Iridium Catalysis Research Articles

Thiocarbonyl‐Directed Iridium‐Catalyzed C−H Silylation of Indoles and Pyrroles with Hydrosilanes

AbstractHerein, hydrogen‐acceptor‐free C2‐selective iridium‐catalyzed C−H silylation of indoles and pyrroles with hydrosilanes via C(sp2)−H bond activation to generate the desired silylated products is presented. The developed protocol allows for the C−H silylation of a wide range of functionalized indoles with monohydrosilanes under iridium catalysis. Significantly, this process represents a rare silylation of C−H bonds using S‐directing groups.

Stereocontrolled Hydrogenation of Conjugated Enones to Alcohols via Dual Iridium-Catalysis.

The concept of dual catalysis is an emerging area holding high potential in terms of preparative efficiency, yet faces severe challenges in compatibility of reaction conditions and interference of catalysts. The transition-metal catalyzed stereoselective hydrogenation of olefins and ketones typically proceeds under different reaction conditions and/or uses a different reductant. As a result, these two types of hydrogenations can normally not be performed in the same pot. Herein, the stereocontrolled hydrogenation of enones to saturated alcohols is described, enabled by orthogonal dual iridium catalysis, using molecular hydrogen for both reductions. In this one-pot procedure, N,P-iridium catalysts (hydrogenation active towards olefins) and NHC,P-iridium catalysts (hydrogenation active towards ketones) operated independently of one another allowing the construction of two contiguous stereogenic centers up to 99% ee, 99/1 d.r. Ultimately, by simple selection of the chirality of either ligands, the enone could be efficiently reducedto allfour stereoisomers of the saturated alcohol in equally high stereopurity. This degree of stereocontrol for the synthesis of different stereoisomers by dual transition-metal catalyzed hydrogenation was previously not attained. The generality in substituted enones (alkyl, aryl, heteroaryl) demonstrate the wide applicability of this concept.

Stereocontrolled Hydrogenation of Conjugated Enones to Alcohols via Dual Iridium‐Catalysis

The concept of dual catalysis is an emerging area holding high potential in terms of preparative efficiency, yet faces severe challenges in compatibility of reaction conditions and interference of catalysts. The transition‐metal catalyzed stereoselective hydrogenation of olefins and ketones typically proceeds under different reaction conditions and/or uses a different reductant. As a result, these two types of hydrogenations can normally not be performed in the same pot. Herein, the stereocontrolled hydrogenation of enones to saturated alcohols is described, enabled by orthogonal dual iridium catalysis, using molecular hydrogen for both reductions. In this one‐pot procedure, N,P‐iridium catalysts (hydrogenation active towards olefins) and NHC,P‐iridium catalysts (hydrogenation active towards ketones) operated independently of one another allowing the construction of two contiguous stereogenic centers up to 99% ee, 99/1 d.r. Ultimately, by simple selection of the chirality of either ligands, the enone could be efficiently reduced to all four stereoisomers of the saturated alcohol in equally high stereopurity. This degree of stereocontrol for the synthesis of different stereoisomers by dual transition‐metal catalyzed hydrogenation was previously not attained. The generality in substituted enones (alkyl, aryl, heteroaryl) demonstrate the wide applicability of this concept.

Sterically Controlled Lewis Acid−Base Interaction Toward para‐Selective Borylation of Aromatic Aldimines and Benzylamines

AbstractSite‐selective C−H bond functionalization of arenes at the para position remains extremely challenging primarily due to its relative inaccessibility from the catalytic site. As a consequence, it is significantly restricted to limited molecular scaffolds. Herein, we report a method for the para‐C−H borylation of aromatic aldimines and benzylamines using commercially available ligands under iridium catalysis. The established method displays excellent para selectivity for variously substituted aromatic aldimines, benzylamines and bioactive molecules. Based on several control experiments, it is proposed that a Lewis acid−base interaction between the nitrogen and boron functionality guides the para selectivity via a steric shield for the aromatic aldimines, where Bpin acts as a transient directing group. However, the steric shield of the in situ generated N−Bpin moiety controlled the overall selectivity for the para borylation of benzylamines.

Molecular Iridium Catalyzed Electrochemical Formic Acid Oxidation: Mechanistic Insights.

Electrochemical formic acid oxidation reaction (FAOR) is a pivotal model for understanding organic fuel oxidation and advancing sustainable energy technologies. Here, we present mechanistic insights into a novel molecular-like iridium catalyst (Ir-N4-C) for FAOR. Our studies reveal that isolated sites facilitate a preferential dehydrogenation pathway, circumventing catalyst poisoning and exhibiting high inherent activity. In situ spectroscopic analyses elucidate that weakly adsorbed intermediates mediate the FAOR and are dynamically regulated by potential-dependent redox transitions. Theoretical and experimental investigations demonstrate a parallel mechanism involving two key intermediates with distinct pH and potential sensitivities. The rate-determining step is identified as the adsorption of formate via coupled or sequential proton-electron transfer, which aligns well with the observed kinetic properties, pH dependence, and hydrogen/deuterium isotope effects in experiments. These findings provide valuable insights into the reaction mechanism of FAOR, advancing our understanding at the molecular level and potentially guiding the design of efficient catalysts for fuel cells and electrolyzers.

Sterically Controlled Lewis Acid-Base Interaction Toward para-Selective Borylation of Aromatic Aldimines and Benzylamines.

Site-selective C-H bond functionalization of arenes at the para position remains extremely challenging primarily due to its relative inaccessibility from the catalytic site. As a consequence, it is significantly restricted to limited molecular scaffolds. Herein, we report a method for the para-C-H borylation of aromatic aldimines and benzylamines using commercially available ligands under iridium catalysis. The established method displays excellent para selectivity for variously substituted aromatic aldimines, benzylamines and bioactive molecules. Based on several control experiments, it is proposed that a Lewis acid-base interaction between the nitrogen and boron functionality guides the para selectivity via a steric shield for the aromatic aldimines, where Bpin acts as a transient directing group. However, the steric shield of the in situ generated N-Bpin moiety controlled the overall selectivity for the para borylation of benzylamines.

Benzothiazole-Directed Enantioselective Borylation of Secondary Benzylic C–H Bonds Using Iridium Catalysis

AbstractReported here is the iridium-catalyzed regio- and enantio­selective secondary benzylic C–H borylation using benzothiazole as the directing group. Various monosubstituted 2-arylalkylbenzo[d]thiazole were well-tolerated, affording the corresponding products in moderate to good yields with good enantioselectivity. The C–B bond in one boryl­ated product could undergo stereospecific transformations to form a series of C–C and C–heteroatom bonds.

Directed C–H Alkylation of Heterobiaryls via Iridium Catalysis

Directed C–H Alkylation of Heterobiaryls via Iridium Catalysis

Asymmetric and Chemoselective Iridium Catalyzed Hydrogenation of Conjugated Unsaturated Oxime Ethers.

Research on the chemoselective metal-catalyzed hydrogenation of conjugated π-systems has mostly been focussed on enones. Herein, we communicate the understudied asymmetric hydrogenation of enimines catalyzed by N,P-iridium complexes and chemoselective toward the alkene. A number of enoxime ethers underwent hydrogenation smoothly to yield the desired products in high yield and stereopurity (up to 99 % yield, up to 99 % ee). No hydrogenation of the C=N π-bond was observed under the applied reaction conditions (20 bar H2, rt, DCM). It was demonstrated that the chiral oxime ether could be hydrolyzed into the ketone with complete preservation of the installed stereogenity at the α-carbon. At last, a binding mode of the substrate to the active iridium catalyst and the consequence for the stereoselective outcome was proposed.

Cyclometalated half‐sandwich iridium complexes: Synthesis, characterization, and catalytic activity in preparation of esters from halides by using formate as both CO source and coupling partner

A highly efficient carbonylation of aryl halides using half‐sandwich iridium catalysis was developed, providing a new avenue for synthesizing carboxylic ester derivatives and yielding consistently impressive results. These iridium complexes demonstrated remarkable catalytic performance in the coupling reaction using phenyl formate derivatives as the source of CO, phenol, and aryl halides as the starting material in the presence of air and possessed good air and moisture stability properties. Ester products with different substituents were synthesized at low reaction temperatures without the need for an inert atmosphere, leading to high yields. The broad substrate scope, impressive catalytic activity, and mild reaction conditions suggest promising industrial applications for this catalytic system. The desired metal complexes 1–4 have been well proven by attenuated total reflectance‐Fourier transform infrared (ATR‐FTIR), nuclear magnetic resonance (NMR), and elemental analysis (EA). The molecular structure of the cyclometalated iridium complexes 2 and 3 was proven through X‐ray crystallography. Additionally, the possible mechanism of this Ir‐catalyzed process is further supported by the density functional theory (DFT) study.

Iridium‐Catalysed C(sp3)−H Activation and Hydrogen Isotope Exchange via Nitrogen‐Based Carbonyl Directing Groups

AbstractGrowing interest in improved structural diversity within the pharmaceutical industry has led to a focus on more sp3‐rich drug frameworks. Meanwhile, spiralling pharmaceutical research and development costs continue to require expedited adsorption, distribution, metabolism, excretion, and toxicity studies, which are heavily reliant on the use of molecules incorporating deuterium and tritium. Herein, we report an iridium catalyzed C(sp3)−H activation and hydrogen isotope exchange (HIE) methodology capable of utilizing pharmaceutically ubiquitous nitrogen‐based carbonyl directing groups. High levels of deuterium incorporation (>80% in 37 of the examples) are demonstrated across a range of substrates (5‐, 6‐, and 7‐membered lactams, cyclic carbamates and ureas, acyclic amides), with tolerance of a range of common functional groups (aryl, alkoxy, halogen, ester, alcohol, sulfonamide) and predictable regioselectivity. The applicability of this methodology was demonstrated with up to 98% deuterium incorporation observed in a range of challenging bioactive molecules such as Nefiracetam, Praziquantel, and Unifiram. Density functional theory has provided mechanistic insight into the C−H activation and HIE at both the expected site of incorporation and an unexpected aryl labelling via a 7‐membered metallocyclic intermediate.

Simultaneous Stereoinvertive and Stereoselective C(sp3)-C(sp3) Cross-Coupling of Boronic Esters and Allylic Carbonates.

With increasing interest in constructing more three-dimensional entities, there has been growing interest in cross-coupling reactions that forge C(sp3)-C(sp3) bonds, which leads to additional challenges as it is not just a more difficult bond to construct but issues of stereocontrol also arise. Herein, we report the stereocontrolled cross-coupling of enantioenriched boronic esters with racemic allylic carbonates enabled by iridium catalysis, leading to the formation of C(sp3)-C(sp3) bonds with single or vicinal stereogenic centers. The method shows broad substrate scope, enabling primary, secondary, and even tertiary boronic esters to be employed, and can be used to prepare any of the four possible stereoisomers of a coupled product with vicinal chiral centers. The new method, which combines the simultaneous enantiospecific reaction of a chiral nucleophile with the enantioselective reaction of a chiral electrophile in a single process, offers a solution for stereodivergent cross-coupling of two C(sp3) fragments.

Asymmetric α-C(sp3)–H Allylic Alkylation of Primary Alkylamines by Merging Iridium and Ketone Catalysis

Asymmetric α-C(sp3)–H Allylic Alkylation of Primary Alkylamines by Merging Iridium and Ketone Catalysis

Asymmetric Deoxygenative Functionalization of Secondary Amides with Vinylpyridines Enabled by a Triple Iridium-Photoredox-Chiral Phosphoric Acid System.

An enantioselective deoxygenative functionalization of secondary amides with vinylpridines is developed by merging relay iridium catalysis and cooperative photoredox-chiral Brønsted acid catalysis, affording a series of valuable chiral amines in moderate to good yields with good enantioselectivities. The intriguing multiple catalytic system invoking triple-catalysis was found to be the key to the success of the current reactions, which may stimulate further development of catalytic methodologies for asymmetric deoxygenative transformations of amides.

Iridium-catalyzed reduction of o-hydroxyl phenyl enaminones for the synthesis of propiophenones and their application in 3-methyl chromone synthesis.

A method of reducing o-hydroxyphenyl enaminones with silane as the reductant to provide o-hydroxyl propiophenones has been achieved with iridium catalysis. The reduction reactions were found to proceed via the assistance of the hydroxyl group in the phenyl ring. In addition, the o-hydroxyl propiophenone products were used for the easy synthesis of 3-methyl chromones by directly incorporating N,N-dimethyl formamide dimethyl acetal (DMF-DMA) without using any catalyst.

Enantioselective Total Synthesis of (+)‐Incargranine A Enabled by Bifunctional Iminophosphorane and Iridium Catalysis

AbstractHerein we report the first enantioselective total synthesis of (+)‐incargranine A, in nine steps. The total synthesis was enabled by an enantioselective intramolecular organocatalysed desymmetrising Michael addition of a malonamate ester to a linked dienone substrate that established pivotal stereocentres with excellent enantio‐ and complete diastereoselectivity. Furthermore, a key hemiaminal intermediate was accessed by developing an iridium‐catalysed reductive cyclisation, and the scope of this transformation was explored to produce a range of bicyclic hemiaminal motifs. Once installed, the hemiaminal motif was used to initiate a biomimetic cascade to access the natural product directly in a single step.

Enantioselective Total Synthesis of (+)-Incargranine A Enabled by Bifunctional Iminophosphorane and Iridium Catalysis.

Herein we report the first enantioselective total synthesis of (+)-incargranine A, in nine steps. The total synthesis was enabled by an enantioselective intramolecular organocatalysed desymmetrising Michael addition of a malonamate ester to a linked dienone substrate that established pivotal stereocentres with excellent enantio- and complete diastereoselectivity. Furthermore, a key hemiaminal intermediate was accessed by developing an iridium-catalysed reductive cyclisation, and the scope of this transformation was explored to produce a range of bicyclic hemiaminal motifs. Once installed, the hemiaminal motif was used to initiate a biomimetic cascade to access the natural product directly in a single step.

Aryl Chloride-Directed Enantioselective C(sp2)-H Borylation Enabled by Iridium Catalysis.

We herein report the iridium-catalyzed enantioselective C-H borylation of aryl chlorides. A variety of prochiral biaryl compounds could be well-tolerated, affording a vast array of axially chiral biaryls with high enantioselectivities. The current method exhibits a high turnover number (TON) of 7000, which represents the highest in functional-group-directed asymmetric C-H activation. The high TON was attributed to a weak catalyst-substrate interaction that was caused by mismatched chirality between catalyst and substrate. We also demonstrated the synthetic application of the current method by C-B, ortho-C-H, and C-Cl bond functionalization, including programmed Suzuki-Miyaura coupling for the synthesis of axially chiral polyarenes.

Selective C-H Iodination of Weinreb Amides and Benzamides through Iridium Catalysis in Solution and under Mechanochemical Conditions.

The acid mediated ortho-iodination of Weinreb amides using a readily available catalyst is described. The selective ortho-iodination of Weinreb amides, challenging substrates in directed C-H activations, and also of benzamides is achieved. The process works under mild conditions and tolerates air and moisture, having a great potential for industrial applications. The methodology can be applied under mechanochemical conditions maintaining the reaction outcome and selectivity.

High-Throughput Experimentation and Machine Learning-Assisted Optimization of Iridium-Catalyzed Cross-Dimerization of Sulfoxonium Ylides.

A novel and convenient approach that combines high-throughput experimentation (HTE) with machine learning (ML) technologies to achieve the first selective cross-dimerization of sulfoxonium ylides via iridium catalysis is presented. A variety of valuable amide-, ketone-, ester-, and N-heterocycle-substituted unsymmetrical E-alkenes are synthesized in good yields with high stereoselectivities. This mild method avoids the use of diazo compounds and is characterized by simple operation, high step-economy, and excellent chemoselectivity and functional group compatibility. The combined experimental and computational studies identify an amide-sulfoxonium ylide as a carbene precursor. Furthermore, a comprehensive exploration of the reaction space is also performed (600 reactions) and a machine learning model for reaction yield prediction has been constructed.