Enantioselective C–H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands

The trityl-substituted bisoxazoline
(TrHBOX) was prepared
as a chiral analogue to a previously reported nickel dipyrrin system
capable of ring-closing amination catalysis. Ligand metalation with
divalent NiI2(py)4 followed by potassium graphite
reduction afforded the monovalent (TrHBOX)­Ni­(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide
to 4 generated the tetrazido (TrHBOX)­Ni­(κ2-N4Ad2) (5) and terminal
iminyl adduct (TrHBOX)­Ni­(NAd) (6). Investigation
of 6 via single-crystal X-ray crystallography, NMR and
EPR spectroscopies, and computations revealed a Ni­(II)-iminyl radical
formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C–H bond amination
to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes.
Catalytic C–H amination occurs under mild conditions (5 mol
% catalyst, 60 °C) and provides pyrrolidine products in decent
yield (29%–87%) with moderate ee (up to 73%).
Substrates with a 3,5-dialkyl substitution on the 4-aryl position
maximized the observed enantioselectivity. Kinetic studies to probe
the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope
effect (1.35 ± 0.03) suggests an H-atom abstraction step with
an asymmetric transition state while the reaction rate is measured
to be first order in catalyst and zeroth order in substrate concentrations.
Enantiospecific deuterium labeling studies show that the enantioselectivity
is dictated by both the H-atom abstraction and radical recombination
steps due to the comparable rate between radical rotation and C–N
bond formation. Furthermore, the competing elements of the two-step
reaction where H-removal from the pro-R configuration
is preferred while the preferential radical capture occurs with the
Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations.
Based on these enantio-determining steps, catalytic enantioselective
synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good
yield (50–78%) and moderate ee (up to 79%).