Leticia V. Rodrigues

Dethreading of Tetraalkylsuccinamide-Based [2]Rotaxanes for Preparing Benzylic Amide Macrocycles

The dethreading of a series of succinamide-based [2]rotaxanes bearing benzylic amide macrocycles is reported herein. These transformations proceeded quantitatively either under flash vacuum pyrolysis, conventional heating, or microwave irradiation. Studying the size complementarity of the stoppers at the ends of the thread and the cavity of the macrocycle allowed us to set up the best substituents for implementing the extrusion of the thread from the interlocked precursors. A variety of (1)H NMR kinetic experiments were carried out in order to evaluate the rate constants of the dethreading process, the half-life times of the rotaxanes, and the influence of temperature and solvents on these processes. The use of dibutylamino groups as stoppers yielded the rotaxane precursor in a reasonable yield and allowed the quantitative deslipping of the rotaxane. The overall process, including the rotaxane formation and its further dethreading, has been exploited for preparing benzylic amide macrocycles enhancing, in most cases, the results of the classical (2 + 2) condensation and other reported stepwise syntheses. The kinetics of the dethreading process is fairly sensitive to the electronic effects of the substituents on the isophthalamide unit or to the electronic nature of the pyridine rings through a conformational equilibrium expanding or contracting the cavity of the interlocked precursor.

Promotion of 1,3-dipolar cycloaddition between azides and β-enaminones by deep eutectic solvents

A simple procedure to obtain 4-acyl-1-substituted-1,2,3-triazoles, using a deep eutectic solvent (DES), ChCl and ethylene glycol at a 1 : 2 ratio, as the reaction medium is described. The products were obtained in high selectivity and good yields (70–84%). The advantages of the method include easy work-up, metal-free conditions, inexpensiveness, and the ability to be used four times without a loss in yield.

Novel ibuprofenate- and docusate-based ionic liquids: emergence of antimicrobial activity

Six new ionic-liquid-based active pharmaceutical ingredients (IL-APIs) were prepared and their molecular structures characterized. Solubility and thermal properties was determined and compared with the salt precursors. Antifungal and antibacterial activities were also investigated. Some of the IL-APIs demonstrated limited water solubility and high thermal stability when compared with the salt precursor. The most interesting observation was that the combination of two pharmacologically active ingredients in an IL-API results in antifungal activity that was not present in the precursors. The antibacterial activities were very promising considering that one of them was active against Staphylococcus, which is a bacterium resistant to penicillin and methicillin. The study of the pharmacological properties of synthesized IL-APIs is essential for evaluating how a drug may interfere with the pharmacological properties of another drug, thus furnishing knowledge about the advantages or disadvantages related to the association of APIs.

Competition between the donor and acceptor hydrogen bonds of the threads in the formation of [2]rotaxanes by clipping reaction

The synthesis of benzylic amide [2]rotaxanes using 1,2-bis(aminocarbonyl-(1′-tert-butyl-1H-pyrazole-[3′]5′-yl))-ethanes as templates is reported. These templates are equipped with tert-butyl pyrazole-based stoppers and have donor (N–H) and acceptor (CO) hydrogen bond groups. The synthesis of [2]rotaxanes has been shown to be highly dependent on the tert-butylpyrazole stoppers. While the thread with 1′,3′-disubstituted pyrazoles as stopper units was shown to be an excellent template for the synthesis of [2]rotaxanes, the thread with 1′,5′-disubstituted pyrazoles as stopper units did not yield the expected [2]rotaxane. The structure of the synthesized [2]rotaxanes was characterized using NMR experiments and X-ray diffraction, with the latter showing that the macrocycle adopts a distorted chair conformation. An in-depth study of the isolated threads X-ray structures and concentration-dependent NMR experiments seem to explain the dependence of the rotaxane formation on the substitution pattern of the threads pyrazole stoppers.

1,1-Difluoro-3-aryl(heteroaryl)-1H-pyrido[1,2-c][1,3,5,2]oxadiazaborinin-9-ium-1-uides: synthesis; structure; and photophysical, electrochemical, and BSA-binding studies

This paper presents a series of six examples of 1,1-difluoro-3-aryl(heteroaryl)-1H-pyrido[1,2-c][1,3,5,2]oxadiazaborinin-9-ium-1-uides (2)—in which aryl(heteroaryl) = phenyl, 4-MeC6H4, 4-N(CH3)2C6H4, 4-NO2C6H4, 2-naphthyl, and 2-thienyl—as pyridine-based boron heterocycles with variable ligand structures. The heterocycles 2 were easily synthesized at yields of 51–70% from reactions—at room temperature for 24 h—of simple N-(pyridin-2-yl)benzamides (1) with BF3·Et2O, and they were fully characterized by 1H-, 13C-, 19F-, and 11B-NMR spectroscopy, GC-MS, and X-ray diffractometry. The optical and electrochemical properties of 2 (UV-vis spectra, fluorescence spectra, quantum yield calculations, Stokes’ shifts, redox potentials, and DFT calculations) were determined and discussed. BSA-binding experiments and molecular docking studies of new complexes 2 were performed and correlated between each other.

Synthesis, antimicrobial activity and cytotoxic investigation of novel trifluoromethylated tetrazolo[1,5-a]pyrimidines

A series of novel trifluoromethylated tetrazolo[1,5-a]pyrimidines were easily prepared via a highly regioselective cyclocondensation reaction between β-alkoxyvinyl trifluoromethyl ketones [CF3C(O)CH=C(R)OMe] (in which R = Ph, 4-F–C6H4, 4-Cl–C6H4, 4-Br–C6H4, 4-I–C6H4, 4-CH3–C6H4, 4-OCH3–C6H4, Thien-2-yl, 4-Ph–C6H4, Me) and 5-aminotetrazole, using conventional heating in an oil bath or microwave irradiation. The results showed that when ionic liquid was used as the reaction medium, the reaction time drastically decreased and the yield improved. Additionally, all the newly synthesized compounds were evaluated to determine their antimicrobial activity. Two of the compounds tested were the most promising because they displayed activity against the Gram-positive and Gram-negative bacteria used in the tests, and they were moderately active against the yeast Candida albicans. And finally, the cytotoxicity of lymphocytes of the two compounds was evaluated by using MTT assay. Results showed at active concentration such compounds would be safe.

Sonochemical heating profile for solvents and ionic liquid doped solvents, and their application in the N-alkylation of pyrazoles.

The heating profile for 25 solvents was determined in ultrasonic probe equipment at amplitudes of 20%, 25%, and 30%. Each solvent was heated in accordance with its boiling point. The effect of vapor pressure, surface tension, and viscosity of the solvents in dissipated ultrasonic power (Up) was evaluated. Multiple regression analysis of these solvent properties and dissipated Up reveals that solvent viscosity is the property that most strongly affected dissipated Up. Experimentation involving acetonitrile doped with [BMIM][BF4] indicated faster heating than MeCN. Aprotic polar solvents such as DMSO, DMF, and MeCN were tested in the N-alkylation of pyrazoles under ultrasonic conditions. After 5min at 90°C, the reactants had been totally converted into product in these solvents. Solvents, with low dissipated Up (e.g., toluene) were tested. Conversions were lower compared to those of aprotic polar solvents. When the reactions were done in hexane, no conversion to product was observed. To check the effect of doping in solvents with low Up, [BMIM][BF4], DMSO, and DMF were selected. The conversions for toluene doped with [BMIM][BF4], DMSO, and DMF were 100%, 59%, and 25%, respectively. These conversions were greater than when done in just toluene (46%). Thus, [BMIM][BF4] was the best polar doping solvent, followed by DMSO. DMF was not considered to be a satisfactory doping solvent. No conversion was observed for reactions in the absence of base performed in DMSO, DMF, and MeCN doped with [BMIM][BF4].

Regiochemistry of cyclocondensation reactions in the synthesis of polyazaheterocycles

The syntheses of several polyazaheterocycles are demonstrated. The cyclocondensation reactions between β-enaminodiketones [CCl3C(O)C(=CNMe2)C(O)-CO2Et] and aromatic amidines resulted in glyoxalate-substituted pyrido[1,2-a]pyrimidinone, thiazolo[3,2-a]pyrimidinone and pyrimido[1,2-a]benzimidazole. Pyrazinones and quinoxalinones were obtained through the reaction of these glyoxalates with ethylenediamine and 1,2-phenylenediamine derivatives. On the other hand, the reaction of glyoxalates with amidines did not lead to the formation of imidazolones, but rather N-acylated products were obtained. All the products were isolated in good yields. DFT-B3LYP calculations provided HOMO/LUMO coefficients, charge densities, and the stability energies of the intermediates, and from these data it was possible to explain the regiochemistry of the products obtained. Additionally, the data were a useful tool for elucidating the reaction mechanisms.

Synthesis of novel [2]rotaxanes using hydrogen-bonding template

The [2]rotaxanes were characterized by 1 H NMR spectra through chemical shift differences between the thread and the [2]rotaxanes. In the Figure 1 are showed the 1 H NMR spectra of (a) thread (R = Pr) and (b) [2]rotaxane (R = Pr). It is possible to establish the significant upfield shifts (e.g., δ = 0.23, 1.24, and 2.69 ppm) corresponding to the signal of hydrogens Hd, Hc, and Hb of the Pr group. The assignment is due to proximity of the meta-diamide portion of the macrocycle to the structural fragments. Additional indication of the formation of [2]rotaxane is given by chemical shift of macrocyclic methylene, HE-axial, and HE’-equatorial (δ = 3.79–5.46 ppm), which are associated with the pirouetting motion between the two subunits. 3