Asymmetric Hydrogenation Of Imines Research Articles

Dissymmetrically Substituted Diphosphines with Two Atropisomeric Axes and Their Application in Asymmetric Hydrogenation of Imines

AbstractDespite the great potential and widespread applications, the majority of diphosphine ligands used in asymmetric catalysis are C2‐symmetric and their structural modifications are often limited. Herein, we reported the design of original enantiopure dissymmetrical diphosphines, BiaxPhos, bearing two atropisomeric axes. Their original chiral architecture combined with important modularity, renders BiaxPhos ligands appealing candidates for asymmetric catalysis, as illustrated by the Ir‐BiaxPhos catalyzed asymmetric imines hydrogenation, furnishing chiral amines with excellent enantioselectivities under mild conditions. Remarkably, combined experimental mechanistic investigations and DFT calculations delineate yet unexplored mechanistic scenario implying the hydrogenation of the enamine tautomeric form instead of the classic reduction of the imine.

Asymmetric Hydrogenation of Imines Using NHC‐Phosphine Iridium Complexes

Abstractα‐Chiral amines represent a frequently observed functional group in pharmaceuticals. Here, the synthesis of such motifs (up to 91% ee) is described by asymmetric hydrogenation of imines catalyzed by NHC,P‐iridium complexes. The hydrogenation proceeded smoothly, even under balloon pressure of hydrogen atmosphere. Mechanistic experiments indicated that the reduction most likely advances by a combination of direct hydrogenation and a hydrogen transfer process using either H2 or iPrOH as the reductant, respectively.

On the Effect of Iodide and Acids in the Metolachlor Process

Iridium-catalyzed asymmetric imine hydrogenation is the key step in the industrial syntheses of dextromethorphan and metolachlor. Nevertheless, the mechanism of this reaction relying on ferrocenyldiphosphine ligands remains unclear. Through computational studies, we propose a mechanism that is in line with all experimental observations including the enantioselectivity. The calculated mechanism reveals the interplay of potentially three rate-determining transition states, namely, the migratory insertion, amido-ligand protonation, and heterolytic H2-activation. Most salient, the mechanism rationalizes the “magic iodide effect” in combination with proton co-catalysis, which improve the reaction rate as well as enantioselectivity. Acid additives accelerate both the protonation- and H2-splitting steps. Iodide further facilitates the protonation and potentially the H2-activation. Thus, these additives prevent that other elementary steps within the catalytic cycle compromise the enantioselectivity control exerted by the migratory insertion step.

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation.

Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, β, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.

Frustrated Lewis Pair Catalyzed Asymmetric Hydrogenation of Imines

Frustrated Lewis Pair Catalyzed Asymmetric Hydrogenation of Imines

A combined experimental and computational study to decipher complexity in the asymmetric hydrogenation of imines with Ru catalysts bearing atropisomerizable ligands

RuCl2(P–OP)(N–N) complexes containing an atropisomerizable phosphine–phosphite and a chiral diamine are effective catalyst precursors for the asymmetric hydrogenation of N-aryl imines following an outer-sphere mechanism.

Origin of Stereoselectivity in FLP-Catalyzed Asymmetric Hydrogenation of Imines

Development of metal-free strategies for stereoselective hydrogenation of unsaturated substrates is of particular interest in asymmetric synthesis. The emerging chemistry of frustrated Lewis pairs ...

Development of heterogeneous catalyst systems for the continuous synthesis of chiral amines via asymmetric hydrogenation

Continuous-flow synthesis of fine chemicals has several advantages over batch synthesis in terms of environmental compatibility, efficiency and safety. Nevertheless, most preparative methods still rely on conventional batch systems. For instance, chiral amines are ubiquitous functionalities in pharmaceutical compounds, but methods for their continuous synthesis with broad substrate generality remain very challenging. Here we show the development of heterogeneous iridium complexes combined with chiral phosphoric acids for the asymmetric hydrogenation of imines towards the continuous synthesis of chiral amines. Direct asymmetric reductive amination of ketones under a hydrogen atmosphere also proceeded smoothly using the same catalyst systems. Various chiral aromatic and aliphatic amines including pharmaceutical intermediates could be prepared in high yields with high enantioselectivities. It was found that continuous-flow reactions that use columns packed with the heterogeneous iridium complexes afforded chiral amines continuously for more than two days even at pressures lower than those in the corresponding batch reactions. The synthesis of chiral amines is of crucial importance for the pharmaceutical industry, but it remains a challenging task and is often inefficient. Now, a heterogeneous iridium complex is developed for the asymmetric hydrogenation of imines and the asymmetric reductive amination of carbonyl compounds in continuous flow with high yields and enantioselectivities.

Enantioselective Hydrogenation of Activated Aryl Imines Catalyzed by an Iron(II) P-NH-P' Complex.

Chiral amines are key building blocks in synthetic chemistry with numerous applications in the agricultural and pharmaceutical industries. Asymmetric imine hydrogenation, particularly with iridium catalysts, is well developed. However, imine reduction still remains challenging in the context of replacing such a precious metal with a cheap, nontoxic, and environmentally friendly substitute such as iron. Here, we report that an unsymmetrical iron P-NH-P' catalyst that was previously shown to be effective for the asymmetric hydrogenation of aryl ketones is also a very effective catalyst for the asymmetric hydrogenation of prochiral aryl imines activated with N-diphenylphosphinoyl or N-tosyl groups. The P-NH-P' abbreviation stands for (S,S)-PPh2CHPhCHPhNHCH2CH2PiPr2. Density functional theory results suggest that, surprisingly, the NH group on the catalyst activates and orients the imine to hydride attack by hydrogen bonding to the PO or SO group on the imine nitrogen, as opposed to the imine nitrogen itself. This may explain why N-Ph and N-Bu imines are not hydrogenated.

Click chemistry enables quantitative chiroptical sensing of chiral compounds in protic media and complex mixtures

Click reactions have become powerful synthetic tools with unique applications in the health and materials sciences. Despite the progress with optical sensors that exploit the principles of dynamic covalent chemistry, metal coordination or supramolecular assemblies, quantitative analysis of complex mixtures remains challenging. Herein, we report the use of a readily available coumarin conjugate acceptor for chiroptical click chirality sensing of the absolute configuration, concentration and enantiomeric excess of several compound classes. This method has several attractive features, including wide scope, fast substrate fixation without by-product formation or complicate equilibria often encountered in reversible substrate binding, excellent solvent compatibility, and tolerance of air and water. The ruggedness and practicality of this approach are demonstrated by comprehensive analysis of nonracemic monoamine samples and crude asymmetric imine hydrogenation mixtures without work-up. Click chemosensing addresses increasingly important time efficiency, cost, labor and chemical sustainability aspects and streamlines asymmetric reaction development at the mg scale.

Pd/Zn(OTf)2 Co‐Catalyzed Asymmetric Hydrogenation of Imines under Normal Pressure of Hydrogen

An efficient method for the asymmetric hydrogenation of cyclic and acyclic N‐sulfonylimines co‐catalyzed by Pd/Zn(OTf)2 using hydrogen gas under ambient pressure was developed. The methodology offers an easy access to generate chiral sulfonylamines in good yields and excellent enantioselectivities.

Asymmetric hydrogenation of imines with chiral alkene-derived boron Lewis acids.

With the aim of developing easily accessible chiral Lewis acids for asymmetric hydrogenation, a variety of binaphthyl-based chiral alkenes were prepared in one step from the corresponding diols. Using the in situ generated chiral boron Lewis acids through the hydroboration of chiral alkenes with Piers' borane, metal-free asymmetric hydrogenations of imines were realized to furnish the desired amine products in high yields with up to 89% ee.

Origin of the chemical stability of phosphine-phosphoramidites: structural study of an UPPhos-type crystal and application of UPPhos in the asymmetric hydrogenation of imines.

Phosphine-phosphoramidites (PPAs) are heterobidentate ligands that have been developed in the last two decades and have been used successfully in asymmetric catalytic reactions. A single crystal of the PPA (11bS)-N-[(2S,4S)-4-(diphenylphosphanyl)pentan-2-yl]-N-methyldinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-amine, C38H35NO2P2, was prepared and structurally characterized by single-crystal X-ray diffraction and density functional theory (DFT) calculations. Structure elucidation revealed unique features which might have a significant effect in the excellent chemical stability of this type of molecule. The conformation of the molecule provides an optimal chelating structure. Iridium complexes of UPPhos were found to be efficient catalysts in the asymmetric hydrogenation of imines {UPPhos is (11bS)-N-[(2S,4S)-4-(diphenylphosphanyl)pentan-2-yl]-N-(propan-2-yl)dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-amine}.

Triply Halide-Bridged Dinuclear Iridium(III) Complexes with Chiral Diphosphine Ligands as New Easy-to-Handle Iridium Catalysts for Asymmetric Hydrogenation of Imines and N-Heteroaromatics.

Iridium(III) complexes bearing chiral ligands have proved to be active species in asymmetric hydrogenation of C=N bonds, though there are only a few iridium(III) precursors. We prepared triply halide-bridged dinuclear iridium complexes bearing chiral diphosphine ligands by simple treatment of the iridium(I) precursor, chiral diphosphine, and aqueous hydrogen halide. The strong advantage of these dinuclear iridium complexes is that they are air and moisture stable, leading to easy handling in asymmetric synthesis. The dinuclear iridium complexes exhibited high catalytic activity toward asymmetric hydrogenation of imines and N-heteroaromatics. Moreover, we demonstrated the application of triply halide-bridged dinuclear ruthenium(II) and rhodium(III) catalyst precursors for the asymmetric hydrogenation of ketonic substrates and simple olefins, respectively.

Achiral Cyclopentadienone Iron Tricarbonyl Complexes Embedded in Streptavidin: An Access to Artificial Iron Hydrogenases and Application in Asymmetric Hydrogenation

We report on the synthesis of biotinylated (cyclopentadienone)iron tricarbonyl complexes, the in situ generation of the corresponding streptavidin conjugates and their application in asymmetric hydrogenation of imines and ketones.

ChemInform Abstract: Pinene‐Derived Monodentate Phosphoramidites for Asymmetric Hydrogenation.

AbstractNewly synthesized phosphoramidite ligands are used in asymmetric catalysis.

Iron/Brønsted Acid Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity-Determining Interactions.

Hydrogenation catalysts involving abundant base metals such as cobalt or iron are promising alternatives to precious metal systems. Despite rapid progress in this field, base metal catalysts do not yet achieve the activity and selectivity levels of their precious metal counterparts. Rational improvement of base metal complexes is facilitated by detailed knowledge about their mechanisms and selectivity-determining factors. The mechanism for asymmetric imine hydrogenation with Knölker's iron complex in the presence of chiral phosphoric acids is here investigated computationally at the DFT-D level of theory, with models of up to 160 atoms. The resting state of the system is found to be an adduct between the iron complex and the deprotonated acid. Rate-limiting H2 splitting is followed by a stepwise hydrogenation mechanism, in which the phosphoric acid acts as the proton donor. C-H⋅⋅⋅O interactions between the phosphoric acid and the substrate are involved in the stereocontrol at the final hydride transfer step. Computed enantiomeric ratios show excellent agreement with experimental values, indicating that DFT-D is able to correctly capture the selectivity-determining interactions of this system.

Pinene‐Derived Monodentate Phosphoramidites for Asymmetric Hydrogenation

AbstractPhosphoramidite ligands based on pinene‐derived chiral amines have been prepared by a straightforward procedure in good yields. The key step of the synthetic protocol is a stereoselective hydrogenation of annulated pinene–pyridine derivatives leading to (diastereoisomeric) secondary amines that were separated and treated with different chlorophosphites to yield the envisaged phosphoramidites. The absolute configurations of the ligands were assigned on the basis of NMR analyses and corroborated by X‐ray diffraction analysis of a borane adduct of a typical ligand. The new ligands were employed in the asymmetric hydrogenation of imines and olefins. The iridium‐catalyzed hydrogenation of imines provided up to 81 % ee, whereas in the rhodium‐catalyzed hydrogenation of functionalized olefins enantioselectivities of up to 99 % ee were achieved. In this particular application, the different chiral elements of the ligand structure led to synergistic effects and the enantioselectivity is dominated by the chiral diol moiety.

ChemInform Abstract: Asymmetric Hydrogenation of Imines via Metal—Organo Cooperative Catalysis

AbstractReview: [19 refs.

Asymmetric Hydrogenation of Imines via Metal–Organo Cooperative Catalysis

The combination of a chiral phosphoric acid with an iridium complex affords a catalyst that allows for highly enantioselective hydrogenation of imines. Mechanistic studies suggest that the hydrogenation proceeds through a ternary transition state at the ­hydride-transfer step, in which the organocatalyst interacts with both the hydride donor and acceptor.