Iridium-Catalyzed Transfer Hydrogenation Research Articles

Iridium-catalyzed chemoselective transfer hydrogenation of α, β-unsaturated ketones to saturated ketones in water

A chemoselective iridium-catalyzed transfer hydrogenation of α, β-unsaturated ketones was realized in water. The CC double bonds of 2-benzylidene indanones and analogues were hydrogenated exclusively catalyzed by an iridium complex (0.1 mol%) bearing a pyridine-imidazoline ligand, using a mixture of formic acid/triethyl amine (molar ratio: 5/2) as a hydrogen source in water. A series of 2-benzyl indanones and analogues were obtained with good functional group tolerance and good yields. The practicability of this approach is also demonstrated by a gram-scale synthesis.

Synthesis of N-alkoxy amines and hydroxylamines via the iridium-catalyzed transfer hydrogenation of oximes.

Cationic iridium (Ir) complexes were found to catalyze the transfer hydrogenation of oximes to access N-alkoxy amines and hydroxylamines, and the reaction was accelerated by trifluoroacetic acid. The practical application of this protocol was demonstrated by a gram-scale transformation and two-step synthesis of the fungicide furmecyclox (BAS 389F) in overall yields of 92 and 85%, respectively. An asymmetric protocol using chiral Ir complexes to afford chiral N-alkoxy amines was demonstrated, but the low yields/ee obtained indicated that further development was required.

Iridium-Catalyzed Transfer Hydrogenation for Construction of Quinolines from 2-Aminobenzyl Alcohols with Enones in Water

AbstractHerein, we describe a method for the synthesis of functionalized quinolines from 2-aminobenzyl alcohols with α,β-unsaturated ketones. This method exhibits tolerance to various functional groups and high efficiency, is environmentally benign, and can be performed on a gram scale. Control experiments suggest that this transformation is accomplished by iridium complex catalyzed transfer hydrogenation, which is then followed by Friedländer cyclization. The results display that alkali is essential for the high selectivities of this catalytic system.

Iridium Complex-Catalyzed Transfer Hydrogenation of N-Heteroarenes and Tentative Asymmetric Synthesis.

An iridium-catalyzed transfer hydrogenation of N-heteroarenes to access a series of substituted 1,2,3,4-tetrahydroquinoline derivatives in excellent yields is disclosed. This transformation is distinguished with water-soluble and air-stable iridium complexes as the catalyst, formic acid as the hydrogen source, mild reaction conditions, and broad functional group compatibility. Most importantly, a tentative chiral N,N-chelated Cp*Ir(III) complex-catalyzed enantioselective transfer hydrogenation is also presented, affording chiral products in excellent yields and good enantioselectivities.

Polypyridyl iridium(III) based catalysts for highly chemoselective hydrogenation of aldehydes

Iridium-catalyzed transfer hydrogenation (TH) of carbonyl compounds using HCOOR (R = H, Na, NH4) as a hydrogen source is a pivotal process as it provides the clean process and is easy to execute. However, the existing highly efficient iridium catalysts work at a narrow pH; thus, does not apply to a wide variety of substrates. Therefore, the development of a new catalyst which works at a broad pH range is essential as it can gain a broader scope of utilization. Here we report highly efficient polypyridyl iridium(III) catalysts, [Ir(tpy)(L)Cl](PF6)2 {where tpy = 2,2′:6′,2′'-Terpyridine, L = phen (1,10-Phenanthroline), Me2phen (4,7-Dimethyl-1,10-phenanthroline), Me4phen (3,4,7,8-Tetramethyl-1,10-phenanthroline), Me2bpy (4,4′-Dimethyl-2–2′-dipyridyl)} for the chemoselective reduction of aldehydes to alcohols in aqueous ethanol and sodium formate as the hydride source. The reaction can be carried out efficiently in broad pH ranges, from pH 6 to 11. These catalysts are air stable, easy to prepare using commercially available starting materials, and are highly applicable for a wide range of substrates, such as electron-rich or deficient (hetero)arenes, halogens, phenols, alkoxy, ketones, esters, carboxylic acids, cyano, and nitro groups. Particularly, acid and hydroxy groups containing aldehydes were reduced successfully in basic and acidic reaction conditions, demonstrating the efficiency of the catalyst in a broad pH range with high conversion rates under microwave irradiation.

Ligand-Promoted Iridium-Catalyzed Transfer Hydrogenation of Terminal Alkynes with Ethanol and Its Application.

A ligand-promoted iridium-catalyzed transfer hydrogenation of terminal alkynes with ethanol and its application has been developed. Highly chemical selectivity control is achieved based on ligand regulation. 1,2-Bis(diphenylphosphino)ethane was found to be critical for the transfer hydrogenation of alkynes. The general applicability of this procedure is highlighted by the synthesis of 30 terminal alkenes with a good yield. In addition, we conducted drug effect studies of phenelzine using zebrafish as the vertebrate model. Phenelzine shows a significant effect on promoting vascular proliferation and inhibiting nerve growth. The results of these studies have an important reference value for promoting drug research in cerebrovascular diseases, epilepsy, mania, and psychosis.

Iridium-Catalyzed Alkene-Selective Transfer Hydrogenation with 1,4-Dioxane as Hydrogen Donor.

The iridium-catalyzed transfer hydrogenation of alkenes using 1,4-dioxane as a hydrogen donor is described. The use of 1,2-bis(dicyclohexylphosphino)ethane (DCyPE), featuring bulky and highly electron-donating properties, led to high catalytic activity. A polystyrene-cross-linking bisphosphine PS-DPPBz produced a reusable heterogeneous catalyst. These homogeneous and heterogeneous protocols achieved chemoselective transfer hydrogenation of alkenes over other potentially reducible functional groups such as carbonyl, nitro, cyano, and imino groups in the same molecule.

Iridium-Catalyzed Transfer Hydrogenation of Ketones and Aldehydes Using Glucose as a Sustainable Hydrogen Donor

A new catalytic system for transfer hydrogenation of carbonyl compounds using glucose as a hydrogen donor was developed. Various ketones and aldehydes were efficiently converted to corresponding alcohols with two equivalents of glucose in the presence of a small amount (0.1 to 1.0 mol%) of iridium catalyst that had a functional ligand. In this catalytic system, transfer hydrogenation reactions proceeded based on the cooperativity of iridium and a functional ligand. It should be noted that environmentally benign water could have been used as a solvent in the present catalytic system for the reduction of various carbonyl substrates. Furthermore, the reaction scope could be extended by using N,N-dimethylacetamide as a reaction solvent.

Artificial Metalloenzymes Based on the Biotin-Streptavidin Technology: Enzymatic Cascades and Directed Evolution.

ConspectusArtificial metalloenzymes (ArMs) result from anchoring a metal-containing moiety within a macromolecular scaffold (protein or oligonucleotide). The resulting hybrid catalyst combines attractive features of both homogeneous catalysts and enzymes. This strategy includes the possibility of optimizing the reaction by both chemical (catalyst design) and genetic means leading to achievement of a novel degree of (enantio)selectivity, broadening of the substrate scope, or increased activity, among others. In the past 20 years, the Ward group has exploited, among others, the biotin–(strept)avidin technology to localize a catalytic moiety within a well-defined protein environment. Streptavidin has proven versatile for the implementation of ArMs as it offers the following features: (i) it is an extremely robust protein scaffold, amenable to extensive genetic manipulation and mishandling, (ii) it can be expressed in E. coli to very high titers (up to >8 g·L–1 in fed-batch cultures), and (iii) the cavity surrounding the biotinylated cofactor is commensurate with the size of a typical metal-catalyzed transition state. Relying on a chemogenetic optimization strategy, varying the orientation and the nature of the biotinylated cofactor within genetically engineered streptavidin, 12 reactions have been reported by the Ward group thus far. Recent efforts within our group have focused on extending the ArM technology to create complex systems for integration into biological cascade reactions and in vivo.With the long-term goal of complementing in vivo natural enzymes with ArMs, we summarize herein three complementary research lines: (i) With the aim of mimicking complex cross-regulation mechanisms prevalent in metabolism, we have engineered enzyme cascades, including cross-regulated reactions, that rely on ArMs. These efforts highlight the remarkable (bio)compatibility and complementarity of ArMs with natural enzymes. (ii) Additionally, multiple-turnover catalysis in the cytoplasm of aerobic organisms was achieved with ArMs that are compatible with a glutathione-rich environment. This feat is demonstrated in HEK-293T cells that are engineered with a gene switch that is upregulated by an ArM equipped with a cell-penetrating module. (iii) Finally, ArMs offer the fascinating prospect of “endowing organometallic chemistry with a genetic memory.” With this goal in mind, we have identified E. coli’s periplasmic space and surface display to compartmentalize an ArM, while maintaining the critical phenotype–genotype linkage. This strategy offers a straightforward means to optimize by directed evolution the catalytic performance of ArMs. Five reactions have been optimized following these compartmentalization strategies: ruthenium-catalyzed olefin metathesis, ruthenium-catalyzed deallylation, iridium-catalyzed transfer hydrogenation, dirhodium-catalyzed cyclopropanation and carbene insertion in C–H bonds. Importantly, >100 turnovers were achieved with ArMs in E. coli whole cells, highlighting the multiple turnover catalytic nature of these systems.

Iridium-Catalyzed Transfer Hydrogenation of 1,10-Phenanthrolines

Key words transfer hydrogenation - phenanthrolines - formic acid - iridium catalysis

Diastereo- and Enantioselective Iridium Catalyzed Carbonyl (α-Cyclopropyl)allylation via Transfer Hydrogenation.

The first examples of diastereo- and enantioselective carbonyl α-(cyclopropyl)allylation are reported. Under the conditions of iridium catalyzed transfer hydrogenation using the chiral precatalyst (R)-Ir-I modified by SEGPHOS, carbonyl α-(cyclopropyl)allylation may be achieved with equal facility from alcohol or aldehyde oxidation levels. This methodology provides a conduit to hitherto inaccessible inaccessible enantiomerically enriched cyclopropane-containing architectures.

Iridium-catalyzed transfer hydrogenation of nitroarenes to anilines

An [Ir(cod)Cl]2/phenanthroline catalytic system shows high activity for the reduction of nitroarenes to aminoarenes using 2-propanol as a hydrogen donor.

ChemInform Abstract: Highly Efficient Transformation of Levulinic Acid into Pyrrolidinones by Iridium Catalyzed Transfer Hydrogenation.

AbstractSimilar transfer hydrogenation of S‐oxohexanoic acid provides access to corresponding pyridinone derivatives (V).

Iridium-Catalyzed Asymmetric Transfer Hydrogenation in Water

Iridium-Catalyzed Asymmetric Transfer Hydrogenation in Water

Catalytic enantioselective Grignard Nozaki–Hiyama methallylation from the alcohol oxidation level: chloride compensates for π-complex instability

Methallyl chloride serves as an efficient allyl donor in highly enantioselective Grignard Nozaki-Hiyama methallylations from the alcohol or aldehyde oxidation level via iridium catalyzed transfer hydrogenation. Under identical conditions, methallyl acetate does not react efficiently. Double methallylation of 1,3-propanediol provides the C(2)-symmetric adduct as a single enantiomer, as determined by HPLC analysis.

Enantioselective Carbonyl Allylation, Crotylation, and tert-Prenylation of Furan Methanols and Furfurals via Iridium-Catalyzed Transfer Hydrogenation

5-Substituted-2-furan methanols 1a-c are subject to enantioselective carbonyl allylation, crotylation and tert-prenylation upon exposure to allyl acetate, alpha-methyl allyl acetate, or 1,1-dimethylallene in the presence of an ortho-cyclometalated iridium catalyst modified by (R)-Cl,MeO-BIPHEP, (R)-C3-TUNEPHOS, and (R)-C3-SEGPHOS, respectively. In the presence of 2-propanol, but under otherwise identical conditions, the corresponding substituted furfurals 2a-c are converted to identical products of allylation, crotylation, and tert-prenylation. Optically enriched products of carbonyl allylation, crotylation, and reverse prenylation 3b, 4b, and 5b were subjected to Achmatowicz rearrangement to furnish the corresponding gamma-hydroxy-beta-pyrones 6a-c, respectively, with negligible erosion of enantiomeric excess.

Diastereo- and Enantioselective anti-Alkoxyallylation Employing Allylic gem-Dicarboxylates as Allyl Donors via Iridium-Catalyzed Transfer Hydrogenation

Enantioselective transfer hydrogenation of gem-dibenzoate 1e in the presence of aromatic, alpha,beta-unsaturated, or aliphatic aldehydes 2a-i mediated by isopropyl alcohol and employing a cyclometalated iridium C,O-benzoate derived from allyl acetate, 4-cyano-3-nitrobenzoic acid, and (R)-SEGPHOS delivers products of alkoxyallylation 3a-i, 4a, 4e, 4f, and 4i in good isolated yields (62-82%) with good to excellent diastereoselectivities (7:1 to 18:1 dr) and exceptional enantioselectivities (90-99% ee). This protocol provides an alternative to the use of premetalated nucleophiles in carbonyl alkoxyallylation.

Elongation of 1,3-Polyols via Iterative Catalyst-Directed Carbonyl Allylation from the Alcohol Oxidation Level

Iterative enantioselective carbonyl allylation from the alcohol oxidation level under the conditions of iridium catalyzed transfer hydrogenation enables chain elongation of 1,3-polyols. High levels of catalyst-directed enantioselectivity and diastereoselectivity are observed.

1,n‐Glycols as Dialdehyde Equivalents in Iridium‐Catalyzed Enantioselective Carbonyl Allylation and Iterative Two‐Directional Assembly of 1,3‐Polyols

Unstable? We're able! 1,n-Glycols serve as synthetic equivalents to unstable dialdehydes in two-directional carbonyl allylation from the alcohol oxidation level under iridium-catalyzed transfer hydrogenation conditions. Iterative asymmetric allylation employing 1,3-propanediol enables the rapid assembly of protected 1,3-polyol substructures with exceptional levels of stereocontrol.

Reductive Alkylation of Proteins Using Iridium Catalyzed Transfer Hydrogenation

An efficient transition metal catalyzed procedure for the reductive alkylation of proteins has been developed. Imines formed from the condensation of aldehydes (1 mM) with lysine residues and the N-terminus can be reduced efficiently by a [Cp*Ir(4,4'-dimethoxy-2,2'-bipyridine)(H2O)]SO4 catalyst in the presence of formate ions. The reaction proceeds readily at pH 7.4 in aqueous phosphate buffer at temperatures ranging from 22 to 37 degrees C, and reaches high levels of conversion for a number of aromatic aldehydes. UV experiments have confirmed that the catalyst does not bind to protein substrates. The utility of the reaction has been demonstrated through an efficient two-step procedure for the attachment of unfunctionalized poly(ethylene glycol) to protein targets.