RESUMEN
Carbon-nitrogen bonds are extremely prevalent in pharmaceuticals, natural products, and other biologically relevant molecules such as nucleic acids and proteins. Intermolecular amination of C(sp3)-H bonds by catalytic nitrene transfer is a promising method for forging C-N bonds. An organocatalytic approach to nitrene transfer by way of an iminium salt offers a site-selective method for C(sp3)-H amination. Understanding of this amination mechanism including the nature of the relevant intermediates and the factors controlling the mechanism of the N-H bond formation step would aid in the design of catalysts and C(sp3)-H amination methods. In this work, the mechanism of the iminium salt-catalyzed C(sp3)-H amination via nitrene transfer was elucidated computationally using quantum mechanical methods and molecular dynamics simulations. Dispersion-corrected density functional theory (DFT) calculations provide support for an open singlet biradical species in equilibrium with the lower energy triplet species. Calculations further reveal that while the singlet biradical species undergoes N-H bond formation by a hydride transfer process, the triplet species forms the N-H bond by H-atom abstraction. Molecular dynamics (MD) simulations rule out the possibility of a fast rebound of the carbon substrate following N-H bond formation. A predictive model for mode of activation and site-selectivity that is consistent with experimental observations is presented.
RESUMEN
The first examples of nonenzymatic N-oxidation of heteroarenes in the presence of amines are reported. Pyridine, quinoline, and isoquinoline N-oxides are selectively formed in the presence of more reactive aliphatic and alicyclic amines by use of an in situ protonation strategy and an iminium salt organocatalyst. Application to late-stage functionalization that mimics phase 1 metabolism of small-molecule drugs is also demonstrated.
