Expanding the Clip-and-Cleave Concept: Approaching Enantioselective C–H Hydroxylations by Copper Imine Complexes Using O2 and H2O2 as Oxidants

Copper-mediated aromatic and aliphatic C–H hydroxylations using benign oxidants (O2 and H2O2) have been studied intensively in recent years to meet the growing demand for efficient and green C–H functionalizations. Herein, we report an enantioselective variant of the so-called clip-and-cleave concept for intramolecular ligand hydroxylations by the application of chiral diamines as directing groups. We tested the hydroxylation of cyclohexanone and 1-acetyladamantane under different oxidative conditions (CuI/O2; CuI/H2O2; CuII/H2O2) in various solvents. As an outstanding example, we obtained (R)-1-acetyl-2-adamantol with a yield of 37% and >99:1 enantiomeric excess from hydroxylation in acetone using CuI and O2. Low-temperature stopped-flow UV–vis measurements in combination with density functional theory (DFT) computations revealed that the hydroxylation proceeds via a bis­(μ-oxido) dicopper intermediate. The reaction product represents a rare example of an enantiopure 1,2-difunctionalized adamantane derivative, which paves the way for potential pharmacological studies. Furthermore, we found that 1-acetyladamantane can be hydroxylated in a one-pot reaction under air with isolated yields up to 36% and enantiomeric ratios of 96:4 using CuII/H2O2 in MeOH.