A Versatile One-pot Synthesis of Symmetrical N-Tosylazamacrocycles

Pappalardo, Sebastiano; Bottino, Francesco A.; Grazia, Michele Di; Finocchiaro, P.; Mamo, Antonino

doi:10.3987/r-1985-08-1881

Cited by 19 publications

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“…The synthesis of L4 was achieved via a 1:1 condensation reaction (Scheme ). A total of 2 equiv of tosylamide monosodium salt (TsNHNa) − was combined with 4-benzyloxy-2,6-bis(chloromethyl)pyridine ( 1 ) , in N , N -dimethylformamide (DMF) under reflux to produce the cyclized and tosyl-protected product 8,17-benzyloxy-4,13-bis( p -toluenesulfonyl)-1,4,11,13-tetraazabis(2,6-pyridinophane) ( 2 ). This cyclization reaction can be visualized as proceeding through a monoalkylated intermediate followed by self-condensation in the presence of excess TsNHNa, which acts as a base, to yield the desired macrocyclic product (Scheme S1).…”

Section: Resultsmentioning

confidence: 99%

“…This cyclization reaction can be visualized as proceeding through a monoalkylated intermediate followed by self-condensation in the presence of excess TsNHNa, which acts as a base, to yield the desired macrocyclic product (Scheme S1). 63 A low-quality solid-state structure of 2 obtained through XRD analysis (Figures S1 and S2) is observed in the lowest-energy syn chair−chair conformation. Concomitant removal of the benzyl and tosyl protecting groups was accomplished with a naphthalene-catalyzed lithiation (Scheme 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…This mixture was placed in a refrigerator for 12 h. Afterward, the mixture was vacuum-filtered and the collected solid was washed with cold MeOH. 2 was isolated as an off-white powder (3.11 g, 4 mmol, 40% yield). − Crystals suitable for X-ray analysis were obtained via solvent diffusion of DMF and MeOH.…”

Section: Experimental Methodsmentioning

confidence: 99%

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Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules

et al. 2019

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Alzheimer's and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed. To target these challenges, a new, water-soluble 12membered tetraaza macrocyclic pyridinophane L4 was designed and produced using a building-block approach. Potentiometric data show that the neutral species of L4 provides interesting zwitterionic behavior at physiological pH, akin to amino acids, and a nearly ideal isoelectric point of 7.3. The copper(II) complex of L4 was evaluated by X-ray diffraction and cyclic voltammetry to show the potential modes of antioxidant activity derived, which was also demonstrated by 2,2-diphenyl-1-picrylhydrazyl and coumarin carboxylic acid antioxidant assays. L4 was shown to have dramatically enhanced antioxidant activity and increased biological compatibility compared to parent molecules reported previously. L4 attenuated hydrogen peroxide (H 2 O 2 )-induced cell viability loss more efficiently than precursor molecules in the mouse hippocampal HT-22 cell model. L4 also showed potent (fM) level protection against H 2 O 2 cell death in a BV2 microglial cell culture. Western blot studies indicated that L4 enhanced the cellular antioxidant defense capacity via Nrf2 signaling activation as well. Moreover, a low-cost analysis and high metabolic stability in phase I and II models were observed. These encouraging results show how the rational design of lead compounds is a suitable strategy for the development of treatments for neurodegenerative diseases where oxidative stress plays a substantial role.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules

et al. 2019

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“…For example, ethylene‐bridged [2.2]metacyclophane 1 exists predominantly in the anti conformation, as reflected in its 1 H NMR spectrum, which contains an unusually upfield‐shifted resonance corresponding to its inner hydrogen atoms (H i ) as a consequence of the benzene ring current effect . In contrast, [3.3]metacyclophanes in which the arene rings are bridged by three carbon atoms, nitrogen‐, oxygen‐, sulfur‐ (compounds 2 , 3 , 4 , respectively), or selenium‐ containing linkages, all exist in the syn conformation; therefore, such upfield shifts were not observed in the 1 H NMR spectra.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Conformational Analysis of 2,11‐Disila[3.3]metacyclophanes

et al. 2016

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Silyl‐tethered [3.3]metacyclophanes were prepared and subjected to conformational analysis. The results show that these compounds exist in unprecedented anti‐rich metacyclophane forms. In the case of 2,2,11,11‐tetrasubstituted 2,11‐disila[3.3]metacyclophanes, anti conformers are lower in energy than their syn counterparts. Evidence for this assignment comes from the results of 1H NMR spectroscopic and X‐ray crystallographic analyses, along with molecular orbital calculations. However, the 2,2,11,11‐tetrahydro derivative displays the opposite behavior, which means that the syn conformer is thermodynamically most stable. The syn/anti ratios of these compounds in solution are governed by temperature and solvent polarity in a manner that can be explained by considering the mixed contributions of ΔΔG and dipole moments.

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“…(2,6)-Pyridinophanes, macrocyclic (poly)pyridine derivatives (Scheme a), can serve as chemically robust polydentate ligands in metal coordination chemistry providing unique environment to the bound metal atoms and capable of affecting dramatically their reactivity. − Mono- and dipyridine-containing macrocycles (Scheme a; n = 1 and 2, respectively) are synthetically the most readily available and have received increased attention as ligands. − In turn, tripyridine-containing macrocycles, [ x . y .…”

Section: Introductionmentioning

confidence: 99%

An Electron-Poor Dioxa-[2.1.1]-(2,6)-pyridinophane Ligand and Its Application in Cu-Catalyzed Olefin Aziridination

et al. 2019

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A novel macrocyclic 1,7-dioxa-[2.1.1]-(2,6)-pyridinophane ligand has been synthesized and crystallographically characterized. Two derived metal complexes, dichloropalladium(II) and chlorocopper(I), were prepared. In the palladium(II) complex LPdCl2, both in the solid state, according to its crystallographic characterization, and in CH2Cl2 solutions at −40 °C, according to 1H NMR spectroscopy, the ligand adapts a C 1-symmetric κ2-N,N-coordination mode in which the metal atom binds to two nonequivalent pyridine fragments of the macrocycle. The complex is fluxional at 20 °C. In the crystalline copper(I) complex LCuCl, the macrocyclic ligand is also κ2-N,N-coordinated to the metal, but it utilizes two equivalent pyridine fragments for the binding. The copper(I) complex is fluxional in CH2Cl2 solutions in the temperature range between 20 and −70 °C and is proposed to be involved in a fast intermolecular macrocyclic ligand exchange which is slowed down below −40 °C. DFT calculations predict a lower thermodynamic stability of the dioxapyridinophane-derived complexes LPdCl2 and LCuCl, as compared to their [2.1.1]-(2,6)-pyridinophane analogs containing bridging CH2 groups instead of the oxygen atoms. The electron poor dioxapyridinophane chlorocopper(I) complex, in combination with NaBArF 4 (BArF 4 = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) in dichloromethane solutions, can serve as an efficient catalyst for aziridination of various olefins with PhINTs at 0–22 °C.

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A Versatile One-pot Synthesis of Symmetrical N-Tosylazamacrocycles

Cited by 19 publications

References 0 publications

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules

Synthesis and Conformational Analysis of 2,11‐Disila[3.3]metacyclophanes

An Electron-Poor Dioxa-[2.1.1]-(2,6)-pyridinophane Ligand and Its Application in Cu-Catalyzed Olefin Aziridination

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