4-substituted Pyridines Research Articles

Dehydrogenative Synthesis of 2,2′‐Bipyridyls through Regioselective Pyridine Dimerization

2,2'-Bipyridyls have been utilized as indispensable ligands in metal-catalyzed reactions. The most streamlined approach for the synthesis of 2,2'-bipyridyls is the dehydrogenative dimerization of unfunctionalized pyridine. Herein, we report on the palladium-catalyzed dehydrogenative synthesis of 2,2'-bipyridyl derivatives. The Pd catalysis effectively works with an AgI salt as the oxidant in the presence of pivalic acid. A variety of pyridines regioselectively react at the C2-positions. This dimerization method is applicable for challenging substrates such as sterically hindered 3-substituted pyridines, where the pyridines regioselectively react at the C2-position. This reaction enables the concise synthesis of twisted 3,3'-disubstituted-2,2'-bipyridyls as an underdeveloped class of ligands.

Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines

Laccase/DDQ as a new bioinspired quinone-based cooperative catalytic system was used for the biomimetic aerobic oxidative synthesis of 2-substituted quinazolines and Hantzsch pyridines from the oxidative cyclocondensation of 2-aminobenzylamine and aldehydes and the oxidative aromatization of 1,4-dihydropyridines, respectively. The products were obtained in good to high yields in a phosphate buffer (0.1 M, 12.5 mL, pH 4.5) and acetonitrile (4 vol%) mixture as a solvent. These methods are more eco-friendly, efficient, simple, and practical than other currently available ones because of mild reaction conditions and because they are free from any halide and toxic and expensive transition metals. Therefore, these methods can be applied in pharmaceutical and other sensitive synthetic procedures.

Ruthenium N-Confused Porphyrins: Selective Reactivity for Ambident 2-Heteroatom-Substituted Pyridines Serving as Axial Ligands.

Three types of ruthenium(II) N-confused porphyrin (NCP) complexes bearing an axial 2-thiopyridine, 2-pyridone, and 2-iminopyridine moiety at the inner carbon atom, respectively, were synthesized. The unique reactivity of the 2-substituted pyridine derivatives (2-X-pyridine; X=SH, OH, NH2 ) toward the inner carbon atom of the NCP allows the formation of two types of coordinated products (i. e., pyridine donor versus 2-heteroatom donors), as inferred from single-crystal X-ray structures. The selective reactivity was investigated by using density functional theory (DFT) calculations. Finally, the catalytic activity of these ruthenium complexes was demonstrated through the styrene oxidation reactions. As a result, the ruthenium(II) NCP complex bearing a 2-thiopyridine moiety, together with aqueous H2 O2 as an oxidant showed the highest selectivity for benzaldehyde (benzaldehyde/styrene oxide=20 : 1).

Dialing in on pharmacological features for a therapeutic antioxidant small molecule.

The pyridinophane molecule L2 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) has shown promise as a therapuetic for neurodegenerative diseases involving oxidative stress and metal ion misregulation. Protonation and metal binding stability constants with Mg2+, Ca2+, Cu2+, and Zn2+ ions were determined to further explore the therapeutic and pharmacological potential of this water soluble small molecule. These studies show that incorporation of an -OH group in position 4 of the pyridine ring decreases the pI values compared to cyclen and L1 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-triene). Furthermore, this approach tunes the basicity of the tetra-aza macrocyclic ligand through the enhanced resonance stabilization of the -OH in position 4 and rigidity of the pyridine ring such that L2 has increased basicity compared to previously reported tetra-aza macrocycles. A metal binding preference for Cu2+, a redox cycling agent known to produce oxidative stress, indicates that this would be the in vivo metal target of L2. However, the binding constant of L2 with Cu2+ is moderated compared to cyclen due to the rigidity of the ligand and shows how ligand design can be used to tune metal selectivity. An IC50 = 298.0 μM in HT-22 neuronal cells was observed. Low metabolic liability was determined in both Phase I and II in vitro models. Throughout these studies other metal binding systems were used for comparison and as appropriate controls. The reactivity reported to date and pharmacological features described herein warrant further studies in vivo and the pursuit of L2 congeners using the knowledge that pyridine substitution in a pyridinophane can be used to tune the structure of the ligand and retain the positive therapeutic outcomes.

Diruthenium complexes having a partially hydrogenated bipyridine ligand: plausible mechanism for the dehydrogenative coupling of pyridines at a diruthenium site.

The reactions of the diruthenium tetrahydrido complex, Cp*Ru(μ-H)4RuCp* (1) (Cp* = η5-C5Me5), with pyridines were investigated in relation to the dehydrogenative coupling of 4-substituted pyridines. Complex 1 reacted with γ-picoline to yield the bis(μ-pyridyl) complex, {Cp*Ru(μ-H)(μ-4-MeC5H3)}2 (2a), with the elimination of dihydrogen. Complex 2a immediately reacted with the liberated dihydrogen to yield μ-η2-dihydrobipyridine (dhbpy) complex 4avia C-C bond formation between the two pyridyl groups, in which one of the pyridine rings underwent partial hydrogenation. The X-ray structure of 4a shows that the dhbpy moiety adopts a μ-η2 coordination mode at the Ru2 site. Complex 4a was reversibly converted to 5avia the elimination of dihydrogen in which the dhbpy moiety adopts a μ-η2:η2 mode. Although 5a was coordinatively saturated, 5a readily reacted with tBuNC to yield 6a. This was owing to the ability of the dhbpy ligand changing its coordination mode between the μ-η2:η2 and μ-η2 modes. This also causes the dehydrogenation from the dhbpy ligand to yield μ-η2:η2-bipyridine complex 7a at 140 °C. However, 7a was not shown to be an intermediate of the catalysis. The reaction of 1 with 1,10-phenanthroline afforded μ-η2-phenanthroline complex 8 containing two hydrides, which can be a model compound for the bipyridine elimination from the Ru2 site. Dynamic NMR studies suggested that 8 was isomerised to an unsaturated μ-N-heterocyclic carbene (NHC) complex. The unsaturated nature of the μ-NHC complex is likely responsible for the uptake of the third pyridine molecule to turn over the catalytic cycle.

Imidazole for Pyridine Substitution Leads to Enhanced Activity Under Milder Conditions in Cobalt Water Oxidation Electrocatalysis.

A previously reported cobalt complex featuring a tetraimidazolyl-substituted pyridine chelate is an active water oxidation electrocatalyst with moderate overpotential at pH 7. While this complex decomposes rapidly to a less-active species under electrocatalytic conditions, detailed electrochemical studies support the agency of an initial molecular catalyst. Cyclic voltammetry measurements confirm that the imidazolyl donors result in a more electron-rich Co center when compared with previous pyridine-based systems. The primary changes in electrocatalytic behavior of the present case are enhanced activity at lower pH and a marked dependence of catalytic activity on pH.

Onydecalins, Fungal Polyketides with Anti- Histoplasma and Anti-TRP Activity.

We report an unusual 3-substituted pyridine polyketide, onydecalin A (1), which was obtained along with 2 as a major constituent from the fungus Aioliomyces pyridodomos (order: Onygenales) following a two-month fermentation. Feeding studies demonstrated that the pyridine subunit originates via an unprecedented biosynthetic process in comparison to other polyketide-linked pyridines or derivatives such as pyridones. The slow growth of the fungus led us to perform a one-year fermentation, leading to production of compounds 2-4 as the major constituents. These compounds showed modest but selective inhibition against a variety of transient receptor potential channels, as well as against the human pathogenic fungus Histoplasma capsulatum.

Does Proton Transfer Always Take Place in Molecules of 2-Substituted Pyridine-N-oxides? The Case of 2-Aminopyridine-N-oxide Crystal Structure and Its 3,5-Dinitrobenzoic Acid Co-crystal

Novel solid-state structures of 2-hydroxypyridine-N-oxide and its co-crystal with 3,5-dinitrobenzoic acid have been determined. The crystallographic results indicate that this pyridine derivative exists in a neutral tautomeric form in a crystal state; these results are in contrast to the 2-hydroxy, 2-mercapto, and 2-nitramino counterparts of the derivative, which were in a zwitterionic form. The phenomenon of tautomerism in this study was subsequently analyzed with quantum chemistry. The results of theoretical DFT calculations were in agreement with experimental findings (apart from the 2-nitramino derivative), indicating that, in low energy difference between the tautomeric forms, a molecule adopts a more profitable structure in terms of crystal stability, even if it is less stable in the gas phase.

Direct ortho-C-H Aminoalkylation of 2-Substituted Pyridine Derivatives Catalyzed by Yttrium Complexes with N,N'-Diarylethylenediamido Ligands.

A mixed ligated amidoyttrium complex, Y(NBn2)(L1)(THF)2 (8, L1 = N, N'-bis(2,6-diisopropylphenyl)ethylenediamine), served as a catalyst for addition of the ortho-pyridyl C(sp2)-H bond of 2-substituted pyridines to nonactivated imines; complex 8 showed superior catalytic performance compared with Y[N(SiMe3)2]3 (1) and Y[N(SiMe3)2]2(NBn2)(THF) (2). Concerning the reaction mechanism, we conducted a stoichiometric reaction of an alkylyttrium complex, Y(CH2SiMe3)(L1)(THF)2 (7), with 2-ethylpyridine (4e), giving a mixture of (η3-pyridylmethyl)yttrium complex 9 and (η2-pyridyl)yttrium complex 10 along with elimination of SiMe4. Furthermore, addition of N-( tert-butyl)-2-methylpropan-1-imine (5i) to the mixture of 9 and 10 afforded (pyridylmethylamido)yttrium complex 11 as a single product, and the catalytic activity of 11 was comparable to that of complex 8. Kinetic analysis of the aminoalkylation reaction in the presence/absence of HNBn2 revealed that the reaction rate in the presence of HNBn2 was four times faster than that without HNBn2 due to acceleration of the product-eliminating step from complex 11 by HNBn2 to regenerate amidoyttrium complex 8 and the product. In addition, we determined that the catalytic reaction obeyed a first-order rate dependence on the catalyst concentration, independent of the imine concentration, and a second-order rate dependence on the concentration of the pyridine substrate in the reaction system, both with and without HNBn2. An enantiomerically pure N, N'-diaryl-1,2-diphenylethylenediamido ligand was applied for the C(sp2)-H aminoalkylation reaction in combination with Lu(CH2SiMe3)3(THF)2 to give chiral aminoalkylated products in moderate yield with good enantioselectivity.

Kinetics and mechanism of pyridine substitution from [(η3-C3H5)Mo(CO)2(X)(py)2] (X = Cl, Br; py = pyridine) by 1,2-bis(diphenylphosphino)ethane

Reactions of [(η3-C3H5)Mo(CO)2(X)(py)2] (X = Cl (1), Br (2); py = pyridine) with 1,2-bis(diphenylphosphino)ethane (= dppe) in toluene solution resulted in replacement of the py ligands and the formation of [(η3-C3H5)Mo(CO)2(X)(κ2-P,Pʹ-dppe)]. Thermal kinetics of these substitution reactions, under pseudo-first-order reaction conditions, indicated that these reactions proceed by a rate law that is first order in the concentration of the metal complex and zero order in dppe concentration. The data suggest a two-step substitution process. The first step is slow and reversible, involving the dissociation of the first py coligand to form a coordinatively unsaturated [(η3-C3H5)Mo(CO)2(X)(py)] transient species. This is followed by an irreversible end-on coordination of the dppe ligand at the transient species to give [(η3-C3H5)Mo(CO)2(X)(py)(κ1-P-dppe)] as an intermediate. The latter complex undergoes a fast and entropy-driven ring closure, resulting in the substitution of the second py ligand to give [(η3-C3H5)Mo(CO)2(X)(κ2-P,Pʹ-dppe)]. Rate constants and activation parameters for these reactions have been determined and discussed. Competition studies for the [(η3-C3H5)Mo(CO)2(X)(py)] intermediates show that these transients are highly reactive and react almost indiscriminately with both py and dppe. Reactions of [(η3-C3H5)Mo(CO)2(X)(py)2] (X = Cl, Br; py = pyridine) with dppe give [(η3-C3H5)Mo(CO)2(X)(κ2-P,Pʹ-dppe)]. Thermal kinetics of these substitution reactions, under pseudo-first-order reaction conditions, indicate that these reactions proceed by a rate law that is first order in the concentration of the metal complex and zero order in dppe concentration. A mechanism is proposed and suggests initial replacement of py, followed by attack of one P-atom of dppe at [(η3-C3H5)Mo(CO)2(X)(py)] to give [(η3-C3H5)Mo(CO)2(X)(py)(κ1-P-dppe)] which losses another py to give [(η3-C3H5)Mo(CO)2(X)(κ2-P,Pʹ-dppe)]. Rate constants and activation parameters for these reactions have been determined and discussed. Competition studies for the [(η3-C3H5)Mo(CO)2(X)(py)] intermediates show that these transients are highly reactive and react almost indiscriminately with both py and dppe.

Competing Pathways in the Photochemistry of Ru(H)2(CO)(PPh3)3

The photochemistry of Ru(H)2(CO)(PPh3)3 (1) has been reinvestigated employing laser and conventional light sources in conjunction with NMR spectroscopy and IR spectroscopy. The sensitivity of NMR experiments was enhanced by use of p-H2-induced polarization (PHIP), and a series of unexpected reactions were observed. The photoinduced reductive elimination of H2 was demonstrated (a) via NMR spectroscopy by the observation of hyperpolarized 1 on pulsed laser photolysis in the presence of p-H2 and (b) via nanosecond time-resolved infrared (TRIR) spectroscopy studies of the transient [Ru(CO)(PPh3)3]. Elimination of H2 competes with photoinduced loss of PPh3, as demonstrated by formation of dihydrogen, triphenylarsine, and pyridine substitution products which are detected by NMR spectroscopy. The corresponding coordinatively unsaturated 16-electron intermediate [Ru(H)2(CO)(PPh3)2] exists in two isomeric forms according to TRIR spectroscopy that react with H2 and with pyridine on a nanosecond time scale. These tw...

Dehydrogenative coupling of 4-substituted pyridines mediated by a zirconium(ii) synthon: reaction pathways and dead ends.

The mechanism of the reductive homocoupling of pyridine derivatives mediated by the ZrII synthon [(PNP)Zr(η6-toluene)Cl] (1) has been investigated. Selective transformation into three different types of product complexes has been observed, depending on the N-heterocyclic substrate employed: the bipyridyl complexes 3-R (R = Me, Et, t Bu, Bn, Ph, CHCHPh), which are the homocoupling products, the η2-((4-dimethylamino)pyridyl) complex 4 as well as the bis(isoquinolinyl) complex 5. By deuterium labelling experiments the participation of the ligand backbone in the pyridine coupling reaction via potential cyclometallation steps was ruled out. Based on DFT modelling of the possible reaction sequences a reaction mechanism for the coupling sequence could be identified. The latter is initiated by a reductive syn C-C coupling rather than based on an initial C-H activation of the pyridine substrate.

Hyperfine Effects in Ligand NMR: Paramagnetic Ru(III) Complexes with 3-Substituted Pyridines.

NMR spectroscopy is an indispensable tool in characterizing molecular systems, including transition-metal complexes. However, paramagnetic transition-metal complexes such as those with ruthenium in the +3 oxidation state are troublemakers because their unpaired electrons induce a fast nuclear spin relaxation that significantly broadens their NMR resonances. We recently demonstrated that the electronic and spin structures of paramagnetic Ru(III) systems can be characterized in unprecedented details by combining experimental NMR results with relativistic density-functional theory ( Novotny et al. J. Am. Chem. Soc. 2016 , 138 , 8432 ). In this study we focus on paramagnetic analogs of NAMI with the general structure [3-R-pyH]+trans-[RuIIICl4(DMSO)(3-R-py)]-, where 3-R-py stands for a 3-substituted pyridine. The experimental NMR data are interpreted in terms of the contributions of hyperfine (HF) NMR shielding and the distribution of spin density calculated using relativistic DFT. The DFT computational methodology is evaluated, and the effects of substituents, environment, and relativity on the hyperfine shielding are discussed. Particular attention is paid to the analysis of the fundamental Fermi-contact (FC), spin-dipole (SD), and paramagnetic spin-orbit (PSO) terms that contribute to the hyperfine 1H and 13C NMR shifts of the individual atoms in the pyridine ligands and the spin-polarization effects in the ligand system that are linked to the character of the metal-ligand bond. The individual HF shielding terms are systematically discussed as they relate to the traditional, but somewhat mixed, contact and pseudocontact NMR contributions used extensively by experimental spectroscopists in biomolecular NMR and the development of PARACEST magnetic-resonance contrast agents.

Structural effect in the reductive vinylation/phosphorylation of pyridines with alkyl propiolates and secondary phosphine chalcogenides: protonation vs. zwitterion generation

The non-catalyzed reaction of 2- and 3-substituted pyridines with alkyl propiolates and secondary phosphine chalcogenides (50–52 °C, MeCN) produces stereo-, regio- and chemoselectively 1-[(E)-2-(alkoxycarbonyl)ethenyl]-4-chalcogenophosphoryl- 1,4-dihydropyridines in 57–90% yields, the adducts of pyridines with alkyl propiolates being the zwitterionic intermediates. 4-Methylpyridine mainly catalyzes nucleophilic addition of secondary phosphine chalcogenides to alkyl propiolates.

Strategy for Stereoselective Metal-free α-Functionalization of 2-Azaaryl Acetates with N-Boc Imines.

We report the first diastereo- and enantioselective formal Mannich reaction of 2-pyridyl acetates which gives rise to α- and β-functionalized 2-substituted pyridines. Key for success is the previous azaarene N-oxide formation enabling α-carbon deprotonation by a mild bifunctional Brønsted base and subsequent reaction with N-Boc imines under almost perfect stereocontrol.

Synthesis and Characterization of Pt(II) Complexes with Pyridyl Ligands: Elongated Octahedral Ion Pairs and Other Factors Influencing 1H NMR Spectra.

Our goal is to develop convenient methods for obtaining trans-[PtII(4-Xpy)2Cl2] complexes applicable to 4-substituted pyridines (4-Xpy) with limited volatility and water solubility, properties typical of 4-Xpy, with X being a moiety targeting drug delivery. Treatment of cis-[PtII(DMSO)2Cl2] (DMSO = dimethyl sulfoxide) with 4-Xpy in acetonitrile allowed isolation of a new series of simple trans-[PtII(4-Xpy)2Cl2] complexes. A side product with very downfield H2/6 signals led to our synthesis of a series of new [PtII(4-Xpy)4]Cl2 salts. For both series in CDCl3, the size of the H2/6 Δδ [coordinated minus "free" 4-Xpy H2/6 shift] decreased as 4-Xpy donor ability increased from 4-CNpy to 4-Me2Npy. This finding can be attributed to the greater synergistic reduction in the inductive effect of the Pt(II) center with increased 4-Xpy donor ability. The high solubility of [PtII(4-Xpy)4]Cl2 salts in CDCl3 (a solvent with low polarity) and the very downfield shift of the [PtII(4-Xpy)4]Cl2 H2/6 signals for the solutions provide evidence for the presence of strong {[PtII(4-Xpy)4]2+,2Cl-} ion pairs that are stabilized by multiple CH···Cl contacts. This conclusion gains considerable support from [PtII(4-Xpy)4]Cl2 crystal structures revealing that a chloride anion occupies a pseudoaxial position with nonbonding (py)C-H···Cl contacts (2.4-3.0 Å). Evidence for (py)C-H···Y contacts was obtained in NMR studies of [PtII(4-Xpy)4]Y2 salts with Y counterions less capable of forming H-bonds than chloride ion. Our synthetic approaches and spectroscopic analysis are clearly applicable to other nonvolatile ligands.

Microwave Synthesis of Coumarinyl Substituted Pyridine Derivatives as Potent Anticancer Agents and Molecular Docking Studies

AbstractCatalyst free new bioactive 2‐amino‐4‐(2‐oxo‐2H‐chromen‐4‐yl)‐6‐arylpyridine‐3‐carbonitrile molecular entities (2 a‐2 o) have been synthesized from 4‐formylcoumarins with malononitrile, different ketones and ammonium acetate via one‐pot four component coupling reaction under neat microwave method. Detailed characterization of all the compounds and anticancer properties for the synthesized compounds are reported. Compounds 2 f and 2 k exhibited promising anticancer activity at low concentration (10−5 M) against NCI‐60 cell lines. Further, IC50 values were calculated for most potent compounds against three cancer cell lines such as HT‐29, Hep‐G2 and KB. Among the eight compounds, 2 f and 2 k are exhibited most promising activity, the potent anticancer molecules 2 f and 2 k were screened for their CT‐DNA cleavage and fluorescence quenching study with transport protein BSA. Molecular docking study has been performed for the synthesized compounds with binding site of the tubulin using podophyllotoxin‐tubulin stathmin‐like domain complex (PDB 1SA1) and results obtained are quite good.

Synthesis of substituted disulfonyl-containing polycyclic azines with the bridgehead nitrogen atom. Effects of the structure of 3-substituted pyridinium ylides on the regioselectivity of their reactions with E-1,2-di(alkylsulfonyl)-1,2-dichloroethenes

Heating the substituted pyridinium and isoquinolinium salts with E-1,2-di(alkylsulfonyl)-1,2-dichloroethenes in either chloroform or acetone in the presence of three-fold excess of Et3N gave high yields of substituted 1,2-di(alkylsulfonyl)indolizines and 1,2-di(alkylsulfonyl) pyrrolo[2,1-a]isoquinolines, respectively. Effects of the structure of 3-substituted pyridinium ylides on the regioselectivity of their reaction with E-1,2-di(alkylsulfonyl)-1,2-dichloroethenes were revealed. It was shown that the presence of electron-releasing and electron-withdrawing substituents in the pyridinium ylide favors the formation of 8-substituted and 6-substituted 1,2-(dialkylsulfonyl)indolizines, respectively.

Regioselective and Transition-Metal-Free Addition of tert-Butyl Magnesium Reagents to Pyridine Derivatives: A Convenient Method for the Synthesis of 3-Substituted 4-tert-Butylpyridine Derivatives

A variety of 3,4-disubstituted pyridine derivatives with a tert-butyl group in the 4-position were synthesized in a transition-metal-free, two-step reaction sequence from 3-substituted pyridine precursors. Highly regioselective addition of t-Bu2Mg to TIPS-activated pyridines and an efficient microwave-assisted aromatization with sulfur as oxidant afforded the desired 3,4-disubstituted pyridine derivatives in moderate to excellent yields. The method is compatible with many functional groups such as ester, amide, halide, nitrile or alkyne groups present in the 3-position.

Computational and Experimental Investigation of Immobilization of CuI Nanoparticles on 3-Aminopyridine Modified Poly(styrene-co-maleic anhydride) and Its Catalytic Application in Regioselective Synthesis of 1,2,3-Triazoles

Cu(I) nanoparticles (NPs) on modified poly(styrene-co-maleic anhydride) was prepared via a facile procedure. In this regard the modified co-polymer (SMA) was initially synthesized from the reaction of poly(styrene-co-maleic anhydride) with 3-aminopyridine. Upon the treatment of CuI with SMA, Cu(I) NPs were immobilized on SMA. This immobilized Cu(I) NPs was fully characterized by FTIR, SEM and EDAX analysis methods. Moreover, the interaction of Cu cations with 3-aminopyridine modified SMI catalyst via density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) computationally was studied. Our calculated results demonstrated that among 2,3 and 4 substituted aminopyridines for the modification of SMA, the 3-amnopyridine has the weakest ligand and Cu(I) interaction. However, the SMI image showed a suitable size of nanoparticles and inductively coupled plasma (ICP) analysis showed a higher Cu content in comparison with those of 2 and 4-substituted pyridines. The catalytic activity and reusability of this nanocatalyst system of 3-substituded aminopyridines was examined in the Huisgen 1,3-dipolar cycloaddition via click reaction. The reactions proceeded smoothly leading to regioselective synthesis of 1,4-disubstitued 1,2,4-triazole derivatives in excellent yields under mild reaction conditions. This heterogeneous catalytic system was separated easily by simple filtration and was reused without pre-activation at least in five runs without appreciable loss in its activity.