Indole Hydrogen Research Articles

A New Dynamic Kinetic Resolution Strategy for Asymmetric Hydrogenation of Indoles

A New Dynamic Kinetic Resolution Strategy for Asymmetric Hydrogenation of Indoles

Ru-NHC-Catalyzed Asymmetric, Complete Hydrogenation of Indoles and Benzofurans: One Catalyst with Dual Function.

The highly enantioselective and complete hydrogenation of protected indoles and benzofurans has been developed, affording facile access to a range of chiral three-dimensional octahydroindoles and octahydrobenzofurans, which are prevalent in many bioactive molecules and organocatalysts. Remarkably, we are in control of the nature of the ruthenium N-heterocyclic carbene complex and employed the complex as both homogeneous and heterogeneous catalysts, providing new avenues for its potential applications in the asymmetric hydrogenation of more challenging aromatic compounds.

Thermodynamics of hydrogen storage: Equilibrium study of the LOHC system indole/octahydroindole

Reversible hydrogenation of indole or its derivatives could be an attractive hydrogen storage technology. Particularly for hydrogen release, the reaction equilibrium is a crucial factor determining the conditions in the respective process. This study is supposed to provide inside into this reaction equilibrium. An experimental study of the chemical equilibrium of hydrogenation/dehydrogenation reactions was performed in a stirred autoclave with n–hexane as a solvent by varying the temperature, pressure, and hydrogen:feedstock ratio. Based on the compositions in stationary state, equilibrium constants have been derived. Furthermore, thermodynamic properties of chemical reactions were derived from the equilibrium constant temperature dependence. This temperature dependence reveals that the enthalpy of reaction for the dehydrogenation of the six-membered ring is significantly larger than in the nitrogen containing five-membered ring. To get deeper insides, the molar enthalpies of formation of intermediates have been calculated using high-level quantum chemical methods. This analysis supports the observations from the equilibrium reactions. Additionally, it show that the heat of reaction for the endothermal dehydrogenation is about 2 kJ mol (H2)–1 smaller in the liquid phase than in case of a gas phase reaction.

Pd/C-Catalyzed transfer hydrogenation of N-H indoles with trifluoroethanol and tetrahydroxydiboron as the hydrogen source.

Under the guidance of the known mechanism of the hydrogenation of indoles and transfer hydrogenation with tetrahydroxydiboron (B2(OH)4), Pd/C catalyzed transfer hydrogenation of N-H indoles with trifluoroethanol and tetrahydroxydiborane as the hydrogen source has been developed. This provides an efficient strategy and catalytic system for the reduction of un-activated N-H indoles, and N-H indolines are obtained with good to excellent yields. In addition, a series of the isotopic labelling experiments were carried out to probe the mechanism.

DFT insights in to the hydrodenitrogenation behavior differences between indole and quinoline

The hydrodenitrogenation behavior differences between indole and quinoline were investigated using density functional theory calculation to explain the phenomena of previous experimental results. Theoretical calculation was carried out to explain the results using GGA-RPBE function with dispersion force correlation. The process of hydrogenation of indole, quinoline and 1,2,3,4-tetrahydroquinoline as well as denitrogenation of o-ethylaniline and o-propylaniline were conducted on a NiMoS nanocluster. The results suggest Ni-S-Edge is suitable for hydrogenation saturation of aromatic rings of nitrogen compounds and Ni-Mo-Edge is responsible for hydrogenolysis of C–N bond via E2 path. Besides, indoline could be directly converted to o-ethylaniline, whereas the C–N bond of 1,2,3,4-tetrahydroquinoline could only be broken after complete saturation of the aromatic ring. The reason is that the N atom and CC bond of indoline could be coplanar and well adsorbed on Ni-Mo-Edge simultaneously, which is beneficial to reduce the activation energy of C–N bond cleavage.

Ring-opening and hydrodenitrogenation of indole under hydrothermal conditions over Ni, Pt, Ru, and Ni-Ru bimetallic catalysts

The activity and selectivity of activated-carbon-supported Ni, Pt, Ru, and Ni-Ru bimetallic catalysts was examined for hydrothermal denitrogenation of indole. The molar yield of pyrrole ring-opening compounds, without an added hydrogen source, are in the order: Ni < Pt < Ni90Ru10 < Ni75Ru25 < Ni50Ru50 ~ Ni25Ru75 ~ Ru. Ru-containing catalysts facilitated production of hydrocarbons (hydrodenitrogenation (HDN) products) when used with added formic acid (hydrogen source). We elucidated catalytic hydrothermal HDN pathways for indole based on the product distributions and the variation of their yields with time. Hydrogenation of indole to indoline is the primary pathway and ring-opening of indoline to form alkyl anilines is faster than forming HDN products (alkyl benzenes). DFT calculations confirmed experimental activity trends, showing Ru is more active than Ni for indole ring opening and for o-toluidine deamination. If no hydrogen source is present, directly breaking the N-C bond in the pyrrole ring is more favorable than breaking the C-N bond with an aromatic carbon. If a H source is provided, the pyrrole ring hydrogenates first, forming indoline, followed by cleavage of the C-N bond.

Iridium-Catalyzed Enantioselective Hydrogenation of Indole and Benzofuran Derivatives.

Enantioselective hydrogenation of a broad spectrum of N-, O-, and S-containing aromatic benzoheterocycles or nonaromatic unsaturated heterocycles has been realized by using an Ir/SpinPHOX (SpinPHOX=spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline) complex as the catalyst, affording an array of the corresponding chiral benzoheterocycles (30 examples) with excellent enantioselectivities (>99 % ee in most cases) and turnover numbers up to 500.

Molecular basis for the P450-catalyzed C-N bond formation in indolactam biosynthesis.

The catalytic versatility of cytochrome P450 monooxygenases is remarkable. Here, we present mechanistic and structural characterizations of TleB from Streptomyces blastmyceticus and its homolog HinD from Streptoalloteichus hindustanus, which catalyze unusual intramolecular C-N bond formation to generate indolactam V from the dipeptide N-methylvalyl-tryptophanol. In vitro analyses demonstrated that both P450s exhibit promiscuous substrate specificity, and modification of the N13-methyl group resulted in the formation of indole-fused 6/5/6 tricyclic products. Furthermore, X-ray crystal structures in complex with substrates and structure-based mutagenesis revealed the intimate structural details of the enzyme reactions. We propose that the generation of a diradical species is critical for the indolactam formation, and that the intramolecular C(sp2)-H amination is initiated by the abstraction of the N1 indole hydrogen. After indole radical repositioning and subsequent removal of the N13 hydrogen, the coupling of the properly-folded diradical leads to the formation of the C4-N13 bond of indolactam.

Correction to Brønsted-Acid-Promoted Rh-Catalyzed Asymmetric Hydrogenation of N-Unprotected Indoles: A Cocatalysis of Transition Metal and Anion Binding.

The incorporation of Bronsted acid, thiourea anion binding, and transition metal catalysis enables an efficient method to synthesize chiral indolines via hydrogenation of indoles. Catalyzed by a rhodium/ZhaoPhos complex, asymmetric hydrogenation of unprotected indoles is performed smoothly with excellent enantioselectivities (up to 99% ee, up to 400 TON). Bronsted acid HCl activates indoles to form iminium ion intermediates. Mechanistic studies support the assumption that anion binding plays a crucial role as a secondary interaction. DFT calculations reveal an outer-sphere mechanism in this chemical transformation.

Brønsted-Acid-Promoted Rh-Catalyzed Asymmetric Hydrogenation of N-Unprotected Indoles: A Cocatalysis of Transition Metal and Anion Binding.

The incorporation of Brønsted acid, thiourea anion binding, and transition metal catalysis enables an efficient method to synthesize chiral indolines via hydrogenation of indoles. Catalyzed by a rhodium/ZhaoPhos complex, asymmetric hydrogenation of unprotected indoles is performed smoothly with excellent enantioselectivities (up to 99% ee, up to 400 TON). Brønsted acid HCl activates indoles to form iminium ion intermediates. Mechanistic studies support the assumption that anion binding plays a crucial role as a secondary interaction. DFT calculations reveal an outer-sphere mechanism in this chemical transformation.

Density Functional Theory Mechanistic Study of Boron-Catalyzed N-Alkylation of Amines with Formic Acid: Formic Acid Activation by Silylation Reaction.

New methodology for the alkylation of amines is an intriguing issue in both academia and industry. Recently, several groups reported the metal-free B(C6 F5 )3 -catalyzed N-alkylation of amines, but the mechanistic details of these important reactions are unclear. Herein, a computational study was performed to elucidate the mechanism of the N-alkylation of amines with formic acid catalyzed by the Lewis acid B(C6 F5 )3 in the presence of hydrosilane. We found that the reaction started with the activation of formic acid through a novel model. Then, the high electrophilicity of the C center of the formic acid unit and the nucleophilic character of the amine resulted in a C-N coupling reaction. Finally, two sequential silyl-group and H- transfer steps occurred to generate the final product. Upon comparing the reaction barrier and the hydrogenation of indole, our mechanism is more favorable than that proposed by the group of Yu and Fu.

Atomic mutagenesis in ion channels with engineered stoichiometry.

C-type inactivation of potassium channels fine-tunes the electrical signaling in excitable cells through an internal timing mechanism that is mediated by a hydrogen bond network in the channels' selectively filter. Previously, we used nonsense suppression to highlight the role of the conserved Trp434-Asp447 indole hydrogen bond in Shaker potassium channels with a non-hydrogen bonding homologue of tryptophan, Ind (Pless et al., 2013). Here, molecular dynamics simulations indicate that the Trp434Ind hydrogen bonding partner, Asp447, unexpectedly 'flips out' towards the extracellular environment, allowing water to penetrate the space behind the selectivity filter while simultaneously reducing the local negative electrostatic charge. Additionally, a protein engineering approach is presented whereby split intein sequences are flanked by endoplasmic reticulum retention/retrieval motifs (ERret) are incorporated into the N- or C- termini of Shaker monomers or within sodium channels two-domain fragments. This system enabled stoichiometric control of Shaker monomers and the encoding of multiple amino acids within a channel tetramer.

Palladium-Catalyzed Asymmetric Hydrogenation of Indoles

Palladium-Catalyzed Asymmetric Hydrogenation of Indoles

Homogenous Pd-catalyzed asymmetric hydrogenation of unprotected indoles: scope and mechanistic studies.

An efficient palladium-catalyzed asymmetric hydrogenation of a variety of unprotected indoles has been developed that gives up to 98% ee using a strong Brønsted acid as the activator. This methodology was applied in the facile synthesis of biologically active products containing a chiral indoline skeleton. The mechanism of Pd-catalyzed asymmetric hydrogenation was investigated as well. Isotope-labeling reactions and ESI-HRMS proved that an iminium salt formed by protonation of the C═C bond of indoles was the significant intermediate in this reaction. The important proposed active catalytic Pd-H species was observed with (1)H NMR spectroscopy. It was found that proton exchange between the Pd-H active species and solvent trifluoroethanol (TFE) did not occur, although this proton exchange had been previously observed between metal hydrides and alcoholic solvents. Density functional theory calculations were also carried out to give further insight into the mechanism of Pd-catalyzed asymmetric hydrogenation of indoles. This combination of experimental and theoretical studies suggests that Pd-catalyzed hydrogenation goes through a stepwise outer-sphere and ionic hydrogenation mechanism. The activation of hydrogen gas is a heterolytic process assisted by trifluoroacetate of Pd complex via a six-membered-ring transition state. The reaction proceeds well in polar solvent TFE owing to its ability to stabilize the ionic intermediates in the Pd-H generation step. The strong Brønsted acid activator can remarkably decrease the energy barrier for both Pd-H generation and hydrogenation. The high enantioselectivity arises from a hydrogen-bonding interaction between N-H of the iminium salt and oxygen of the coordinated trifluoroacetate in the eight-membered-ring transition state for hydride transfer, while the active chiral Pd complex is a typical bifunctional catalyst, effecting both the hydrogenation and hydrogen-bonding interaction between the iminium salt and the coordinated trifluoroacetate of Pd complex. Notably, the Pd-catalyzed asymmetric hydrogenation is relatively tolerant to oxygen, acid, and water.

ChemInform Abstract: Highly Enantioselective Hydrogenation of N‐Unprotected Indoles Using (S)‐C10—BridgePHOS as the Chiral Ligand.

AbstractIt appears that substituents at the 2‐position play a significant role in the Pd‐catalyzed asymmetric hydrogenation of indoles in the presence of a macrocyclic PHOS‐type ligand.

Importance of indole N[sbnd]H hydrogen bonding in the organization and dynamics of gramicidin channels

The linear ion channel peptide gramicidin represents an excellent model for exploring the principles underlying membrane protein structure and function, especially with respect to tryptophan residues. The tryptophan residues in gramicidin channels are crucial for the structure and function of the channel. In order to test the importance of indole hydrogen bonding for the biophysical properties of gramicidin channels, we monitored the effect of N-methylation of gramicidin tryptophans, using a combination of steady state and time-resolved fluorescence approaches along with circular dichroism spectroscopy. We show here that in the absence of the hydrogen bonding ability of tryptophans, tetramethyltryptophan gramicidin (TM-gramicidin) is unable to maintain the single stranded, head-to-head dimeric channel conformation in membranes. Our results show that TM-gramicidin displays a red-shifted fluorescence emission maximum, lower red edge excitation shift (REES), and higher fluorescence intensity and lifetime, consistent with its nonchannel conformation. This is in agreement with the measured location (average depth) of the 1-methyltryptophans in TM-gramicidin using the parallax method. These results bring out the usefulness of 1-methyltryptophan as a fluorescent tool to examine the hydrogen bonding ability of tryptophans in proteins and peptides. We conclude that changes in the hydrogen bonding ability of tryptophans, along with coupled changes in peptide backbone structure induce the loss of single stranded β6.3 helical dimer conformation. These results agree with earlier results from size-exclusion chromatography and single-channel measurements for TM-gramicidin, and confirm the importance of indole hydrogen bonding for the conformation and function of ion channels and membrane proteins.

Highly enantioselective hydrogenation of N-unprotected indoles using (S)-C10–BridgePHOS as the chiral ligand

(S)-C10–BridgePHOS was successfully applied to a highly efficient Pd-catalyzed enantioselective hydrogenation of substituted indoles. The methodology was suitable for the hydrogenation of indoles substituted at the 2-, 3- and 2,3-positions. Products were obtained in quantitative conversion and up to 98% ee. The role the 2-position substituent plays in the hydrogenation process has been proposed. The methodology could be used as an alternative method to synthesize extremely important chiral indolines from N-unprotected indoles.

Asymmetric Hydrogenation of Unprotected Indoles

Chiral indolines are often found in natural products and other biologically active molecules. Many groups have explored asymmetric hydrogenation of indoles as a method to access this family. While success has been achieved with reduction of protected indoles, the use of unprotected substrates would provide a more direct route. The authors present the first example of a general, enantioselective hydrogenation of unprotected indoles to synthesize chiral indolines. Key to this finding was the use of a palladium catalyst under a high pressure of hydrogen gas in the presence of one equivalent of l-(-)-camphorsulfonic acid (l-CSA).

A comprehensive study on the 5-hydroxytryptamine 3A receptor binding of agonists serotonin and m-chlorophenylbiguanidine

Serotonin type 3 receptors (5-HT 3R) are members of the ligand gated ion channel receptor family. In this study, the interactions of the agonists serotonin (5-HT) and m-chlorophenylbiguanidine ( mCPBG) at the binding site of the 5-HT 3AR were investigated at an atomic level. Site-directed mutagenesis studies in Loop B and E along with our earlier published results from mutations within Loops A, C, and D provide comprehensive data on the interaction of 5-HT and mCPBG with 5-HT 3ARs. Using this data we have constructed a refined homology model of the 5-HT 3AR that considers all of the available experimental data. 5-HT and mCPBG were docked into the newly constructed homology model and the amino acid residues critical in binding of these agonists were compared and analyzed. Our docking results reveal many similar binding interactions for 5-HT and mCPBG. Namely, residues THR181, TRP183, PHE226, ILE228, TYR234 and GLU129 were all found to play key roles in binding of both 5-HT and mCPBG. However, the results also revealed two important differences that exist between the interactions of the two agonists. In our model, a hydrogen bond is formed between the indole hydrogen of 5-HT and the residue TYR153. This interaction is not present in the case of mCPBG. Conversely, a hydrogen bond exists between SER182 and a protonated nitrogen of mCPBG, which does not exist in 5-HT. Our modeling results were found to be in accordance with experimental data.

複素芳香族化合物インドールの触媒的不斉水素化

Catalytic asymmetric hydrogenation of olefins, ketones, and imines has widely been used to prepare various optically active compounds. Meanwhile, few asymmetric hydrogenations of aromatic groups had been reported until recently. We found hydrogenation of indoles to proceed with high enantioselectivity in the presence of a rhodium catalyst modified with a trans-chelating chiral ligand PhTRAP. The rhodium catalyst transformed N-acetylindoles bearing a substituent at 2-position into the corresponding indolines with up to 95% ee. 3-Substituted indoles were hydrogenated with high enantioselectivity (up to 98% ee) when their nitrogen was protected with a sulfonyl group. A PhTRAP-ruthenium catalyst exhibited high enantioselectivity (up to 95% ee) for the hydrogenation of N-Boc-indoles. The ruthenium complex catalyzed the hydrogenation of 2, 3-disubstituted indoles as well as 2- or 3-monosubstituted indoles. Furthermore, the recent progress of asymmetric hydrogenation of aromatic compounds was surveyed in this paper.