Iridium-Catalyzed Enantioselective Hydrogenation of Oxocarbenium Ions: A Case of Ionic Hydrogenation

Ionic hydrogenation has not been extensively explored, but is advantageous for challenging substrates such as unsaturated intermediates. Reported here is an iridium-catalyzed hydrogenation of oxocarbenium ions to afford chiral isochromans with high enantioselectivities. A variety of functionalities are compatible with this catalytic system. In the presence of a catalytic amount of the Brønsted acid HCl, an α-chloroether is generated in situ and subsequentially reduced. Kinetic studies suggest first-order kinetics in the substrate and half-order kinetics in the catalyst. A positive nonlinear effect, together with the half kinetic order, revealed a dimerization of the catalyst. Possible reaction pathways based on the monomeric iridium catalyst were proposed and DFT computational studies revealed an ionic hydrogenation pathway. Chloride abstraction and the cleavage of dihydrogen occur in the same step.     

A Simple Iridicycle Catalyst for Efficient Transfer Hydrogenation of N‐Heterocycles in Water

A cyclometalated iridium complex is shown to catalyse the transfer hydrogenation of various nitrogen heterocycles, including but not limited to quinolines, isoquinolines, indoles and pyridinium salts, in an aqueous solution of HCO₂H/HCO₂Na under mild conditions. The catalyst shows excellent functional‐group compatibility and high turnover number (up to 7500), with catalyst loadings as low as 0.01 mol % being feasible. Mechanistic investigation of the quinoline reduction suggests that the transfer hydrogenation proceeds via both 1,2‐ and 1,4‐addition pathways, with the catalytic turnover being limited by the step of hydride transfer.     

Asymmetric Hydrogenation of Cationic Intermediates for the Synthesis of Chiral N,O-Acetals

For over half a century, transition-metal-catalyzed homogeneous hydrogenation has been mainly focused on neutral and readily prepared unsaturated substrates. Although the addition of molecular hydrogen to C=C, C=N, and C=O bonds represents a well-studied paradigm, the asymmetric hydrogenation of cationic species remains an underdeveloped area. In this study, we were seeking a breakthrough in asymmetric hydrogenation, with cationic intermediates as targets, and thereby anticipating applying this powerful tool to the construction of challenging chiral molecules. Under acidic conditions, both N- or O-acetylsalicylamides underwent cyclization to generate cationic intermediates, which were subsequently reduced by an iridium or rhodium hydride complex. The resulting N,O-acetals were synthesized with remarkably high enantioselectivity. This catalytic strategy exhibited high efficiency (turnover number of up to 4400) and high chemoselectivity. Mechanistic studies supported the hypothesis that a cationic intermediate was formed in situ and hydrogenated afterwards. A catalytic cycle has been proposed with hydride transfer from the iridium complex to the cationic sp² carbon atom being the rate-determining step. A steric map of the catalyst has been created to illustrate the chiral environment, and a quantitative structure–selectivity relationship analysis showed how enantiomeric induction was achieved in this chemical transformation.     

Asymmetric Synthesis of Alkyl Fluorides: Hydrogenation of Fluorinated Olefins

The development of new general methods for the synthesis of chiral fluorine‐containing molecules is important for several scientific disciplines. We herein disclose a straightforward method for the preparation of chiral organofluorine molecules that is based on the iridium‐catalyzed asymmetric hydrogenation of trisubstituted alkenyl fluorides. This catalytic asymmetric process enables the synthesis of chiral fluorine molecules with or without carbonyl substitution. Owing to the tunable steric and electronic properties of the azabicyclo thiazole‐phosphine iridium catalyst, this stereoselective reaction could be optimized and was found to be compatible with various aromatic, aliphatic, and heterocyclic systems with a variety of functional groups, providing the highly desirable products in excellent yields and enantioselectivities.     

Chemoselective Hydrogenation of Functionalized Nitroarenes and Imines by Using Carbon Nanofiber‐Supported Iridium Nanoparticles

The reaction of three types of carbon nanofibers (CNFs; platelet: CNF‐P, tubular: CNF‐T, herringbone: CNF‐H) with Ir₄(CO)₁₂ in mesitylene at 165 °C provided the corresponding CNF‐supported iridium nanoparticles, Ir/CNFs (Ir content=2.3–2.6 wt. %). Transmission electron microscopy (TEM) studies of these Ir/CNF samples revealed that size‐controlled Ir nanoparticles (average particle size of 1.1–1.5 nm) existed on the CNFs. Among the three Ir/CNF samples, Ir/CNF‐T showed an excellent catalytic activity and chemoselectivity towards hydrogenation of functionalized nitroarenes and imines; the corresponding aniline derivatives were obtained with high turnover numbers at ambient temperature under 10 atm of H₂, and the catalyst is reusable. Ir/CNF‐T was also effective for the reductive N‐alkylation of anilines with carbonyl compounds.     

Catalytic Asymmetric Hydrogenation of Pyrimidines

The asymmetric hydrogenation of pyrimidines proceeded with high enantioselectivity (up to 99 % ee) using an iridium catalyst composed of [IrCl(cod)]₂, a ferrocene‐containing chiral diphosphine ligand (Josiphos), iodine, and Yb(OTf)₃ (cod=1,5‐cyclooctadiene). The chiral catalyst converted various 4‐substituted pyrimidines into chiral 1,4,5,6‐tetrahydropyrimidines in high yield. The lanthanide triflate is crucial for achieving the high enantioselectivity as well as for activating the heteroarene substrate.     

Dual Catalysis with an IrIII–AuI Heterodimetallic Complex: Reduction of Nitroarenes by Transfer Hydrogenation using Primary Alcohols

A triazolyl‐di‐ylidene ligand has been used for the preparation of a homodimetallic complex of gold, and a heterodimetallic compound of gold and iridium. Both complexes have been fully characterized and their molecular structures have been determined by means of X‐ray diffraction. The catalytic properties of these two complexes have been evaluated in the reduction of nitroarenes by transfer hydrogenation using primary alcohols. The two complexes afford different reaction products; whereas the Au^I–Au^I catalyst yields a hydroxylamine, the Ir^III–Au^I complex facilitates the formation of an imine.     

Asymmetric Hydrogenation of Maleic Acid Diesters and Anhydrides

Asymmetric hydrogenation of maleic and fumaric acid derivatives with iridium catalysts based on N,P ligands provides an efficient route to chiral enantioenriched succinates. A new catalyst derived from a 2,6‐difluorophenyl‐substituted pyridine‐phosphinite ligand was developed and enables the conversion of a wide range of 2‐alkyl and 2‐arylmaleic acid diesters into the corresponding succinates in high enantiomeric purity. Mixtures of cis/trans substrates can be hydrogenated in an enantioconvergent fashion with high enantioselectivity, and further enhances the scope of this transformation. The products are valuable chiral building blocks with a structural motif found in many bioactive compounds, such as metalloproteinase inhibitors.     

巴豆醛气相选择性加氢催化剂

巴豆醛是α, β-不饱和醛中最具代表性的一类有机化合物,采用气相催化巴豆醛选择加氢制备巴豆醇符合原子经济和绿色化学要求,具有重要的工业应用和学术价值。本文综述了近十年国内外巴豆醛气相选择性加氢合成巴豆醇的负载型催化剂的研究成果,评述了贵金属催化剂(铂、金、铱、银、钯)和非贵金属催化剂(钴、铜)上巴豆醛选择性加氢性能,分析了活性组分、载体、助剂以及活性组分粒径对催化剂性能的影响,探讨了巴豆醛选择性加氢的反应机理和失活机理。最后,对气相巴豆醛选择性加氢催化剂所存在的问题进行总结,并对催化剂的发展趋势作出了展望。指出了非贵金属催化剂的巴豆醛选择性加氢性能因具有价廉易得等优势,将是该领域的研究方向之一。催化剂失活是巴豆醛气相选择性加氢工业化的最大障碍,因此研究和认识反应机理,解决催化剂失活问题是重点研究方向。     

Iridium-catalyzed hydrogenation of N-heterocyclic compounds under mild conditions by an outer-sphere pathway

A new homogeneous iridium catalyst gives hydrogenation of quinolines under unprecedentedly mild conditions-as low as 1 atm of H(2) and 25 °C. We report air- and moisture-stable iridium(I) NHC catalyst precursors that are active for reduction of a wide variety of quinolines having functionalities at the 2-, 6-, and 8- positions. A combined experimental and theoretical study has elucidated the mechanism of this reaction. DFT studies on a model Ir complex show that a conventional inner-sphere mechanism is disfavored relative to an unusual stepwise outer-sphere mechanism involving sequential proton and hydride transfer. All intermediates in this proposed mechanism have been isolated or spectroscopically characterized, including two new iridium(III) hydrides and a notable cationic iridium(III) dihydrogen dihydride complex. DFT calculations on full systems establish the coordination geometry of these iridium hydrides, while stoichiometric and catalytic experiments with the isolated complexes provide evidence for the mechanistic proposal. The proposed mechanism explains why the catalytic reaction is slower for unhindered substrates and why small changes in the ligand set drastically alter catalyst activity.     

Mechanism of the Asymmetric Hydrogenation of Exocyclic α,β‐Unsaturated Carbonyl Compounds with an Iridium/BiphPhox Catalyst: NMR and DFT Studies

The mechanism of the asymmetric hydrogenation of exocyclic α,β‐unsaturated carbonyl compounds with the (aS)‐Ir/iPr‐BiphPhox catalyst was studied by NMR experiments and DFT computational analyses. Computed optical yields of the asymmetric hydrogenation proceeding by an iridium(I)/iridium(III) mechanism involving a transition state stabilized through two intramolecular hydrogen bonds are in good accordance with the experimental ee values.     

L-脯氨酸稳定的铱催化苯乙酮及其衍生物不对称加氢反应

以L-脯氨酸为稳定剂制备了负载型金属铱催化剂, 并用于苯乙酮及其衍生物不对称加氢反应. 考察了载体以及L-脯氨酸的量对催化剂性能的影响, 以透射电镜(TEM)和X射线光电子能谱(XPS)对催化剂进行了表征. 结果表明L-脯氨酸对金属铱粒子具有较好的分散和稳定作用. 通过考察反应条件发现: 碱金属离子对反应有较大影响; L-脯氨酸与手性修饰剂对催化活性和对映选择性存在一定的协同促进作用. 在手性二胺(1S,2S)-1,2- 二苯基乙二胺 ((1S,2S)-DPEN) 修饰下, 催化剂 5% (w, 质量分数)Ir/15( 脯氨酸与铱的摩尔比)(L-Proline)-γ-Al2O3催化苯乙酮不对称加氢获得了71.3%的对映选择性(ee), 2?-(三氟甲基)苯乙醇的对映选择性达到了79.8%. 该催化剂制备方法简单, 不需要膦配体做稳定剂, 催化剂性能稳定, 通过简单的离心分离可循环使用5次而无明显的活性和对映选择性降低.     

Enantioselective Hydrogenation of Olefins with Iridium–Phosphanodihydrooxazole Catalysts

High turnover numbers and up to 98% ee were obtained in the catalytic hydrogenation of unfunctionalized aryl-substituted olefins with iridium–phosphanyldihydrooxazole complexes 1 (see reaction scheme). The anion of the complex—for example, hexafluorophosphate or tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (BARF⁻)—has a remarkable effect on the reactivity and longevity of the catalyst.     

Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins

Asymmetric hydrogenation has evolved as one of the most powerful tools to construct stereocenters. However, the asymmetric hydrogenation of unfunctionalized tetrasubstituted acyclic olefins remains the pinnacle of asymmetric synthesis and an unsolved challenge. We report herein the discovery of an iridium catalyst for the first, generally applicable, highly enantio‐ and diastereoselective hydrogenation of such olefins and the mechanistic insights of the reaction. The power of this chemistry is demonstrated by the successful hydrogenation of a wide variety of electronically and sterically diverse olefins in excellent yield and high enantio‐ and diastereoselectivity.     

金鸡纳碱衍生物修饰的负载铱催化剂催化芳香酮不对称加氢

以金鸡纳碱衍生物作为手性修饰剂, 研究了三苯基膦稳定的Ir/SiO₂催化剂催化芳香酮多相不对称加氢. 通过电感耦合等离子体原子发射发谱(ICP-AES)、高分辨透射电镜(HRTEM)、X 射线光电子能谱(XPS)、Brunauer-Emmett-Teller (BET)比表面积测试等固体表面分析手段对负载铱催化体系进行了表征; 利用红外(IR)光谱、固体核磁共振(NMR)等分析手段初步表征了负载铱多相催化体系中手性修饰剂-金属-稳定剂在载体上的相互作用; 利用“均相与多相催化体系的对比”、“催化剂稳定性实验”、“汞中毒实验”等方法阐明了手性修饰的负载铱催化体系是多相催化体系. 还考察了稳定剂种类、修饰剂种类、金属负载量、溶剂、碱添加剂种类等因素对不对称加氢反应的影响. 结果表明, 金鸡纳碱衍生物对Ir/SiO₂催化剂具有较好的修饰作用, 在优化反应条件下苯乙酮及其衍生物加氢反应的对映选择性为52%-96%, 4-乙酰基吡啶、2-乙酰基噻吩及2-乙酰基呋喃加氢反应的对映选择性可分别达到74%、75%及63%.     

Homogeneous hydrogenation of electron‐deficient alkenes by iridium complexes

The catalytic homogeneous hydrogenation of electron‐deficient alkenes (nucleophilic hydrogenation) was achieved in the presence of iridium complexes and a base as co‐catalyst. Contrary to hydrogenation of electron‐rich alkenes, which is inactivated by bases, the hydrogenation of the electron‐deficient alkenes turned out to be base activated. Here, we present a more thorough study on the capacities but also limitations of this new reaction mechanism using screenings of the reaction conditions as well as different Ir complexes and substrates. The formation of a catalytically active Ir complex is proposed. The active complex usually attacks a soft electron‐deficient atom, if more than one possibility exists (as shown by density functional theory computations). Additionally, first examples of enantiomeric enrichments in the presence of chiral Ir complexes are presented. The high catalyst load needed and the moderate yields show that the active complex is very unstable under conditions of nucleophilic hydrogenation and is quickly deactivated, which has to be addressed in further studies. Copyright © 2011 John Wiley & Sons, Ltd.     

Diastereo‐ and Enantioselective anti‐Selective Hydrogenation of α‐Amino‐β‐keto Ester Hydrochlorides and Related Compounds Using Transition‐Metal–Chiral‐Bisphosphine Catalysts

This review describes our recent works on the diastereo‐ and enantioselective synthesis of anti‐β‐hydroxy‐α‐amino acid esters using transition‐metal–chiral‐bisphosphine catalysts. A variety of transition metals, namely ruthenium (Ru), rhodium (Rh),iridium (Ir), and nickel (Ni), in combination with chiral bisphosphines, worked well as catalysts for the direct anti‐selective asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides, yielding anti‐β‐hydroxy‐α‐amino acid esters via dynamic kinetic resolution (DKR) in excellent yields and diastereo‐ and enantioselectivities. The Ru‐catalyzed asymmetric hydrogenation of α‐amino‐β‐ketoesters via DKR is the first example of generating anti‐β‐hydroxy‐α‐amino acids. Complexes of iridium and axially chiral bisphosphines catalyze an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides via dynamic kinetic resolution. A homogeneous Ni–chiral‐bisphosphine complex also catalyzes an efficient asymmetric hydrogenation of α‐amino‐β‐keto ester hydrochlorides in an anti‐selective manner. As a related process, the asymmetric hydrogenation of the configurationally stable substituted α‐aminoketones using a Ni catalyst via DKR is also described.     

An Environmentally Benign Process for the Hydrogenation of Ketones with Homogeneous Iron Catalysts

Iron complexes generated in situ catalyze homogeneously the transfer hydrogenation of aliphatic and aromatic ketones by utilizing 2‐propanol as a hydrogen donor in the presence of base. The influence of different reaction parameters on the catalytic activity is investigated in detail by applying a three‐component catalyst system composed of an iron salt, 2,2′:6′,2′′‐terpyridine, and PPh₃. The scope and limitations of the described catalyst is shown in the reduction of 11 different ketones. In most cases, high conversion and excellent chemoselectivity are obtained. Mechanistic studies indicate a monohydride reaction pathway for the homogeneous iron catalyst.     

Nickel‐Catalyzed Asymmetric Hydrogenation of N‐Sulfonyl Imines

An efficient nickel‐catalyzed asymmetric hydrogenation of N‐tBu ‐ sulfonyl imines was developed with excellent yields and enantioselectivities using (R,R)‐QuinoxP* as a chiral ligand. The use of a much lower catalyst loading (0.0095 mol %, S/C=10500) represents the highest catalytic activity for the Ni‐catalyzed asymmetric hydrogenations reported so far. Mechanistic studies suggest that a coordination equilibrium exists between the nickel salt and its complex, and that excess nickel salt promotes the formation of the active Ni‐complex, and therefore improved the efficiency of the hydrogenation. The catalytic cycle was also investigated by calculations to determine the origin of the enantioselectivity. An extensive network of numerous weak attractive interactions was found to exist between the catalyst and substrate in the transition state and may also contribute to the high catalytic activity.     

Cooperative Catalysis: Combining an Achiral Metal Catalyst with a Chiral Brønsted Acid Enables Highly Enantioselective Hydrogenation of Imines

Asymmetric hydrogenation of imines leads directly to chiral amines, one of the most important structural units in chemical products, from pharmaceuticals to materials. However, highly effective catalysts are rare. This article reveals that combining an achiral pentamethylcyclopentadienyl (Cp*)–iridium complex with a chiral phosphoric acid affords a catalyst that allows for highly enantioselective hydrogenation of imines derived from aryl ketones, as well as those derived from aliphatic ones, with ee values varying from 81 to 98 %. A range of achiral iridium complexes containing diamine ligands were examined, for which the ligands were shown to have a profound effect on the reaction rate, enantioselectivity and catalyst deactivation. The chiral phosphoric acid is no less important, inducing enantioselection in the hydrogenation. The induction occurs, however, at the expense of the reaction rate.