Kwangmin Shin

Transition-Metal-Catalyzed C–N Bond Forming Reactions Using Organic Azides as the Nitrogen Source: A Journey for the Mild and Versatile C–H Amination

Owing to the prevalence of nitrogen-containing compounds in functional materials, natural products and important pharmaceutical agents, chemists have actively searched for the development of efficient and selective methodologies allowing for the facile construction of carbon-nitrogen bonds. While metal-catalyzed C-N cross-coupling reactions have been established as one of the most general protocols for C-N bond formation, these methods require starting materials equipped with functional groups such as (hetero)aryl halides or their equivalents, thus generating stoichiometric amounts of halide salts as byproducts. To address this aspect, a transition-metal-catalyzed direct C-H amination approach has emerged as a step- and atom-economical alternative to the conventional C-N cross-coupling reactions. However, despite the significant recent advances in metal-mediated direct C-H amination reactions, most available procedures need harsh conditions requiring stoichiometric external oxidants. In this context, we were curious to see whether a transition-metal-catalyzed mild C-H amination protocol could be achieved using organic azides as the amino source. We envisaged that a dual role of organic azides as an environmentally benign amino source and also as an internal oxidant via N-N2 bond cleavage would be key to develop efficient C-H amination reactions employing azides. An additional advantage of this approach was anticipated: that a sole byproduct is molecular nitrogen (N2) under the perspective catalytic conditions. This Account mainly describes our research efforts on the development of rhodium- and iridium-catalyzed direct C-H amination reactions with organic azides. Under our initially optimized Rh(III)-catalyzed amination conditions, not only sulfonyl azides but also aryl- and alkyl azides could be utilized as facile amino sources in reaction with various types of C(sp(2))-H bonds bearing such directing groups as pyridine, amide, or ketoxime. More recently, a new catalyst system using Ir(III) species was developed for the direct C-H amidation of arenes and alkenes with acyl azides under exceptionally mild conditions. As a natural extension, amidation of primary C(sp(3))-H bonds could also be realized on the basis of the superior activity of the Cp*Ir(III) catalyst. Mechanistic investigations revealed that a catalytic cycle is operated mainly in three stages: (i) chelation-assisted metallacycle formation via C-H bond cleavage; (ii) C-N bond formation through the in situ generation of a metal-nitrenoid intermediate followed by the insertion of an imido moiety to the metal carbon bond; (iii) product release via protodemetalation with the concomitant catalyst regeneration. In addition, this Account also summarizes the recent advances in the ruthenium- and cobalt-catalyzed amination reactions using organic azides, developed by our own and other groups. Comparative studies on the relative performance of those catalytic systems are briefly described.

Rhodium-Catalyzed Direct CH Amination of Benzamides with Aryl Azides: A Synthetic Route to Diarylamines†

No muss, no fuss: A rhodium-catalyzed direct intermolecular C-H amination of benzamides and ketoximes using aryl azides as the amine source has been developed. The reaction exhibits a broad substrate scope with excellent functional-group tolerance, requires no external oxidants, releases N(2) as the only by-product, and produces diarylamines in high yields.

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.

Ir(III)-Catalyzed Mild C–H Amidation of Arenes and Alkenes: An Efficient Usage of Acyl Azides as the Nitrogen Source

Reported herein is the development of the Ir(III)-catalyzed direct C-H amidation of arenes and alkenes using acyl azides as the nitrogen source. This procedure utilizes an in situ generated cationic half-sandwich iridium complex as a catalyst. The reaction takes place under very mild conditions, and a broad range of sp(2) C-H bonds of chelate group-containing arenes and olefins are smoothly amidated with acyl azides without the intervention of the Curtius rearrangement. Significantly, a wide range of reactants of aryl-, aliphatic-, and olefinic acyl azides were all efficiently amidated with high functional group tolerance. Using the developed approach, Z-enamides were readily accessed with a complete control of regio- and stereoselectivity. The developed direct amidation proceeds in the absence of external oxidants and releases molecular nitrogen as a single byproduct, thus offering an environmentally benign process with wide potential applications in organic synthesis and medicinal chemistry.

Copper-mediated sequential cyanation of aryl C-B and arene C-H bonds using ammonium iodide and DMF.

The cyanation of aromatic boronic acids, boronate esters, and borate salts was developed under copper-mediated oxidative conditions using ammonium iodide and DMF as the source of nitrogen and carbon atom of the cyano unit, respectively. The procedure was successfully extended to the cyanation of electron-rich benzenes, and regioselective introduction of a cyano group at the arene C-H bonds was also achieved. The observation that the reaction proceeds via a two-step process, initial iodination and then cyanation, led us to propose that ammonium iodide plays a dual role to provide iodide and nitrogen atom of the cyano moiety.

Iridium-Catalyzed C–H Amination with Anilines at Room Temperature: Compatibility of Iridacycles with External Oxidants

Described herein is the development of an iridium-catalyzed direct C-H amination of benzamides with anilines at room temperature, representing a unique example of an Ir catalyst system that is compatible with external oxidants. Mechanistic details, such as the isolation and characterization of key iridacycle intermediates, are also discussed.

Iridium(III)-Catalyzed Direct C-7 Amination of Indolines with Organic Azides

Iridium-catalyzed regioselective C-7 amination of indolines has been achieved with organic azides as a facile nitrogen source. The developed procedure is convenient to perform even at room temperature and applicable to a wide range of substrates with high catalytic activity. Various types of organic azides (sulfonyl, aryl, and alkyl derivatives) were all successfully reacted under the present conditions as the viable reactant. Furthermore, indoline substrates bearing easily removable N-protecting groups such as N-Boc or N-Cbz could readily be employed, highlighting the synthetic utility of this methodology.

Cp*Ir(III)-Catalyzed Mild and Broad C−H Arylation of Arenes and Alkenes with Aryldiazonium Salts Leading to the External Oxidant-Free Approach

Reported herein is the development of Cp*Ir(III)-catalyzed direct C-H arylation of arenes and alkenes using aryldiazonium tetrafluoroborates, the use of which as an aryl precursor and also as an oxidant via C-N2 bond cleavage was a key to success in achieving a mild and external oxidant-free procedure. Mechanistic experiments and DFT calculations revealed the turnover-limiting step to be closely related to the formation of an Ir(V)-aryl intermediate rather than the presupposed C-H cleavage. Under the developed mild arylation conditions, a wide range of benzamides were smoothly arylated. In addition, synthetic utility of the current C-H arylation procedure was also demonstrated successfully for the (Z)-selective arylation of enamides and C8-selective reaction of quinoline N-oxides.

Orthogonal Reactivity of Acyl Azides in C–H Activation: Dichotomy between C–C and C–N Amidations Based on Catalyst Systems

The dual reactivity of acyl azides was utilized successfully in C-H activation by the choice of catalyst systems: while selective C-C amidation was achieved under thermal Rh catalysis, a Ru catalyst was found to mediate direct C-N amidation also highly selectively. Investigations of the mechanistic dichotomy between two catalytic systems are also presented.

Rh(III)- and Ir(III)-Catalyzed Direct C–H Bond Transformations to Carbon–Heteroatom Bonds

The direct manipulation of C–H bonds is now a powerful tool in chemical synthesis. In achieving the current high standard of research progresses, Rh(III) and Ir(III) complexes played an important role to understand the nature of C–H bond activation. While numerous stoichiometric reactions of hydrocarbons with Rh(III) or Ir(III) complexes were scrutinized, their use in catalytic transformations has been relatively undeveloped until recently. Given their outstanding reactivity in C–H activation, they are highly promising candidates for inducing mild C–H functionalizations. In spite of a short development history, numerous contributions from leading research groups made big strides in highly efficient and selective C–H bond transformations for the C–C and C–heteroatom bond formation. In this report, we specifically focus on the Rh(III)- or Ir(III)-mediated direct C–H functionalizations for the C–heteroatom bond formation that is now a rapidly growing area. This report presents the current status of such catalytic systems including scope of substrates and coupling partners as well as brief mechanistic descriptions.