Racemization is considered to be an intrinsic stereochemical feature of free radical chemistry as can be seen in traditional radical halogenation reactions of optically active tertiary C-H bonds. If the facile process of radical racemization could be effectively combined with an ensuing step of bond formation in an enantioselective fashion, then it would give rise to deracemizative functionalization of racemic tertiary C-H bonds for stereoselective construction of chiral molecules bearing quaternary stereocenters. As a demonstration of this unique potential in radical chemistry, we herein report that metalloradical catalysis can be successfully applied to devise Co(II)-based catalytic system for enantioconvergent radical amination of racemic tertiary C(sp3)-H bonds. The key to the success of the radical process is the development of Co(II)-based metalloradical catalyst with fitting steric, electronic, and chiral environments of the D2-symmetric chiral amidoporphyrin as the supporting ligand. The existence of optimal reaction temperature is recognized as an important factor in the realization of the enantioconvergent radical process. Supported by an optimized chiral ligand, the Co(II)-based metalloradical system can effectively catalyze the enantioconvergent 1,6-amination of racemic tertiary C(sp3)-H bonds at the optimal temperature, affording chiral α-tertiary amines in excellent yields with high enantiocontrol of the newly created quaternary stereocenters. Systematic studies, including experiments utilizing optically active deuterium-labeled C-H substrates as a model system, shed light on the underlying mechanistic details of this new catalytic process for enantioconvergent radical C-H amination. The remarkable power to create quaternary stereocenters bearing multiple functionalities from ubiquitous C-H bonds, as showcased with stereoselective construction of bicyclic N-heterocycles, opens the door for future synthetic applications of this new radical technology.

Enantioconvergent Amination of Racemic Tertiary C-H Bonds.

N-N linkages are found in many natural compounds and endow fascinating structural and functional properties. In comparison to the myriad methods for the construction of C-N bonds, chemistry for N-N coupling, especially in an intermolecular fashion, remains underdeveloped. Here, we report a nitrene-mediated intermolecular N-N coupling of dioxazolones and arylamines under iridium or iron catalysis. These reactions offer a simple and efficient method for the synthesis of various hydrazides from readily available carboxylic acid and amine precursors. Although the Ir-catalysed conditions usually give higher N-N coupling yield than the Fe-catalysed conditions, the reactions of sterically more demanding dioxazolones derived from α-substituted carboxylic acids work much better under the Fe-catalysed conditions. Mechanistic studies revealed that the nitrogen atom of Ir acyl nitrene intermediates has strong electrophilicity and can undergo nucleophilic attack with arylamines with the assistance of Cl···HN hydrogen bonding to form the N-N bond with high efficiency and chemoselectivity.

Nitrene-mediated intermolecular N-N coupling for efficient synthesis of hydrazides.

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-...

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

The transition-metal-catalyzed nitrenoid transfer reaction is one of the most attractive methods for installing a new C-N bond into diverse reactive units. While numerous selective aminations are known, understanding complex structural effects of the key intermediates on the observed chemoselectivity is still elusive in most cases. Herein, we report a designing approach to enable selective nitrenoid transfer leading to sp2 spirocyclization and sp3 C-H insertion by cooperative two-point modulation of ligands in the CpXIr(III)(κ2-chelate) catalyst system. Computational analysis led us to interrogate structural motifs that can be attributed to the desired mechanistic dichotomy. Multivariate linear regression analysis on the perturbation on the η5-cyclopentadienyl ancillary (CpX) and LX coligand, wherein we prepared over than 40 new catalysts for screening, allowed for construction of an intuitive yet robust statistical model that predicts a large set of chemoselective outcomes, implying that the catalysts' structural effects play a critical role on the chemoselective nitrenoid transfer. On the basis of this quantitative analysis, a new catalytic platform is now established for the unique lactam formation, leading to the unprecedented chemoselective reactivity (up to >20:1) toward a diverse array of competing sites, such as tertiary, secondary, benzylic, allylic C-H bonds, and aromatic π system.

Quantitative Analysis on Two-Point Ligand Modulation of Iridium Catalysts for Chemodivergent C–H Amidation

Herein, we report the development of a tailored cobalt catalyst system of Cp*Co(III)(LX) toward intramolecular C–H nitrene insertion of azidoformates to afford cyclic carbamates The cobalt complex

Versatile Cp*Co(III)(LX) Catalyst System for Selective Intramolecular C-H Amidation Reactions.

Carbon–hydrogen bond functionalization methods are important tools for efficiently upgrading simple precursors to more valuable compounds. The ubiquity of amines in pharmaceuticals and natural products has led to considerable interest in strategies for the selective amidation of C–H bonds in a tunable manner. An ongoing challenge involves achieving control in situations where targeted bonds have varying bond strengths or similar steric/electronic environments. Herein, we report two complementary silver catalysts that are capable of selecting between β- or γ-C–H bonds that reside in similar steric/electronic environments, overriding a reaction at a weaker C–H bond in favour of a stronger one and activating primary C–H bonds. The mild conditions, low cost of silver, good yields and easy purification make this approach ideal for late-stage functionalizations to furnish valuable 1,2- and 1,3-aminoalcohols from easily prepared carbamate esters. One of the major challenges in C–H functionalization is to achieve selectivity when multiple bonds of similar reactivity are present. Now, a method to selectively amidate sterically and electronically similar β- or γ-C–H bonds that utilize different silver catalysts is reported, giving access to valuable 1,2- and 1,3-aminoalcohols.

Tunable catalyst-controlled syntheses of β- and γ-amino alcohols enabled by silver-catalysed nitrene transfer

Nitrene transfer (NT) is a convenient strategy to directly transform C–H bonds into more valuable C–N bonds and exciting advances have been made to improve selectivity. Our work in silver-based NT has shown the unique ability of this metal to enable tunable chemo-, site-, and stereoselective reactions using simple N-dentate ligand scaffolds. Manipulation of the coordination environment and noncovalent interactions around the silver center furnish unprecedented catalyst control in selective NT and provide insights for further improvements in the field. 1 	Introduction 1.1 	Strategies for Nitrene Transfer 1.2 	Brief Summary of Chemocatalyzed Nitrene Transfer 1.3 	Focus of this Account 2 	Challenges in Chemocatalyzed Nitrene Transfer 2.1 	Reactivity Challenges 2.2 	Selectivity Challenges 2.3 	Chemoselective Nitrene Transfer 2.4 	Site-Selective Nitrene Transfer 2.5 	Enantioselective Nitrene Transfer 3 	Summary and Perspective 3.1 	Future Opportunities and Challenges 3.2 	Conclusion

Taming Nitrene Reactivity with Silver Catalysts

Scope and Mechanistic Investigations of Pd-Catalyzed Coupling/Cyclization and Cycloisomerization of Allenyl Malonates

A highly stereoselective Pd-catalyzed Heck-type reaction of allenes in which the stereochemistry of both olefins is set simultaneously was developed. The ligand CyJohnPhos was crucial to achieving stereoselectivity, while minimizing isomerization of the starting material through hydropalladation. The stereodetermining factors were proposed to be A1,3 strain between the catalyst and allene substituent, which influences the σ-π-σ equilibrium of the coupled allene intermediate, as well as eclipsing interactions of R groups in the β-hydride elimination. Good functional group tolerance and stereoselectivities for formation of the Z,E isomer were demonstrated. The methodology was further expanded to include the regioselective formation of 2,4-dienoates and 2,4-dienamides with a variety of substitution patterns, albeit in reduced stereoselectivities favoring the E,E isomer. A plausible mechanism is proposed to account for the observed selectivities and substituent effects.

Pd-Catalyzed Heck-Type Reactions of Allenes for Stereoselective Syntheses of Substituted 1,3-Dienes.

Metal-catalyzed allene cycloisomerizations provide rapid entry into five-membered carbocyclic frameworks, a common motif in natural products and pharmaceuticals. While both Au(I) and Pd(0)-catalyzed allene cycloisomerizations give 5-endo-dig cyclization, Pd prefers the syn diastereomer in contrast to the anti isomer observed with Au. The change in stereoselectivity is proposed to arise from buildup of A1,3 strain during the key carbopalladation step to furnish the cycloisomerized products in moderate to good dr with yields comparable to Au(I) catalysts.

Logan E. Vine

Papers

Tunable catalyst-controlled syntheses of β- and γ-amino alcohols enabled by silver-catalysed nitrene transfer

Taming Nitrene Reactivity with Silver Catalysts

Scope and Mechanistic Investigations of Pd-Catalyzed Coupling/Cyclization and Cycloisomerization of Allenyl Malonates

Pd-Catalyzed Heck-Type Reactions of Allenes for Stereoselective Syntheses of Substituted 1,3-Dienes.

Stereodivergent Metal-Catalyzed Allene Cycloisomerizations.