N-heterocyclic Carbene Precursors Research Articles

Synthesis and Medicinal Applications of N-Heterocyclic Carbene Complexes based on Caffeine and other Xanthines.

Xanthines are purine derivatives predominantly found in plants. These include compounds such as caffeine, theophylline, and theobromine and exhibit a variety of pharmacological properties, demonstrating efficacy in treating neurodegenerative disorders, respiratory dysfunctions, and also in cancer. The versatile attributes of these materials render them privileged scaffolds for the development of compounds for various biological applications. Xanthines are N-heterocyclic carbene precursors that combine a pyrimidine and an imidazole ring. Owing to their biological relevance, xanthines have been employed as N-heterocyclic carbenes in the development of metallodrugs for anticancer and antimicrobial purposes. In this conceptual review, we examine key examples of N-heterocyclic carbene complexes derived from caffeine and other xanthines, elucidating their synthetic methods and describing their pertinent medicinal applications.

A 12-Vertex Metallacarborane of Silver(I).

The discovery of ferrocene in 1951 was a significant landmark in the field of organometallic chemistry, and since then, numerous sandwich- or half-sandwich metallic complexes have been reported. However, silver stands as an intriguing exception in this regard, and knowledge of its bonding situation has remained undisclosed. Herein, unprecedented 12-vertex metallacarboranes of Ag(I) (2a and 2b) were synthesized through the reaction of sodium hexamethyldisilazide (NaHMDS) with the mixture of nido-C2B9 carborane anion-supported N-heterocyclic carbene precursors (1a and 1b) and [Ag(PPh3)Cl]4. The X-ray structural analysis of the resulting metallacarboranes revealed a unique "slipped" half-sandwich structure, which is a rarity among cyclopentadienyl analogues. DFT calculations provided insights into the asymmetric π-interactions between the pentagonal C2B3 face and the silver ion.

Synthesis of Six-Membered N-Heterocyclic Carbene Precursors Based on Camphor.

The endo- and exo-N-heterocyclic carbene precursors based on camphor were prepared diastereoselectively in five synthetic steps starting from (1S)-(+)-ketopinic acid. The obtained N-heterocyclic carbene precursors were investigated in an asymmetric benzoin reaction. All new compounds were fully characterized, and the absolute configurations were determined via X-ray diffraction and NOESY measurements.

New sugar-incorporated N-heterocyclic carbene precursors and their Ag(I) and Pd(II) complexes: Synthesis, characterization, and cytotoxicity studies

In the present work, a new series of sugar-incorporated N-heterocyclic carbene precursors namely 1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]imidazolium bromide (7a), 4-methyl-1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]imidazolium bromide (7b), 4,5-diphenyl-1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]imidazolium bromide (7c), and 1-(3,4,5-trimethoxybenzyl)-3-[2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl]benzimidazolium bromide (8) were synthesized by the direct reaction of the N-alkylated benzimidazoles with 2-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-ethyl bromide. Ag(I)–NHC complexes (9a-c, 10) of the abovementioned precursors were synthesized by in-situ reaction with Ag2O in light-excluded conditions. The transmetallation reaction technique was used to synthesize Pd(II)–NHC complexes (11a-c, 12) by the reaction of [PdCl2(MeCN)2] with corresponding Ag(I)–NHC complexes. All NHC precursors and their corresponding Ag(I) and Pd(II) complexes were spectrally characterized using 1H &13C NMR, and mass spectrometry. Further, Pd(II) complexes were evaluated for their anticancer activity against eight diverse cancer cell lines, namely; Pancreatic Adenocarcinoma (Capan-1), Colorectal Carcinoma (HCT-116), Glioblastoma (LN229), Lung Carcinoma (NCI-H1975), Acute Lymphoblastic Leukemia (DND-41), Acute Myeloid Leukemia (HL-60), Chronic Myeloid Leukemia (K562), and non-Hodgkin Lymphoma (Z138). Standard antineoplastic drugs docetaxel and etoposide were included as reference compounds. Among the tested complexes, complex 11c displayed broad activity against all tested cancer types, albeit at higher concentrations when compared to the reference drugs.

Interaction analysis of a new NHC precursor and its Ag-NHC complex with bovine serum albumin by spectrophotometric and molecular docking methods

Potential bioactive molecules must reach the target tissue safely and serum albumin, which is a well-known major component in human blood, is an efficient transporter. Therefore, the interactions of possible bioactive species with serum albumin must be determined. In the current study, an N-heterocyclic carbene precursor and its silver complex were synthesized, characterized, and analyzed for interactions with bovine serum albumin. Stern-Volmer constant was recorded as 4.50 × 105 for Ag-NHC with a 1.255 binding number at 298 K. Also, the molecules have spontaneously interacted with bovine serum albumin with a negative ΔG value (−32.93 kJ mol−1) for the complex at 298 K. Additionally, the effects of Ca2+, Mg2+, and Zn2+ on binding properties were evaluated by fluorescence spectroscopy. The binding constant of the complex was recorded as 6.76 × 103 in the presence of Zn2+ and 5.93 × 105 without the metals. The molecules were optimized by DFT-based calculations and the details of the bindings were investigated by molecular docking methods. Ag-NHC has interacted with the IIA subdomain region of bovine serum albumin with −8.46 kcal/mol.

Surface Modification of ITO with N-Heterocyclic Carbene Precursors Results in Electron Selective Contacts in Organic Photovoltaic Devices.

Surface modification of indium tin oxide (ITO) electrodes with organic molecules is known to tune their work function which results in higher charge carrier selectivity in corresponding organic electronic devices and hence influences the performance of organic solar cells. In recent years, N-heterocyclic carbenes (NHCs) have also been proven to be capable to modify the work function of metals and semimetals compared to the unfunctionalized surface via the formation of strong covalent bonds. In this report, we have designed and performed the modification of the ITO surface with NHC by using the zwitterionic bench stable IPr-CO2 as the NHC precursor, applied via spin coating. Upon modification, the work function of ITO electrodes was reduced significantly which resulted in electron selective contacts in corresponding organic photovoltaic devices. In addition, various characterization techniques and analytical methods are used to elucidate the nature of the bound species and the corresponding binding mechanism of the material to the ITO surface.

Cu−NHC Complex for Chan‐Evans‐Lam Cross‐Coupling Reactions of N‐Heterocyclic Compounds and Arylboronic Acids

AbstractAn efficient copper(II) N‐heterocyclic carbene (NHC) complex with an NCN coordination mode was optimized to catalyze the Chan–Evans‐Lam (CEL) cross‐coupling reaction of imidazole and other N‐heterocyclic nucleophiles with arylboronic acid. This air‐stable copper catalyst shows robust catalytic performance and tolerates a diverse array of functional groups on both the N‐nucleophile and arylboronic acid coupling partners in C−N bond forming reactions with up to 95 % yield. Formation of the Cu−NHC complex in situ generated similar catalytic performance for CEL coupling. Alternative metal ions (Mn2+, Fe2+, Co2+, Ni2+, Zn2+, Ru2+, and Pd2+) were also screened in the presence of the NHC precursor as CEL catalysts.

Cu(I)–N-heterocyclic carbene complexes bearing a naphthyl substituent: synthesis, characterization, and antimicrobial activities

A series of 1-(alkyl)-3-(1-naphthyl)imidazolinium bromides (2a–d) as N-heterocyclic carbene (NHC) precursors were synthesized from 3-(1-naphthyl)-1H-imidazolinium chloride (1). By reacting these NHC precursors with fresh CuCl, Cu(I)–NHC complexes (3a–d) were synthesized. The structures of the compounds were elucidated using 1H, 13C-NMR, FT-IR, ESI-MS, X-ray diffraction, scanning electron microscopy with energy-dispersive X-ray spectroscopy analysis, and elemental analysis techniques. The thermal properties of selected complexes were determined. Salts (1, 2a–d) and Cu(I)–NHC complexes (3a–d) were investigated against test microorganisms to determine their antimicrobial potency. The imidazolinium salts 2b and 2d displayed remarkable antibacterial efficacy, particularly against gram-positive bacteria; however, the corresponding Cu(I)–NHC derivatives (3a–d) did not exhibit a similar level of potency probably due to limited solubility. Overall, it can be concluded that incorporation of N-substituent species with O-heteroatoms, instead of benzyl, allyl, or hexyl groups on NHC, can enhance the activity against microbial derivatives.

Synthesis of Tetrahydrobenzo[b]pyrans Catalyzed by 1,3-Dibenzyl-1H-benzo[d] imidazole-3-ium Chloride

Abstract: Tetrahydrobenzo[b]pyrans are fused oxygen-containing heterocycles that are found in many biologically active compounds. Therefore, researchers in organic synthesis are searching for suitable, efficient, and useful methods for their synthesis. In this contribution, a series of tetrahydrobenzo[b]pyran derivatives was synthesized using aryl aldehydes, malononitrile, and cyclohexane-1,3-dione or dimedone as the available starting materials. The three-component reactions were catalyzed by 1,3-dibenzyl-1H-benzo[d]imidazol-3-ium chloride as the N-heterocyclic carbene precursor. The heterocyclic oxygen-containing products were obtained in good to excellent isolated yields within relatively shorter reaction times. Optimizing the reaction conditions was performed from the point of view of various parameters of the reaction. The results of these experiments showed that the best solvent system includes water-ethanol, the most suitable reaction temperature is 60ºC, and the optimal amount of the imidazolium catalyst loading is 5 mol%. Operational simplicity, no need for chromatographic methods for purification, simple work-up for pure products, and avoiding hazardous solvents are remarkable features of this three-component reaction. Moreover, in these multicomponent cyclo-condensations, no by-products were observed.

Hydrodehalogenation of aryl halides by the mixture of palladium(II) and a newly synthesized chiral macrocyclic bis(N-heterocyclic carbene) ligand

A novel macrocyclic bis(N-heterocyclic carbene) precursor was designed and prepared, which manifested high catalytic efficiency when combining Pd(OAc)2 in hydrodehalogenation of aryl halides. The generation of a little amount of the intermediate product chlorobenzene is closely related with the synergistic effect of two imidazoline protons lying on the two opposite sides of the macrocycle.

Hexafluoroisopropanol (HFIP) as a Multifunctional Agent in Gold-Catalyzed Cycloisomerizations and Sequential Transformations

Despite the unique position of gold catalysis in contemporary organic synthesis, this area of research is notorious for requiring activators and/or additives that enable catalysis by generating cationic forms of gold catalysts. Cycloisomerization reactions occupy a significant portion of the gold-catalyzed reaction space, while they represent a diverse family of reactions that are frequently utilized in synthesis. Herein, hexafluoroisopropanol (HFIP) is shown to be a uniquely simple tool for gold-catalyzed cycloisomerizations, rendering the use of external activators obsolete and leading to highly active catalytic systems with ppm levels of catalyst loading in certain cases. HFIP assumes a dual role as a solvent and an activator, operating via the dynamic activation of the Au–Cl bond through hydrogen bonding, which initiates the catalytic cycle. This special mode of catalysis can enable efficient and scalable cyclization reactions of propargylamides and ynoic acids with simple [AuCl(L)] complexes. A thorough screening of ancillary ligands and counter anions has been performed, establishing this methodology as an alternative to elaborate ligand/catalyst design and to the use of activators. Additionally, this concept is applied in C–C bond-forming cycloisomerization reactions leading to 2H-chromenes and to the design of catalytic systems for sequential or one-pot transformations leading to activated ketoesters, a functionalized N-heterocyclic carbene (NHC) precursor salt, and a compound bearing the bioactive indole core, among others. Importantly, through mechanistic investigations, including a “snapshot” of the species of interest in the solid state, we were able to unambiguously detect the key H-bonding interaction between HFIP and the gold catalyst, shedding light on the intermolecular mode of activation that enables catalysis. In the cases examined herein, HFIP is not only an excellent solvent but also a potent activator and a valuable synthetic handle when incorporated into functional groups of products.

Cytotoxic potential of silver, palladium, rhodium, ruthenium, and iridium complexes of a cycloheptyl-substituted lipophilic N-heterocyclic carbene ligand

Lipophilicity is a crucial parameter for cytotoxicity of metal complexes, in many cases associated with increased activity. In the present study, we synthesized a series of N-heterocyclic carbene (NHC) complexes of different metals with a lipophilic benzimidazolium chloride to investigate and compare their cytotoxicity. Rh– (4), Ru– (5), and Ir–NHC (6) complexes of a cycloheptyl-substituted benzimidazole-based NHC ligand (1) have been prepared by transmetalation reaction between Ag–NHC and the corresponding metal compound. The newly synthesized complexes have been characterized by NMR, IR, LC-MS spectroscopy, and elemental analyses. The anti-growth effects of the newly synthesized Rh–, Ru–, and Ir–NHC complexes and previously reported NHC precursor (1), Ag– (2), and Pd–NHC (3) complexes against human breast (MCF-7), colorectal (Caco-2), ovarian (A2780), and prostate (LNCaP) cancer cell lines have been investigated by MTT assay. The results revealed that the compounds provide stronger anti-growth effects against all cell lines compared to standard drug cisplatin. Among the compounds, benzimidazolium chloride, and Ag–NHC complex showed promising activities.

Hydrosilylation of Terminal Alkynes Catalyzed by an Air-Stable Manganese-NHC Complex.

In recent years, catalysis with base metal manganese has received a significant amount of interest. Catalysis with manganese complexes having N-heterocyclic carbenes (NHCs) is relatively underdeveloped in comparison to the extensively investigated manganese catalysts possessing pincer ligands (particularly phosphine-based ligands). Herein, we describe the synthesis of two imidazolium salts decorated with picolyl arms (L1 and L2) as NHC precursors. Facile coordination of L1 and L2 with MnBr(CO)5 in the presence of a base resulted in the formation manganese(I)-NHC complexes (1 and 2) as an air-stable solid in good isolated yield. Single-crystal X-ray analysis revealed the structure of the cationic complexes [Mn(CO)3(NHC)][PF6] with tridentate N,C,N binding of the NHC ligand in a facile fashion. Along with a few known manganese(I) complexes, these Mn(I)-NHC complexes 1 and 2 were tested for the hydrosilylation of terminal alkynes. Complex 1 was proved to be an effective catalyst for the hydrosilylation of terminal alkynes with good selectivity toward the less thermodynamically stable β-(Z)-vinylsilanes. This method provided good regioselectivity (anti-Markovnikov addition) and stereoselectivity (β-(Z)-product). Experimental evidence suggested that the present hydrosilylation pathway involved an organometallic mechanism with manganese(I)-silyl species as a possible reactive intermediate.

“Greening” Ruthenium–Arene Catalyst Precursors with N-Heterocyclic Carbene Ligands Derived from Caffeine and Theophylline

Two ruthenium–arene complexes with the generic formula [RuCl2(p-cymene)(NHC)] were readily obtained from natural, abundant, and renewable methylxanthine alkaloids used as N-heterocyclic carbene (NHC) precursors. After optimization, the known compound Ru-1 featuring the 1,3,7,9-tetramethylxanthine-8-ylidene ligand was isolated in three steps and 72% overall yield starting from caffeine. Four steps were needed to synthesize complex Ru-2, which sported the bulkier 7-isobutyl-1,3,9-trimethylxanthine-8-ylidene ligand, in 41% overall yield starting from theophylline. Multinuclear NMR analysis confirmed the presence of p-cymene and an NHC ligand within the coordination sphere of both products. Yet, they exhibited a significantly different dynamic behavior in solution at room temperature, due to the larger size of the isobutyl chain compared to a methyl group, which severely restricted the rotation of the arene ligand and caused a loss of symmetry. Complexes Ru-1 and Ru-2 were both highly active catalyst precursors for the transfer hydrogenation of unsaturated substrates with isopropanol under basic conditions (11 examples). They were also efficient promoters for the oxidation of alkenes with sodium periodate. Last but not least, they triggered the synthesis of vinyl esters from 1-hexyne and benzoic acid. For this later reaction, the product distribution varied markedly with the nature of the NHC ligand. Altogether, this study demonstrated that the combination of a labile p-cymene ligand and an ancillary NHC ligand derived from caffeine or theophylline provided an efficient and sustainable access to a wealth of highly active Ru–hydride, −oxo, or −alkyne species that were able to catalyze three miscellaneous organic transformations.

Synthesis, Characterization, Antimicrobial Properties, and Antioxidant Activities of Silver-N-Heterocyclic Carbene Complexes.

The emergence of antimicrobial resistance has become a major handicap in the fight against bacterial infections, prompting researchers to develop new, more effective, and multimodal alternatives. Silver and its complexes have long been used as antimicrobial agents in medicine because of their lack of resistance to silver, their low potency at low concentrations, and their low toxicity compared to most commonly used antibiotics. N-Heterocyclic carbenes (NHCs) are widely used for coordination of transition metals, mainly in catalytic chemistry. In this study, several N-alkylated benzimidazolium salts 2a-j were synthesized. Then, the N-heterocyclic carbene (NHC) precursor was treated with Ag2O to give silver (I) NHC complexes (3a-j) at room temperature in dichloromethane for 48 h. Ten new silver-NHC complexes were fully characterized by nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FT-IR), elemental analysis, and LC-MSMS (for complexes) techniques. The antibacterial and antioxidant activities of salt 2 and its silver complex 3 were evaluated. All of these complexes were more effective against bacterial strains than comparable ligands. With MIC values ranging from 6.25 to 100 g/ml, the Ag-NHC complex effectively showed strong antibacterial activity. Antioxidant activity was also tested using conventional techniques, such as 2, 2-diphenyl-1-picrylhydrazine (DPPH) and hydrogen peroxide scavenging assays. In DPPH and ABTS experiments, compounds 3a, 3b, 3c, 3e, 3g, and 3i showed significant clearance.

Metal-N-Heterocyclic Carbene Chemistry Directed toward Metallosupramolecular Synthesis and Beyond.

ConspectusAs versatile, modular, and strongly coordinating moieties in organometallic compounds, N-heterocyclic carbenes (NHCs) have led to numerous breakthroughs in transition-metal catalysis, main group chemistry, and organocatalysis. In contrast, the chemistry of NHC-based metallosupramolecular assemblies, in which discrete individual components are held together via metal (M)-CNHC bonds, has been underdeveloped. Integrating NHCs into supramolecular assemblies would endow them with some unforeseen functions. However, one of the most critical challenges is seeking an appropriate combination of the rigid CNHC-M-CNHC units with the resulting topologies and applications. Toward this goal, for the last decade we have focused on the development of M-NHC directed toward metallosupramolecular synthesis. This Account aims to summarize our contributions to the application of M-NHC chemistry toward supramolecular synthesis from structural design to postassembly modification (PAM) and their functional applications since integrating NHCs into supramolecular assemblies has garnered much attention among organometallic, photochemical, and supramolecular researchers. While presenting representative examples of NHC-based architectures, we try to illustrate the purposes and concepts behind the systems developed to aid the rational approach to the design and fabrication of complex assemblies and M-NHC-templated photochemical reactions.We present synthetic approaches for new architectures by the rational design of starting NHC precursors, including the poly-NHC-based mechanically interlocked metallacages and the heteroleptic architectures based on electronic complementary and self-sorting mechanisms. The structural regulation of poly-NHC-based architectures with increasing topological complexity is elaborated on by selective combinations of tetraphenylethylene (TPE) units, NHC backbones, and N-wingtip substituents in a controllable manner.Subsequently, we move to elucidating an M-NHC-templated PAM approach that leads to functional organic cages featuring polyimidazolium/triazolium groups of different shapes and sizes that are difficult to access using alternative organic approaches. These organic cages possess well-defined cavities, and their in situ-generated NHC sites are ideal platforms for stabilizing metal nanoparticles (MNPs) within their cavities for improved catalytic performance.Finally, we demonstrate how to design supramolecular M-NHC templates to synthesize cyclobutane derivatives in homogeneous solutions in a catalytic fashion. Selected examples of M-NHC template-dependent structural transformations and photoreactions are discussed. Their applications in molecular recognition, aggregation-induced emission (AIE), cell imaging, anticancer activity, radical chemistry, and stimuli-responsive materials are also described.Taken together, M-NHC-templated approaches have proven to be powerful methods for constructing diverse architectures with functional applications. The development of this methodology is still in its infancy, with tremendous growth potential and a promising future. We believe that this Account will guide researchers to design fascinating and valuable M-carbene species for diverse applications.

Bioactivities of Triazolium-Based N-Heterocyclic Carbene Salts.

1,2,4-Triazolium salts are precursors of N-heterocyclic carbenes (NHCs), which have been extensively used as effective catalysts and ligands for both asymmetric and non-enantioselective reactions. Nevertheless, they are also a kind of quaternary ammonium compounds (QACs) that possess amphipathic properties. The unique chemical and physical properties of 1,2,4-triazolium salts have received significant attention from scientists focusing on the development of novel bioactive molecules as pesticides and medicines. It is timely and meaningful to summarize the bioactivities of 1,2,4-triazolium salt derivatives against various bacteria, fungi, cancer cells, and other pathogens in the past 30 years. Meanwhile, the structure-activity relationship (SAR) of 1,2,4-triazolium salts was also summarized. Finally, our perspective on the future development and applications of triazolium salts as agrichemicals or human drugs is presented.

Chiral Atropisomeric-NHC Catechodithiolate Ruthenium Complexes for Z-Selective Asymmetric Ring-Opening Cross Metathesis of Exo-Norbornenes.

A set of 16 chiral ruthenium complexes containing atropisomerically stable N-Heterocyclic Carbene (NHC) ligands was synthesized from prochiral NHC precursors. After a rapid screening in asymmetric ring-opening-cross metathesis (AROCM), the most effective chiral atrop BIAN-NHC Ru-catalyst (up to 97 : 3 er) was then converted to a Z-selective catechodithiolate complex. The latter proved to be highly efficient in Z-selective AROCM of exo-norbornenes affording valuable trans-cyclopentanes with excellent Z-selectivity (>98 %) and high enantioselectivity (up to 96.5 : 3.5 er).

Water-soluble N-heterocyclic carbene precursors bearing benzimidazole core: synthesis, characterization, in vitro antioxidant and anticancer studies

Water-soluble N-heterocyclic carbene precursors bearing benzimidazole core: synthesis, characterization, in vitro antioxidant and anticancer studies

Fluorinated benzimidazolium salts: Synthesis, characterization, molecular docking studies and inhibitory properties against some metabolic enzymes

Here, a number of symmetric and unsymmetric N-heterocyclic carbene (NHC) precursors based on benzimidazol-2-ylidene are synthesized. The N-benzyl substituent in these compounds has an electron-withdrawing group (F) at the para position. The structure of these compounds was characterized using elemental analysis and various spectroscopic methods (FTIR and NMR). The molecular and crystal structures of compound 1f and compound 1h were unambiguously elucidated through single-crystal X-ray diffraction analysis. According to the X-ray studies, compound 1f exhibits the formation of a U-shaped molecule whereas compound 1h has a Z-shape formation. In addition, the enzyme inhibition activities of these compounds were investigated against acetylcholinesterase (AChE) and carbonic anhydrases (hCAs). They showed a highly potent inhibition effect on AChE and hCAs (Ki values are in the range of 14.84±1.91 to 174.80±23.60 nM for AChE, 22.41±1.93 to 188.67±27.05 nM for hCA I and 35.29±7.21 to 136.55±17.61 nM for hCA II). These results may contribute to the design and development of new drug candidates, particularly for treatment of some widespread disorders displayed in the world including Alzheimer's disease and glaucoma.