Methylene Linker Research Articles

Syntheses of Bis‐Triazole Linked Carbohydrate Based Macrocycles and Their Applications for Accelerating Copper Sulfate Mediated Click Reaction

Macrocyclic compounds play an important role in many research fields including drug discovery and development, bioorganic chemistry, and materials sciences. Carbohydrate‐based macrocycles are important compounds with unique structures and many potential applications. In this study, we have designed and synthesized a series of 1,2,3‐triazole linked and pyranose embedded macrocycles in short steps through the copper (I) catalyzed azide and alkyne cycloaddition reactions (CuAACs). Eight non‐symmetrical glucosamine based and bis‐triazole linked macrocycles have been synthesized starting from the readily available N‐acetyl‐d‐glucosamine. These triazole‐linked glycomacrocycles showed remarkable reaction rate accelerations for CuSO4 mediated azide and alkyne cycloaddition reactions in aqueous mixtures. Several azides including a sugar azide, which react sluggishly with alkynes, have been accelerated with the synthesized macrocycles. The benzoylated macrocycles with three methylene linkage at anomeric positions were the most effective among the eight macrocycles.

1,2,4-Oxadiazole-derived polynitro energetic compounds with sensitivity reduced by a methylene bridge

This is a new family of energetic compounds combining a high-energy polynitro group with an insensitive methylene linkage and thermostable 1,2,4-oxadiazole skeleton.

A green chemical oligomerization of phloroglucinol induced by plasma as novel α-glucosidase inhibitors.

A new facile method was developed for simple green synthesis of methylene-bridged phloroglucinol oligomers using nonthermal dielectric barrier discharge (DBD) plasma in methanolic solution. The chemical structures of these newly generated oligomers 2-5 were determined by interpretation of the spectroscopic data, and the inhibitory activity toward α-glucosidase of all isolates was evaluated. The unusual phloroglcuinol pentamer 5 connected by four methylene linkages showed a much higher potential inhibitory effect against α-glucosidase than the other generated oligomers 2-4 and appeared to be a promising lead for development as a potential antidiabetic agent. Abbreviations: T2DM, type2 diabetes mellitus; DBD, dielectric barrier discharge; HPLC, high-performance liquid chromatography; IC50, 50% inhibition concentration; NMR, nuclear magnetic resonance; FABMS, fastatom bombardment mass spectrometry.

An efficient method for the synthesis of 2-thiazoleacetic acid N-sulfonyl amidines

A three-step method was designed and developed on the basis of retrosynthetic analysis for the synthesis of hybrid molecules containing a thiazole ring and an N-sulfonyl amidine fragment, connected by a methylene linker. The mechanism of the last step involves the formation of intermediate 1,2,3,4-thiatriazoles and their transformation into the final products as a result of the elimination of molecular nitrogen and sulfur.

Synthesis and comparative study on the anti-corrosion potentials of some Schiff base compounds bearing similar backbone

The synthesis of (E)-4-((p-tolylimino)methyl) phenol (TMPOL), (E)-4-((benzylimino)methyl) phenol (BMPOL) and (E)-4-((p-phenylimino)methyl) phenol (PMPOL) were carried out by the condensation reaction of 4-methylaniline, phenylmethanamine and aniline, respectively, with 4-hydroxybenzaldehyde. Molecular identities of the Schiff base compounds were probed using NMR (1H and 13C), Fourier transform infrared (FTIR) and mass spectroscopic techniques. The anticorrosion potency of the compounds was investigated for mild steel (MS) in 1 M HCl solution using electrochemical methods. Potentiodynamic polarization (PDP) data revealed that all three compounds were mixed-type inhibitors, with TMPOL showing remarkable cathodic effect at high inhibitor concentrations. Electrochemical impedance spectroscopy (EIS) data revealed improved adsorption of inhibitor species on mild steel surface at increased inhibitor concentrations with TMPOL, BMPOL and PMPOL reaching a maximum efficiency of 75, 88 and 74%, respectively. Scanning electron microscopy (SEM) reaffirmed the conditioning layer on the mild steel surface. Quantum chemical calculations provided molecular based explanations of the roles of heteroatoms and π electron centers on the corrosion inhibition activities of the studied compounds. The better anticorrosion activities of BMPOL compared to its isomeric compound (TMPOL) can be ascribed to the presence of a methylene linkage which enhanced the donor-acceptor interactions. The three inhibitors were inclined towards the Freundlich adsorption isotherm via a spontaneous chemical and physical adsorption of inhibitor molecules on the MS surface.

Synthesis of Isoflavone-Anabasine Conjugates

Possible Mannich aminomethylation of isoflavone chromone rings was studied using the alkaloid anabasine. Anabasine-isoflavone conjugates in which the benzopyrone core was connected to anabasine through a methylene linker were synthesized.

Iridium-Catalyzed, β-Selective C(sp3)-H Silylation of Aliphatic Amines To Form Silapyrrolidines and 1,2-Amino Alcohols.

The functionalization of unactivated C(sp3)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond β to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of unactivated C(sp3)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.

BDPA-Nitroxide Biradicals Tailored for Efficient Dynamic Nuclear Polarization Enhanced Solid-State NMR at Magnetic Fields up to 21.1 T.

Dynamic nuclear polarization (DNP) solid-state nuclear magnetic resonance (NMR) has developed into an invaluable tool for the investigation of a wide range of materials. However, the sensitivity gain achieved with many polarizing agents suffers from an unfavorable field and magic angle spinning (MAS) frequency dependence. We present a series of new hybrid biradicals, soluble in organic solvents, that consist of an isotropic narrow electron paramagnetic resonance line radical, α,γ-bisdiphenylene-β-phenylallyl (BDPA), tethered to a broad line nitroxide. By tuning the distance between the two electrons and the substituents at the nitroxide moiety, correlations between the electron-electron interactions and the electron spin relaxation times on one hand and the DNP enhancement factors on the other hand are established. The best radical in this series has a short methylene linker and bears bulky phenyl spirocyclohexyl ligands. In a 1.3 mm prototype DNP probe, it yields enhancements of up to 185 at 18.8 T (800 MHz 1H resonance frequency) and 40 kHz MAS. We show that this radical gives enhancement factors of over 60 in 3.2 mm sapphire rotors at both 18.8 and 21.1 T (900 MHz 1H resonance frequency), the highest magnetic field available today for DNP. The effect of the rotor size and of the microwave irradiation inside the MAS rotor is discussed. Finally, we demonstrate the potential of this new series of polarizing agents by recording high field 27Al and 29Si DNP surface enhanced NMR spectra of amorphous aluminosilicates and 17O NMR on silica nanoparticles.

Induced-fit adsorption of diol-based porous organic polymers for tetracycline removal

Adsorption is recognized as one of the most efficient approaches for antibiotics removal from water. Inspired by the enzyme-substrate interaction model, we proposed induced-fit adsorption (IFA) model, and rationally designed and fabricated diol-based porous organic polymers (POPs) as adsorbents for tetracycline (TC) removal. For 2,3-naphthalenediol-based POP (NTdiol-POP), the preferable geometry of diol-groups contributed to the high binding energy with TC species and flexible methylene linkages between neighboring rigid naphthalene rings gave rise to precisely matching between TC species and adsorbents, that is, the induced-fit conformation change. As a result, NTdiol-POP exhibited a high saturated adsorption capacity of 155.8 mg g−1. More importantly, NTdiol-POP exhibited excellent TC removal efficiencies in both concentrated solution (96% for 4 p.p.m) and trace level solution (97% for 250 p.p.b).

Role of hardener, crosslinker, and pH in bare process of urea–formaldehyde polymerization and forin situencapsulation of linseed oil

ABSTRACTIn this study, urea–formaldehyde polymerizations in bare process and forin situencapsulation of linseed oil (LO) have been scrutinized either at pH 3.5 or in inherently developing acidic pH. The solid‐state carbon nuclear magnetic resonance (13C‐NMR) revealed that the hardener and the crosslinker (NH4Cl and resorcinol) resulted in the formation of methylene linkage. The addition of NH4Cl and resorcinol slightly decreased the thermal stability of poly(urea formaldehyde) (PUF) resin. Optical microscopy (OM) images and scanning electron microscopy (SEM) micrographs show that most regular shapes of capsules were obtained when NH4Cl and resorcinol were used in the regular reaction medium. The increment of NH4Cl amount up to 0.124 mol resulted in a 41% decrement of capsule size, whereas increment resorcinol amount up to 0.062 mol increased the size by 14%. The capsule size range was found to be between 60 and 100 μm. The capsules had a hardness of 22–74 MPa and an elasticity of 0.5–1.5 GPa. © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2019,136, 46947.

Discovery of novel spiro[chromane-2,4′-piperidine] derivatives as potent and orally bioavailable G-protein-coupled receptor 119 agonists

Herein, we describe the discovery, synthesis, and evaluation of a novel series of spiro[chromane-2,4′-piperidine] derivatives as G-protein-coupled receptor 119 agonists. Their initial design exploited the conformational restriction in the linker-to-tail moiety, which was a key concept in this study, to give lead compound 11 (EC50 = 369 nM, Emax = 82%). An extensive structure–activity relationship study resulted in the identification of the optimized drug candidate (R)-29 (EC50 = 54 nM, Emax = 181%). The defining structural features of the series were a terminal benzyl-type bulky substituent and a methylene linker between the sulfonyl and phenyl groups, both of which were in the head moiety as well as the spiro-type scaffold in the linker-to-tail moiety. An in vivo oral glucose-tolerance test using C57BL/6N mice showed that (R)-29 reduced glucose excursion at a dose of 3 mg/kg in a dose-dependent manner.

Triphenylantimony(V) 6-alkoxymethyl-3,5-di-tert-butylcatecholates. Structure and redox-properties

A number of mononuclear triphenylantimony(V) 3,5-di-tert-butylcatecholates of the type (6-AlkOCH2-3,5-DBCat)SbPh3 functionalized with alkoxymethyl group in the 6th position of aromatic ring in catecholato ligand, where Alk = Me (1), Et (2), iPr (3), tBu (4), n-Hexyl (5), and binuclear bis-catecholate Ph3Sb(3,5-DBCat-CH2OCH2-3,5-DBCat)SbPh3 (6) have been synthesized and characterized in details. The molecular structures of 1·0.5 (n-hexane), 2, 3, 4, 5·2MeOH, 6·2 (n-hexane) and 6·acetone have been determined by means of single-crystal X-ray analysis. The presence of alkoxymethyl-group in catecholate ligand does not lead to its coordination to the central antimony atom. Complexes 1–4 and 6 possess pentacoordinated environment of the central antimony atoms varying from the trigonal bipyramidal to the distorted tetragonal pyramidal. In crystal, molecules of complexes 1–5 form pairs where the “CPh–H … π-system” interactions were found. The coordination environment of the central antimony atom in 5∙2MeOH is a distorted octahedral with coordinated methanol; the second methanol molecule is fixed between thehydroxyl group of coordinated methanol and the oxygen atom of hexyloxymethyl-group in the 6th position of catecholate ligand through the intramolecular hydrogen bonding.The electrochemical oxidations of complexes 1–4 proceed as two one-electron oxidations (the quasireversible oxidation “catecholate/o-semiquinolate” and the irreversible oxidation “o-semiquinolate/o-benzoquinone”). The first half-wave potential (E11/2) depends weakly on the alkyloxy substituent in AlkO-CH2 group due to a weak inductive effect of AlkO group to the catecholate aromatic ring through the methylene linker. For binuclear bis-catecholate 6, the first redox stage is two-electronic quasi-reversible peak without the separation of two stages into two one-electron processes, which indicates the absence of the electronic interaction between the two catecholate fragments.

Thermomechanical characterization of thermoplastic polyimides containing 4,4'‐methylenebis(2,6‐dimethylaniline) and polyetherdiamines

In this work, we synthesized polyimides by incorporating an aromatic diamine monomer with a methylene linker, 4,4'‐methylenebis(2,6‐dimethylaniline) (MBDMA), to make a robust main chain along with aliphatic polyetherdiamine backbone linkers to reduce rigidity. We designed the polymers to exhibit thermal properties in between those of conventional aromatic polyimides and polymers with wholly aliphatic ether diamine links. Through dynamic mechanical analysis and differential scanning calorimetry, it is shown that control of the molar ratios of the aromatic MBDMA (4,4'‐methylenebis(2,6‐dimethylaniline)) and the composition and size of the aliphatic polyetherdiamine can be used to tune the glass transition. The polymers were characterized by GPC, FTIR, NMR, thermomechanical and calorimetric analysis, and microhardness testing. POLYM. ENG. SCI., 59:221–232, 2019. © 2018 Society of Plastics Engineers

Characterization of the Low Molar Ratio Urea⁻Formaldehyde Resin with 13C NMR and ESI⁻MS: Negative Effects of the Post-Added Urea on the Urea⁻Formaldehyde Polymers.

The structural changes during three-step synthesis of low-molar ratio urea–formaldehyde (UF) resin were tracked by quantitative 13C nuclear magnetic resonance (13C NMR) analysis and electrospray ionization-mass spectrometry (ESI–MS). Condensations that produced polymers were found to be linked by ether bonds in addition to hydroxymethylation reactions at the first alkaline stage with a formaldehyde to urea ratio of 2:1. Considerable formation of branched methylene linkages, with the highest content among all the condensed structures, was the key feature of the acidic stage. Notable changes were observed for the chemical structures and molecular masses of the resin components after the formaldehyde to urea molar ratio was lowered to 1.2 by adding post-urea at the final alkaline stage. Specifically, most of the branched hydroxymethyl groups on the polymers were cleaved, resulting in a significant decrease in the branching degree of the polymers. The performance degradation of the UF resin was attributed to this debranching effect and the production of components with low molecular masses. Based on the observations, the curing pattern of low molar ratio UF resin was postulated and branched polymeric formaldehyde catcher bearing urea-reactivity was proposed.

Analysis of the hydrolysates from cured and uncured urea-formaldehyde (UF) resins with two F/U mole ratios

Abstract Uncured and cured urea-formaldehyde (UFcured) resins prepared with formaldehyde/urea (F/U) mole ratios of 1.0 and 1.2 and at the catalyst levels of 1, 2 and 3% NH4Cl were hydrolyzed for 5, 15 and 30 min and the degradation products were evaluated using gel permeation chromatography, Fourier-transform infrared (FTIR) and liquid carbon-13 nuclear magnetic resonance (13C-NMR) spectroscopies. The molar masses of the degradation products, their functional groups and structures were determined. An extended hydrolysis time and higher catalyst levels resulted in compounds with higher molar masses. Similar functional groups and distribution of chemical species were found by both FTIR and 13C-NMR spectroscopies in the hydrolysates of UFcured, indicating water hydrolysis of hydroxymethyl groups and then methylene linkages. Methylene linkages and mono- and tri-hydroxymethyl ureas were mainly responsible for the liberation of formaldehyde from UFcured during hydrolysis. The indicated compounds are believed to contribute to the long-term release of formaldehyde from the resins. This is the first systematic report on the composition of UFcured hydrolysates.

Rationale Design, Synthesis, Cytotoxicity Evaluation, and Molecular Docking Studies of 1,3,4-oxadiazole Analogues.

1,3,4-Oxadiazole heterocycles possess a broad spectrum of biological activities. They were reported as potent cytotoxic agents and tubulin inhibitors; hence it is of great interest to explore new oxadiazoles as cytotoxic agents targeting tubulin polymerization. Two new series of oxadiazoles (5a-h and 12a-h) were synthesized, structurally related to the heterocyclic linked aryl core of IMC-038525, NSC 776715, and NSC 776716, with further modification by incorporating methylene linker. The 2,5-disubstituted-1,3,4-oxadiazoles (5a-h and 12a-h) were synthesized by refluxing an equimolar mixture of the intermediates [(4) and (8a-d)] and aromatic aldehydes in water-ethanol system using sodium bisulphite catalyst. The cytotoxicity evaluation was carried out according to the National Cancer Institute (NCI US) Protocol, while the tubulin polymerization assay kits from Cytoskeleton ™(bk011p) was used to perform an in vitro tubulin polymerization assay. 2-(5-{[(4-Chlorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)phenol (5f) and 2-[(2,4-dichlorophenoxy) methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole (12c) showed maximum cytotoxicity with the mean percent growth inhibitions (GIs) of 71.56 and 72.68 respectively at 10 µM drug concentrations. Both the compounds (5f and 12c) showed superior cytotoxicity than clinically prevalent anticancer drugs, Imatinib and Gefitinib in one dose assay. The compound 12c showed promising results in five dose assay, with GI50 values varies between 1.61 and >100 µM. Furthermore, the compounds, 5f and 12c also inhibited the polymerization of tubulin with, an IC50 of 2.8 and 2.2 µM, respectively. The oxadiazoles reported herein are tubulin inhibitors and cytotoxic agents. These findings will be helpful in future drug design of more potent tubulin inhibitor cytotoxic agents.

Methylene-Bridged Bisphosphine Monoxide Ligands for Palladium-Catalyzed Copolymerization of Ethylene and Polar Monomers.

A series of palladium complexes bearing a bisphosphine monoxide with a methylene linker, that is, [κ2-P,O-(R12P)CH2P(O)R22]PdMe(2,6-lutidine)][BArF4] (Pd/BPMO), were synthesized and evaluated as catalysts for the homopolymerization of ethylene and the copolymerization of ethylene and polar monomers. X-ray crystallographic analyses revealed that these Pd/BPMO complexes exhibit significantly narrower bite angles and longer Pd-O bonds than Pd/BPMO complexes bearing a phenylene linker, while maintaining almost constant Pd-P bond lengths. Among the complexes synthesized, menthyl-substituted complex 3f (R1 = (1R,2S,5R)-2-isopropyl-5-methylcyclohexan-1-yl; R2 = Me) showed the best catalytic performance in the homo- and copolymerization in terms of molecular weight and polymerization activity. Meanwhile, complex 3e (R1 = t-Bu; R2 = Me) exhibited a markedly higher incorporation of comonomers in the copolymerization of ethylene and allyl acetate (≤12.0 mol %) or methyl methacrylate (≤0.6 mol %). The catalytic system represents one of the first examples of late-transition-metal complexes bearing an alkylene-bridged bidentate ligand that afford high-molecular-weight copolymers from the copolymerization of ethylene and polar monomers.

Synthesis and biological evaluation of aminothiazoles against Histoplasma capsulatum and Cryptococcus neoformans

The design and synthesis of a library of forty novel 2-aminoazole analogues as well as their evaluation as antifungal compounds against Histoplasma capsulatum and Cryptococcus neoformans is described. These structures were derived from N-[5-(1-naphthalenylmethyl)-2-thiazolyl]cyclohexanecarboxamide (41F5), a fungistatic agent previously identified through phenotypic screening (Antimicrob Agents Chemother. 2013;57:4349). Modifications to improve potency and water-solubility of 41F5 focused primarily on the 5-naphthalenyl group, the thiazole core, and the methylene linker between these two structural elements. In general, compounds with lipophilic [5+6] bicyclic ring systems, such as the 7-benzothiophenyl- and 4-indanyl groups, at the 5-position were 2–3 times more active against both fungal species as compared to 41F5. Also, introduction of a carbonyl group at the methylene linker of 41F5 resulted in a 2–3-fold increase in potency. These highly active compounds also showed generally low toxicities against murine P388D1 macrophages resulting in selectivity indices ranging from 63 to >200. Compounds that were highly active against fluconazole-sensitive C. neoformans strains had almost identical activity against fluconazole-resistant variants of this fungus indicating that 14α-demethylase is not their molecular target. Highly active compounds also retained activity against H. capsulatum phagocytosed into P388D1 macrophages.

AGT Activity Towards Intrastrand Crosslinked DNA is Modulated by the Alkylene Linker.

DNA oligomers containing dimethylene and trimethylene intrastrand crosslinks (IaCLs) between the O4 and O6 atoms of neighboring thymidine (T) and 2'-deoxyguanosine (dG) residues were prepared by solid-phase synthesis. UV thermal denaturation (Tm ) experiments revealed that these IaCLs had a destabilizing effect on the DNA duplex relative to the control. Circular dichroism spectroscopy suggested these IaCLs induced minimal structural distortions. Susceptibility to dealkylation by reaction with various O6 -alkylguanine DNA alkyltransferases (AGTs) from human and Escherichia coli was evaluated. It was revealed that only human AGT displayed activity towards the IaCL DNA, with reduced efficiency as the IaCL shortened (from four to two methylene linkages). Changing the site of attachment of the ethylene linkage at the 5'-end of the IaCL to the N3 atom of T had minimal influence on duplex stability and structure, and was refractory to AGT activity.

Synthesis of hybrid compounds composed of daunorubicin covalently linked with Cp2Fe and CpMn(CO)3

Hybrid molecules wherein five-membered rings of ferrocene or cymanthrene are covalently bonded with the amino group of daunorubicin through a methylene linker, have been synthesized by reductive amination of the corresponding aldehydes [M]C5H4CHO {[M] = CpFe or (CO)3Mn} using daunorubicin as an amine component.