Heterocyclic Salts Research Articles

Orthoamide und Iminiumsalze, IC. Synthese und Reaktionen von N,N,N′,N′,N′′-Pentaalkyl-N′′-[2-(N,N,N′,N′,N′′-pentaalkylguanidinio)ethyl]-guanidiniumsalzen

Abstract Bis[bis(dibutylamino)methylen]hydrazine 8 is prepared from N,N,N′,N′-tetrabutylchloroformamidinium chloride (4c) and hydrazine. Bromine transforms 8 to the heterocyclic guanidinium salt 15a which is isolated as tetraphenylborate. From N,N,N′,N′-tetraalkylchloroformamidiniumchlorides and ethylendiamine the diguanidines are prepared which are alkylated to give diguanidinium salts, From these salts guanidinium salts can be prepared by anion metathesis with tetraphenylborate-, iodide-, hexafluorphosphate-, trifluoromethansulfonat-, bis(trifluormethansulfonyl)imide and tricyanmethanide as counteranions. The structure of the compounds 15 and 17b is confirmed by crystal structure analyses.

Orthoamide und Iminiumsalze, IIC. Darstellung von N-(ω-Ammonioalkyl)-N,N′,N′,N″,N″-peralkylierten Guanidiniumsalzen und N-(ω-Aminoalkyl)-N′,N′,N″,N″-tetramethylguanidinen

Abstract N,N,N′,N′-Tetraalkylchlorformamidiniumchlorides 1a, b react with ω-dimethylaminoalkylamines 19, 20 to give mixtures of N-(ω-dimethylammonioalkyl)-guanidinium salts 12, 13 and N-(ω-dimethylaminoalkyl)-guanidinium salts 21, 22. These mixtures are transformed to mixtures of the ureas 15, 17 and N-(ω-dimethylaminoalkyl)-guanidines 23, 25 on treatment with aqueous sodium hydroxide. The reaction of N-(3-dimethylammoniopropyl)-guanidin 25a with dimethylsulfate in a molar ratio of 1:1 delivers a mixture of the N-(3-dimethylaminopropyl)-N,N,N′,N′,N″,N″-pentamethyl-guanidinium salt 29a and the N-(3-dimethylammoniopropyl)-N,N′,N′,N″,N″-pentamethyl-guanidinium-bis (methylsulfate) 33a. The action of dimethylsulfate on the guanidines 23a, 25a in a molar ratio of 2:1 affords the bisquarternary salts 32a, 33a. Alkylating reagents as methyliodide, benzylbromide, allylbromide and chloroacetonitrile attack N-(2-dimethylaminoethyl)-N′,N′,N″,N″-tetraethylguanidine (23b) in a molar ratio of 1:1 cleanly at the dimethylaminoethylgroup to give the ammonium salts 30a–d. As a strong base the guanidine 23b dehydrochlorinates β-Chlorpropionitrile and chloroacetone under formation of the guanidinium salt 21c. In contrast to this the reaction of ethyl bromoacetate with the N-(2-dimethylaminoethyl)guanidine 23b occurs at the guanidinogroup giving the guanidinium salt 28c. The methylation of the guanidinium chlorides 21a, 22a with dimethyl sulfate affords the bis-quaternary salts 35b, 36b with mixed anions. From the heterocyclic guanidines 14, 16 and the alkylating reagents benzylbromide and ethyl bromoacetate the heterocyclic guanidinium salts 37a, b, 39a, b can be obtained. The reactions with ethyl chloroformiate proceed in an analogous way giving the guanidinium salts 37c, 39c. The N-alkyl-N,N,N′,N′-tetramethyl-(3-ureidopropyl)guanidinium salts 41a, b can be prepared from the N′,N′,N″,N″-tetramethyl-N′′-(3-ureidopropyl) guanidine 17a and the alkylating compounds dimethyl sulfate and benzyl bromide. Several compounds obtained that way were transformed to the corresponding tetraphenyloborates and bis(tetraphenylborates), respectively.

Pagoda[4]arene and i-Pagoda[4]arene.

A new type of macrocyclic arenes, named pagoda[4]arene (P4) and i-pagoda[4]arene (i-P4), were conveniently synthesized by the TFA-catalyzed one-pot condensation of 2,6-dimethoxylanthracene and paraformaldehyde in dichloromethane at room temperature. P4 and i-P4 showed unique square pagoda structures and fixed conformations in solution and also exhibited strong blue fluorescence. Moreover, P4 and i-P4 with deep and rich-electron cavities could not only encapsulate n-hexane and one or two dichloromethane molecules in the solid state but also showed strong binding abilities toward neutral dinitriles with different chain lengths and various nitrogen-containing heterocyclic salts to form 1:1 stable host-guest complexes in both solution and the solid state. In particular, it was also found that with the increase in the alkyl chain length of the dinitriles, the association constants for their complexes with both P4 and i-P4 were markedly increased from glutaronitrile to octanedinitrile as a result of the deep cavities of the macrocycles and multiple intermolecular interactions. Since P4 and i-P4 had stable planar chirality, their efficient resolutions were further achieved by HPLC with a chiral column. Interestingly, the two enantiomers showed mirror-imaged CD signals and excellent CPL properties, which could allow them to have potential applications in chiral luminescent materials.

Synthesis of Polycationic Aza-Belted Heterocyclic Iodomethane Salts

Novel belt shapes of a diazabicyclo[n,n,5.5]alkane center combined with double iodomethane salts were prepared in two steps by a reaction of phenylethylamine or 3,4-dimethoxyphenylethylamine with ortho-bis(chloromethyl)benzenes. The syntheses and characteristics of these polycationic systems containing aza-belt rings are described. Judicious choice of the reaction conditions allowed these polycationic heterocycles to be generated in good yields, and 1H and 13C nuclear magnetic resonance spectroscopy revealed a change in chemical shifts caused by interactions between the functional groups.

ACID-BASE EQUILIBRIA IN SOLUTIONS OF NEW 4-HYDROXYSTYRYL DYES BASED ON 1-OCTILPIRIDINIUM

In this paper, the acid-base properties of a number of new 4-hydroxystyryl dyes based on 1-octylpyridinium in solutions have been studied by tristimulus colorimetry and spectrophotometry. The studied dyes are obtained by the interaction of equivalent amounts of corresponding heterocyclic methylene bases salts with 4-hydroxyaldehydes in acetonitrile. The advantages of the tristimulus colorimetric method in the study of acid-base equilibria in dyes solutions were noted. It was shown that the use of data on the change in the values of colorimetric functions (specific color discrimination), depending on the medium acidity allows us to determine the constants of ionization of the functional groups of 4-hydroxystyryl dyes. It was shown that the quantitative description of the color of objects of different nature by calculating their color coordinates on the basis of spectrophotometric data allows obtaining information about their state in solutions. Using the values of the colorimetric functions of the ionic-molecular forms of 4-hydroxystyryl dyes as an analytical signal allows us to obtain a coherent picture of existing acid-base equilibria in a wide range of the medium acidity. Based on the obtained experimental data, a probable scheme of acid-base equilibrium in aqueous solutions of 4-hydroxystyryl dyes was proposed. It was shown that in the acidic medium 4-hydroxystyryl dyes exist in a protonated single-charged cationic form, and with pH rise dissociation of phenolic hydroxyl and tautomerization with the formation of a merocyanine form occurs. The corresponding diagrams for the distribution of ion-molecular forms of 4-hydroxystyryl dyes have been constructed, depending on the acidity of the medium.

Cobalt-Catalyzed Alkylation of Drug-Like Molecules and Pharmaceuticals Using Heterocyclic Phosphonium Salts.

Alkylated pyridines are common in pharmaceuticals, and metal catalysis is frequently used to prepare this motif via Csp2-Csp3 coupling processes. We present a cobalt-catalyzed coupling reaction between pyridine phosphonium salts and alkylzinc reagents that can be applied to complex drug-like fragments and for late-stage functionalization of pharmaceuticals. The reaction generally proceeds at room temperature, and 4-position pyridine C-H bonds are the precursors in this strategy. Given the challenges in selectively installing (pseudo)halides in complex pyridines, this two-step process enables sets of molecules to be alkylated that would be challenging using traditional cross-coupling methods.

Intramolecular Phosphacyclization: Polyaromatic Phosphonium P-Heterocycles with Wide-Tuning Optical Properties.

Rationally designed cationic phospha‐polyaromatic fluorophores were prepared through intramolecular cyclization of the tertiary ortho‐(acene)phenylene‐phosphines mediated by CuII triflate. As a result of phosphorus quaternization, heterocyclic phosphonium salts 1 c–3 c, derived from naphthalene, phenanthrene, and anthracene cores, exhibited very intense blue to green fluorescence (Φ em=0.38–0.99) and high photostability in aqueous medium. The structure–emission relationship was further investigated by tailoring the electron‐donating functions to the anthracene moiety to give dyes 4 c–6 c with charge‐transfer character. The latter significantly decreases the emission energy to reach near‐IR region. Thus, the intramolecular phosphacyclization renders an ultra‐wide tuning of fluorescence from 420 nm (1 c) to 780 nm (6 c) in solution, extended to 825 nm for 6 c in the solid state with quantum efficiency of approximately 0.07. The physical behavior of these new dyes was studied spectroscopically, crystallographically, and electrochemically, whereas computational analysis was used to correlate the experimental data with molecular electronic structures. The excellent stability, water solubility, and attractive photophysical characteristics make these phosphonium heterocycles powerful tools in cell imaging.

5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid based heterocyclic dyes

5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid was selected as the coupling component to react with three S/N-containing heterocyclic (2-amino-4-chloro-5-formylthiophene-3-carbonitrile, 5-nitrobenzo[c]isothiazol-3- amine, 5-amino-1-ethyl-6-hydroxy-4-methyl-2-oxo-1,2-dihydropyridine-3- carbonitrile) diazo salts and three aniline derivatives with different electron-pulling/electron-pushing substituents, so as to produce six carboxylic pyrazolone based mono-/bi-heterocyclic dyes. Our results show that λmax of carboxylic pyrazolone based heterocyclic dyes depends on the substituent effects on aromatic rings and type of the heterocyclic rings. Compared with methyl pyrazolone/2,3-dimethylaniline based mono-heterocyclic dye, corresponding carboxylic pyrazolone based one with stronger D–π–A system brings a red shift of 37 nm. In contrast, carboxylic pyrazolone/thiophene and carboxylic pyrazolone/benzisothiazole based bi-heterocyclic dyes display blue shifts of 39 and 47 nm compared with relative methyl pyrazolone ones because of the role transformation for donor and acceptor (D−π−A to A−π−D) originating from the electron-withdrawing groups of S-containing heterocycles. Furthermore, different azo⇌hydrazone tautomeric transformations have been confirmed by the acid-base titration experiments. Namely, the mono-heterocyclic dyes, which would be transferred into the azo form in the alkaline condition, exhibit dominating hydrazone form in MeOH. However, the azo form of bi-heterocyclic dyes, which would convert to the hydrazone one under the acidic condition, is overwhelming in MeOH.

Rh-Catalyzed tandem C-C/C-N bond formation of quinoxalines with alkynes leading to heterocyclic ammonium salts.

An efficient Rh-catalyzed oxidative C-H activation/annulation of 2-arylquinoxalines with internal alkynes is described using Cu(OAc)2·H2O and AgBF4 to afford a diverse variety of substituted quarternary ammonium salts at room temperature. The mechanism of the protocol is established on the basis of isolation of the 5-membered rhodacycle intermediate and kinetic isotope studies. The mild reaction conditions, substrate scope and functional group diversity are the salient practical features.

Unsymmetrical 2,6-Di-tert-butyl-Substituted Pyrylo-4-squaraines

Triethylammonium salt of pyran semisquaraine reacted with N-methyl-substituted heterocyclic salts to give unsymmetrical di-tert-butyl-substituted squarylium dyes. The effect of the terminal heterocycles on the spectral properties of the obtained dyes was studied, and the electronic structure of squaraines and electronic transitions therein were analyzed by quantum chemical methods.

Anticancer, antimicrobial and antioxidant potential of sterically tuned bis-N-heterocyclic salts.

The current study was conducted to evaluate the antimicrobial, antioxidant, antileishmanial and cytotoxic potential of designed derivatives of 1,1'-(1,3-phenylenebis(methylene))bis(3-alkyl/aryl-1H-benzimidazol-3-ium) salts. The antibacterial potential of the test compounds was investigated against Staphylococcus aureus, Pseudomonas aeruginosa and two methicillin-resistant S. aureus (MRSA) strains (MRSA10, MRSA11), where compound 6 showed the best results. For brine shrimp lethality bioassay (BSLB), compound 6 again showed up to 100% mortality at 200 μg/mL and 56.7% mortality at 6.25 μg/mL. Antileishmanial assay was performed against Leishmania tropica at 20 μg/mL dosage, where 6 showed the most promising activity with 16.26% survival (83.74% mortality; IC50=14.63 μg/mL). The anticancer potential of the selected benzimidazole derivatives was evaluated against two selected cell lines (human colorectal cancer, HCT-116 and breast adenocarcinoma, MCF-7) using sulforhodamine B (SRB) assay. Compound 6 was found to be the most effective cytotoxic compound with 75% inhibition of HCT-116 proliferation at 1 mg/mL concentration. Succinctly, 6 exhibited impressive pharmacological potential that might be attributed to its higher lipophilic character owing to the longer N-substituted alkyl chains when compared to the other test compounds.

An Interrupted Pummerer/Nickel-Catalysed Cross-Coupling Sequence.

An interrupted Pummerer/nickel-catalysed cross-coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one-pot process, involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp-, sp2 -, and sp3 -hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo- and heterocyclic alkenyl sulfonium salts for cross-coupling.

Organocatalytic Atom-Transfer C(sp3)–H Oxidation

Predictably site-selective catalytic methods for intermolecular C(sp3)–H hydroxylation and amination hold great promise for the synthesis and late-stage modification of complex molecules. Transition-metal catalysis has been the most common approach for early investigations of this type of reaction. In comparison, there are far fewer ­reports of organocatalytic methods for direct oxygen or nitrogen insertion into C–H bonds. Herein, we provide an overview of early efforts in this area, with particular emphasis on our own recent development of an iminium salt that catalyzes both oxygen and nitrogen insertion.1 Introduction2 Background: C–H Oxidation Capabilities of Heterocyclic Oxidants3 Oxaziridine-Mediated Catalytic Hydroxylation4 Dioxirane-Mediated Catalytic Hydroxylation5 Iminium Salt Catalysis of Hydroxylation and Amination6 Conclusion and Outlook

A General Strategy for Site-Selective Incorporation of Deuterium and Tritium into Pyridines, Diazines, and Pharmaceuticals.

Methods to incorporate deuterium and tritium atoms into organic molecules are valuable for medicinal chemistry. The prevalence of pyridines and diazines in pharmaceuticals means that new ways to label these heterocycles will present opportunities in drug design and facilitate absorption, distribution, metabolism, and excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines, and pharmaceuticals are converted into heterocyclic phosphonium salts and then isotopically labeled. The isotopes are incorporated in high yields and, in general, with exclusive regioselectivity.

Curtin-Hammett-Driven Intramolecular Cyclization of Heteroenyne-Allenes to Phenanthridine-Fused Quinazoliniminiums.

Intramolecular cyclization of the heteroenyne-allene 2-((biphenyl-2-ylimino)methyleneamino)benzonitrile 1 to phenanthridine-fused quinazoliniminium salt PQ in the presence of a Lewis acid at room temperature involves formation of two new bonds: a C-C bond and a C-N bond. In this article, density functional theory (B3LYP and M06-2X) was employed in conjunction with 6-311G* basis set to gain insights into the mechanism of this cyclization reaction. The solvent effects were considered using Polarizable Continuum Model with nitromethane as the solvent. Our calculations show that C-C bond formation precedes the C-N bond formation. Precisely, the mechanism involves initial protonation of 1 at Nα and Nβ of the carbodiimide to form rapidly equilibrating conformers of the tautomers 2a,b and 3a,b. The Curtin-Hammett principle is invoked to determine the course of the reaction from these protonated species, which predicts that the intramolecular Friedel-Crafts type N-acylation (C-C bond formation) occurs between the protonated carbodiimide and biphenyl ring of the isomer 3b to form phenanthridinium cation 6b via transition state TS3b6b. Once 6b is formed, it converts to its most stable tautomers 8R and 9a. Once again, the Curtin-Hammett principle suggests that intramolecular nucleophilic attack is preferred from the tautomer 8R, where phenanthridine N-atom (Nβ) attacks the protonated nitrile group (C-N bond formation) and results in the formation of intermediate 11 via TS8R11. 11 then tautomerizes to the most stable cation 13. The coordination of the latter with the chloride anion yields the phenanthridine-fused heterocyclic salt PQ with overall release of energy. The pathways involving protonation at the nitrile (Nγ) of 1 were found to be energetically unfavorable and thus insignificant to the mechanism of cyclization.

Synthesis, characterization and biological application of 5-quinoline 1,3,5-trisubstituted pyrazole based platinum(ii) complexes.

Square planar mononuclear platinum(ii) complexes were synthesized in the presence of neutral bidentate heterocyclic (5-quinoline 1,3,5-tri-substituted pyrazole scaffold) ligands and K2PtCl4 salt. The synthesized compounds were characterized by micro-elemental analysis, FT-IR, UV-vis, 1H NMR, 13C NMR, TGA, mass spectrometry and molar conductivity. Their biological activities were investigated by in vitro brine shrimp lethality bioassay, in vitro antimicrobial study against five different pathogens, in vivo cellular level cytotoxicity against Schizosaccharomyces pombe cells, and in vitro anti-proliferation assay. The binding constant Ksv, Kb, Ka values of the complexes were determined by DNA interaction studies. The gel electrophoresis assay was carried out to examine the effect of the complexes on the DNA nuclease of pUC19 plasmid DNA. The docking energies of the ligands (L1-L5 ) and complexes (I-V) were observed in the range of -265.14 to -284.33 kJ mol-1. The synthesized Pt(ii) complexes (I-V) were screened against the MCF-7 (human breast adenocarcinoma) and HCT-116 (human colon carcinoma) cancer cell lines.

Selective formation of heteroaryl thioethers via a phosphonium ion coupling reaction

Heteroaryl thioethers, comprised of pyridines and diazines, are an important class of compounds with relevance to medicinal chemistry. Metal-catalyzed cross-couplings and SNAr reactions are traditionally used to form C–S bonds in these systems but are limited by available halogenated precursors. An alternative approach is presented where pyridines and diazines are transformed into heterocyclic phosphonium salts and then C–S bonds are formed by adding thiolate nucleophiles. The process is 4-selective for pyridines, simple to execute and can be used to make derivatives of complex pharmaceuticals.

4-Selective Pyridine Functionalization Reactions via Heterocyclic Phosphonium Salts

Pyridines are widely used across the chemical sciences in applications ranging from pharmaceuticals, ligands for metal complex and battery technologies. Direct functionalization of pyridine C–H bonds is an important strategy to make useful pyridine derivatives, but there are few ways to selectively transform the 4-position of the scaffold. We recently reported that pyridines can be converted into heterocyclic phosphonium salts that can serve as generic handles for multiple subsequent bond-forming processes. Reactions with nucleophiles and transition-metal cross-couplings will be described to make C–O, C–S, C–N, and C–C bonds in a diverse range of pyridines including those embedded in complex pharmaceuticals.1 Introduction2 Direct, Regioselective Functionalization of Pyridines3 4-Position Selectivity via Metal Catalysis4 Versatile Functional Groups versus Specific Bond Constructions5 Phosphonium Salts as Reagents for Pyridine Functionalization6 Conclusions

A Quantitative Analysis of Factors Influencing Ease of Formation and σ-Bonding Strength of Oxa- and Thia-N-Heterocyclic Carbenes.

The index described previously (carbene relative energy of formation) has been extended to oxygen and sulfur heterocycles. This provides a quantitative overview of factors determining ease of formation of (i) neutral N-heterocyclic carbenes (NHCs) by deprotonation of heterocyclic salts and (ii) anionic NHCs by deprotonation of heterocyclic mesomeric betaines. The influence of the nature and ring position of oxygen and sulfur is discussed for a range of known and unknown systems. Attention is directed to unexplored systems of potential interest.

Isothermal Crystallization of Isotactic Polypropylene Nucleated with a Novel Aromatic Heterocyclic Phosphate Nucleating Agent

ABSTRACTThe incorporation of a nucleating agent into isotactic polypropylene (iPP) is one of the most important and widely used methods to improve performance in the polypropylene industry. Aromatic heterocyclic phosphate salt is a kind of highly effective nucleating agent for iPP and one of the typical products is a compound nucleating agent based on 2, 2-methylene-bis (4, 6-di-tert-butylphenyl) phosphate hydroxyl aluminum (commercial product name: ADK NA-21). In this paper the isothermal crystallization kinetics of iPP nucleated with the α-nucleating agent NA-21, investigated using differential scanning calorimetry (DSC), is described with the crystallization data being analyzed by using the classic Avrami method. During isothermal crystallization the addition of nucleating agent NA-21 dramatically shortened the crystallization half time (t1/2) of iPP under the same conditions and the crystallization activation energy, ΔE, decreased from 422 kJ/mol for virgin iPP to 369 kJ/mol with the addition of NA-21. Thus, the addition of NA-21 significantly increased the crystallization rate of iPP.