Yoonsu Park

Transition Metal-Catalyzed C–H Amination: Scope, Mechanism, and Applications

Catalytic transformation of ubiquitous C-H bonds into valuable C-N bonds offers an efficient synthetic approach to construct N-functionalized molecules. Over the last few decades, transition metal catalysis has been repeatedly proven to be a powerful tool for the direct conversion of cheap hydrocarbons to synthetically versatile amino-containing compounds. This Review comprehensively highlights recent advances in intra- and intermolecular C-H amination reactions utilizing late transition metal-based catalysts. Initial discovery, mechanistic study, and additional applications were categorized on the basis of the mechanistic scaffolds and types of reactions. Reactivity and selectivity of novel systems are discussed in three sections, with each being defined by a proposed working mode.

Mechanistic Studies of the Rhodium-Catalyzed Direct C–H Amination Reaction Using Azides as the Nitrogen Source

Direct C-H amination of arenes offers a straightforward route to aniline compounds without necessitating aryl (pseudo)halides as the starting materials. The recent development in this area, in particular in the metal-mediated transformations, is significant with regard to substrate scope and reaction conditions. Described herein are the mechanistic details on the Rh-catalyzed direct C-H amination reaction using organic azides as the amino source. The most important two stages were investigated especially in detail: (i) the formation of metal nitrenoid species and its subsequent insertion into a rhodacycle intermediate, and (ii) the regeneration of catalyst with concomitant release of products. It was revealed that a stepwise pathway involving a key Rh(V)-nitrenoid species that subsequently undergoes amido insertion is favored over a concerted C-N bond formation pathway. DFT calculations and kinetic studies suggest that the rate-limiting step in the current C-H amination reaction is more closely related to the formation of Rh-nitrenoid intermediate rather than the presupposed C-H activation process. The present study provides mechanistic details of the direct C-H amination reaction, which bears both aspects of the inner- and outer-sphere paths within a catalytic cycle.

Mechanistic Studies on the Rh(III)-Mediated Amido Transfer Process Leading to Robust C–H Amination with a New Type of Amidating Reagent

Mechanistic investigations on the Cp*Rh(III)-catalyzed direct C-H amination reaction led us to reveal the new utility of 1,4,2-dioxazol-5-one and its derivatives as highly efficient amino sources. Stepwise analysis on the C-N bond-forming process showed that competitive binding of rhodium metal center to amidating reagent or substrate is closely related to the reaction efficiency. In this line, 1,4,2-dioxazol-5-ones were observed to have a strong affinity to the cationic Rh(III) giving rise to dramatically improved amidation efficiency when compared to azides. Kinetics and computational studies suggested that the high amidating reactivity of 1,4,2-dioxazol-5-one can also be attributed to the low activation energy of an imido-insertion process in addition to the high coordination ability. While the characterization of a cationic Cp*Rh(III) complex bearing an amidating reagent was achieved, its facile conversion to an amido-inserted rhodacycle allowed for a clear picture on the C-H amidation process. The newly developed amidating reagent of 1,4,2-dioxazol-5-ones was applicable to a broad range of substrates with high functional group tolerance, releasing carbon dioxide as a single byproduct. Additional attractive features of this amino source, such as they are more convenient to prepare, store, and use when compared to the corresponding azides, take a step closer toward an ideal C-H amination protocol.

Rh(III)-Catalyzed Traceless Coupling of Quinoline N-Oxides with Internal Diarylalkynes

Quinoline N-oxides were found to undergo Cp*Rh(III)-catalyzed coupling with internal diarylalkynes to provide 8-functionalized quinolines through a cascade process that involves remote C-H bond activation, alkyne insertion, and intramolecular oxygen atom transfer. In this reaction, the N-oxide plays a dual role, acting as a traceless directing group as well as a source of oxygen atom, as confirmed by an (18)O-labeling experiment.

Regiodivergent Access to Five- and Six-Membered Benzo-Fused Lactams: Ru-Catalyzed Olefin Hydrocarbamoylation

We report herein a new strategy of the Ru-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of five- and six-membered benzo-fused lactams starting from N-(2-alkenylphenyl)formamides. Using a combined catalyst of Ru3(CO)12/Bu4NI in DMSO/toluene cosolvent (catalytic system A), a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yield. When the reaction was conducted in the absence of halide additives in DMA/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yield via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. It was found that while the selective cyclization was controlled primarily by the choice of catalytic systems employed, it was also greatly influenced by the structural nature of substrates. A halide-bridged trinuclear complex [Ru3(CO)10(μ2-I)](-) is postulated to be an active species in the catalytic system A. Two reaction pathways are proposed, in which the Ru-catalyzed oxidative addition of formyl C-H or N-H bond initiates the subsequent cyclization processes.

Why is the Ir(III)-Mediated Amido Transfer Much Faster Than the Rh(III)-Mediated Reaction? A Combined Experimental and Computational Study

The mechanism of the Ir(III)- and Rh(III)-mediated C-N coupling reaction, which is the key step for catalytic C-H amidation, was investigated in an integrated experimental and computational study. Novel amidating agents containing a 1,4,2-dioxazole moiety allowed for designing a stoichiometric version of the catalytic C-N coupling reaction and giving access to reaction intermediates that reveal details about each step of the reaction. Both DFT and kinetic studies strongly point to a mechanism where the M(III)-complex engages the amidating agent via oxidative coupling to form a M(V)-imido intermediate, which then undergoes migratory insertion to afford the final C-N coupled product. For the first time, the stoichiometric versions of the Ir- and Rh-mediated amidation reaction were compared systematically to each other. Iridium reacts much faster than rhodium (∼1100 times at 6.7 °C) with the oxidative coupling being so fast that the activation of the initial Ir(III)-complex becomes rate-limiting. In the case of Rh, the Rh-imido formation step is rate-limiting. These qualitative differences stem from a unique bonding feature of the dioxazole moiety and the relativistic contraction of the Ir(V), which affords much more favorable energetics for the reaction. For the first time, a full molecular orbital analysis is presented to rationalize and explain the electronic features that govern this behavior.

Mechanism of Rh-Catalyzed Oxidative Cyclizations: Closed versus Open Shell Pathways

A conceptual theory for analyzing and understanding oxidative addition reactions that form the cornerstone of many transition metal mediated catalytic cycles that activate C-C and C-H bonds, for example, was developed. The cleavage of the σ- or π-bond in the organic substrate can be envisioned to follow a closed or an open shell formalism, which is matched by a corresponding electronic structure at the metal center of the catalyst. Whereas the assignment of one or the other mechanistic scenario appears formal and equivalent at first sight, they should be recognized as different classes of reactions, because they lead to different reaction optimization and control strategies. The closed-shell mechanism involves heterolytic bond cleavages, which give rise to highly localized charges to form at the transition state. In the open-shell pathway, bonds are broken homolytically avoiding localized charges to accumulate on molecular fragments at the transition states. As a result, functional groups with inductive effects may exert a substantial influence on the energies of the intermediate and transition states, whereas no such effect is expected if the mechanism proceeds through the open-shell mechanism. If these functional groups are placed in a way that opens an electronic communication pathway to the molecular sites where charges accumulate, for example, using hyperconjugation, electron donating groups may stabilize a positive charge at that site. An instructive example is discussed, where this stereoelectronic effect allowed for rendering the oxidative addition diastereoselective. No such control is possible, however, when the open-shell reaction pathway is followed, because the inductive effects of functional groups have little to no effect on the stabilities of radical-like substrate states that are encountered when the bonds are broken in a homolytic fashion. Whether the closed-shell or open-shell mechanism for oxidative addition is followed is determined by the ordering of the d-orbital dominated frontier orbitals. If the highest occupied molecular orbital (HOMO) is oriented in space in such a way that will give the organic substrate easy access to the valence electron pair, the closed-shell mechanism can be followed. If the shape and orientation of the HOMO is not appropriate, however, an alternative pathway involving singlet excited states of the metal that will invoke the matching radicaloid cleavage of the organic substrate will dominate the oxidative addition. This novel paradigm for formally analyzing and understanding oxidative additions provides a new way of systematically understanding and planning catalytic reactions, as demonstrated by the in silico design of room-temperature Pauson-Khand reactions.

Selective formation of γ-lactams via C–H amidation enabled by tailored iridium catalysts

Guiding nitrenes away from a migration Nitrogen conventionally shares its electrons in three bonds with one or more partners. A singly bonded nitrogen, or nitrene, is exceptionally reactive and can insert itself into normally inert C–H bonds. If the nitrene forms next to a carbonyl center, though, it tends to react with the C–C bond on the other side instead. Hong et al. used theory to guide the design of an iridium catalyst that inhibits this rearrangement, steering the nitrene toward C–H insertion to form a variety of useful lactam rings. Science, this issue p. 1016 Theory guides design of a catalyst to cyclize amides via a nitrene intermediate otherwise prone to a competing rearrangement. Intramolecular insertion of metal nitrenes into carbon-hydrogen bonds to form γ-lactam rings has traditionally been hindered by competing isocyanate formation. We report the application of theory and mechanism studies to optimize a class of pentamethylcyclopentadienyl iridium(III) catalysts for suppression of this competing pathway. Modulation of the stereoelectronic properties of the auxiliary bidentate ligands to be more electron-donating was suggested by density functional theory calculations to lower the C–H insertion barrier favoring the desired reaction. These catalysts transform a wide range of 1,4,2-dioxazol-5-ones, carbonylnitrene precursors easily accessible from carboxylic acids, into the corresponding γ-lactams via sp3 and sp2 C–H amidation with exceptional selectivity. The power of this method was further demonstrated by the successful late-stage functionalization of amino acid derivatives and other bioactive molecules.

Mechanism-Driven Approach To Develop a Mild and Versatile C−H Amidation through IrIII Catalysis

Described herein is a mechanism-based approach to develop a versatile C-H amidation protocol under IrIII catalysis. Reaction kinetics of a key C-N coupling step with acyl azide and 1,4,2-dioxazol-5-one led us to conclude that dioxazolones are much more efficient in mediating the formation of a carbon-nitrogen bond from an iridacyclic intermediate. Computational analysis revealed that the origin of higher reactivity is asynchronous decarboxylation motion, which may facilitate the formation of Ir-imido species. Importantly, stoichiometric reactivity was successfully translated into catalytic activity with a broad range of substrates (18 different types), many of which are regarded as challenging to functionalize. Application of the new method enables late-stage functionalization of drug molecules.

Iridium-catalysed arylation of C–H bonds enabled by oxidatively induced reductive elimination

Direct arylation of C–H bonds is in principle a powerful way of preparing value-added molecules that contain carbon–aryl fragments. Unfortunately, currently available synthetic methods are not sufficiently effective to be practical alternatives to conventional cross-coupling reactions. We propose that the main problem lies in the late portion of the catalytic cycle where reductive elimination gives the desired carbon–aryl bond. Accordingly, we have developed a strategy where the Ir(III) centre of the key intermediate is first oxidized to Ir(IV). Density functional theory calculations indicate that the barrier to reductive elimination is reduced by nearly 19 kcal mol–1 for this oxidized complex compared with that of its Ir(III) counterpart. Various experiments confirm this prediction, affording a new methodology capable of directly arylating C–H bonds at room temperature with a broad substrate scope and in good yields. This work highlights how the oxidation states of intermediates can be targeted deliberately to catalyse an otherwise impossible reaction. The direct arylation of C–H bonds is an attractive synthetic step, but the reductive elimination of an organometallic catalyst carrying the desired C–H and aryl functionalities has remained challenging. Now, this step has been achieved by first oxidizing the iridium centre of the catalyst, which facilitates the arylation of arene C–H bonds of a range of substrates.