Imidazoline Ring Research Articles

S‐Nucleophilic Imidazoline Ring Expansion: a Novel Approach to the Formation of Medium‐Sized Thiolactames

AbstractA novel method has been successfully developed for the synthesis of medium‐sized heterocycles containing thioamide groups. This approach facilitates the expansion of the imidazoline moiety within the condensed ring system through the action of S‐nucleophiles, enabling access to a broader and more diverse chemical space for natural product analogs and bioactive compounds. A series of [1,4,7]thia‐(oxa−)diazecin‐9‐thiones were efficiently synthesized from diarene‐fused [1.4]heteroazepines using this transformation, achieving yields ranging from 28–58 %.

Novel synthesis of 11C-labeled imidazolines via Pd(0)-mediated 11C-carbomethoxylation using [11C]CO and arylborons.

A labeling technique was developed for the imidazoline I2 receptor ligand 2-(3-fluoro-tolyl)-4, 5-dihydro-1H-imidazole (FTIMD) using Pd(0)-mediated 11C-carbomethoxylation with [11C]CO, followed by imidazoline ring formation with ethylenediamine-trimethylaluminium (EDA-AlMe3). To achieve this, [11C]CO was passed through a methanol (MeOH) solution containing 3-fluoro-4-methylphenylboronic acid (1), palladium (II) acetate (Pd [OAc]2), triphenylphosphine (PPh3), and p-benzoquinone (PBQ). The mixture was then heated at 65°C for 5min. EDA was introduced into the reaction mixture, and MeOH was completely evaporated at temperatures exceeding 100°C. The dried reaction mixture was combined with an EDA-AlMe (1:1) toluene solution and heated at 145°C for 10min. Portions of the reaction mixture were analyzed through high-performance liquid chromatography, resulting in [11C]FTIMD with 26% (n= 2) decay-corrected radiochemical yield (RCY). This method could be utilized for various arylborons to produce [2-11C]imidazolines 4a-h with RCYs ranging from low to moderate. Notably, [2-11C]benazoline was obtained with a moderate RCY of 65%. The proposed technique serves as an alternative to the Grignard method, which uses [11C]CO to generate a [2-11C]-labeled imidazoline ring.

Synthesis and structures of dinuclear palladium complexes with 1,3-benzimidazolidine-2-thione and 1,3-imidazoline-2-thione.

The synthesis and structures of dinuclear palladium complexes with 1,3-benz-imidazolidine-2-thione (bzimtH) and 1,3-imidazoline-2-thione (imtH) are reported, namely, bis-(μ-1H-benzimidazole-2-thiol-ato)-κ2 N 3:S;κ2 S:N 3-bis-[cyanido(tri-phenyl-phosphine-κP)palladium(II)], [Pd2(C7H5N2S)2(CN)2(C18H15P)2] or [Pd2(μ-N,S-bzimtH)2(CN)2(PPh3)2] (1), and bis-(μ-1H-imidazole-2-thiol-ato)-κ2 N 3:S;κ2 S:N 3-bis-[cyanido(tri-phenyl-phosphine-κP)palladium(II)] aceto-nitrile 0.58-solvate, [Pd2(C3H3N2S)2(CN)2(C18H15P)2]·0.58C2H3N or [Pd2(μ-N,S-imtH)2(CN)2(PPh3)2]·0.58C2H3N (2). The compound [Pd2(μ-N,S-bzimtH)2(CN)2(PPh3)2] is located on a crystallographic twofold axis while [Pd2(μ-N,S-imtH)2(CN)2(PPh3)2]. 0.58(C2H3N) contains two partially occupied aceto-nitrile solvent mol-ecules with occupancies of 0.25 and 0.33. In both of these compounds, the anionic bzimtH- and imtH- ligands coordinate through N,S-donor atoms in a bridging mode, covering four coordination sites of two metal centers and other two sites are occupied by two PPh3 ligand mol-ecules. Finally, the remaining two sites of two metal centers are occupied by cyano groups, abstracted by the metals from the solvent during reaction. In the packing of the 1,3-benzimidazolidine- 2-thione and 1,3-imidazoline-2-thione complexes, there are intra-molecular π-π inter-actions involving the thione moiety as well as an N-H⋯N hydrogen bond linking the thione and cyano ligands. In addition, in 2, as well as the π-π inter-action involving the thione moieties, there is an additional π-π inter-action involving one of the thione moieties and an adjacent phenyl ring from the tri-phenyl-phosphine ligand. There are also C-H⋯N inter-actions between the imidazoline rings and the aceto-nitrile N atoms.

Molecular docking and in vitro evaluations reveal the role of human cytochrome P450 3A4 in the cross-coupling metabolism of phenolic xenobiotics

Metabolism generally transforms xenobiotics into more polar and hydrophilic products, facilitating their elimination from the body. Recently, a new metabolic pathway that transforms phenolic xenobiotics into more lipophilic and bioactive dimer products was discovered. To elucidate the role of cytochrome P450 (CYP) enzymes in mediating this cross-coupling metabolism, we used high-throughput screening to identify the metabolites generated from the coupling of 20 xenobiotics with four endogenous metabolites in liver microsomes. Endogenous vitamin E (VE) was the most reactive metabolite, as VE reacted with seven phenolic xenobiotics containing various structures (e.g., an imidazoline ring or a diphenol group) to generate novel lipophilic ethers such as bakuchiol-O-VE, phentolamine-O-VE, phenylethyl resorcinol-O-VE, 2-propanol-O-VE, and resveratrol-O-VE. Seven recombinant CYP enzymes were successfully expressed and purified in Escherichia coli. Integration of the results of recombinant human CYP incubation and molecular docking identified the central role of CYP3A4 in the cross-coupling metabolic pathway. Structural analysis revealed the π–π interactions, hydrogen bonds, and hydrophobic interactions between reactive xenobiotics and VE in the malleable active sites of CYP3A4. The consistency between the molecular docking results and the in vitro human cytochrome P450 evaluation shows that docking calculations can be used to screen molecules participating in cross-coupling metabolism. The results of this study provide supporting evidence for the overlooked toxicological effects induced by direct reactions between xenobiotics and endogenous metabolites during metabolic processes.

Steric Push towards the [n+3] Hydrated Imidazoline Ring Expansion (HIRE) of Dibenzo[1.4]oxazepines and Thiazepines

AbstractThe influence of introducing substituents of increasing bulk in α position of tetracyclic imidazoline‐fused heteroazepinones on the course of hydrated imidazoline ring expansion (HIRE) reaction was established. Under certain conditions, substituted β‐aminoethanols can be used to obtain solely the ring expanded products from dibenzo[b,f][1,4]ox(thi)azepin‐11(10H)‐ones while with their unsubstituted counterparts, side chain expulsion was the only observable outcome.

The catalytic mechanism of the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2)

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using computational modeling and simulations, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate , while together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate , and further stabilizes Pi by forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of , and Pi. Our computational study at the empirical valence bond level allowed us also to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution connected to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues, Ser197/Arg233, are important factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer treatment.

Tuning StackPhim Ligands: Applications in Enantioselective Borylation and Alkynylation

AbstractHere we present a new stack ligand with a modified imidazoline backbone prepared from cyclohexanediamine. This new stack ligand­, Cy-StackPhim, has been found to complement the parent StackPhim ligand in an enantioselective borylation reaction. Additionally, a correlation between the nature of substituents on the imidazoline ring and the substituents on the electrophile is also discussed.

Constructing unconventional fluorescent molecules by imidazoline ring and its salt of carboxylic acid and their application

Recently, fluorescent compounds without conventional chromophores have attracted considerable attention. One of the effective strategies for forming unconventional fluorescent compounds is to figure out the unconventional chromophores, then to develop more excellent fluorescent molecules with these structures. The imidazoline ring is one of the unconventional chromophores exhibiting fluorescence because of its planarity and rigidity. The imidazoline ring was used as the raw material for constructing unconventional fluorescent molecules in this paper. When acetic acid was introduced into imidazoline (2-MZ) to form 2-methylimidazoline acetate (2-MZA), the fluorescence significantly increased. Furthermore, by analyzing the change in fluorescence during the crystal and solution states of 2-MZ and 2-MZA, the result demonstrated the intermolecular interaction, that is, clusters of aggregated oxygen atoms influenced molecular fluorescence. Moreover, we explored the applications of 2-MZ and its ionic liquid in metal ion recognition, pH sensing, and fluorescent staining in living HeLa cells.

Heteroatom is not needed: Access to dibenzo[e,h][1,4]diazecin-9-ones from dibenzo[b,e]azepin-6-one via the hydrated imidazoline ring expansion (HIRE) approach

5,11-Dihydro-6H-dibenzo[b,e]azepin-6-ones were for the first time expanded into 5,7,8,14-tetrahydrodibenzo[e,h][1,4]diazecin-9(6H)-ones via the so-called “hydrated imidazoline ring expansion” (HIRE).

Significant Broadening of the Substrate Scope for the Hydrated Imidazoline Ring Expansion (HIRE) via the Use of Lithium Hexamethyldisilazide

AbstractSubstrates that are insufficiently activated towards the hydrated imidazoline ring expansion (HIRE) process have been previously found to deliver exclusively the products of aminoalkyl side-chain ring expansion. Attempted reversal of the process by thermal activation towards HIRE failed. We have found that for such problematic substrates the HIRE-type ring expansion can be effectively achieved by applying lithium hexamethyldisilazide (LHMDS) in toluene. LHMDS is thought to promote intramolecular transamidation, which leads to ring-expanded 10- and 11-membered heterocyclic products in modest to good yields. The process significantly broadens the substrate scope amenable to the HIRE strategy.

An Attempt to Achieve Hydrated Imidazoline Ring Expansion (HIRE) of Diarene-Fused [1,4]Diazepinones Delivers Selective Dopamine D2 Receptor Ligands

AbstractAttempts to extend the hydrated imidazoline ring expansion (HIRE) strategy to a series of diarene-fused [1,4]diazepinones (earlier applied successfully to bis-pyrido substrate nevirapine) did not result in ring expansion but, rather, led to 2-aminoethyl side chain expulsion. This seeming setback (setting the limitations to the HIRE methodology substrate scope) led to the discovery of selective dopamine D2 ligands with elements of structure–activity relationships.

Characterization of a Solvent-Tolerant Amidohydrolase Involved in Natural Product Heterocycle Formation

Heterocycles are important building blocks in pharmaceutical drugs and their enzymatic synthesis is attracting increasing interest. In recent years, various enzymes of the amidohydrolase superfamily were reported to catalyze heterocycle-forming condensation reactions. One of these enzymes, MxcM, is biochemically and kinetically characterized in this study. MxcM generates an imidazoline moiety in the biosynthesis of the natural product pseudochelin A, which features potent anti-inflammatory properties. The enzyme shows maximal activity at 50 °C and pH 10 as well as a kcat/Km value of 22,932 s−1 M−1 at its temperature optimum. Experimental data suggest that the activity of MxcM does not depend on a catalytic metal ion, which is uncommon among amidohydrolases. MxcM is highly active in diverse organic solvents and concentrated salt solutions. Furthermore, we show that MxcM is also capable to introduce imidazoline rings into derivatives of its natural substrate myxochelin B. Overall, MxcM is a solvent-stable, halotolerant enzyme with promising biochemical and kinetic properties and, in future, might become a valuable biocatalyst for the manufacturing of pharmaceutical drugs.

Novel medium-sized di(het)areno-fused 1,4,7-(oxa)thiadiazecines as probes for aminergic receptors

Di(het)areno-fused 1,4,7-(oxa)thiadiazecanes were synthesized by the reduction of the corresponding ten-membered lactams obtained, in turn, via the ‘hydrated imidazoline ring expansion’ (HIRE) methodology. Two of them displayed micromolar agonistic activity towards trace amine-associated receptor 1 (TAAR1) and no affinity towards a panel of dopamine (D2) and serotonin (5-HT1A, 5-HT2A and 5-HT7) receptors. These findings validate compounds of this chemotype as scaffolds for the design of selective aminergic receptor modulators.

Structural Characterization of Heterodinuclear ZnII-LnIII Complexes (Ln\u2009=\u2009Pr, Nd) with a Ring-Contracted H2valdien-Derived Schiff Base Ligand

Synthesis and structural characterization of two heterodinuclear ZnII-LnIII complexes with the formula [ZnLn(HL)(µ-OAc)(NO3)2(H2O)x(MeOH)1-x]NO3 · n H2O · n MeOH [Ln = Pr (1), Nd (2)] and the crystal and molecular structure of [ZnNd(HL)(µ-OAc)(NO3)2(H2O)] [ZnNd(HL)(OAc)(NO3)2(H2O)](NO3)2 · n H2O · n MeOH (3) are reported. The asymmetrical compartmental ligand (E)-2-(1-(2-((2-hydroxy-3-methoxybenzylidene)amino)-ethyl)imidazolidin-2-yl)-6-methoxyphenol (H2L) is formed from N1,N3-bis(3-methoxysalicylidene)diethylenetriamine (H2valdien) through intramolecular aminal formation, resulting in a peripheral imidazoline ring. The structures of 1–3 were revealed by X-ray crystallography. The smaller ZnII ion occupies the inner N2O2 compartment of the ligand, whereas the larger and more oxophilic LnIII ions are found in the outer O2O2’ site.Graphic Synthesis and structural characterization of two heterodinuclear ZnII-LnIII complexes (Ln = Pr, Nd) bearing an asymmetrical compartmental ligand formed in situ from N1,N3-bis(3-methoxysalicylidene)diethylenetriamine (H2valdien) through intramolecular aminal formation are reported.

Solid-Phase Synthesis of an Insect Pyrokinin Analog Incorporating an Imidazoline Ring as Isosteric Replacement of a trans Peptide Bond.

A facile solid-phase synthetic method for incorporating the imidazoline ring motif, a surrogate for a trans peptide bond, into bioactive peptides is reported. The example described is the synthesis of an imidazoline peptidomimetic analog of an insect pyrokinin neuropeptide via a cyclization reaction of an iminium salt generated from the preceding amino acid and 2,4-diaminopropanoic acid (Dap).

Quantum modeling design of imidazoline-based corrosion inhibitors for oil industry applications

We applied the Density Functional Theory to investigate the performance of imidazoline-based corrosion inhibitors for protecting iron surfaces under aggressive environment containing O2, H2S or CO2. We found that the performance of these corrosion inhibitors correlates with their adsorption energies over the corroded surfaces, i.e., the better (worst) performance is reached under presence of CO2 (O2) because the adsorption energies are more (less) intense. Likewise, amino substituents attached to the imidazoline ring allow to form chelates with the corroded surfaces, substantially enhancing the inhibition performance. Additionally, benzene-based substituents help to the inhibition properties.

Sulfur Oxidation Increases the Rate of HIRE-Type [1.4]Thiazepinone Ring Expansion and Influences the Conformation of a Medium-Sized Heterocyclic Scaffold.

The hydrated imidazoline ring expansion (HIRE-type) reaction was investigated for a series of di(hetero)arene-fused [1.4]thiazepinones in comparison with their sulfone counterparts. The sulfones were found to undergo ring expansion at a much higher rate compared to the thioethers, much in line with the current mechanistic understanding of the process. Moreover, the amide bond cis- and trans-isomers of the ring-expanded products were found, in the case of sulfones, to be stabilized through an intramolecular hydrogen bond. The latter phenomenon was studied in detail by NMR experiments and corroborated by X-ray crystallographic information.

Effects of the number of imidazoline ring and the length of alkyl group chain of imidazoline derivatives on corrosion inhibition of carbon steel in HCl solution: Molecular simulation and experimental validation

Abstract The effects of the number of imidazoline ring and the length of alkyl group chain of imidazoline derivatives were investigated using quantum chemical calculation, molecular dynamics simulation and experimental techniques. Three corrosion inhibitors including Symmetrical lauric acid imidazoline (SAI), Tetracyclic lauric acid imidazoline (LAI), and Symmetric stearic acid imidazoline (SPI) were synthesized and their inhibition performance was evaluated using weight loss measurement, electrochemical techniques and surface characterization. The results show that SAI and LAI with the same length of alkyl group chain, LAI with more imidazoline rings could supply a better inhibition performance since the increase of active sites. The increase of active sites attached to the metal surface may also change the distribution of corrosion inhibitor, which could limit inhibition performance improvement. While, SAI and SPI with the same number of imidazoline rings, SPI with longer alkyl group chain shows a better inhibition efficiency due to the better hydrophobic performance of alkyl groups. Among the three inhibitors, SPI show the best inhibition performance, indicating that the alkyl group chain length affects the inhibition performance more obvious than the number of the imidazoline rings.

Chiral Imidazoline Ligands and Their Applications in Metal‐Catalyzed Asymmetric Synthesis†

AbstractAs a structural analog of oxazoline, imidazoline (4,5‐dihydroimidazole) has received much attention in the rational design of chiral ligands. The additional N‐substituent provides broader space for fine‐tuning of electronic and steric effects, and it offers a good handle for immobilizing onto solid supports. In the past decades, imidazoline ring has emerged as a powerful candidate for the design of chiral nitrogen‐containing ligands, as well as a significant alternative for oxazoline ring. Various chiral imidazoline ligands have been designed and utilized in asymmetric organic reactions. These new catalysts can not only be applied in classical reactions, but also be employed to develop new organic reactions with high enantioselectivities. This review provides an overview of chiral imidazoline ligands. Their applications in asymmetric synthesis are also summarized.

Understanding the relationship between the structural properties of three corrosion inhibitors and their surface protectiveness ability in different environments

All-atom molecular simulations and chemical quantum calculations were used to understand the effect of the environment on the surface adsorption of corrosion inhibitor (CI) molecules. Three CIs abbreviated: TEPA, iTEPA and HC-iTEPA studied in this work, were selected to systematically investigate the influence of the alkyl tail, N-pendant group, imidazoline and benzene rings, on the CIs adsorption behavior. A relationship is provided between their structural properties and their surface protectiveness ability in different environments. Chemical quantum calculations revealed the electron distribution in inhibitors structures, indicating their ability to accept/donate charges from the Fe atoms in vacuum and in water solvation. The quantum molecular parameters in water solvation anticipated higher electron transfer ability of iTEPA in aqueous conditions compared to TEPA and iTEPA, thus, leading to stronger adsorption on iron surface, corroborated by the molecular dynamics (MD) classical simulations. MD simulations showed that nearly 53%, 39%, 59% reduction in adsorption energies was detected for single inhibitor molecule of TEPA, iTEPA, and HC-iTEPA shifting from water to CO2-saline media, respectively. The formation of water double adsorption layer contributed to decreasing the CIs adsorption energies by the larger surface separation distances spotted in the density profiles. Nevertheless, the multi-inhibitors study revealed strong adsorption of TEPA and iTEPA on the iron surface, while HC-iTEPA neglected cooperative adsorption and aggregated as a spherical-like micelle with lower surface coverage propensity. Radial distribution functions g(r) explored the preferential interactions of inhibitor-H2O and inhibitor-CO2 that guided the CIs adsorption conformation. Self-diffusivity coefficients of competing adsorbates with the three CIs were found to be one to two orders of magnitude lower near the interface than in the bulk.