Pyridine Amine Research Articles

Mechanistic Approach Toward the C4‐Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen

AbstractThe development of site‐selective functionalization of N‐heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4‐aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4‐selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4‐pyridyl pyridinium salt intermediates, 4‐aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C−H pyridination of additional N‐heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Mechanistic Approach Toward the C4-Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen.

The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C-H pyridination of additional N-heteroarenes, presenting a strategic avenue for installation of diverse functional groups.

Suzuki–Miyaura Cross-Coupling of 2-Pyridyl Trimethylammonium Salts by N–C Activation Catalyzed by Air- and Moisture-Stable Pd–NHC Precatalysts: Application to the Discovery of Agrochemicals

We report the first Suzuki-Miyaura cross-coupling of 2-pyridyl ammonium salts by highly selective N-C activation catalyzed by air- and moisture-stable Pd(II)-NHC (NHC = N-heterocyclic carbene) precatalysts. The use of well-defined and highly reactive [Pd(IPr)(3-CF3-An)Cl2] (An = aniline) or [Pd(IPr)(cin)Cl] (cin = cinnamyl) Pd(II)-NHC catalysts permits an exceptionally broad scope of the cross-coupling to furnish valuable biaryl and heterobiarylpyridines that are ubiquitous in medicinal chemistry and agrochemistry research. The overall process leverages the Chichibabin C-H amination of pyridines with N-C activation to enable an attractive strategy to the 2-pyridyl problem. The utility of the method to the discovery of potent agrochemicals is presented. Considering the importance of 2-pyridines and the versatility of N-C activation methods, we envision that this new C-H/N-C activation strategy will find broad application.

Photoluminescence Behaviors in Self-Assembly Supramolecular Pyridinium Salts

The host–guest supramolecular organic salts would be of great interest due to their excellent optical and electronic properties. Herein, we report three supramolecular materials, o-2MAP, m-3MAP, and p-4MAP, composed of 18-crown-6 and pyridine amine salts, which are crystallized in space groups P1̅, P1̅, and P21/n with a pendulum-like structural variation at room temperature. They all show blue photoluminescence with photoluminescence quantum yields (PLQYs) of 26.85, 77.08, and 32.67%, respectively. The experimental and theoretical analyses reveal that PL emission is associated with strong π–π * and n–π* absorption and charge transition, while hydrogen bond nonvalent interactions affect their structures and cause the enhancement of PLQY. Especially, deep-blue PL materials m-3MAP with the highest PLQY have been used as excellent color conversion media to fabricate ultraviolet light-emitting diodes (UV-LEDs) and anticounterfeiting inks for handwriting and transfer-printing. This work caters to a reliable strategy to design novel optical supramolecular materials and extends their applications for PL materials.

Homogeneous electrochemical water oxidation catalyzed by cobalt complexes with an amine–pyridine ligand

Two cobalt complexes were reported as homogeneous electrocatalysts for water oxidation. Compared with the inert triamine–dipyridine ligand, the diamine–tripyridine ligand endows higher catalytic activity to the corresponding complex.

Late Transition Metal Catalysts with Chelating Amines for Olefin Polymerization

Polyolefins are the most consumed polymeric materials extensively used in our daily life and are usually generated by coordination polymerization in the polyolefin industry. Olefin polymerization catalysts containing transition metal–organic compound combinations are undoubtedly crucial for the development of the polyolefin industry. The nitrogen donor atom has attracted considerable interest and is widely used in combination with the transition metal for the fine-tuning of the chemical environment around the metal center. In addition to widely reported olefin polymerization catalysts with imine and amide donors (sp2 hybrid N), late transition metal catalysts with chelating amine donors (sp3 hybrid N) for olefin polymerization have never been reviewed. In this review paper, we focus on late transition metal (Ni, Pd, Fe, and Co) catalysts with chelating amines for olefin polymerization. A variety of late transition metal catalysts bearing different neutral amine donors are surveyed for olefin polymerization, including amine–imine, amine–pyridine, α-diamine, and [N, N, N] tridentate ligands with amine donors. The relationship between catalyst structure and catalytic performance is also encompassed. This review aims to promote the design of late transition metal catalysts with unique chelating amine donors for the development of high-performance polyolefin materials.

Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-β Aggregation in Alzheimer's Disease.

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aβ peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aβ-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (AS)-derived compounds (AS-HL1 and AS-HL2), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aβ-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-β, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aβ-Cu complex as studied by the UV-visible spectroscopic assay. Molecular docking studies were also performed with Aβ and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer's disease.

Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido Complexes Based on Pyridine-Amine Ligands: Structural Diversity Arising from Reaction Conditions, Substituent Variation, and Metal Centers.

Herein, we present the different coordination modes of half-sandwich iridium(III) and rhodium(III) complexes based on pyridine-amine ligands. The pyridyl-amine iridium(III) and rhodium(III) complexes, the corresponding oxidation pyridyl-imine products, and 16-electron pyridyl-amido complexes can be obtained through the change in reaction conditions (nitrogen/adventitious oxygen atmosphere, reaction time, and solvents) and structural variations in the metal and ligand. Overall, the reaction of pyridine-amine ligands with [(η5-C5(CH3)5)MCl2]2 (M = Ir or Rh) in the presence of adventitious oxygen afforded the oxidized pyridyl-imine complexes. The possible mechanism for the oxidation of iridium(III) and rhodium(III) amine complexes was confirmed by the detection of the byproduct hydrogen peroxide. Moreover, the formation of pyridyl-amine complexes was favored when nonpolar solvent CH2Cl2 was used instead of CH3OH. The rarely reported complex with [(η5-Cp*)IrCl3] anions can also be obtained without the addition of NH4PF6. The introduction of the sterically bulky i-Bu group on the bridge carbon of the ligand led to the formation of stable 16-electron pyridyl-amido complexes. The pyridyl-amine iridium(III) and rhodium(III) complexes were also synthesized under a N2 atmosphere, and no H2O2 was detected in the whole process. In particular, the aqueous solution stability and in vitro cytotoxicity toward A549 and HeLa human cancer cells of these complexes were also evaluated. No obvious selectivity was observed for cancer cells versus normal cells with these complexes. Notably, the represented complex 5a can promote an increase in the reactive oxygen species level and induce cell death via apoptosis.

Reexamining Povarov Reaction’s Scope and Limitation in the Generation of HCV-NS4A Peptidomimetics

Chronic Hepatitis C is a global health threat and a silent killer. Regardless of the profound progress in preventing and treating this disease, research continues to discover new direct antiviral agents (DAAs), especially against novel targets. Our research has been directed to leverage the NS4A binding site to develop peptidomimetic inhibitors of the hepatitis C virus (HCV) NS3 protease. In previous reports, we could provide evidence of tunability of this site by peptide and nonpeptide NS3/4A inhibitors. In this report, we used structure-based techniques to design 1,2,3,4-tetrahydro-1,7-naphthyridine derivative as NS4A core mimics that cover the region between residues Ile-25′ to Arg-28′. The synthetic plan featured the Povarov reaction as an efficient strategy to construct the 1,7-naphthyridine core. Although this reaction has been reported in many literatures, critical assessments for its scope and limitations are scarce. In our work, we found that Povarov was extremely sensitive to alkene and aldehyde reactants. Moreover, using pyridine amines was not as successful as anilines. The most striking results were the lack of stability of compounds during purification and storage. The four compounds that survived the stability problems (1a-1d) did not show significant binding potency with NS3, because their structures were too simple to resemble the originally planned compounds.

Solid-state and solution characterizations of [(TMPA)Cu(II)(SO3)] and [(TMPA)Cu(II)(S2O3)] complexes: Application to sulfite and thiosulfate fast detection

Sulfite (SO32−) and thiosulfate (S2O32−) ions are used as food preservative and antichlor agent respectively. To detect low levels of such anions we used Cu(II) complex of the Tris-Methyl Pyridine Amine (TMPA) ligand, denoted L. Formation of [LCu(SO3)] (1) and [LCu(S2O3)] (2) in solution were monitored using UV–Vis, EPR and cyclic voltammetry, while the solid-state X-ray structures of both complexes were solved. In addition, we also evaluated the pH range in which the complexes are stable, and the anions binding affinity values for the [LCu(solvent)]2+ (3) parent complex. As a matter of illustration, we determined the sulfite content in a commercial crystal sugar.

Pyridylphosphonium salts as alternatives to cyanopyridines in radical-radical coupling reactions.

Radical couplings of cyanopyridine radical anions represent a valuable technology for functionalizing pyridines, which are prevalent throughout pharmaceuticals, agrochemicals, and materials. Installing the cyano group, which facilitates the necessary radical anion formation and stabilization, is challenging and limits the use of this chemistry to simple cyanopyridines. We discovered that pyridylphosphonium salts, installed directly and regioselectively from C–H precursors, are useful alternatives to cyanopyridines in radical–radical coupling reactions, expanding the scope of this reaction manifold to complex pyridines. Methods for both alkylation and amination of pyridines mediated by photoredox catalysis are described. Additionally, we demonstrate late-stage functionalization of pharmaceuticals, highlighting an advantage of pyridylphosphonium salts over cyanopyridines.

Influence of Surface Polarity on Catalytic Properties of Aminopyridine Functionalized Polyacrylonitrile Fiber Catalyst

This work has been developed to study the effect of fiber catalyst surface polarity on catalyst performance. Taking 4-dimethyl amine pyridine (DMAP) derivative functionalized polyacrylonitrile fiber catalyst (PANDMAPF) as the template catalyst, its surface property was adjusted through the introduction of phenyl and hydroxyl groups on PANDMAPF. Elemental analysis (EA), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and mechanical strength test are used to characterize and demonstrate the successful synthesis of different fiber catalysts. The catalytic performance of different fiber catalysts was tested by the reaction of one-pot three-component synthesis 2-amino-2-chromenes. The results showed that reducing the surface polarity of the catalyst could not only improve the activity of the catalyst, but also make the three-component reaction which could only be carried out in high polar solvents (water and methanol), but also proceed effectively in lower polar solvents (such as ethanol and n-butanol). Therefore, the activity and selectivity of the catalyst can be effectively regulated by introducing different polar auxiliary functional groups on the surface of the fiber catalyst, which provides a theoretical basis for the design and synthesis of high activity and selectivity fiber catalyst.

Thieno[2,3-b]pyridine amines: Synthesis and evaluation of tacrine analogs against biological activities related to Alzheimer's disease.

In search of safer tacrine analogs, various thieno[2,3-b]pyridine amine derivatives were synthesized and evaluated for their inhibitory activity against cholinesterases (ChEs). Among the synthesized compounds, compounds 5e and 5d showed the highest activity towards acetylcholinesterase and butyrylcholinesterase, with IC50 values of 1.55 and 0.23 µM, respectively. The most active ChE inhibitors (5e and 5d) were also candidates for further complementary assays, such as kinetic and molecular docking studies as well as studies on inhibitory activity towards amyloid-beta(βA) aggregation and β-secretase 1, neuroprotectivity, and cytotoxicity against HepG2 cells. Our results indicated efficient anti-Alzheimer's activity of the synthesized compounds.

A Multifunctional Reagent Designed for the Site-Selective Amination of Pyridines.

We report the development of a multifunctional reagent for the direct conversion of pyridines to Boc-protected 2-aminopyridines with exquisite site selectivity and chemoselectivity. The novel reagent was prepared on 200-g scale in a single step, reacts in the title reaction under mild conditions without precautions toward air or moisture, and is tolerant of nearly all common functionality. Experimental and in situ spectroscopic monitoring techniques provide detailed insights and unexpected findings for the unique reaction mechanism.

Revisiting the Chichibabin Reaction: C2 Amination of Pyridines with a NaH−Iodide Composite

AbstractA NaH‐iodide composite was found capable of mediating the Chichibabin amination under mild reaction conditions, allowing efficient access to a range of 2‐aminopyridines and their derivatives.

Inhibiting Aβ toxicity in Alzheimer's disease by a pyridine amine derivative

Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid β-peptide (Aβ) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Aβ aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Aβ-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Aβ toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting Aβ toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs.

Fishing for Isotopes: Capturing Beryllium-7 from Brookhaven LINAC Isotope Producer's 300 gallons of Cooling Water.

The ability of capturing metals and/or radionuclides from large amounts of water is important for radioisotope waste treatment and environmental cleanup. We have developed an approach that rapidly optimizes the capturing of radioisotopes in large-volume aqueous environments. The approach was scaled up to capture beryllium-7 from 300 gallons of cooling water associated with a linear accelerator. Solid supports with the functional groups sulfonic acid, iminodiacetate, pyridine amine, pyridine amine acid, or quaternary amine were incubated in the cooling water for 1 week. One sulfonic acid solid support was able to capture 2.1 mCi of Be-7. Subsequent studies with the sulfonic acid solid support focused on the uptake over time of Be-7, scale-up of capturing Be-7, and subsequent purification of Be-7. The uptake over time of Be-7 was found to be linear in the first 24 h, with an equation of Y = 4.11X (% uptake/time (h)) (R2 = 0.998). The uptake of Be-7 reached the maximum at 24 h and was identical to the uptake at 168 h. To purify Be-7, the optimal purification approach was to release the Be-7 from the solid support with 10 M HCl, which could be immediately passed through an AG1 resin to remove radioimpurities. The radiopurity of the purified Be-7 was greater than 99%, and this method was used to purify 65 mCi of the isotope.

Facile, Efficient Copolymerization of Ethylene with Norbornene-Containing Dienes Promoted by Single Site Non-Metallocene Oxovanadium(V) Catalytic System.

Non-metallocene oxovanadium(V) complexes bearing either [ONNO]-type amine pyridine bis(phenolate) ligands or [ONN]-type amine pyridine phenolate ligands were employed as efficient catalysts to copolymerize ethylene with several unsymmetrical norbornene-containing dienes, such as 5-vinyl-2-norbornene (VNB), 5-ethylidene-2-norbornene (ENB) or dicyclopentadiene (DCPD), producing copolymers with high comonomer incorporations (VNB: 33.0 mol %; ENB: 30.4 mol %; DCPD: 31.6 mol %, respectively) and high molecular weight (VNB: 86.4 kDa; ENB: 256 kDa; DCPD: 86.4 kDa, respectively). The enchainment of the dienes was proven to be exclusive of vinyl-addition via the C=C double bond of the norbornene ring while the other double bond was retained near the backbone without crosslinking. During the copolymerization of ethylene with ENB, a positive ‘comonomer effect’ was observed. The catalytic activities of the catalysts as well as the molecular weights and comonomer incorporations of the resultant copolymers could be tuned within a wide range by varying the structures of the catalysts and copolymerization conditions. The [ONN]-type oxovanadium(V) complexes showed higher catalytic activities than those of [ONNO]-type oxovanadium(V) complexes, irrespective of the structure of the dienes. In addition, the dominant chain transfer pathway of the non-metallocene oxovanadium(V) catalytic system promoted copolymerization was proven to be transfer to aluminum compounds.

In Situ Preparation and Consumption of O-Mesitylsulfonylhydroxylamine (MSH) in Continuous Flow for the Amination of Pyridines

The paper demonstrates a safe method in which highly unstable O-mesitylsulfonylhydroxylamine (MSH) can be prepared and consumed in continuous flow. MSH was prepared in situ and used for the flow amination of a range of pyridines, which were subsequently transformed into useful pyrazolopyridine building blocks.

Silver-Free Palladium-Catalyzed sp3 and sp2 C–H Alkynylation Promoted by a 1,2,3-Triazole Amine Directing Group

Triazole amine was identified as an effective directing group in promoting C-H alkynylation under silver-free conditions. No other external oxidant was required, and the alkynylation products were received in good to excellent yields. X-ray crystallographic analysis confirmed a direct C-H activation intermediate. Other typical directing groups, including pyridine amine (PIP) and 8-aminoquinoline (QA), gave almost no reaction under identical conditions, which highlighted the unique reactivity of the triazole directing group in direct C-H functionalization.