Amination Of Arenes Research Articles

Cu-α-diimine Compounds Encapsulated in Porous Materials as Catalysts for Electrophilic Amination of Aromatic C-H Bonds.

Electrophilic amination has emerged as a more environmentally benign approach to construct arene C-N bonds. However, heterogeneous catalysts remain largely unexplored in this area, even though their use could facilitate product purification and catalyst recovery. Here we investigate strategies to heterogenize a Cu(2,2'-bipyridine) catalyst for the amination of arenes lacking a directing group with hydroxylamine-O-sulfonic acid (HOSA). Besides immobilization of Cu on a metal-organic framework (MOF) or covalent organic framework (COF) with embedded 2,2'-bipyridines, a ship-in-a-bottle approach was followed in which the Cu complex is encapsulated in the pores of a zeolite. Recyclability and hot centrifugation tests show that zeolite Beta-entrapped CuII(2,2'-bipyridine) is superior in terms of stability. With N-methylmorpholine as a weakly coordinating, weak base, simple arenes, such as mesitylene, could be aminated with yields up to 59%, corresponding to a catalyst TON of 24. The zeolite could be used in three consecutive runs without a decrease in activity. Characterization of the catalyst by EPR and XAS showed that the active catalytic complex consisted of a site-isolated CuII species with one 2,2'-bipyridine ligand.

Photocatalytic C-H Activation and Amination of Arenes with Nonactivated N-Hydroxyphthalimides Involving Phosphine-Mediated N-O Bond Scission.

Herein, we reported a metal-free photoredox/phosphine-catalyzed C-H amination of arenes. This allows for concise synthesis of highly functionalized N-arylphthalimides from readily available N-hydroxyphthalimides directly, without the preparation of activated N-hydroxyphthalimide intermediates. Mechanistic studies reveal that the radical is produced via phosphine-mediated N-O bond scission.

Carbonyl-Assisted Iridium-Catalyzed C-H Amination Using 2,2,2-Trichloroethoxycarbonyl Azide.

The carbonyl-directed, mono C-H amination of arenes has been achieved using [Cp*Ir(III)Cl2]2 as the catalyst and 2,2,2-trichloroethoxycarbonyl (Troc) azide as an aminating reagent. The amination proceeds smoothly with a variety of arylcarbonyl compounds, including alkyl and vinyl arylketones, secondary and tertiary aryl amides, and acetyl indoles. The resulting ortho-TrocNH arylcarbonyl compounds are easily transformed to the corresponding free arylamines, aryl carbamates, or aryl ureas. Taking advantage of the electrophilic nature of both Troc and carbonyl groups in ortho-TrocNH arylcarbonyl compounds, the subsequent cyclization with dinucleophilic reagents has also been demonstrated. This provides an efficient strategy for the construction of aryl-fused N-heterocycles.

Mechanistic Investigations into Amination of Unactivated Arenes via Cation Radical Accelerated Nucleophilic Aromatic Substitution.

A mechanistic investigation into the amination of electron-neutral and electron-rich arenes using organic photoredox catalysis is presented. Kinetic and computational data support rate-limiting nucleophilic addition into an arene cation radical using both azole and primary amine nucleophiles. This finding is consistent with both fluoride and alkoxide nucleofuges, supporting a unified mechanistic picture using cation radical accelerated nucleophilic aromatic substitution (CRA-SNAr). Electrochemistry and time-resolved fluorescence spectroscopy confirm the key role solvents play in enabling selective arene oxidation in the presence of amines. The synthetic limitations of xanthylium salts are elucidated via photophysical studies. An alternative catalyst scaffold with improved turnover numbers is presented.

Nickel‐Catalysed Amination of Arenes and Heteroarenes

AbstractC(sp2)−N cross‐coupling is one of the most powerful transformations in organic synthesis to construct highly ubiquitous anilines and aniline derivatives. The dominance of Pd‐ and Cu‐based catalytic systems is evident in the field for a long time. However, Ni‐catalysed methodologies to achieve this reaction have grown gradually as sustainable alternatives in the last two decades. Recent reports of highly applicable photocatalytic and electrochemical amination strategies sufficiently enhanced the potential of Ni‐catalysed aminations. This review summarizes the advancement of this cross‐coupling reaction as a general and efficient method over the last 5 years.

Direct C–H amination reactions of arenes with N-hydroxyphthalimides catalyzed by cuprous bromide

An efficient Cu-catalyzed strategy for the direct C–H amination of arenes in high yields using N-hydroxyphthalimide as the amidyl radical precursor under air is reported. A possible mechanism is proposed that proceeds via a radical reaction in the presence of CuBr and triethyl phosphite.

Nitrogen-Centered Radicals in Functionalization of sp2 Systems: Generation, Reactivity, and Applications in Synthesis

The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp2 moieties without prefunctionalization, allowing for faster and more streamlined synthesis. This Review addresses the generation, reactivity, and application of NCRs, including, but not limited to, iminyl, aminyl, amidyl, and aminium species. Contributions from early discovery up to the most recent examples have been highlighted, covering radical initiation, thermolysis, photolysis, and, more recently, photoredox catalysis. Radical-mediated intermolecular amination of (hetero)arenes can occur with a variety of complex amine precursors, generating aniline derivatives, an important class of structures for drug discovery and development. Functionalization of olefins is achievable in high anti-Markovnikov regioselectivity and allows access to difunctionalized structures when the intermediate carbon radicals are trapped. Additionally, the reactivity of NCRs can be harnessed for the rapid construction of N-heterocycles such as pyrrolidines, phenanthridines, quinoxalines, and quinazolinones.

Facile synthesis of N-aryl phenothiazines and phenoxazines via Brønsted acid catalyzed C-H amination of arenes.

N-Aryl phenothiazines and phenoxazines are of significant importance in various disciplines throughout academia and industry. The conventional synthetic strategy for the construction of these structures centers on the transition-metal-catalyzed cross-coupling of aryl halides with phenothiazines or phenoxazines. Here we present an organocatalytic approach to access N-naphthyl phenothiazine and phenoxazine scaffolds through a straightforward C-H amination of arenes as enabled by an azo group. This reaction features operational simplicity, adequate substrate generality and excellent functional group compatibility. Notably, the efficiency of the catalyst could be perfectly preserved after 5 catalytic cycles.

The advent of electrophilic hydroxylamine-derived reagents for the direct preparation of unprotected amines.

Electrophilic aminating reagents have seen a renaissance in recent years as effective nitrogen sources for the synthesis of unprotected amino functionalities. Based on their reactivity, several noble and non-noble transition metal catalysed amination reactions have been developed. These include the aziridination and difunctionalisation of alkenes, the amination of arenes as well as the synthesis of aminated sulfur compounds. In particular, the use of hydroxylamine-derived (N–O) reagents, such as PONT (PivONH3OTf), has enabled the introduction of unprotected amino groups on various different feedstock compounds, such as alkenes, arenes and thiols. This strategy obviates undesired protecting-group manipulations and thus improves step efficiency and atom economy. Overall, this feature article gives a recent update on several reactions that have been unlocked by employing versatile hydroxylamine-derived aminating reagents, which facilitate the generation of unprotected primary, secondary and tertiary amino groups.

Regioselective Radical Arene Amination for the Concise Synthesis of ortho-Phenylenediamines.

The formation of arene C–N bonds directly from C–H bonds is of great importance and there has been rapid recent development of methods for achieving this through radical mechanisms, often involving reactive N-centered radicals. A major challenge associated with these advances is that of regiocontrol, with mixtures of regioisomeric products obtained in most protocols, limiting broader utility. We have designed a system that utilizes attractive noncovalent interactions between an anionic substrate and an incoming radical cation in order to guide the latter to the arene ortho position. The anionic substrate takes the form of a sulfamate-protected aniline and telescoped cleavage of the sulfamate group after amination leads directly to ortho-phenylenediamines, key building blocks for a range of medicinally relevant diazoles. Our method can deliver both free amines and monoalkyl amines allowing access to unsymmetrical, selectively monoalkylated benzimidazoles and benzotriazoles. As well as providing concise access to valuable ortho-phenylenediamines, this work demonstrates the potential for utilizing noncovalent interactions to control positional selectivity in radical reactions.

Post-Transition State Bifurcation in Iron-Catalyzed Arene Aminations

Recently, an iron-catalyzed meta-selective arene amination strategy was reported to show excellent regiocontrol, operational simplicity, and high atom and cost efficiencies. In this work, density functional theory (DFT) calculations and quasiclassical molecular dynamics (MD) simulations were carried out to study the mechanism of this reaction. Our computations revealed an unreported ambimodal attack of arene by hydroxylamine-O-sulfate, which forms not only σ-complex via electrophilic addition but also an aziridinium intermediate through energetically concerted electrophilic–nucleophilic additions. Quasiclassical trajectories suggest the orientation of the attacking NH2+ group with respect to arene control: (a) site selectivity of the post-transition state nucleophilic attack and (b) σ-complex/aziridinium selectivity on the bifurcating surface. The final amination products can be favorably generated via the ring opening of aziridinium intermediates, rearrangement of σ-complexes, and deprotonation of the resultant carbocations. Overall, our study illustrates a novel pathway in which an ambimodal reaction is incorporated into the standard SEAr mechanism.

Arene Amination Instead of Fluorination: Substitution Pattern Governs the Reactivity of Dialkoxybenzenes with Selectfluor.

Arene substitution patterns are well-known to affect the regioselectivity of a given transformation but not necessarily the type of reactivity. Herein, we report that the substitution pattern of alkoxyarenes dictates whether a putative one-electron or two-electron reaction predominates in reactions with Selectfluor. A series of amination products is presented, resulting from the single-electron oxidation of electron-rich arenes followed by direct C-H to C-N bond formation. We demonstrate the ability of this transformation to synthesize medicinally and biologically relevant nitrogen heterocycles. Lastly, this unusual "mechanistic switch" is probed with computational chemistry and competition experiments.

Synthesis of N-Alkyl Anilines from Arenes via Iron-Promoted Aromatic C-H Amination.

We report both an intermolecular C-H amination of arenes to access N-methylanilines and an intramolecular variant for the synthesis of tetrahydroquinolines. A newly developed, highly electrophilic aminating reagent was key for the direct synthesis of unprotected N-methylanilines from simple arenes. The reactions display a broad functional group tolerance and employ catalytic amounts of a benign iron salt under mild reaction conditions.

C-H Amidation and Amination of Arenes and Heteroarenes with Amide and Amine using Cu-MnO as a Reusable Catalyst under Mild Conditions.

An atom-economical and efficient route for the direct amidation and amination of aryl C-H bonds using our synthesized recyclable heterogeneous Cu-MnO catalyst is reported here. The direct C-H amidation was carried out using a simple amide without any preactivated coupling partner, and simple air was used as the sole oxidant. The reaction proceeds very smoothly with a broad range of substrates containing numerous functional groups in very good to excellent yields. Direct C-H aminations with a secondary amine were carried out under base-, ligand-, and external oxidant-free conditions in very good to excellent yields in very mild conditions. Both the amidation and amination can be scaled up on a gram scale with similar yields. The major advantage is that our catalyst is recyclable and reused several times without any significant loss of reactivity.

Cp*Ir(iii)- and Cp*Rh(iii)-catalyzed C(sp2)–H amination of arenes using thioethers as directing groups

A mild and selective Cp*Ir(iii)- and Cp*Rh(iii)-catalyzed direct C(sp2)–H amination of arenes and three types of nitrene precursor reagents is reported, with the assistance of a thioether directing group.

Chiral phosphoric acid catalyzed atroposelective C–H amination of arenes: mechanisms, origin and influencing factors of enantioselectivity

The amination reaction between azonaphthalene and carbazole catalyzed by chiral phosphoric acid was theoretically investigated, and the mechanism, origin and influencing factors of enantioselectivity were elaborated.

Iridium-Catalyzed C-H Amination of Weinreb Amides: A Facile Pathway toward Anilines and Quinazolin-2,4-diones.

C-H amination of arenes directed by weakly coordinating Weinreb amides has been achieved with an iridium catalyst and 2,2,2-trichloroethoxycarbonyl (Troc) azide as an aminating agent, providing a robust method of producing synthetic useful ortho-TrocNH aryl Weinreb amides. Taking advantage of the reactivity of Weinreb amide and Troc groups in the amination products, selective hydrolysis was achieved as an attractive process for the synthesis of ortho-NH2 aryl Weinreb amides, which are the building blocks useful in the synthesis of bioactive compounds, and cascade aminocyclization with primary amines was successful and provided an efficient pathway for the construction of quinazolin-2,4-diones, which are present in various alkaloids and natural products.

C-H Amination of Arenes with Hydroxylamine.

This Letter describes the development of a TiIII-mediated reaction for the C-H amination of arenes with hydroxylamine. This reaction is applied to a variety of electron-rich (hetero)arene substrates, including a series of natural products and pharmaceuticals. It offers the advantages of mild conditions (room temperature), fast reaction rates (<30 min), compatibility with ambient moisture and air, scalability, and the use of inexpensive commercial reagents.

Chiral Phosphoric Acid Catalyzed Atroposelective C-H Amination of Arenes.

N-arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C-H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition-metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C-N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N-arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N-arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal-catalyzed C-N cross-coupling, but also brings about opportunities for the exploitation of structurally diverse N-aryl atropisomers and OLED materials.

Chiral Phosphoric Acid Catalyzed Atroposelective C−H Amination of Arenes

AbstractN‐arylcarbazole structures are important because of their prevalence in natural products and functional OLED materials. C−H amination of arenes has been widely recognized as the most efficient approach to access these structures. Conventional strategies involving transition‐metal catalysts suffer from confined substrate generality and the requirement of exogenous oxidants. Organocatalytic enantioselective C–N chiral axis construction remains elusive. Presented here is the first organocatalytic strategy for the synthesis of novel axially chiral N‐arylcarbazole frameworks by the assembly of azonaphthalenes and carbazoles. This reaction accommodates broad substrate scope and gives atropisomeric N‐arylcarbazoles in good yields with excellent enantiocontrol. This approach not only offers an alternative to metal‐catalyzed C–N cross‐coupling, but also brings about opportunities for the exploitation of structurally diverse N‐aryl atropisomers and OLED materials.