Origins of Catalyst-Controlled Selectivity in Ag-Catalyzed Regiodivergent C–H Amination

Abstract

Ag-catalyzed nitrene transfer (NT) converts C–H bonds into valuable C–N bonds. These reactions offer a promising strategy for catalyst-controlled regiodivergent functionalization of different types of reactive C–H bonds, as the regioselectivity is tunable by varying the steric and electronic environments around the Ag nitrene, as well as the identity of the nitrene precursors and the tether length. Therefore, a unified understanding of how these individual factors affect the regioselectivity is key to the rational design of highly selective and regiodivergent C–H amination reactions. Herein, we report a computational study of various Ag-catalyzed NT reactions that indicates a concerted H-atom transfer (HAT)/C–N bond formation mechanism. A detailed analysis was carried out on the effects of the C–H bond dissociation enthalpy (BDE), charge transfer, ligand–substrate steric repulsions, and transition state ring strain on the stability of the C–H insertion transition states with different Ag nitrene complexes. The ancillary ligands on the Ag and the nitrene precursor identity both affect transition state geometries to furnish differing sensitivities to the BDE, tether length, and electronic effects of the reactive C–H bonds. Based on our understanding of the dominant factors that control selectivity, we established a rational catalyst and precursor selection approach for regiodivergent amination of diverse C–H bonds. The computationally predicted regiodivergent amination of β- and γ-C–H bonds of aliphatic alcohol derivatives was validated by experimental studies.

C–N Bond Forming Radical Rebound Is the Enantioselectivity-Determining Step in P411-Catalyzed Enantioselective C(sp3)–H Amination: A Combined Computational and Experimental Investigation

“…Lastly, the five-membered cyclic transition state TS2 suffers from relatively high ring-strain energy. Based on computed values derived from hypothetical homodesmotic reactions (Figure S9), the ring strain energies of the five-membered ring transition state 5 TS2 and the cyclic amination product 2 are 7.7 and 5.1 kcal/mol, respectively. Therefore, the ring strain energy of the cyclization transition state makes the intramolecular C–N rebound slower than the corresponding intermolecular process. ,,, Taken together, the QM/MM-computed reaction energy profiles revealed an unusual mechanism with a high-barrier radical rebound, indicating relatively long lifetimes of the carbon-centered radical intermediates, which may lead to the ablation of stereochemistry prior to radical rebound.…”

Tunable Silver-Catalyzed Nitrene Transfer: From Chemoselectivity to Enantioselective C–H Amination

“…A recent report from the Schomaker and Liu groups shows that the nature of the nitrene precursor can also exert a big impact on the outcome of the nitrene transfer reaction . Further investigations into a broader range of nitrene precursor/catalyst combinations are likely to reveal interesting trends and other strategies to tune the chemo-, site, and enantioselectivity.…”

“…(−)-Menthol derivative 83 bearing two competing tertiary C(sp 3 )−H bonds was also examined for control over the ring size in the amination event. 55,56 The use of a dimethylbis-(oxazoline) (dmBOX) ligand, which generates a monomeric silver complex, favored the formation of a six-membered heterocycle (Table 9, entry 1). In contrast, a [(Py 5 Me 2 )Ag-(ClO 4 )] 2 catalyst, which is dimeric in solution and sterically congested, resulted in excellent selectivity for reaction at the δ site (Table 9, entry 5).…”

“…A recent report from the Schomaker and Liu groups shows that the nature of the nitrene precursor can also exert a big impact on the outcome of the nitrene transfer reaction. 56 Further investigations into a broader range of nitrene precursor/catalyst combinations are likely to reveal interesting trends and other strategies to tune the chemo-, site, and enantioselectivity. These insights can be extended to achieve ligand-controlled, intermolecular site-and enantioselective aminations of C−H bonds, a long-standing challenge in the field that has not yet been solved.…”

Silver Catalyzed Site-Selective C(sp3)−H Bond Amination of Secondary over Primary C(sp3)−H Bonds

“…To date, the selective amination of aliphatic C(sp 3 )–H bonds has mainly been limited to the site-selectivity of unactivated substrates (e.g., tertiary alkyl C–H bonds and benzylic γ-C–H bonds) and activated substrates (e.g., allylic and benzylic C–H bonds)23, [ 25 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. Due to the similar high bond-dissociation energy of aliphatic C-H bonds, only a handful of studies have been conducted to identify the selective amination of aliphatic C(sp 3 )–H bonds.…”