Mechanism of Iminium Salt-Catalyzed C(sp³)–H Amination: Factors Controlling Hydride Transfer versus H-Atom Abstraction

Abstract

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 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 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.

Racemic Benzenesulfonohydrazide Enantioconvergent Tertiary C(sp3)−H Amination Catalyzed by Copper and Chiral Phosphoric Acid: Mechanistic Insights and Computational Prediction

“…In addition to the above experimental work, some theoretical studies on the mechanisms of chiral amine synthesis have also been reported [25–28] . Zheng and co‐workers [26] studied Ir catalyzed α‐amidation of 2‐acylimidazoles and demonstrated a significant effect of nitrene insertion.…”

“…[23,24] In addition to the above experimental work, some theoretical studies on the mechanisms of chiral amine synthesis have also been reported. [25][26][27][28] Zheng and co-workers [26] studied Ir catalyzed α-amidation of 2-acylimidazoles and demonstrated a significant effect of nitrene insertion. Sunoj et al [27] investigated the mechanistic insights into asymmetric amination of diazoacetate catalyzed by dirhodium tetra(trifluoro)acetate with chiral SPINOL-phosphoric acid and found a stereo-controlling transition state with cooperative participation of both catalysts.…”