Pyridine Framework Research Articles

Ligand Basicity and Chelate Effects on Sulfur Insertion vs. Sulfur Reduction by Zinc Thiolate Complexes.

4- and 5-coordinate zinc thiolate complexes supported either by bis(carboxamide)pyridine frameworks or by substituted tris(pyrazolyl)borate ligands react with elemental sulfur (S8) following two distinct pathways. Some zinc thiolate moieties insert sulfur atoms to form zinc polysulfanide complexes, while others reduce sulfur and oxidize the thiolate. Here, we compare the effects of ligand electronics, strain, and sterics for selecting the respective reaction pathway. These results show that chelating and electron-deficient thiolate ligands better stabilize persistent zinc-bound polysulfanide species.

Cu‐Catalyzed Synthesis of Coumarin‐1,2,3‐Triazole Hybrids connected with Quinoline or Pyridine Framework**

AbstractCoumarin‐1,2,3‐triazole hybrids connected to quinoline or pyridine framework have been synthesized in good to excellent yield by the 1,3‐dipolar azide alkyne cycloaddition reaction (CuACC) of 4‐azidocoumarin with propargyl quinoline or propargyl pyridine derivatives in the presence of CuSO4.5H2O or CuI as catalyst. Similar reaction of 4‐azidocoumarin or tetrazolo[1,5‐a]pyridine with 4‐propargyloxycoumarin and 4‐propargylaminocoumarin resulted in the synthesis of the corresponding coumarin‐1,2,3‐triazole hybrids. Some preliminary screening test for some biological activities of new compounds have been performed.

Carbon-phosphorus stapled Au(I) anticancer agents via bisphosphine induced reductive elimination.

Towards the goal of generating new stabilized gold complexes as potent anticancer agents, we report here a novel class of Au(I) agents from Au(III)-mediated Caryl-P bond formation captured within the same complex by reacting a C^N cyclometalated Au(III) complex with bisphosphines. Cyclometalated Au(III) complexes of the type [Au(C^N)Cl2], where C^N represent different aryl pyridine framework reacted with bis(2-diphenylphosphino)phenyl ether in refluxing methanol to access an unsymmetrical gold complex featuring C-P coupling and Au(I)-phosphine. The complexes were characterized by 1H-NMR, 13C-NMR, and 31P-NMR and mass spectrometry. The structures of the complexes were characterized by X-ray crystallography and purity ascertained by HPLC and elemental analysis. The complexes demonstrate promising anticancer activity in a broad panel of cancer cell lines of different tumor origin. Mechanistically, the complexes induce apoptosis, generate mitochondrial ROS, depolarize mitochondrial membrane potential and modulate mitochondrial respiration in cancer cells. Overall, we developed a new structural class of Au(I) complexes with promising anticancer potential with potential utility in other applications.

Heat‐Resistant and Low Sensitivity Energetic Material Constructed with [1, 2, 4]Triazolo[4,3‐a]pyridine Framework

AbstractIn this study, fused [1, 2, 4]triazolo[4,3‐a]pyridine framework was applied to construct a new energetic compound with high thermal stability and low sensitivity. 5‐Imino‐6,8‐dinitro‐2,3,5,6‐tetrahydro‐[1,2,4]triazolo[4,3‐a]pyridin‐3‐amine (6) was synthesized by a simple method and fully characterized by NMR (1H, 13C), IR, elemental analysis, differential scanning calorimetry (DSC) and thermogravimetric (TG). The structure of compound 6 was further determined by X‐ray diffraction. Physicochemical and energetic properties of the target compound, such as thermal behavior, friction sensitivity, impact sensitivity, density and detonation property, were tested. Compound 6 possesses high thermal stability (Td=337 °C), desirable insensitivity (IS >40 J, FS >360 N), positive calculated heat of formation (ΔfH=307.05 kJ mol−1) and good detonation property (D=8227 m s−1, P=26.3 GPa), which are all superior to the traditional heat‐resistant explosive HNS (Td=318 °C, IS=5 J, FS=240 N, ΔfH=78.2 kJ mol−1, D=7612 m s−1). These results imply that compound 6 has potential application as a heat‐resistant and insensitive explosive.

Synthesis of Diversified Pyrazolo[3,4-b]pyridine Frameworks from 5-Aminopyrazoles and Alkynyl Aldehydes via Switchable C≡C Bond Activation Approaches.

A cascade 6-endo-dig cyclization reaction was developed for the switchable synthesis of halogen and non-halogen-functionalized pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and alkynyl aldehydes via C≡C bond activation with silver, iodine, or NBS. In addition to its wide substrate scope, the reaction showed good functional group tolerance as well as excellent regional selectivity. This new protocol manipulated three natural products, and the arylation, alkynylation, alkenylation, and selenization of iodine-functionalized products. These reactions demonstrated the potential applications of this new method.

Cover Picture: Recent Advances in Synthesis of Multiply Arylated/Alkylated Pyridines (Chem. Rec. 9/2022)

The Front Cover shows categorization of synthetic methods for multiply arylated/alkylated pyridines according to the reaction patterns. Versatile pyridine frameworks possessing less polar and inactive aryl/alkyl groups are constructed by condensation of building blocks, cycloaddition, and ring transformation altering the substrates. Suzuki–Miyaura cross-coupling reaction is also used for introducing aryl groups to the pyridine ring. The graphic image represents chemistry reactions drawn with chalk on a board by a professor for a lecture to students. See the Review by N. Nishiwaki and co-workers (DOI:10.1002/tcr.202200099).

Recent Advances in Synthesis of Multiply Arylated/Alkylated Pyridines.

Multiply aryl/alkyl-substituted pyridines are some of the untapped synthetic targets because of the challenge in regioselectively introducing less polar aryl/alkyl groups at the desired positions in the pyridine framework. Interestingly, the importance of this family of compounds has increased annually, particularly in biological and materials engineering applications. The syntheses of such pyridines have been extensively reported, but there is a lack of comprehensive review articles. Hence, this review discusses recent advances by grouping reaction patterns that generally deliver tri-, tetra-, and penta-aryl/alkyl pyridines.

Sonochemical Synthesis and In Silico Evaluation of Imidazo[1,2-a]Pyridine Derivatives as Potential Inhibitors of Sirtuins

Encouraged by the reported sirtuin modulating ability of an imidazopyridazine derivative the structurally relevant imidazo[1,2-a]pyridine framework was explored for the design and synthesis of prospective inhibitors of sirtuins. The synthesis of targeted imidazo[1,2-a]pyridine derivatives was carried out via a NBS (N-bromosuccinimide) promoted reaction of 2-aminopyridines with β-keto esters (or 1,3-dione derivatives) in PEG-400 under ultrasound irradiation. This sonochemical method afforded the desired product in good yield when 2-aminopyridines containing electron donating methyl group were employed whereas the corresponding products were obtained in low yields when the electron withdrawing chloro group was present in 2-aminopyridines. The use of 1,3-diones in place of β-keto esters generally afforded the corresponding products in moderate to low yields. The compounds obtained from 1,3-diones were evaluated in silico against SIRT1, 2 and 3 for their potential inhibitory properties against these proteins. The carbonyl group generally played an important role in the interaction of test compounds with the target protein via formation of H-bond(s) with the appropriate residue(s). The docking studies also indicated the selective inhibition of SIRT1 over SIRT2 and 3 by the compound 4a whereas the selective SIRT3 inhibition was specified for compound 3x. Additionally, the in vitro SIRT1 inhibition e.g. 66.7 ± 2.1, 76.8 ± 1.3, 51.9 ± 3.0 and 70.1 ± 1.9% shown by 3x, 4a, 4b and 4c, respectively at 10 µM corroborated the in silico findings concerning this protein.

Construction of sublimable pure organic ionic material with high solid luminescence efficiency based on anion-π+ interactions tuning strategy

Charged species with π-conjugated moieties play a vital role in the development of organic electronic field, but the executable strategy of attaining high luminescent efficiency with sublimable pure organic salts is rare due to their inherent ionic nature and low vapor pressure, extremely restricting their application in the field of organic optoelectronics via common vacuum evaporation method. In this work, a series of central-type organic salts based polycyclic aromatic hydrocarbon (PAH) core are developed because of their potential higher luminescence efficiency than that of reported terminal-type organic salts like protonated pyridine framework, and they are equipped with aggregation-induced emission enhancement performance and tunable emission. The analyses of spectral data, crystal packing, and theoretical simulation demonstrate that rationally dispersing surface charge of large π cation by regulating donor–acceptor (D-A) distribution facilitates to increase anion-π+ interactions and suppress the free rotation of phenyl groups, contributing to the fluorescence enhancement in the solid state. Notably, after tuning counter-ions’ steric hindrance and dispersed charges (BArF24−), the sublimable pure organic ionic materials are obtained with high solid luminescence efficiency, and its vacuum-evaporated organic light-emitting diode (OLED) is prepared based on pure organic salt with bright yellow emission. Such inspiring results offer us new alternative material system for the organic optoelectronics.

Cover Picture: Construction of Enantioenriched 4,5,6,7‐Tetrahydrofuro[2,3‐b]pyridines through a Multicatalytic Sequence Merging Gold and Amine Catalysis (Adv. Synth. Catal. 19/2021)

The inside cover picture, designed by Fabrice Goursaud, holder of a PhD in organic chemistry and recently graduated from art school, illustrates the stereoselective synthesis of tetrahydro[2,3-b]pyridine frameworks via one-pot metal-organo relay catalysis. The strategy, which involves a gold-catalyzed cycloisomerization and a chiral amine mediated cycloaddition reaction, provides the targeted molecules in yields ranging from 27 to 90% and high levels of stereoselectivity (de>95%, 93–99% ee). Details can be found in the Communication by Manon Genet, Abdelilah Takfaoui, Jérôme Marrot, Christine Greck and Xavier Moreau. (M. Genet, A. Takfaoui, J. Marrot, C. Greck, X. Moreau, Adv. Synth. Catal. 2021, 363, 4516–4520; DOI: 10.1002/adsc.202100756).

Synthesis of 2‐O‐Functionalized‐5‐salicyloyl Pyridine Derivatives Catalyzed by 2‐Mercaptobenzimidazole

AbstractA concise and efficient one‐pot sequential approach for the synthesis of 5‐salicyloyl pyridine frameworks was developed from a reaction of 3‐formylchromones, malononitrile, various alcohols, and 2‐mercaptobenzimidazole as a catalyst. Malononitrile is the nitrogen source in this reaction. In this method, the variety of 2‐alkoxypyridines derivatives containing alkoxy, allyloxy, and acetylene functional groups can increase the bathochromic effect of the λmax of pyridine to the longer wavelengths. According to experimental and theoretical investigations by the DFT method, long‐wavelength bands of 5‐salicyloyl pyridine derivatives related to the HOMO→LUMO and HOMO→LUMO+1 transitions have the π→π* nature and are caused by intramolecular charge transfer from the phenol fragment to the pyridine ring.

Optimized Scalable Synthesis of Chiral Iridium Pyridyl‐Phosphinite (Pyridophos) Catalysts

AbstractIridium catalysts with chiral P,N ligands have greatly enhanced the scope of asymmetric olefin hydrogenation because they do not require a coordinating group near the C=C bond like Rh and Ru catalysts. Pyridophos ligands, possessing a conformationally restricted annulated pyridine framework linked to a phosphinite group, proved to be particularly effective, inducing high enantioselectivities in the hydrogenation of a remarkably broad range of substrates. Here we report the development of an efficient scalable synthesis for the two most versatile Ir‐pyridophos catalysts, derived from 2‐phenyl‐8‐hydroxy‐5,6,7,8‐tetrahydroquinoline or the analogue with a five‐membered carbocyclic ring, respectively, by modification and optimization of the original synthetic route. The optimized route renders both catalysts readily accessible in multi‐gram quantities in analytically pure form in overall yields of 26–37 %, starting from acetophenone and cyclopentanone or cyclohexanone, respectively. A major advantage of the new synthesis is the efficient and practical kinetic resolution of the late‐stage pyridyl alcohol intermediates with commercial immobilized Candida antarctica lipase B, giving access to both enantiomers of these catalysts as essentially enantiopure compounds. The catalysts are obtained as crystalline solids, which are air‐stable and can be stored for years at −20 °C without notable decomposition.

Synthesis of 2-substituted Furo[3,2-b]pyridines Under Pd/C-Cu Catalysis Assisted by Ultrasound: Their Evaluation as Potential Cytotoxic Agents.

Compounds containing furo[3,2-b]pyridine framework have shown interesting pharmacological properties, including anticancer activities. Though these compounds are generally synthesized via the heteroannulation processes involving acetylenic derivatives, some of them are complex. The study aimed to explore a series of 2-substituted furo[3,2-b]pyridines for their cytotoxic properties against cancer cell lines in vitro. We developed a convenient synthesis of 2-substituted furo[3,2-b]pyridines via sequential (i) C-C coupling followed by (ii) C-O bond-forming reactions in a single pot. The reactions were performed under ultrasound irradiation in the presence of Pd/C as an inexpensive, stable and widely used catalyst. A range of 2- substituted furo[3,2-b]pyridines were synthesized via coupling of 3-chloro-2-hydroxy pyridine with terminal alkynes in the presence of 10% Pd/C-CuI-PPh3-Et3N in EtOH. The in vitro evaluation of all these compounds was carried out against MDA-MB-231 and MCF-7 cell lines and subsequently against SIRT1. The furo[3,2-b]pyridine derivative 3b showed encouraging growth inhibition of both MDAMB-231 and MCF-7 cell lines and inhibition of SIRT1. The compound 3b also showed apoptosis-inducing potential when tested against MCF-7 cells. The Pd/C-Cu catalysis under ultrasound accomplished a one-pot and direct access to 2-substituted furo[3,2-b]pyridine derivatives, some of which showed anticancer properties.

Synthetic progress toward the marine natural product zamamiphidin A.

An asymmetric synthetic approach to the octahydrofuro[3,4-b]pyridine framework of marine natural product zamamiphidin A has been described. The key steps include an asymmetric Michael addition of (R)-N-tert-butanesulfinyl imidate with enamidomalonate to install the C10 stereocenter, an intramolecular alkoxide exchange/Michael addition/hydrogenation sequence to construct the bicyclic ring system.

Catalytic Enantioselective Pyridine N-Oxidation.

The catalytic, enantioselective N-oxidation of substituted pyridines is described. The approach is predicated on a biomolecule-inspired catalytic cycle wherein high levels of asymmetric induction are provided by aspartic-acid-containing peptides as the aspartyl side chain shuttles between free acid and peracid forms. Desymmetrizations of bis(pyridine) substrates bearing a remote pro-stereogenic center substituted with a group capable of hydrogen bonding to the catalyst are demonstrated. Our approach presents a new entry into chiral pyridine frameworks in a heterocycle-rich molecular environment. Representative functionalizations of the enantioenriched pyridine N-oxides further document the utility of this approach. Demonstration of the asymmetric N-oxidation in two venerable drug-like scaffolds, Loratadine and Varenicline, show the likely generality of the method for highly variable and distinct chiral environments, while also revealing that the approach is applicable to both pyridines and 1,4-pyrazines.

A comparison between (a/n-NHC)PdX2(pyridine) and (a/n-NHC)2PdX2 (X = I, Cl) type complexes of abnormal fused-bicyclic imidazo[1,2-a]pyridine based N-heterocyclic carbene (a-NHC) and of normal imidazole based N-heterocyclic carbene (n-NHC) ligands in the Suzuki-Miyaura coupling reactions

A comparison between (a/n-NHC)PdX2(pyridine) (1b, 2b and 3) and (a/n-NHC)2PdX2 (X = halide) (1c, 2c and 4) type complexes of abnormal fused-bicyclic imidazo[1,2-a]pyridine framework derived N-heterocyclic carbenes (a-NHC) and of the ubiquitous normal imidazole based N-heterocyclic carbenes (n-NHC) in Suzuki-Miyaura coupling reactions, revealed near comparable yields between the two (a/n-NHC)PdX2(pyridine) and (a/n-NHC)2PdX2 type complexes of the (a-NHC) and the (n-NHC) ligands. Indeed, the Density Functional Theory (DFT) studies performed on all of the (a/n-NHC)PdX2(pyridine) (1b, 2b and 3) and (a/n-NHC)2PdX2 type complexes (1c, 2c and 4), indicated that as the latter (1c, 2c and 4), with two (a/n-NHC) ligands bound to the metal center were only marginally electron rich than the former (1b, 2b and 3), containing only one (a/n-NHC) ligand bound to metal center, no correlation of the electron richness of the metal centers with the catalysis yields was observed for these complexes. In this regard, the (a-NHC)PdI2(pyridine) (1b and 2b) and the (a-NHC)2PdI2 (1c and 2c) type complexes of two new abnormal fused-bicyclic imidazo[1,2-a]pyridine framework derived N-heterocyclic carbenes (a-NHC) have been synthesized and structurally characterized.

β‐Enaminone Synthesis from 1,3‐Dicarbonyl Compounds and Aliphatic and Aromatic Amines Catalyzed by Iron Complexes of Fused Bicyclic Imidazo[1,5‐a]pyridine Derived N‐Heterocyclic Carbenes

A series of Fe–NHC complexes (1–2)c of the fused bicyclic imidazo[1,5‐a]pyridine framework of the type [CpFe(2‐R‐imidazo[1,5‐a]pyridin‐3‐ylidene)(CO)2]BF4 {R = mesityl (1c), nPr (2c)} successfully carried out the synthesis of β‐enamino ketones (3–10) and (17–27) and β‐enamino esters (11–16) and (28–36) by the condensation of acyclic and cyclic 1,3‐dicarbonyl compounds and various aliphatic and aromatic amines in the presence of light irradiation. Quite significantly, the catalytically relevant substrate adduct species of the type [CpFe(NHC)(acac)] (2e) and the product adduct species of the type [CpFe(NHC)(β‐enaminone)] (2f) of the Fe–NHC precatalyst (2c) have been detected by mass spectrometry study. The [CpFe(2‐R‐imidazo[1,5‐a]pyridin‐3‐ylidene)(CO)2]BF4 {R = mesityl (1c), nPr (2c)} complexes were obtained from their respective N–heterocyclic carbene precursors namely, the 2‐R‐imidazo[1,5‐a]pyridin‐2‐ium chloride {R = mesityl (1a), nPr (2a)} by the reaction with CpFe(CO)2I in the presence of KN(SiMe3)2 followed by the salt metathesis reaction with AgBF4.

Photocatalytic regeneration of brominating agent in the visible light-mediated synthesis of imidazo[1,2-a]pyridines

Regenerating the brominating agent by erythrosine B closes a catalytic cycle for the construction of the imidazo[1,2-a]pyridine framework.

A family of solution processable ligands and their Re(I) complexes towards light emitting applications

A series of triimine ligands incorporating 2,2′:6′,2″-terpyridine (terpy), 2,6-di(thiazol-2-yl)pyridine (dtpy), and 2,6-di(pyrazin-2-yl)pyridine (dppy) frameworks, as well as their corresponding Re(I) tricarbonyl complexes were successfully designed and synthesized to investigate the impact of the peripheral rings (pyridine, thiazole and pyrazine) and phenyl– or naphthyl–based substituents attached to the triimine skeleton on their photophysical and electroluminescent properties. The experimental studies were accompanied with DFT/TDDFT calculations. DSC investigations showed that both the free ligands and Re(I) complexes melted at high temperature (164–309 °C) and some of them are able to form amorphous materials. CV measurements revealed that energy band gaps calculated on the basis of ionization potential and electron affinity of the Re(I) complexes, which are correlated with energy levels of frontier molecular orbitals, fall in the range of 2.14–2.32 eV, being lower than the corresponding ligands, what makes the complexes promising for organoelectronic applications. The photophysical properties of the synthesized triimine ligands and Re(I) complexes were studied in detail by electronic absorption and emission. In solution they exhibited photoluminescence quantum yields ranging from 0.15% to 84.42% depending on the chemical structure. The presence of pyrazine units significantly reduced ability for radiative emission. All the compounds were emissive also in a solid state. Preliminary tests of electroluminescence ability demonstrated that most of the devices with Re(I) complexes exhibited red or orange emission, while diodes with ligands showed maximum of emission band located mainly in the green region. It should be noticed that diodes with active layer consisting of a neat complex (ITO:PEDOT:PSS/complex/Al) emitted light under applied voltage.

Ruthenium(II)-Catalyzed Regioselective Ortho Amidation of Imidazo Heterocycles with Isocyanates

Direct ortho amidation at the phenyl ring of 2-phenylimidazo heterocycles with aryl isocyanates has been achieved via a chelation-assisted cationic ruthenium(II) complex catalyzed mechanism. The methodology provides a straightforward, high-yielding regioselective approach toward the synthesis of an array of ortho-amidated phenylimidazo heterocycles without prior activation of C(sp2)-H. This also reports the first method for coupling of aryl isocyanates with the imidazo[1,2-a]pyridine system via a pentacyclometalated intermediate. The methodology is found to be easily scalable and could be applied toward the selective ortho amidation of 2-heteroarylimidazo[1,2-a]pyridine frameworks.