Investigation of transition metal-catalyzed nitrene transfer reactions in water.

Transition metal-catalyzed nitrene transfer is a powerful method for incorporating new CN bonds into relatively unfunctionalized scaffolds. In this communication, we report the first examples of site- and chemoselective CH bond amination reactions in aqueous media. The unexpected ability to employ water as the solvent in these reactions is advantageous in that it eliminates toxic solvent use and enables reactions to be run at increased concentrations with lower oxidant loadings. Using water as the reaction medium has potential to expand the scope of nitrene transfer to encompass a variety of biomolecules and highly polar substrates, as well as enable pH control over the site-selectivity of CH bond amination.

Tunable, Chemo- and Site-Selective Nitrene Transfer Reactions through the Rational Design of Silver(I) Catalysts.

Carbon-nitrogen (C-N) bonds are ubiquitous in pharmaceuticals, agrochemicals, diverse bioactive natural products, and ligands for transition metal catalysts. An effective strategy for introducing a new C-N bond into a molecule is through transition metal-catalyzed nitrene transfer chemistry. In these reactions, a metal-supported nitrene can either add across a C═C bond to form an aziridine or insert into a C-H bond to furnish the corresponding amine. Typical catalysts for nitrene transfer include Rh2Ln and Ru2Ln complexes supported by bridging carboxylate and related ligands, as well as complexes based on Cu, Co, Ir, Fe, and Mn supported by porphyrins and related ligands. A limitation of metal-catalyzed nitrene transfer is the ability to predictably select which specific site will undergo amination in the presence of multiple reactive groups; thus, many reactions rely primarily on substrate control. Achieving true catalyst-control over nitrene transfer would open up exciting possibilities for flexible installation of new C-N bonds into hydrocarbons, natural product-inspired scaffolds, existing pharmaceuticals or biorenewable building blocks. Silver-catalyzed nitrene transfer enables flexible control over the position at which a new C-N bond is introduced. Ag(I) supported by simple N-donor ligands accommodates a diverse range of coordination geometries, from linear to tetrahedral to seesaw, enabling the electronic and steric parameters of the catalyst to be tuned independently. In addition, the ligand, Ag salt counteranion, Ag/ligand ratio and the solvent all influence the fluxional and dynamic behavior of Ag(I) complexes in solution. Understanding the interplay of these parameters to manipulate the behavior of Ag-nitrenes in a predictable manner is a key design feature of our work. In this Account, we describe successful applications of a variety of design principles to tunable, Ag-catalyzed aminations, including (1) changing Ag/ligand ratios to influence chemoselectivity, (2) manipulating the steric environment of the catalyst to achieve site-selective C-H bond amination, (3) promoting noncovalent interactions between Ag/substrate or substrate/ligand to direct C-H functionalization, and (4) dictating the substrate's trajectory of approach to the Ag-nitrene. Our catalysts distinguish between the aminations of various types of C-H bonds, including tertiary C(sp3)-H, benzylic, allylic, and propargylic C-H bonds. Efforts in asymmetric nitrene transfer reactions catalyzed by Ag(I) complexes are also described.

Tandem Oxidative Derivatization of Nitrene Insertion Products for the Highly Diastereoselective Synthesis of 1,3-aminoalcohols.

Transition-metal-catalyzed nitrene insertion into tertiary C-H bonds located at stereogenic carbons often results in mixtures of diastereomeric products, especially if the reaction proceeds through a concerted pathway. In this communication, we report a solution to this problem that invokes a one-pot, silver-catalyzed C-H nitrene transfer reaction. Nitrene insertion is followed by facile oxidation of the amine to an imine and nucleophilic addition to furnish α-tertiary amine 1,3-aminoalcohol products in high diastereoselectivities. The silver catalyst, PhIO oxidant, and TEMPO additive are crucial to success in this unusual oxidation, which is proposed to occur via hydrogen-atom abstraction from pre-activation of the initial nitrene insertion product by additional oxidant.

Ligand-controlled, tunable silver-catalyzed C-H amination.

The development of readily tunable and regioselective C-H functionalization reactions that operate solely through catalyst control remains a challenge in modern organic synthesis. Herein, we report that simple silver catalysts supported by common nitrogenated ligands can be used to tune a nitrene transfer reaction between two different types of C-H bonds. The results reported herein represent the first example of ligand-controlled and site-selective silver-promoted C-H amination.

Tunable, chemoselective amination via silver catalysis.

Organic N-containing compounds, including amines, are essential components of many biologically and pharmaceutically important molecules. One strategy for introducing nitrogen into substrates with multiple reactive bonds is to insert a monovalent N fragment (nitrene or nitrenoid) into a C-H bond or add it directly to a C═C bond. However, it has been challenging to develop well-defined catalysts capable of promoting predictable and chemoselective aminations solely through reagent control. Herein, we report remarkable chemoselective aminations that employ a single metal (Ag) and a single ligand (phenanthroline) to promote either aziridination or C-H insertion by manipulating the coordination geometry of the active catalysts.