Enantioselective Access to ß-Amino Carbonyls via Ni-Catalyzed Formal Olefin Hydroamidation.

We herein describe a Ni-catalyzed formal hydroamidation of readily available α,ß-unsaturated carbonyl compounds to afford valuable chiral ß-amino acid derivatives (up to >99:1 e.r.) using dioxazolones as a robust amino source. A wide range of alkyl-substituted olefins conjugated to esters, amides, thioesters, and ketones were successfully amidated at the ß-position with excellent enantioselectivity for the first time. Combined experimental and computational mechanistic studies supported our working hypothesis that this unconventional ß-amidation of unsaturated carbonyl substrates can be attributed to the polar-matched migratory olefin insertion of an (amido)(Cl)NiII intermediate, in situ generated from the dioxazolone precursor.

Amidative ß-Scission of Alcohols Enabled by Dual Catalysis of Photoredox Proton-Coupled Electron Transfer and Inner-Sphere Ni-Nitrenoid Transfer.

The photoredox/Ni dual catalysis is an appealing strategy to enable unconventional C-heteroatom bond formation. While significant advances have been achieved using this system, intermolecular C(sp3)-N bond formation has been relatively underdeveloped due to the difficulty in C(sp3)-N reductive elimination. Herein, we present a new mechanistic approach that utilizes dioxazolones as the Ni(II)-nitrenoid precursor to capture carbon-centered radicals by merging proton-coupled electron transfer (PCET) with nickel catalysis, thus forming synthetically versatile N-alkyl amides using alcohols. Based on mechanistic investigations, the involvement of (κ2-N,O)Ni(II)-nitrenoid species was proposed to capture photoredox PCET-induced alkyl radicals, thereby playing a pivotal role to enable the C(sp3)-N bond formation.

Mechanistic Approach Toward the C4-Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen.

The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C-H pyridination of additional N-heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Photoinduced Group Transposition via Iridium-Nitrenoid Leading to Amidative Inner-Sphere Aryl Migration.

We herein report a fundamental mechanistic investigation into photochemical metal-nitrenoid generation and inner-sphere transposition reactivity using organometallic photoprecursors. By designing Cp*Ir(hydroxamate)(Ar) complexes, we induced photo-initiated ligand activation, allowing us to explore the amidative σ(Ir-aryl) migration reactivity. A combination of experimental mechanistic studies, femtosecond transient absorption spectroscopy, and density functional theory (DFT) calculations revealed that the metal-to-ligand charge transfer enables the σ(N-O) cleavage, followed by Ir-acylnitrenoid generation. The final inner-sphere σ(Ir-aryl) group migration results in a net amidative group transposition.

Iridium-Catalyzed Migratory Terminal C(sp3)-H Amidation of Heteroatom-Substituted Internal Alkenes via Olefin Chain Walking.

Hydroamination facilitated by metal hydride catalysis is an appealing synthetic approach to access valuable nitrogen-containing compounds from readily available unsaturated hydrocarbons. While high regioselectivity can be achieved usually for substrates bearing polar chelation groups, the reaction involving simple alkenes frequently provides nonselective outcomes. Herein, we report an iridium-catalyzed highly regioselective terminal C(sp3)-H amidation of internal alkenes utilizing dioxazolones as an amino source via olefin chain walking. Most notably, this mechanistic motif of double bond migration to the terminal position operates not only with dialkyl-substituted simple alkenes including styrenes but also with heteroatom-substituted olefins such as enol ethers, vinyl silanes, and vinyl borons, thus representing the first example of the terminal methyl amidation of the latter type of alkenes through a nondissociative chain walking process.

Regio- and Enantioselective Catalytic δ-C-H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer.

Controlling regio- and enantioselectivity in C-H functionalization reactions is of paramount importance due to their versatile synthetic utilities. Herein, we describe a new approach for the asymmetric δ-C(sp3)-H amidation catalysis of dioxazolones using a Cu(I) precursor with a chiral bisoxazoline ligand to access six-membered lactams with high to excellent regio- and enantioselectivity (up to >19:1 rr and >99:1 er). Combined experimental and computational mechanistic studies unveiled that the open-shell character of the postulated Cu-nitrenoids enables the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates. The synthetic utility of this asymmetric cyclization was demonstrated in the diastereoselective introduction of additional functional groups into the chiral δ-lactam skeleton as well as in the rapid access to biorelevant azacyclic compounds.

Iridium Acylnitrenoid-Initiated Biomimetic Cascade Cyclizations: Stereodefined Access to Polycyclic δ-Lactams.

Ring-fused azacyclic compounds are important building units in the synthesis of biorelevant natural products, pharmaceutical agents, and molecular materials. Herein, we present a new approach to these condensed azacycles by a biomimetic cascade cyclization of arylalkenyl dioxazolones. This cascade reaction was found to proceed with excellent stereoselectivity and a high functional group tolerance. The substrate scope of arylalkenyl dioxazolones turned out to be highly flexible and extendable to additional terminating subunits, such as heteroaryl and alkynyl moieties. This biomimetic cyclization was elucidated to be initiated by an intramolecular transfer of the in situ generated electrophilic Ir-acylnitrenoid to the tethered olefinic double bond, leading to a key N-acylaziridine intermediate, which is in turn reacted with pendant (hetero)arenes or alkynes in a highly regio- and stereoselective manner to produce ring-fused azacyclic compounds.

A Formal γ-C-H Functionalization of Carboxylic Acids Guided by Metal-Nitrenoids as an Unprecedented Mechanistic Motif.

Harnessing the key intermediates in metal-catalyzed reactions is one of the most essential strategies in the development of selective organic transformations. The nitrogen group transfer reactivity of metal-nitrenoids to ubiquitous C-H bonds allows for diverse C-N bond formation to furnish synthetically valuable aminated products. In this study, we present an unprecedented reactivity of iridium and ruthenium nitrenoids to generate remote carbocation intermediates, which subsequently undergo nucleophile incorporation, thus developing a formal γ-C-H functionalization of carboxylic acids. Mechanistic investigations elucidated a unique singlet metal-nitrenoid reactivity to initiate an abstraction of γ-hydride to form the carbocation intermediate that eventually reacts with a broad range of carbon, nitrogen, and oxygen nucleophiles, as well as biorelevant molecules. Alternatively, the same intermediate can lead to deprotonation to afford ß,γ-unsaturated amides in a less nucleophilic solvent.

On the Origin of Rh-Catalyzed Selective Ring-Opening Amidation of Substituted Cyclopropanols to Access ß2-Amino Ketones.

ß2-Amino carbonyls, an α-substituted ß-amino scaffold, hold a prominent place in the development of new pharmaceuticals and peptidomimetics. Herein, we report a highly efficient Rh-catalyzed ring-opening amidation of substituted cyclopropanols, which turned out to serve as a linchpin for the selective synthesis of ß2-amino ketones to outcompete the formation of ß3-isomers. Instead of the generally accepted rationale to consider steric factors for the ß2-selectivity, orbital interaction was elucidated to play a more critical role in the amidative ring-opening of cyclopropanols to generate the key Rh-C intermediate. Subsequent inner-sphere acylnitrene transfer was achieved in excellent efficiency (TON > 5000) by using readily accessible dioxazolones as the amino source to afford ß2-amino ketones with broad applicability.

Access to ß-Lactams via Iron-Catalyzed Olefin Oxyamidation Enabled by the π-Accepting Phthalocyanine Ligand.

Herein, we report the development of an iron-catalyzed olefin oxyamidation by utilizing tethered dioxazolones as the nitrenoid precursor to produce valuable ß-lactam scaffolds. Mechanistic studies revealed that a relatively strong π-accepting ability of the phthalocyanine ligand is critical in generating the key triplet iron-imidyl radical intermediate to enable the 4-exo-trig-lactamization with the incorporation of oxygen nucleophiles in high diastereoselectivity. This cyclization approach was readily extended to the highly efficient γ-lactam synthesis (TON > 300).

Endo-Selective Intramolecular Alkyne Hydroamidation Enabled by NiH Catalysis Incorporating Alkenylnickel Isomerization.

Intramolecular alkyne hydroamidation represents a straightforward approach for the access to synthetically valuable cyclic enamides. Despite some advances made in this realm, the ability to attain a precise regiocontrol still remains challenging, especially for endo cyclization that leads to six-membered and larger azacyclic rings. Herein, we report a NiH-catalyzed intramolecular hydroamidation of alkynyl dioxazolones that allows for an excellent endo selectivity, thus affording a range of six- to eight-membered endocyclic enamides with a broad scope. Mechanistic investigations revealed that Ni(I) catalysis is operative in the current system, proceeding via regioselective syn-hydronickelation, alkenylnickel E/Z isomerization, and Ni-centered inner-sphere nitrenoid transfer. In particular, the key alkenylnickel isomerization step, which previously lacked mechanistic understandings, was found to take place through the η2-vinyl transition state. The synthetic value of this protocol was demonstrated by diastereoselective modifications of the obtained endocyclic enamides to highly functionalized δ-lactam scaffolds.

Photoinduced Transition-Metal-Free Chan-Evans-Lam-Type Coupling: Dual Photoexcitation Mode with Halide Anion Effect.

Herein, we report a photoinduced transition-metal-free C(aryl)-N bond formation between 2,4,6-tri(aryl)boroxines or arylboronic acids as an aryl source and 1,4,2-dioxazol-5-ones (dioxazolones) as an amide coupling partner. Chloride anion, either generated in situ by photodissociation of chlorinated solvent molecules or added separately as an additive, was found to play a critical cooperative role, thereby giving convenient access to a wide range of synthetically versatile N-arylamides under mild photo conditions. The synthetic virtue of this transition-metal-free Chan-Evans-Lam-type coupling was demonstrated by large-scale reactions, synthesis of 15N-labeled arylamides, and applicability toward biologically relevant compounds. On the basis of mechanistic investigations, two distinctive photoexcitations are proposed to function in the current process, in which the first excitation involving chloro-boron adduct facilitates the transition-metal-free activation of dioxazolones by single electron transfer (SET), and the second one enables the otherwise-inoperative 1,2-aryl migration of the thus-formed N-chloroamido-borate adduct.

Chain Walking as a Strategy for Iridium-Catalyzed Migratory Amidation of Alkenyl Alcohols to Access α-Amino Ketones.

Catalytic carbon-nitrogen bond formation in hydrocarbons is an appealing synthetic tool to access valuable nitrogen-containing compounds. Although a number of synthetic approaches have been developed to construct a bifunctional α-amino carbonyl scaffold in this realm, installation of an amino functionality at the remote and unfunctionalized aliphatic sites remains underdeveloped. Here we present a tandem iridium catalysis that enables the redox-relay amidation of alkenyl alcohols via chain walking and metal-nitrenoid transfer, which eventually offers a new route to various α-amino ketones with excellent regioselectivity. The virtue of this transformation is that an unrefined isomeric mixture of alkenyl alcohols can be utilized as the readily available starting materials to lead to the regioconvergent amidation. Mechanistic investigations revealed that the reaction proceeds via a tandem process involving two key components of redox-relay chain walking and intermolecular nitrenoid transfer with the assistance of hydrogen bonding, thus representing the competence of Ir catalysis for the olefin migratory C-N coupling with high efficiency and exquisite selectivity.

C2-Selective, Functional-Group-Divergent Amination of Pyrimidines by Enthalpy-Controlled Nucleophilic Functionalization.

Synthesis of heteroaryl amines has been an important topic in organic chemistry because of their importance in small-molecule discovery. In particular, 2-aminopyrimidines represent a highly privileged structural motif that is prevalent in bioactive molecules, but a general strategy to introduce the pyrimidine C2-N bonds via direct functionalization is elusive. Here we describe a synthetic platform for site-selective C-H functionalization that affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products in situ. Mechanism-based reagent design allowed for the C2-selective amination of pyrimidines, opening the new scope of site-selective heteroaryl C-H functionalization. Our method is compatible with a broad range of pyrimidines with sensitive functional groups and can access complex aminopyrimidines with high selectivity.

Mechanism-Guided Development of Transition-Metal-Catalyzed C-N Bond-Forming Reactions Using Dioxazolones as the Versatile Amidating Source.

Catalytic reactions that construct carbon-nitrogen bonds are one of central themes in both synthetic and medicinal chemistry since the obtainable nitrogen-containing motifs are commonly encountered in natural products and have also seen a growing prominence as key structural features in marketed drugs and preclinical candidates. Pd-catalyzed cross-couplings, such as Buchwald-Hartwig amination, are at the forefront of such synthetic methods in practical settings. However, they require prefunctionalized substrates such as (hetero)aryl halides that must be prepared independently, often by multiple operations. One emerging way to circumvent these preparatory steps and directly convert ubiquitous C-H bonds into valuable C-N bonds is catalytic C-H amination, which allows synthetic chemists to devise shorter and more efficient retrosynthetic schemes. The past two decades have witnessed considerable progress in expanding the repertoire of this strategy, especially by identifying effective amino group precursors. In this context, dioxazolones have experienced a dramatic resurgence in recent years as a versatile nitrogen source in combination with transition-metal catalyst systems that facilitate decarboxylation to access key metal-acylnitrenoid intermediates. In addition to their high robustness and easy accessibility from abundant carboxylic acids, the unique reactivity of the transient intermediates in the amido group transfer has led to a fruitful journey for mild and efficient C-H amidation reactions.This Account summarizes our recent contributions to the development of C-N bond-forming reactions using dioxazolones as effective nitrenoid precursors, which are categorized into two subsets according to their mechanistic differences: inner- versus outer-sphere pathways. The first section describes how we could unveil the synthetic potential of dioxazolones in the realm of the inner-sphere C-H amidation, where we demonstrated that dioxazolones serve not only as manageable alternatives to acyl azides but also as highly efficient reagents to significantly reduce the catalyst loading and temperature. Taking advantage of the mild conditions in combination with group 9 Cp*M complexes (M = Rh, Ir, Co) or isoelectronic Ru species, we have dramatically expanded the accessible synthetic scope. Mechanistic investigations revealed that the putative metal-nitrenoid species is involved as a key intermediate during catalysis, which leads to facile C-N bond formation. On the basis of the mechanistic underpinning, we have succeeded in developing novel catalytic platforms that harness the intermediacy of metal-nitrenoids to explore C-H insertion chemistry via an outer-sphere pathway. Indeed, the tailored catalysts were capable of suppressing the competitive Curtius-type decomposition, thus granting access to versatile lactam products. We have further repurposed the catalytic systems upon modification of chelating ligands and also the identity of the transition metal to achieve three goals: (i) addressing selectivity issues to control the regio-, chemo-, and enantioselectivities, (ii) developing sustainable catalysis by first-low metals, and (iii) navigating chemical space for (di)functionalization of alkenes/alkynes. Together with our own research efforts, highlighted herein are some important relevant advances by other groups. We finally conclude with a brief overview with an eye toward further developments.

Photoinduced α-C-H Amination of Cyclic Amine Scaffolds Enabled by Polar-Radical Relay.

Herein, we report a polar-radical relay strategy for α-C-H amination of cyclic amines with N-chloro-N-sodio-carbamates. The relay is initiated by in situ generation of cyclic iminium intermediate using N-iodosuccinimide (NIS) oxidant as an initiator, which then operates through a series of polar (addition and elimination) and radical (homolysis, hydrogen- and halogen atom transfer) reactions to enable the challenging C-N bond formation in a controlled manner. A broad range of α-amino cyclic amines were readily accessed with excellent regioselectivity, and the superb applicability was further demonstrated by functionalization of biologically relevant compounds.

Cobalt-Nitrenoid Insertion-Mediated Amidative Carbon Rearrangement via Alkyl-Walking on Arenes.

We herein disclose the Cp*Co(III)(LX)-catalyzed amidative alkyl migration using 2,6-disubstituted phenyl azidoformates. Upon the cobalt-nitrenoid insertion toward the substituted ortho carbon, an arenium cationic species bearing a quaternary carbon is generated, and a subsequent alkyl migration process is suggested to occur through an unforeseen alkyl-walking mechanism. A quinolinol ligand of the cobalt catalyst system is proposed to facilitate the final product-releasing rearomatization process by serving as an internal base. This new mechanistic mode enabled both [1,2]- and [1,4]-alkyl rearrangements to allow the structural variation of N-heterocyclic compounds.

Enantioselective Access to Spirolactams via Nitrenoid Transfer Enabled by Enhanced Noncovalent Interactions.

Described herein is the Ir-catalyzed enantioselective access to chiral spirolactam products via the nitrenoid transfer to aromatic ipso-carbons. The key strategy for precise stereocontrol is to enhance the secondary attractive and repulsive interactions between the chiral catalyst and substrates by the introduction of a traceless O-silyl achiral auxiliary, thus effectively differentiating two prochiral faces of arenol-derived 1,4,2-dioxazol-5-one substrates.

Merging NiH Catalysis and Inner-Sphere Metal-Nitrenoid Transfer for Hydroamidation of Alkynes.

The formal hydroamination/hydroamidation utilizing metal hydride is an appealing synthetic tool for the construction of valuable nitrogen-containing compounds from unsaturated hydrocarbons. While significant advances have been made for the functionalizations of alkenes in this realm, the direct hydroamidation of alkynes remains rather limited due to the high feasibility of the key metal-alkenyl intermediate to choose other reaction pathways. Herein, we report a NiH-catalyzed strategy for the hydroamidation of alkynes with dioxazolones, which allows convenient access to synthetically useful secondary enamides in (E)-anti-Markovnikov or Markovnikov selectivity. The reaction is viable for both terminal and internal alkynes and is also tolerant with a range of subtle functional groups. With H2O found as an essential component for high catalyst turnovers, the involvement of inner-sphere nitrenoid transfer is proposed that outcompetes an undesired semireduction process, thus representing the first example to show the competence of Ni catalysis for metal-nitrenoid formation from dioxazolones.

Cobalt-Catalyzed Intermolecular C-H Amidation of Unactivated Alkanes.

Alkanes are an abundant and inexpensive source of hydrocarbons; thus, development of new methods to convert the hydrocarbon feedstocks to value-added chemicals is of high interest. However, it is challenging to achieve such transformation in a direct and selective manner mainly due to the intrinsic inertness of their C-H bonds. We herein report a tailored Cp*Co(III)(LX)-catalyzed efficient and site-selective intermolecular amidation of unactivated hydrocarbons including light alkanes. Electronic modulation of the cobalt complexes led to the enhanced amidation efficiency, and these effects were theoretically rationalized by the FMO analysis of presupposed cobalt nitrenoid species. Under the current cobalt protocol, a secondary C-H bond selectivity was observed in various nonactivated alkanes to reverse the intrinsic tertiary preference, which is attributed to the steric demands of the cobalt system that imposes difficulties in accessing tertiary C-H bonds. Experimental and computational studies suggested that the putative triplet Co nitrenoids are transferred to the C-H bonds of alkanes via a radical-like hydrogen abstraction pathway.