Asymmetric Hydrogenation Research Articles

Ruthenium-Catalyzed Carbocycle-Selective Hydrogenation of Fused Heteroarenes.

The homogeneous catalytic hydrogenation of benzo-fused heteroarenes generally provides partially hydrogenated products wherein the heteroaryl ring is preferentially reduced, such as quinoline hydrogenation, leading to 1,2,3,4-tetrahydroquinoline. Herein, we report a carbocycle-selective hydrogenation of fused N-heteroarenes (quinoline, isoquinoline, quinoxaline, etc.) using the Ru complex of a chiral spiroketal-based diphosphine (SKP) as the catalyst, affording the corresponding 5,6,7,8-tetrahydro products in high chemoselectivities. This catalytic system is also effective for the asymmetric carbocycle hydrogenation of fused heteroarenes bearing a boryl or amino group. Experimental studies provided a strong support for the homogeneous nature of the catalysis, and an inner-sphere mechanism was proposed for the hydrogenation. DFT calculations indicated that the hydrogenation is initiated by η4-coordinative activation of quinoline carbocycle to Ru dihydride complex of SKP, followed by metal-to-ligand hydride transfer. Subsequent carbocycle reduction proceeds via consecutive steps of the H2 oxidative addition and C-H reductive elimination.

Pure spin currents induced by asymmetric H-passivation in B3C2P3 nanoribbons.

Inspired by the recently reported novel two-dimensional material B3C2P3, we performed one-dimensional shearing along the zigzag direction to obtain four B3C2P3 nanoribbons with various edge atom combinations. An asymmetric hydrogen passivation scheme was employed to modulate the electronic properties and successfully open the band gap, especially the 2H-1H passivation with dihydrogenation and monohydrogenation at the top and bottom edges, respectively, achieving bipolar magnetic semiconductors with edge P-atoms contributing to the main magnetism. Furthermore, three crucial spin-polarized transmission spectra yielded a significant spin-dependent Seebeck effect (SDSE), displaying superior thermoelectric conversion capabilities by generating pure spin currents. Our work shows that this asymmetric H-passivation effectively enables the enhancement of the spin caloritronic transport properties of the B3C2P3, which is of great significance for the exploitation of novel materials and their applications in spintronics.

Asymmetric Hydrogenation of Exocyclic α,β-Unsaturated Nitriles: An Access to Chiral 2-Benzocyclic Acetonitriles and Ramelteon.

A highly efficient and enantioselective hydrogenation of exocyclic α,β-unsaturated nitriles catalyzed by the Rh-JosiPhos complex for synthesis of the chiral 2-benzocyclic acetonitriles has been developed. Both (Z)- and (E)-isomers of exocyclic α,β-unsaturated nitriles with various benzocyclic structures, including heterocyclic (chroman and tetrahydroquinoline) scaffolds, were hydrogenated successfully, achieving excellent enantioselectivities (up to 97% ee) and high turnover numbers (TON up to 4000). Furthermore, this methodology provides an efficient, concise, and practical synthetic route to the sleep agent (S)-Ramelteon.

Highly Enantioselective Synthesis of 3,3-Diarylpropyl Amines and 4-Aryl Tetrahydroquinolines via Ir-Catalyzed Asymmetric Hydrogenation.

Chiral nitrogen-containing compounds are crucial for the chemical, pharmaceutical, and agrochemical industries. Nevertheless, the synthesis of certain valuable scaffolds remains underdeveloped due to the vast chemical space available. In this work, we present a diastereoselective methodology for synthesizing 3,3-diarylallyl phthalimides, which, following iridium-catalyzed asymmetric hydrogenation using Ir-UbaPHOX, yield 3,3-diarylpropyl amines with high enantioselectivity (98-99% ee). The importance of alkene purity to achieve high enantioselectivity is discussed. The synthetic utility of the chiral propylamines obtained is demonstrated through the preparation of medicinally useful bioactive compounds like the drugs tolterodine and tolpropamine and 4-aryl tetrahydroquinolines. This strategy enables the synthesis of these compounds with the highest enantioselectivity reported to date.

‘‘Study of the electrochemical properties of polyaniline-integrated chromium oxide composite with metal–organic framework electrode (Cr2O3/Sn-MOF (PANI)) for asymmetric supercapacitors and hydrogen production applications’’

‘‘Study of the electrochemical properties of polyaniline-integrated chromium oxide composite with metal–organic framework electrode (Cr2O3/Sn-MOF (PANI)) for asymmetric supercapacitors and hydrogen production applications’’

Enhanced ethanol synthesis via CO2 hydrogenation using La-Doped CuFeOx catalysts

CO2 hydrogenation is an effective solution for direct ethanol production as it realizes a high-value utilization of waste CO2. As it requires a synergistic multi-step process of CO2 activation, asymmetric hydrogenation of CO, and precise coupling of C-C bonds, the design of highly active and selective catalysts for such procedures remains challenging. In this study, we prepared a series of La-doped CuFe catalysts using a simple and green solvent-free ball milling method to accelerate the rate of CO2 hydrogenation to ethanol generation. HRTEM, in situ XRD, EPR, and CO2-TPD analyses indicated that the doping of moderate amounts of La can significantly improve the dispersion of the Cu and Fe species, enhance the interaction between the CuFe species, decrease the reduction temperatures of CuO and Fe2O3, promote the formation of oxygen vacancies during the reaction process, and enhance CO2 adsorption and activation ability. DFT calculations, XPS, in situ FTIR, and CO-TPSR-MS analyses indicated that the transfer of electrons from the Fe to La species decreased their electron cloud densities, weakened the bridge type adsorption of CO, enhanced the linear adsorption of CO, and optimized the ratio of the dissociative and non-dissociative adsorption of CO intermediates, which ultimately resulted in a better matching of the rates of generation of CHx* and C(H)O* intermediates. The occurrence of C-C coupling at the abundant Cu0-Fe5C2 interface promoted the highly efficient synthesis of ethanol, achieving yields as high as 13.5 % over the 5La-CuFeOx catalyst, ranking the top level among the reported catalysts in the literature. This study presents a feasible strategy for the targeted regulation of multicomponent active centers.

Advances in Asymmetric Hydrogenation of Unfunctionalized Enol Ethers

Advances in Asymmetric Hydrogenation of Unfunctionalized Enol Ethers

Cyclometalated IrIII Complex Possessing Chiral MIC ligand: Regiospecific sp3 C-H Activation and Asymmetric Transfer Hydrogenation of Ketone.

Cyclometalation offers a wide number of organometallic metallacycles showing diverse applications. However, such NHC complexes synthesized via an sp3 C-H bond activation are rare. An iridium(III) complex with a chiral mesoionic N-heterocyclic carbene (MIC) ligand, where the IrIII forms an additional Ir-C bond via a regiospecific sp3 C-H bond activation at the N-methylbenzyl wingtip, was synthesized and characterized. To our best knowledge, this represents the first example of cyclometalated iridium(III) complex possessing a chiral MIC donor ligand. The formation of the complex was followed by 2D correlation NMR spectroscopy and the molecular formula mass was evidenced by ESI-HRMS mass spectrometry. The molecular structure of the IrIII-MIC complex was unambiguously established by the single crystal XRD data. This cyclometalated IrIII complex was employed in the asymmetric transfer hydrogenation of 4-bromoacetophenone, and the complex was successful to transfer chirality to the final alcohol molecules (up to 92% ee).

Catalytic Asymmetric Transfer Hydrogenation of β,γ-Unsaturated α-Diketones.

Asymmetric transfer hydrogenation (ATH) has been recognized as a highly valuable strategy that allows access to enantioenriched substances and has been widely applied in the industrial production of drug molecules. However, despite the great success in ATH of ketones, highly efficient, regio- and stereoselective ATH on enones remains underdeveloped. Moreover, optically pure acyloins and 1,2-diols are both extremely useful building blocks in organic synthesis, medicinal chemistry, and materials science, but concise asymmetric approaches allowing access to different types of acyloins and 1,2-diols have scarcely been discovered. We report in this paper the first highly efficient ATH of readily accessible β,γ-unsaturated α-diketones. The protocol affords four types of enantioenriched acyloins and four types of optically pure 1,2-diols in highly regio- and stereoselective fashion. The synthetic value of this work has been showcased by the divergent synthesis of four related natural products. Moreover, systematic mechanistic studies and density functional theory (DFT) calculations have illustrated the origin of the reactivity divergence, revealed the different roles of aromatic and aliphatic substituents in the substrates, and provided a range of unique mechanistic rationales that have not been disclosed in ATH-related studies.

Highly Efficient and Enantioselective Iridium-Catalyzed Asymmetric Reductive Cycloetherification.

A catalytic protocol for the iridium-catalyzed asymmetric hydrogenation (AH) of γ- or δ-hydroxy ketones to rapidly assemble various aliphatic enantioenriched tetrahydrofurans (THFs) or tetrahydropyrans (THPs) is disclosed. A wide range of enantioenriched THFs or THPs were obtained in high yields and excellent enantioselectivities (up to 99% and up to 96.5:3.5 er). The dynamic kinetic resolution asymmetric hydrogenation (DKR-AH) process was also achieved, simultaneously constructing enantioenriched THP scaffolds with two contiguous stereogenic centers with high yields and stereoselectivities (up to 92% yield, up to 98.5:1.5 er and >20:1 dr). Mechanistic investigation indicates that the key step of the reaction involves the AH of the challenging cyclic, aliphatic oxocarbenium ions. Furthermore, this catalytic enantioselective approach could be carried out on a gram scale, and various enantioenriched cyclic ethers were further transformed into an array of useful building blocks for enantioenriched natural products and bioactive molecules.

Manganese-Catalyzed Asymmetric Hydrogenation for Atroposelective Dynamic Kinetic Resolution of Heterobiaryl Ketone N-Oxides

Manganese-Catalyzed Asymmetric Hydrogenation for Atroposelective Dynamic Kinetic Resolution of Heterobiaryl Ketone <i>N</i>-Oxides

Heterogeneous Asymmetric Hydrogenation of C═C and C═O Double Bonds

AbstractNowadays, heterogeneous catalysts play a crucial role in the field of asymmetric catalysis to produce enantiopure compounds for various applications. The unique properties of heterogeneous systems, such as high stability, reusability, or ease of separation, allow effective catalysis of asymmetric transformations and their further implementation in industrial processes. In this mini‐review, we address the recent trend in the synthesis of chiral heterogeneous catalysts and their subsequent application in asymmetric hydrogenation reactions. We focus on current advances in asymmetric hydrogenation reactions of C═C and C═O bonds due to their high relevance in the fine chemicals industry. Our main aim is to provide a short overview of this expanding field, its current challenges, and future perspectives.

Rhodium-Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of α-Nitro Ketones.

A catalytic protocol for the enantioselective hydrogenation and transfer hydrogenation of α-nitro ketones was developed, providing a wide range of β-nitro-α-phenylethanols with high yields and excellent enantioselectivities (up to 98% yield and up to >99.9% ee). Compatibility with a wide range of solvents and bases demonstrates the robustness of this reaction. The synthetic potential of the protocol was demonstrated by the high TON experiment as well as the application in the synthesis of key intermediates of mirabegron (S/C = 10,000, 95% yield, 99% ee).

Asymmetric Transfer Hydrogenation of 3‐Substituted 2H‐1,4‐Benzoxazines under Tethered Cp*Rh(III)‐Diamine Catalysis with Unexpected Reversal of Enantioselectivity

The asymmetric transfer hydrogenation of 3‐substituted 2H‐1,4‐benzoxazines with an azeotropic mixture of HCO2H/NEt3 (5/2) using tethered Cp*Rh(III)‐diamine catalysis has been realized. This process allows access to a broad range of chiral 3,4‐dihydro‐2H‐1,4‐benzoxazines in high yields with up to 99% ee, and tolerates a variety of functional groups. The enantiocontrol is achieved by the judicious choice of catalyst and hydrogen source. This reaction proceeds with unexpected reversal of enantioselectivity, which is attributed to the acidic reaction conditions and the hydrogen bond between the N−H of the rhodium species and the O atom in the substrate.

Palladium Single Atom-supported Covalent Organic Frameworks for Aqueous-phase Hydrogenative Hydrogenolysis of Aromatic Aldehydes via Hydrogen Heterolysis.

Developing a method for the tandem hydrogenative hydrogenolysis of bio-based furfuryl aldehydes to methylfurans is crucial for synthesizing sustainable biofuels and chemicals; however, it poses a challenge due to the easy hydrogenation of the C=C bond and difficult cleavage of the C-O bond. Herein, a palladium (Pd) single-atom-supported covalent organic framework was fabricated and showed a unique 2,5-dimethylfuran yield of up to 98.2% when reacted with 5-methyl furfuryl aldehyde in an unprecedented water solvent at 30°C. Furthermore, it exhibited excellent catalytic universality while converting various furfuryl-, benzyl-, and heterocyclic aldehydes at room temperature. The analysis of the catalytic mechanism confirmed that H2 was heterolytically activated on the Pd-N pair and triggered the keto-enol tautomerism of the covalent organic frameworks (COFs) host, resulting in H--Pd∙∙∙O-H+ sites. These sites served as novel asymmetric hydrogenation sites for the C=O group and hydrogenolysis sites for the C-OH group through a scarce SN2 mechanism. This study demonstrated remarkable bifunctional catalysis through the H2-induced keto-enol tautomerism of COF catalysts for the atypical preparation of methyl aromatics in a water solvent at room temperature.

Palladium Single Atom‐supported Covalent Organic Frameworks for Aqueous‐phase Hydrogenative Hydrogenolysis of Aromatic Aldehydes via Hydrogen Heterolysis

Developing a method for the tandem hydrogenative hydrogenolysis of bio‐based furfuryl aldehydes to methylfurans is crucial for synthesizing sustainable biofuels and chemicals; however, it poses a challenge due to the easy hydrogenation of the C=C bond and difficult cleavage of the C–O bond. Herein, a palladium (Pd) single‐atom‐supported covalent organic framework was fabricated and showed a unique 2,5‐dimethylfuran yield of up to 98.2% when reacted with 5‐methyl furfuryl aldehyde in an unprecedented water solvent at 30°C. Furthermore, it exhibited excellent catalytic universality while converting various furfuryl‐, benzyl‐, and heterocyclic aldehydes at room temperature. The analysis of the catalytic mechanism confirmed that H2 was heterolytically activated on the Pd–N pair and triggered the keto‐enol tautomerism of the covalent organic frameworks (COFs) host, resulting in H––Pd∙∙∙O–H+ sites. These sites served as novel asymmetric hydrogenation sites for the C=O group and hydrogenolysis sites for the C–OH group through a scarce SN2 mechanism. This study demonstrated remarkable bifunctional catalysis through the H2‐induced keto‐enol tautomerism of COF catalysts for the atypical preparation of methyl aromatics in a water solvent at room temperature.

Iridium‐Catalyzed Asymmetric Transfer Hydrogenation for Facile Access to Optically Active Dihydrodibenzo‐Fused Azepines

The asymmetric transfer hydrogenation of various dibenzo‐fused azepines including 5H‐dibenzo[b,e][1,4]diazepines, dibenzo[b,f][1,4]thiazepines and 11H‐dibenzo[b,e]azepines using chiral iridium diamine catalysts and HCO2H/NEt3 as the hydrogen source has been accomplished. A rang of chiral 10,11‐dihydro‐5H‐dibenzo[b,e][1,4]diazepines, 10,11‐dihydrodibenzo[b,f][1,4]thiazepine and 6,11‐dihydro‐5H‐dibenzo[b,e]azepines have been prepared in 82‐94% yields with 82‐99% ee. Diversely substituted substrates are suitable for this transformation, and a number of functional groups are tolerated. The enantiocontrol is achieved via judicious choice of catalyst, additive and hydrogen source. The synthetic potential of this reaction is explored through gram‐scale reactions without loss of reactivity and optical purity and further transformations on products.

Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Ketones Involving Free Phenolic Hydroxyl Group(s).

A straightforward asymmetric transfer hydrogenation for accessing enantiomerically enriched secondary benzyl alcohols involving free phenolic hydroxyl group(s) under mild conditions was developed. Various of optical pure aryl alcohols with a remarkable functional group compatibility were achieved with 78 %-97 % yields, 84 %->99 % ee's and up to 10 000 TON. This rhodium-catalyzed reaction could be performed in a gram-scale without loss of the efficiency. Furthermore, the synthetic utility has also been demonstrated in the asymmetric synthesis of (S)-adrenaline and (S)-phenylephrine.

Copper‐Catalyzed Asymmetric Hydrogenation of Unsymmetrical ortho‐Br Substituted Benzophenones

AbstractThe asymmetric hydrogenation of benzophenones, catalyzed by low‐activity earth‐abundant metal copper, has hitherto remained a challenge due to the substrates equipped with two indistinguishably similar aryl groups. In this study, we demonstrated that the prochiral carbon of the ortho‐bromine substrate exhibits the highest electrophilicity and high reactivity among the ortho‐halogen substituted benzophenones, as determined by the Fukui function (f+) analysis and hydrogenation reaction. Considering that the enantiodirecting functional bromine group can be easily derivatized and removed in the products, we successfully achieved a green copper‐catalyzed asymmetric hydrogenation of ortho‐bromine substituted benzophenones. This method yielded a series of chiral benzhydrols with excellent results. The utility of this protocol has been validated through a gram‐scale reaction and subsequent product transformations. Independent gradient model based on Hirshfeld partition (IGMH) and energy decomposition analysis (EDA) indicate that the CH⋅⋅⋅HC multiple attractive dispersion interactions (MADI) effect between the catalyst and substrate enhances the catalyst's activity.

Copper-Catalyzed Asymmetric Hydrogenation of Unsymmetrical ortho-Br Substituted Benzophenones.

The asymmetric hydrogenation of benzophenones, catalyzed by low-activity earth-abundant metal copper, has hitherto remained a challenge due to the substrates equipped with two indistinguishably similar aryl groups. In this study, we demonstrated that the prochiral carbon of the ortho-bromine substrate exhibits the highest electrophilicity and high reactivity among the ortho-halogen substituted benzophenones, as determined by the Fukui function (f+) analysis and hydrogenation reaction. Considering that the enantiodirecting functional bromine group can be easily derivatized and removed in the products, we successfully achieved a green copper-catalyzed asymmetric hydrogenation of ortho-bromine substituted benzophenones. This method yielded a series of chiral benzhydrols with excellent results. The utility of this protocol has been validated through a gram-scale reaction and subsequent product transformations. Independent gradient model based on Hirshfeld partition (IGMH) and energy decomposition analysis (EDA) indicate that the CH⋅⋅⋅HC multiple attractive dispersion interactions (MADI) effect between the catalyst and substrate enhances the catalyst's activity.