Quinolinium Salts Research Articles

Tandem synthesis of benzo[d]naphtho[2,3-g][1,3]oxazocine-8,13(6H,14H)-dione derivatives

An efficient and facile method for the synthesis of novel naphthooxazocines from 2-hydroxy-1,4-naphthoquinone and quinolinium salts at room temperature is described. The reaction proceeds through C-alkylation and intramolecular O-alkylation, affording the desired products in good yields.

3‐Aryl Substituted 1‐Methylquinolinium Salts as Carbene Precursors

1‐Methylquinolinium salts substituted at the C3 position with phenyl, naphthalen‐1‐yl, phenanthren‐9‐yl, and pentaphenyl phenyl as well as aryl ethynyl substituents were prepared. The phenyl, naphthalen‐1‐yl, and phenanthren‐9‐yl substituents are in conjugation with the quinolinium ring, and the sterically crowded pentaphenyl phenyl residue causes a propeller‐type molecule possessing a calculated dihedral angle between aryl substituent and the quinolinium ring of approximately 54°. The different influences of the substituents including the aryl ethynyl residues on the π‐architecture is well reflected in their frontier orbital profiles, their spectroscopic properties, and in their ability to form N‐heterocyclic carbenes. The latter were generated from the C3‐aryl substituted quinolinium salts and trapped as sulfur and selenium adducts, whereas the aryl ethynyl substituted derivatives failed to undergo the NHC generation under the conditions applied. 77Se NMR measurements of the corresponding selenones reveal that quinolin‐2‐ylidenes are electron poor carbenes with strong π‐acceptor character.

Copper-catalyzed selective difunctionalization of N-heteroarenes through a halogen atom transfer radical process

A highly regioselective Cu-catalyzed difunctionalization of quinolinium and benzothiazolim salts was developed with ether and halide (X = Br, Cl) as the halogen source under mild conditions.

The reductive C3 functionalization of pyridinium and quinolinium salts through iridium-catalysed interrupted transfer hydrogenation.

Aromatic rings are ubiquitous in organic chemistry and form the basis of many commercial products. Despite the numerous routes available for the preparation of aromatic compounds, there remain few methods that allow their conversion into synthetically useful partially saturated derivatives and even fewer that allow new C-C bonds to be formed at the same time. Here we set out to address this problem and uncover a unique catalytic partial reduction reaction that forms partially saturated azaheterocycles from aromatic precursors. In this reaction, methanol and formaldehyde are used for the reductive functionalization of pyridines and quinolines using catalytic iridium; thus, inexpensive and renewable feedstocks are utilized in the formation of complex N-heterocycles. By harnessing the formation of a nucleophilic enamine intermediate, the C-C bond-forming process reverses the normal pattern of reactivity and allows access to the C3 position of the arene. Mechanistic investigations using D-labelling experiments reveal the source of hydride added to the ring and show the reversible nature of the iridium-hydride addition.

Chemo-selective couplings of anilines and acroleins/enones under substrate control and condition control

Rh(III)-catalyzed C–H activation of N-protected anilines and chemo-divergent couplings with acroleins/enones have been realized for synthesis of three classes of heterocycles. The oxidative coupling of N-pyridylaniline afforded dihydroquinolones with the acrolein being a major hydrogen acceptor. When the directing group was replaced by pyrimidyl in the same system, redox-neutral coupling occurred to afford hemiaminal ethers. Oxidative annulation of N-pyridylanilines with enones using AgBF4 oxidant afforded atropisomeric quinolinium salts.

Rational design of carbamate-based dual binding site and central AChE inhibitors by a “biooxidisable” prodrug approach: Synthesis, in vitro evaluation and docking studies

Herein, we report a new class of dual binding site AChE inhibitor 4 designed to exert a central cholinergic activation thanks to a redox-activation step of a prodrug precursor 3. Starting from potent pseudo-irreversible quinolinium salts AChE inhibitors 2 previously reported, a new set of diversely substituted quinolinium salts 2a-p was prepared and assayed for their inhibitory activity against AChE. Structure-activity relationship (SAR) analysis of 2a-p coupled with molecular docking studies allowed us to determine which position of the quinolinium scaffold may be considered to anchor the phtalimide fragment presumed to interact with the peripheral anionic site (PAS). In addition, molecular docking provided insight on the linker length required to connect both quinolinium and phatlimide moieties without disrupting the crucial role of quinolinium salt moiety within the catalytic active site (CAS); namely placing the carbamate in the correct position to trigger carbamylation of the active-site serine hydroxyl. Based on this rational design, the putative dual binding site inhibitor 4 and its prodrug 3 were synthesized and subsequently evaluated in vitro against AChE. Pleasingly, whereas compound 4 showed to be a highly potent inhibitor of AChE (IC50 = 6 nM) and binds to AChE-PAS to the same extent as donepezil, its prodrug 3 revealed to be inactive (IC50 > 10 μM). These preliminary results constitute one of the few examples of carbamate-based dual binding site AChE inhibitors.

A mechanistic study on the potential of quinolinium salts as photocatalysts for the abatement of chlorinated pollutants

Photocatalytic degradation of three highly chlorinated contaminants, namely 2,4,6-trichlorophenol (TCP), 2,4,6-trichloroanisole (TCA) and 5-chloro-2-(2,4-dichlorophenoxy)phenol (triclosan, TCS) has been investigated in the presence of N-methylquinolinium tetrafluoroborate (NMQ+), a photocatalyst able to act via Type I or Type II mechanism. Photodegradation of contaminants under aerobic conditions was achieved within hours; and it was accompanied by mineralization, as demonstrated by trapping of the evolved carbon dioxide as barium carbonate. Moreover, a high degree of detoxification, based on % inmobilization of daphnids (Daphnia magna bioassay), was reached after 70 h of irradiation. Quenching of the NMQ+ fluorescence by the pollutants was evidenced by a decrease in the emission intensity and lifetime. Detection of the reduced NMQ· by laser flash photolysis in the presence of the pollutants provided an unambigous evidence of the electron transfer process. Quenching of singlet oxygen by the contaminants showed the typical singlet oxygen quenching constants (105–106 M−1 s−1). Evaluation of the relative contribution of both pathways (Type I vs Type II) point to the photodegradation occurring via a Type I mechanism, being the contribution of Type II mechanism negligible at any concentration range.

Synthesis and crystal structure of quinolinium salt: Assignment on nonsteroidal anti-inflammatory activity and DNA cleavage activity

To develop new anti-inflammatory and DNA cleavage agent with improved pharmaceutical profile, five quilinium salt based compounds have been synthesized and x-ray characterization of these quinolinium salts have been reported here. These quinolinium salts have potential to show the better anti-inflammatory activity as well as DNA cleavage activity. The anti-inflammatory activities of quinolinium salts 1–5 have been evaluated by complete Freund's adjuvant (CFA) induced rat paw edema method. The DNA cleavage activities of quinolinium salts 1–5 were analyzed by using plasmid pBR322. The crystal structure of quinolium salt 1, 2 and 3 have shown the intermolecular non-covalent interactions such as cation···π, π···π, CH···π, CH···X (X = I and Br) and CH⋯N interactions.

Synthesis and Antimicrobial Activity of Sulfur Derivatives of Quinolinium Salts.

A novel method for cleavage of the dithiine ring in 5,12-(dimethyl)-thioqinantrenium bis-chloride 1 “via” reaction with sodium hydrosulfide leads to 1-methyl-3-mercaptoquinoline-4(1H)-thione 2. Further transformation of thiol and thione functions of compound 2 leads to a series of sulfide and disulfide derivatives of quinolinium salts 4 and 6. 1-Methyl-4-chloro-3-benzylthioquinoline chloride 8 was obtained by N-alkylating 4-chloro-3-benzylthioquinoline using dimethyl sulfate. Antimicrobial activity of the obtained compounds was investigated using six Gram-positive and six Gram-negative bacterial strains, as well as Candida albicans yeast. Greater activity was demonstrated towards Gram-positive strains. MIC values for compounds and with benzylthio 4d and benzoylthio 4f substituents in 3-quinoline position were found to be in the 0.5–1 μg/mL range, at a level similar to that of ciprofloxacin (reference). Compounds 4d and 4f also demonstrated interesting antifungal properties (MIC = 1).

Synthesis of substituted quaternary quinolinium salts and their evaluation as antifungal agents

Synthesis of substituted quaternary quinolinium salts and their evaluation as antifungal agents

Toxicity and Apoptosis Related Effects of Benzimidazo [3,2-α] Quinolinium Salts Upon Human Lymphoma Cells.

Objectives:The present study evaluates novel cationic quinoline derivatives known as benzimidazo[3,2-a]quinolinium salts (BQS) named NBQ-48 and ABQ-48 that have structural similarities to known anti-cancer substances such as ellipticine and berberine.Methods:Toledo human lymphoma (ATCC CRL2631) cells were treated for 24 to 48 hours. Apoptosis related endpoints such as cell cycle arrest, mitochondrial damage, RNS and ROS generation and the activity of several apoptosis related proteins such as caspases and apoptosis inducing factor (AIF) were studied using fluorescence staining and western blot respectively.Results:Results indicated a higher toxicity from the amino substituted ABQ-48 versus the NBQ-48 (GI50’s of 50uM versus 100uM respectively). Both compounds induced cell death through various apoptosis related endpoints including a decrease in mitochondrial membrane potential with an increase in ROS and activation of the effector caspase 3. Interestingly, AIF release was observed on cells treated with the amino substituted ABQ-48 but not on the nitro substituted NBQ-48 samples suggesting a caspase independent mechanism for ABQ-48.Conclusions:The results obtained presents the toxic effects of two novel benzimidazo[3,2-a]quinolinium salts in human lymphoma tumor cells. The identified mechanism of action includes multiple apoptosis related effects. Furthermore the data presents a clear variation in caspase dependent or independent mechanism for each compound.

Rhodium(III)-Catalyzed Annulation of Pyridinones with Alkynes via Double C-H Activation: A Route to Functionalized Quinolizinones.

A Rh(III)-catalyzed oxidative annulation of pyridin-2(1H)-ones with alkynes via double C-H activation to produce highly functionalized 4H-quinolizin-4-ones is disclosed. This reaction features easily available starting materials, simple manipulation, a relatively wide substrate scope, and good functional group tolerance. The application of this protocol is demonstrated by the synthesis of a known fluorescent quinolizino[3,4,5,6-ija]quinolinium salt.

Mesomeric betaines constructed of quinolinium cations and carboxylate anions separated by thiophene-ethynyl spacers as fluorescent dipoles

4- and 5-((1-Methylquinolinium-3-yl)ethynyl)thiophene-2-carboxylates were prepared starting from 3-ethynylquinoline which was subjected to a Sonogashira-Hagihara coupling with ethyl 4- and 5-bromothiophenecarboxylates, respectively. Methylation to give the corresponding quinolinium salts, saponification under basic conditions, acidification to give the carboxylic acids, and basification finally yielded the title compounds. Calculations of the frontier orbital profiles confirm the classification of these mesomeric betaines as cross-conjugated systems, as the HOMO is essentially located in the carboxylate group which is connected to the spacer by a nodal position. Fluorescence spectroscopic investigations were performed.

Hydroheteroarylation of Unactivated Alkenes Using N-Methoxyheteroarenium Salts.

We report the first reductive coupling of unactivated alkenes with N-methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts under hydrogen atom transfer (HAT) conditions, and an expanded scope for the coupling of alkenes with N-methoxy pyridinium salts. N-Methoxy pyridazinium, imidazolium, quinolinium, and isoquinolinium salts are accessible in 1-2 steps from the commercial arenes or arene N-oxides (25-99%). N-Methoxy imidazolium salts are accessible in three steps from commercial amines (50-85%). In total 36 discrete methoxyheteroarenium salts bearing electron-donating, electron-withdrawing, alkyl, aryl, halogen, and haloalkyl substituents were prepared (several in multigram quantities) and coupled with 38 different alkenes. The transformations proceed under neutral conditions at ambient temperature, provide monoalkylation products exclusively, and form a single alkene addition regioisomer. Preparatively useful and complementary site selectivities in the addition of secondary and tertiary radicals to pyidinium salts are documented: harder secondary radicals favor C-2 addition (2->10:1), while softer tertiary radicals favor bond formation to C-4 (4.7->29:1). A diene possessing a 1,2-disubstituted and 2,2-disubstituted alkene undergoes hydropyridylation at the latter exclusively (61%) suggesting useful site selectivities can be obtained in polyene substrates. The methoxypyridinium salts can also be employed in dehydrogenative arylation, borono-Minisci, and tandem arylation processes. Mechanistic studies support the involvement of a radical process.

New antibacterial-core structures based on styryl quinolinium.

Quaternary quinolinium salts have been widely used as alternative antimicrobial agents. In an effort to improve the current quinolinium compounds and determine the relation between antibacterial activity and substituted functional groups, 10 different styryl quinolinium derivatives with various quaternary ammonium electron acceptors, electron donors, and counter anions were rationally designed. Among the 10 styryl quinoliniums, six compounds exhibited bactericidal effects against Gram-positive bacteria, with minimum inhibitory concentrations (MICs) of 2.4-37.5 μg/mL. In addition, two compounds, namely DA-DMQ1,4-T and DA-DMQ1,4-TMS, showed low MICs of 18.75-75 μg/mL with Gram-negative bacteria. In general, compounds possessing electron acceptor groups with a strong electron-withdrawing ability exhibited high bactericidal activity against diverse bacterial species. Co-administration of quinolinium (1.17-9.36 μg/mL) and broad-spectrum β-lactam antibiotic ampicillin (0.02-2.34 μg/mL) showed synergistic bactericidal effects on both Gram-positive and Gramnegative bacteria. This study provides guidelines for the development of new quinolinium salts with a prominent antimicrobial activity.

Synthesis of Iodine‐Substituted Quinolines, Quinolinium Salts, and Isoquinolinium Salts via a Three‐Component Tandem Reaction of Aryl Azides, Propargylic Alcohols, and Iodine

AbstractAn efficient three‐component tandem reaction of aryl azides, propargylic alcohols, and iodine has been developed. The products of the reaction hinge on the type of the propargylic alcohols: for tertiary alcohols, the reaction proceeded via a cascade Friedel–Crafts‐type reaction/electrophilic cyclization/1,2‐aryl migratory shift sequence to provide 3‐iodoquinolinium salt products, while in the case of secondary alcohols, 3‐iodoquinoline products could be obtained. For aryl azides with certain substituents, this method gave novel isoquinoline skeletons.

ChemInform Abstract: Synthesis of Conjugated Polycyclic Quinoliniums by Rhodium(III)‐Catalyzed Multiple C—H Activation and Annulation of Arylpyridiniums with Alkynes.

A simple method for the efficient synthesis of highly substituted pyrido[1,2-a]quinolinium- and quinolizino[3,4,5,6-ija]quinolinium-based polyheteroaromatic compounds via rhodium(III)-catalyzed multiple C–H activation annulation reactions has been developed. Moreover, some of the quinolizino[3,4,5,6-ija]quinolinium salts exhibit intense fluorescence and have potential application in optoelectronic materials.

Evaluation of Tribological Properties of Sulfur- and Phosphorous-Free Quinolinium Salts and Their Correlation with Quantum Chemical Parameters

ABSTRACTFor developing antiwear additives with high efficiency but with low sulfated ash, phosphorous, and sulfur (SAPS), N-substituted quinolinium halides, [DIP-Q]+Br− [DIP-Q=1-(3-(1,3-dioxoisoindolin-2-yl)propyl)quinolon-1-ium], [DIE-Q]+Br− [DIE-Q=1-(3-(1,3-dioxoisoindolin-2-yl)ethyl)quinolon-1-ium], [P-Q]+I− [P-Q=propylquinolon-1-ium], and [M-Q]+I− [M-Q=methylquinolon-1-ium] have been prepared and characterized by 1H- and 13C-NMR spectroscopic techniques. The tribological performance of these quinolone-based quaternary salts as antiwear additives in paraffin oil has been assessed on a four-ball test rig. The observed results have been compared with those of zinc dialkyldithiophosphate (ZDDP), a high SAPS additive. The tribotesting of these additives has been performed using 1% w/v additives concentration at different loads and times. The potential of these compounds as antiwear additives is evident from their observed tribological data: mean wear scar diameter (MWD), friction coefficient (µ), mean wear volume (MWV), and wear rates. All of the quinolinium derivatives prove to be better antiwear additives than ZDDP. Among the tested synthesized compounds, [DIP-Q]+Br− exhibits the best tribological behavior followed by [DIE-Q]+Br−, [P-Q]+I−, and [M-Q]+I−. The surface topography of worn surface studied by scanning electron microscopy (SEM) and atomic force microscopy (AFM) shows that surface roughness is reduced to a greater extent in case of quinolinium derivatives than lubrication with ZDDP or base oil alone. Energy-dispersive X-ray (EDX) and X-ray photoelectron spectroscopy (XPS) analysis of worn surfaces in the presence of quinolinium additives shows that the tribofilm is composed of FeBr3, Fe3O4, and organic compounds containing carbonyl and imine bonds. Theoretical investigations using quantum chemical calculations are indicative of significant chemical interactions of these quinolinium additives with metal surfaces, which is strongly supported by the observed experimental data.

Solvent-Regulated Asymmetric Hydrogenation of Quinoline Derivatives in Oligo(Ethylene Glycol)s through Host-Guest Interactions.

The asymmetric hydrogenation of quinolines in oligo(ethylene glycol)s (OEGs) and poly(ethylene glycol)s (PEGs) with chiral cationic ruthenium diamine complexes has been investigated. Interestingly, in liquid PEGs or long-chain OEGs, the Ru catalysts lost their reactivity. Upon the addition of a little MeOH, the hydrogenation of quinoline was switched "ON". Evidence from mass spectrometry and control experiments revealed that encapsulation of the quinolinium salt by PEG or long-chain OEG molecules through supramolecular interactions is possibly the main reason for such a switchable hydrogenation reaction. Moreover, the asymmetric hydrogenation of 2-substituted quinoline derivatives was achieved in triethylene glycol (3-OEG), thereby affording 1,2,3,4-tetrahydroquinolines with excellent reactivities and enantioselectivities (up to 99 % ee). Furthermore, the Ru catalyst could be readily recycled for both pure 3-OEG and biphasic 3-OEG/n-hexane systems without a clear loss of reactivity and enantioselectivity.

ChemInform Abstract: Enantioselective Rhodium‐Catalyzed Dearomative Arylation or Alkenylation of Quinolinium Salts.

AbstractThe enantioselective rhodium‐catalyzed nucleophilic addition of aryl and alkenyl boronic acids to quinolinium salts tolerates a wide range of functional groups with respect to both the organic boronic acids and the quinoline starting materials.