predominantly restricted to intramolecular atroposelective coupling, likely due tothe steric and entropic effects in the reductive elimination of Pd(II) species with sterically congested aryl and nitrogen groups. We now report two intermolecular Buchwald−Hartwig coupling systems of bulky NH lactams and halohydrocarbons enabled by rerouting themechanism of C−N reductive elimination to one that accom-modates sterically challenging substrates. Both atroposelective coupling systems exhibited functional group tolerance, excellent enantioselectivity, and high Z selectivity (if applicable), affording C−N atropisomeric biaryl and olefins through de novo construction of a C−N chiral axis. Experimental and computational studies were performed to elucidate the mechanism, and the switch of the reaction pathways is traced to the steric effect (ortho substituent) ofthe aryl halide substrate. A bulky 2,6-disubstituted aryl halide reorients the proximal lactamide ligand to its unusual O-ligation mode.With the amide oxygen participation, this intermediate undergoes C−N reductive elimination with an accessible barrier through a five-membered ring transition state, a pathway as well as a chiral induction mode that has been much underexplored in asymmetric catalysis.
(https://pubs.acs.org/doi/10.1021/jacs.4c03342)
Congratulations to Wei Wang. Special thanks also go to our collaborators.