Catalysts For Asymmetric Transfer Hydrogenation Research Articles

Polymeric Micelles with Chiral Diamine-Ru(II) Catalysts for Asymmetric Transfer Hydrogenation of Ketones in Water

Polymeric Micelles with Chiral Diamine-Ru(II) Catalysts for Asymmetric Transfer Hydrogenation of Ketones in Water

Tailored Particle Catalysts for Multistep One‐pot Chemoenzymatic Cascade in Pickering Emulsions

AbstractChemoenzymatic cascades are an important tool for advanced synthesis in chemistry. However, these cascades are often limited due to the incompatibility issue between two distinct catalysts and reactions. To address this issue, we present a simple multistep one‐pot platform, in which nanoparticle catalysts are prepared to allow chemo‐ and biocatalytic reactions performed sequentially in water and Pickering emulsions. The preparation of particle catalysts is accomplished in just two steps by polymer modifications and [RuCl2(p‐cymene)]2 coordination, while the benefits of using them for chemoenzymatic synthesis are multifaceted. They act not only as asymmetric catalysts for asymmetric transfer hydrogenation from acetophenone to 1‐phenylethanol in water with up to 99 % conversion and 93 % ee, but also as an emulsifier to form stable Pickering emulsions. By the addition of Candida antarctica lipase B into the emulsions, the second‐step reaction of enantioselective acylation was achieved with 38 % conversion and 99 % ee. Therefore, we successfully present a simple method to enable chemoenzymatic cascades by combining particle catalysts and enzymes in water and Pickering emulsions in a sequential fashion, which can be generalized for other cascade syntheses with different chemo‐ and biocatalysts in the future.

Density functional theory investigation of Ru(II) and Os(II) asymmetric transfer hydrogenation catalysts.

Transition metal ions have a unique ability to organise and control the steric and electronic effects around a substrate in the active site of a catalyst. We consider half-sandwich Ru(II) (Noyori-type) and Os(II) sulfonyldiamine 16-electron active catalysts [Ru/Os(η6-p-cymene)(TsDPEN-H2)], where TsDPEN is N-tosyl-1,2-diphenylethylenediamine containing S,S or R,R chiral centres, which catalyse the highly efficient asymmetric transfer hydrogenation of aromatic ketones to chiral alcohols using formic acid as a hydride source. We discuss the recognition of the prochiral ketone acetophenone by the catalyst, the protonation of a ligand NH and transfer of hydride from formate to the metal, subsequent transfer of hydride to one enantiotopic face of the ketone, followed by proton transfer from metal-bound NH2, and regeneration of the catalyst. Our DFT calculations illustrate the role of the two chiral carbons on the N,N-chelated sulfonyldiamine ligand, the axial chirality of the π-bonded p-cymene arene, and the chirality of the metal centre. We discuss new features of the mechanism, including how a change in metal chirality of the hydride intermediate dramatically switches p-cymene coordination from η6 to η2. Moreover, the calculations suggest a step-wise mechanism involving substrate docking to the bound amine NH2 followed by hydride transfer prior to protonation of the O-atom of acetophenone and release of the enantio-pure alcohol. This implies that formation and stability of the M-H hydride intermediate is highly dependent on the presence of the protonated amine ligand. The Os(II) catalyst is more stable than the Ru(II) analogue, and these studies illustrate the subtle differences in mechanistic behaviour between these 4d6 and 5d6 second-row and third-row transition metal congeners in group 8 of the periodic table.

Does the Configuration at the Metal Matter in Noyori-Ikariya Type Asymmetric Transfer Hydrogenation Catalysts?

Noyori–Ikariya type [(arene)RuCl(TsDPEN)] (TsDPEN, sulfonated diphenyl ethylenediamine) complexes are widely used C=O and C=N reduction catalysts that produce chiral alcohols and amines via a key ruthenium–hydride intermediate that determines the stereochemistry of the product. Whereas many details about the interactions of the pro-chiral substrate with the hydride complex and the nature of the hydrogen transfer from the latter to the former have been investigated over the past 25 years, the role of the stereochemical configuration at the stereogenic ruthenium center in the catalysis has not been elucidated so far. Using operando FlowNMR spectroscopy and nuclear Overhauser effect spectroscopy, we show the existence of two diastereomeric hydride complexes under reaction conditions, assign their absolute configurations in solution, and monitor their interconversion during transfer hydrogenation catalysis. Configurational analysis and multifunctional density functional theory (DFT) calculations show the λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to be both thermodynamically and kinetically favored over its λ-(R,R)RRu isomer with the opposite configuration at the metal. Computational analysis of both diastereomeric catalytic manifolds show the major λ-(R,R)SRu configured [(mesitylene)RuH(TsDPEN)] complex to dominate asymmetric ketone reduction catalysis with the minor λ-(R,R)RRu [(mesitylene)RuH(TsDPEN)] stereoisomer being both less active and less enantioselective. These findings also hold true for a tethered catalyst derivative with a propyl linker between the arene and TsDPEN ligands and thus show enantioselective transfer hydrogenation catalysis with Noyori–Ikariya complexes to proceed via a lock-and-key mechanism.

Integrated Suzuki Cross-Coupling/Reduction Cascade Reaction of meta-/para-Chloroacetophenones and Arylboronic Acids under Batch and Continuous Flow Conditions.

Overcoming the incompatibility of a pair of conflicting catalysts via a flow methodology has great significance in the practical applications for multistep organic transformations. In this study, a multiple continuous-flow system is developed, which can boost the reactivity and selectivity in a sequential enantioselective cascade reaction. During this process, a periodic mesoporous organosilica-supported Pd/carbene species as a Suzuki cross-coupling catalyst is packed in the first column reactor, whereas another periodic mesoporous organosilica-supported Ru/diamine species as an asymmetric transfer hydrogenation catalyst is packed in the second column reactor. As we envisioned, the initially Pd-catalyzed cross-coupling reaction of meta-/para-chloroacetophenones and aryl boronic acids followed by the subsequentially Ru-catalyzed reduction provides chiral biarylols with enhanced yields and enantioselectivities. Furthermore, the advantages of the easy handling and the simple procedure make this system an attractive application in a scale-up preparation of optically pure organic molecules under environmentally-friendly conditions.

Amino Acid Derived Chiral Aminobenzimidazole Manganese Catalysts for Asymmetric Transfer Hydrogenation of Ketones

Amino Acid Derived Chiral Aminobenzimidazole Manganese Catalysts for Asymmetric Transfer Hydrogenation of Ketones

Design of Iridium N-Heterocyclic Carbene Amino Acid Catalysts for Asymmetric Transfer Hydrogenation of Aryl Ketones

A series of chiral complexes of the form Ir(NHC)2(aa)(H)(X) (NHC = N-heterocyclic carbene, aa = chelated amino acid, X = halide) was synthesized by oxidative addition of α-amino acids to iridium(I) bis-NHC compounds and screened for asymmetric transfer hydrogenation of ketones. Following optimization of the reaction conditions, NHC, and amino acid ligands, high enantioselectivity was achieved when employing the Ir(IMe)2(l-Pro)(H)(I) catalyst (IMe = 1,3-dimethylimidazol-2-ylidene), which asymmetrically reduces a range of acetophenone derivatives in up to 95% enantiomeric excess.

A phosphine-free Mn(I)-NNS catalyst for asymmetric transfer hydrogenation of acetophenone: a theoretical prediction.

The density functional theory (DFT) method was employed to investigate the reaction mechanism of the hydrogen activation and asymmetric transfer hydrogenation (ATH) of acetophenone catalyzed by a well-defined phosphine-free Mn(I)-NNS complex. The calculation results indicate that the Mn-NNS complex has potential high catalytic hydrogenation activity. Meanwhile, the hydrogen transfer step of this reaction is proposed to be a concerted but asynchronous process, and the hydride transfer precedes proton transfer. This work also pointed out that the stereoselectivity of ATH catalyzed by the Mn(I)-NNS complex mainly originates from the noncovalent interaction between the substrate and the catalyst. Additionally, the catalytic activities of Mn-NNS complexes with different X ligands (X = CO, Cl, H, OMe, NCMe, CCMe, and CHCHMe) were compared, and the calculated total reaction energy barriers were all viable, which indicates that these Mn-NNS complexes show higher CO bond hydrogenation activity under mild conditions. This theoretical study predicts that the reactions catalyzed by complexes with H and NCMe ligands exhibit high stereoselectivity with enantiomeric excess (ee) values of 97% and 93%, respectively.

Escaping from Flatland: Stereoconvergent Synthesis of Three-Dimensional Scaffolds via Ruthenium(II)-Catalyzed Noyori-Ikariya Transfer Hydrogenation.

Noyori-Ikariya-type ruthenium(II)-catalysts for asymmetric transfer hydrogenation (ATH) have been known for 25 years and have proved as a well-behaved and user-friendly platform for the synthesis of chiral secondary alcohols. A progress has been made in the past five years in understanding the asymmetric reduction of complex ketones, where up to four stereocenters can be controlled in a single chemical transformation. Intriguing multi-chiral molecular architectures are therefore available in few well understood and robust synthetic steps from commercially available building blocks and possess handles for additional functionalization. The aim of this Review is to showcase the availability of three-dimensional scaffolds and homochiral lead-like compounds via ATH and inspire their direct use in drug discovery endeavors. Basic mechanistic insights are provided to demystify the stereo-chemical outcomes, as well as examples of diastereoselective transformations of enantiopure alcohols to give a feeling of how these rigid non-planar molecules can be further elaborated.

Synthesis and Applications of (Pyridyl)imine Fe(II) Complexes as Catalysts in Transfer Hydrogenation of Ketones

Chiral (pyridyl)imine Fe(II) complexes, [Fe(L1)3]2+[PF6−]2, (Fe1), [Fe(L2)3]2+[PF6−]2, (Fe2), [Fe(L3)3]2+[PF6−]2 (Fe3), and [Fe(L4)3]2+[PF6−]2 (Fe4) were synthesised by reactions of synthons (S-)-1-phenyl-N-(pyridine-2-yl) ethylidine)ethanamine (L1), (R-)-1-phenyl-N-(pyridine-2-yl) ethylidine) ethanamine (L2), (S)-1-phenyl-N-(pyridine-2-yl methylene) ethanamine (L3) and (S)-1-phenyl-N-(pyridine-2-yl methylene)ethanamine (L4) with the FeCl2 salt. The solid-state structure of complex Fe4 showed that the Fe atom contains three units of bidentate bound ligand L4 to form a six-coordinate cationic compound. The Fe(II) complexes were evaluated as catalysts in asymmetric transfer hydrogenation of ketones reactions and showed moderate catalytic activities with low enantioselectivity. Catalytic activities of the respective complexes were regulated by the nature of the metal complexes, ketone substrate and reaction conditions. Mercury and sub-stoichiometric poisoning experiments implicate possible formation of both active Fe(0) nanoparticles and Fe(II) homogeneous intermediates.

Stepwise Construction of Ru(II)Center Containing Chiral Thiourea Ligand on Graphene Oxide: First Efficient, Reusable, and Stable Catalyst for Asymmetric Transfer Hydrogenation of Ketones

Heterogenization of homogenous catalysts on solid support has attracted tremendous attention in organic synthesis due to the key benefits of heterogenized catalysts such as easy recovery and reusability. Although a considerable number of heterogenized catalysts are available, to the best of our knowledge, there is no efficient and reusable heterogenized catalyst reported for asymmetric reactions to date. Herein, we prepared a [RuCl2(η6-p-cymene)]/chiralthiourea ligand covalently bonded to graphene nanosheets (G-CLRu(II), where G represents graphene oxide (GO), CL denotes chiral N-((1-phenylethyl)carbamothioyl)acetamide and Ru(II) symbolizes [RuCl2(η6-p-cymene)]), for the asymmetric transfer hydrogenation of ketones. Five simple steps were involved in the preparation of the G-CLRu(II) catalyst. The structure of G-CLRu(II) was investigated by means of various spectroscopic and microscopic techniques. Coordination mode and covalent bonding involved in the G-CLRu(II) structure we reconfirmed. G-CLRu(II) demonstrated good catalytic performance towards the asymmetric transfer hydrogenation of ketones (conversion of up to 95%, enantiomeric excesses (ee) of up to 99%, and turnover number (TON) and turnover frequency (TOF) values of 535.9 and 22.3 h−1, respectively). A possible mechanism is proposed for the G-CLRu(II)-catalyzed asymmetric transfer hydrogenation of ketones. Recovery (~95%), reusability (fifth cycle, yield of 89% and ee of 81%), and stability of G-CLRu(II) were found to be good. We believe that the present stepwise preparation of G-CLRu(II) opens a new door for designing various metal-centered heterogenized chiral catalysts for asymmetric synthesis.

Probing the Effects of Heterocyclic Functionality in [(Benzene)Ru(TsDPENR)Cl] Catalysts for Asymmetric Transfer Hydrogenation.

A range of TsDPEN catalysts containing heterocyclic groups on the amine nitrogen atom were prepared and evaluated in the asymmetric transfer hydrogenation of ketones. Bidentate and tridentate ligands demonstrated a mutual exclusivity directly related to their function as catalysts. A broad series of ketones were reduced with these new catalysts, permitting the ready identification of an optimal catalyst for each substrate and revealing the subtle effects that changes to nearby donor groups can exhibit.

Water soluble Ru (II)–p‐cymene complexes of chiral aroylthiourea ligands derived from unprotected D/L‐alanine as proficient catalysts for asymmetric transfer hydrogenation of ketones

The newfangled chiral aroylthiourea ligands (L1‐L6) were produced from unprotected D/L‐alanine and their water soluble Ru (II) organometallic catalysts (1–6) were designed from their reaction with [RuCl2(η6‐p‐cymene)]2. The analytical and spectral methods were used to confirm the structure of the ligands and complexes. The solid state structure of L1, 5 and 6 was confirmed by single crystal XRD. The organometallic compounds (1–6) catalyzed the asymmetric transfer hydrogenation of aromatic, heteroaromatic and bulky ketones to yield respective enantiopure secondary alcohols with admirable conversions (up to 99%) and attractive enantiomeric excesses (ee up to 98%), in presence of formic acid and triethylamine in water medium under non‐inert atmospheric conditions.

A N,O hope

Iridium chelates are attractive catalysts for asymmetric transfer hydrogenation. The mode through which a chelating ligand binds iridium turns out to have a striking effect on catalytic activity and enantioselectivity.

Accessible Bifunctional Oxy-Tethered Ruthenium(II) Catalysts for Asymmetric Transfer Hydrogenation.

A concise synthesis of new oxy-tethered ruthenium complexes effective for the asymmetric transfer hydrogenation of aromatic ketones is described. The oxy-tether was constructed via a defluorinative etherification arising from an intramolecular nucleophilic substitution of a perfluorinated phenylsulfonyl substituent. The obtained tethered complexes exhibited desirable catalytic activity and selectivity, especially in the asymmetric transfer hydrogenation of functionalized aromatic ketones. The robustness and rigidity of the tether contribute to their superior catalytic performance relative to the nontethered prototype complex.

Chiral Amino‐Acid‐Amide Based Ionic Liquids as a Stereoselective Organocatalyst in Asymmetric Transfer Hydrogenation of Acetophenone at Room‐Temperature

AbstractChiral Ionic Liquids (CILs) of amino acid amide were synthesized and used as novel organo catalyst for Asymmetric Transfer Hydrogenation (ATH) of acetophenone at room temperature. The developed CILs show very high yield and excellent enantio‐selectivity in transfer hydrogenation of acetophenone.

Semipermeable Organic–Inorganic Hybrid Microreactors for Highly Efficient and Size-Selective Asymmetric Catalysis

A highly efficient and size-selective organic–inorganic hybrid microreactor was fabricated successfully by assembling the semipermeable microporous silica hollow nanospheres at the interface of organic polymers containing an asymmetric transfer hydrogenation catalyst. The small micropores in the silica shells (1.0–1.5 nm) of the microreactors provide short mass-transfer channels for small molecules but prevent the diffusion of large reactants through the shell. At the same time, the combination of the outer microporous silica and inner polymers endows the microreactor with hydrophobic@hydrophilic property, which helps its dispersion in water as well as the adsorption of reactant molecules from water, yielding an ideal microenvironment for water medium catalysis reactions. Such microreactors could efficiently catalyze the aqueous asymmetric transfer hydrogenation (ATH) of small-sized ketones with catalytic activity comparable to the homogeneous Rh-VBSDPEN catalyst (TOF 625 vs 724 h–1). Meanwhile, the micro...

Iron Complexes with Chiral N/P Macrocycles as Catalysts for Asymmetric Transfer Hydrogenation

AbstractThe present account describes the development of chiral, C2‐symmetric N/P macrocyclic ligands that attune to the size and electronic properties of the iron(II) ion to give robust complexes under catalysis conditions. This is not trivial, as the complexes of base metals are substantially less stable than those of precious metals. Also, as these N2P2 macrocycles feature stereogenic P atoms, the control of the stereochemistry at phosphorus is a key synthetic issue. Still, as the macrocyclic effect was insufficient to give robust catalysts under hydrogen transfer conditions, we had to dig deeper into the toolbox of coordination chemistry and use strong‐field ancillary ligands other than CO, specifically isonitriles, which additionally offer a further handle to tune the catalyst. The reward was the discovery of the first iron(II) catalyst for the asymmetric transfer hydrogenation of polar double bonds that is highly enantioselective for a broad scope of substrates.

Mechanistic Aspects of Using Formate as a Hydrogen Donor in Aqueous Transfer Hydrogenation

Asymmetric transfer hydrogenation of ketones is an important chemical reaction. In aqueous solution, Ru(p-cymene)[TsDPEN] is an efficient catalyst for asymmetric transfer hydrogenation via a metal–ligand bifunctional mechanism with either 2-propanol or formate as hydrogen donors. Here, we provide novel insight for two key steps in the catalytic cycle of transfer hydrogenation cycle, using a computational model of Ru(p-cymene)[TsDPEN] with an explicit aqueous solvent. Employing ab initio molecular dynamics simulations, we model the hydride transfer between formate and the protonated and deprotonated catalyst, and the dissociation of the ruthenium-formato complex. It is shown that the aqueous solvent provides a significant contribution to the reaction barriers, increasing the hydride transfer barrier, while decreasing the dissociation barrier for ruthenium-formato complex, when compared with a gas-phase model. These effects can be attributed to hydrogen-bond structure around the formate, which favors the fo...

ChemInform Abstract: Synthesis of Planar Chiral Shvo Catalysts for Asymmetric Transfer Hydrogenation.

AbstractSeveral examples for transfer hydrogenations are given which may proceed with high yields and moderate enantiomeric excesses.