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

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 ß- and γ-C-H bonds of aliphatic alcohol derivatives was validated by experimental studies.

Silver-Catalyzed Enantioselective Propargylic C-H Bond Amination through Rational Ligand Design.

Asymmetric C-H amination via nitrene transfer is a powerful tool to prepare enantioenriched amine precursors from abundant C-H bonds. Herein, we report a regio- and enantioselective synthesis of γ-alkynyl γ-aminoalcohols via a silver-catalyzed propargylic C-H amination. The protocol was enabled by a new bis(oxazoline) (BOX) ligand designed via a rapid structure-activity relationship (SAR) analysis. The method utilizes accessible carbamate esters bearing γ-propargylic C-H bonds and furnishes versatile products in good yields and excellent enantioselectivity (90-99% ee). The putative Ag-nitrene is proposed to undergo enantiodetermining hydrogen-atom transfer (HAT) during the C-H amination event. Density functional theory calculations shed insight into the origin of enantioselectivity in the HAT step.

Au(I)-Catalyzed Synthesis of Trisubstituted Indolizines from 2-Propargyloxypyridines and Methyl Ketones.

A new Au(I)-catalyzed method for the preparation of trisubstituted indolizines from easily accessible 2-propargyloxy-pyridines is reported. The reaction tolerates a wide range of functionality, allowing for diversity to be introduced in four distinct regions of the product (R, R1, R2, and Ar). The proposed mechanism proceeds via enol addition to an allenamide intermediate and explains the observed increase in yields when electron poor methyl ketones are utilized.