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The synthetic potential of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one toward the catalyst-free synthesis of

Boron dipyrromethene type molecules (BODIPYs) are versatile molecules which have been used for applications ranging from photodynamic therapy to solar cells (DSSC). However, these molecules usually do not present high two-photon absorption cross-sections, limiting their use in nonlinear optical applications. Herein, we study a series of BF

An efficient sequential three-step reaction methodology for the synthesis of three new series-1-(prop-2-yn-1-yl)-1H-pyrroles, methyl 4-acetyl-1-((1H-1,2,3-triazol-4-yl)methyl)-1H-pyrrole-3-carboxylates and 6-((1H-1,2,3-triazol-4-yl)methyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-ones-is reported. The methodology comprises: (i) N-alkylation reactions of polyfunctionalized 1H-pyrroles-which were previously obtained from (E)-methyl 2-azido-3-arylacrylates-with propargyl bromide in order to obtain 1H-pyrroles; (ii) standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) involving organic azides (benzyl-, 4-methoxybenzyl- and 4-chlorobenzyl, as well as n-octyl azide) and N-propargylated 1H-pyrroles to give triazolyl derivatives, as methyl 1H-pyrrole-3-carboxylates (click chemistry); and (iii) [4 + 2] cyclocondensation reactions of the ketoesters in the presence of hydrazine hydrochloride in order to furnish the desired series of pyrrolo[3,4-d]pyridazin-1-ones at total yields up to 54%.

Boron dipyrromethene type molecules (BODIPYs) are versatile molecules which have been used for applications ranging from photodynamic therapy to solar cells (DSSC). However, these molecules usually do not present high two-photon absorption cross-sections, limiting their use in nonlinear optical applications. Herein, we study a series of BF2–naphthyridine based boron-complexes with electron-donating and withdrawing groups to increase their two-photon absorption. We have found two-photon absorption cross-sections up to approximately 270 GM, which corresponds to an increase of approximately five times in comparison to the average cross-section value reported for molecules with similar conjugation length, indicating such compounds as potential materials for nonlinear applications in both the visible and infrared spectral regions.

The structural characterization of a new pentacoordinated semicarbazone copper complex, [Cu(N,N',O-HSCPy)(N,N'-HSCPy)][ClO4]2 (1) is reported. The structure of 1 was compared to the hexacoordinated complex, [Cu(N,N',O-HSCPy)2][ClO4]2⋅H2O (2), which was already published, to shed some light on the formation of both forms. Energetic data of Cu-ligand bonds showed that the absence of a Cu-O bond in cation 1 does not significantly change the total stabilization energy in the pentacoordinate cation relative to the hexacoordinate cation (less than 4%). This is because the Cu-ligand bonds have their energies redistributed into the five existing bonds of 1. Additionally, we extended the study revisiting analogous HSCPy complexes with other coordinated metals (M), with general formula [M(N,N',O-HSCPy)2][X]2⋅solvent, where M = Ni (3), Co (4), Zn (5), Fe (6), and Mn (7); X = ClO4, and solvent = H2O (3-6) or EtOH (7); and complex [Cu(N,N',O-HSCPy)2][ClO4][I3] (8) was included in this series. In general, all additional complexes showed similar behavior to that of the Cu-hexacoordinated complex (2). In this sense, was possible to observe that the energies of the bonds M-O and M-N have strong linear correlation in the three groups: M-O3′//M-O3, M-N1′//M-N1, and M-N2′//M-N2, for complexes 2-7 (r = 0.9766; N = 18). Also, a strong correlation between stabilization energy data of metal-ligand and their respective bond lengths (r =0.9393; N = 47) was observed in all studied complexes (1-8). The supramolecular geometric similarity index ID was calculated comparing 2 with 1, 3-8. It was observed a high geometric similarity between 2 and 3-6 (ID

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1′-cycloalkanes] — in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane — were synthesized at yields of 42–56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1′-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 μM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.

5-Bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one was used as an efficient precursor for the synthesis of a new series of (1,2,3-triazol-1-yl)methyl-pyrimidine biheterocycles. For this stepwise synthesis, the 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one was first converted into 5-azido-1,1,1-trifluoro-4-methoxypent-3-en-2-one through a nucleophilic substitution of the bromine by an azide group. This was then followed by an azide–alkyne cycloaddition reaction (click chemistry) to give the key intermediate 5-[4-alkyl(aryl)-1H-1,2,3-triazol-1-yl]-1,1,1-trifluoro-4-methoxypent-3-en-2-ones. These were cyclocondensed with 2-methylisothiourea sulfate to give a series of 2-(methylthio)-4-(1,2,3-triazol-1-yl)methyl-6-(trifluoromethyl)pyrimidines. Additionally, the 2-methylthiopyrimidine products were used to prepare a new series of 2-amino-4-(1,2,3-triazol-1-yl)methyl-6-(trifluoromethyl)pyrimidines.

A new series of nine examples of 9-aryl-3-(aryl/heteroaryl)-1,1-difluoro-7-(trifluoromethyl)-1H-[1,3,5,2]oxadiazaborinino[3,4-a][1,8]naphthyridin-11-ium-1-uides, which contained 1,8-naphthyridine-based boron complexes with variable ligand structures, were synthesized at yields of 50–65% from the reaction of unpublished 2-benzoylamino-7-aryl(heteroaryl)-5-trifluoromethyl-1,8-naphthyridines—in which aryl(heteroaryl) = phenyl, 4-MeC6H4, 4-FC6H4, 4-BrC6H4, 4-OMeC6H4, 4-NO2C6H4, and 2-thienyl—with BF3·Et2O and fully characterized by 1H-, 13C-, 19F-, and 11B NMR spectroscopy and X-ray diffractometry. The optical and electrochemical properties of the new complexes were investigated, and the results for quantum yield calculations, Stokes shift, UV–vis, fluorescence, and redox potential data analysis indicated an important relationship with the aryl(heteroaryl) substituents attached to the 3- and 9-position of the naphthyridine boron complexes.

Molecular solvents, ionic liquids, and choline chloride-based DES were evaluated for the synthesis of a methylthiotriazolo[1,5-a]pyrimidines series via the cyclocondensation reaction between 4-dimethylamino-1-aryl-3-alken-2-ones (RC(O)CH = CHNMe2, in which R = C6H5, 4-Me-C6H4, 4-OMe-C6H4, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, Fur-2-yl, and Thien-2-yl) and 3-amino-5-methylthio-1H-1,2,4-triazole. The best result was obtained using ChCl with TsOH at a ratio of 1:2, and it drastically reduced the reaction time from 1.5 h to 5 min, with high regioselectivity and good yields (82–98%). Quantum chemical calculations helped to show the mechanism for high regioselectivity of the reaction. Up until now, ChCl:TsOH (1:2) has not been completely characterized and used as a catalyst in organic synthesis. Thus, it was fully characterized by NMR, DSC, TGA, and ICP-AES. The results showed that ChCl:TsOH (1:2) presents two forms that can act as catalyst: acid form (17%) and its conjugate base (83%).

A facile and regioselective synthesis of a series of new methyl 3-ferrocenyl-1H-pyrrole-2-carboxylates obtained from methyl ferrocenyl azido acrylate and symmetrical or non-symmetrical 1,3-dicarbonyl compounds under microwave-assisted conditions is reported. 3-Ferrocenyl substituted pyrroles, which are normally difficult to obtain via the known reported methods, can now be regioselectively prepared by this protocol. Compared to already known acidic, basic, or metal-catalyzed methodologies for polysubstituted pyrrole synthesis, the present synthetic route is mild, quick, simple, and it furnishes new functionalized tetrasubstituted-pyrroles in short reaction times (30 min) and at satisfactory to good yields (32–75%).

A useful synthetic route for an initial new series of 2-substituted 4-(trifluoromethyl)-5,6-dihydrobenzo[h]quinazolines (3), as well as an evaluation of their analgesic effect in a mice pain model, is reported. Five new quinazolines were formed from the cyclocondensation reactions of 2,2,2-trifluoro-1-(1-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)ethanone (1) with some well-known amidine salts [NH2CR(=NH)] (2), in which R = H, Me, Ph, NH2 and SMe, at a 40–70% yield. Subsequently, due to the importance of the pyrrole nucleus, a 2-(pyrrol-1-yl)quinazoline (4) was obtained through a Clauson–Kaas reaction from the respective 2-(amino)quinazoline, in a reaction with 2,5-dimethoxy-tetrahydrofuran. The analgesic evaluation demonstrated that four 5,6-dihydrobenzo[h]quinazolines (compounds of 3c (R = Ph), 3d (R = NH2), 3e (R = SMe), and 4 (R = pyrrol-1-yl); 100 mg/kg, p.o.) and ketoprofen (100 mg/kg, p.o.) significantly reduced the spontaneous nociception in a capsaicin-induced test. Moreover, in comparison with ketoprofen (100 and 300 mg/kg, p.o.), compound 3c (30–300 mg/kg, p.o.) showed an anti-hyperalgesic action in an arthritic pain model without locomotor alterations in the mice, suggesting that quinazoline 3c is a promising prototype scaffold for new analgesic drugs in the treatment of pathological pain such as that in arthritis.

A convergent synthesis of a series of 16 new polysubstituted (5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)(quinolin-4-yl)methanones, starting from isatin and alky(aryl/heteroaryl) ketones, is described. The diheteroaryl methanones were achieved at yields of up to 95% by a [3 + 2] cyclocondensation reaction involving 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trifluorobut-3-en-2-ones (by two-step reaction) and 2-alkyl(aryl/heteroaryl)-4-carbohydrazides (by three-step reaction). Subsequently, representative dehydrated heterocyclic derivatives were obtained from the respective 5-hydroxy-2-pyrazoline moieties by classical dehydration reactions, which resulted in the corresponding (5-(trifluoromethyl)-1H-pyrazol-1-yl)(quinolin-4-yl)methanones (three examples) at yields of 69–82%. The subsequent cytotoxicity evaluation showed that compounds with aromatic groups at the 2-position of the quinoline and a methyl moiety at the 3-position of the pyrazole have significant cytotoxicity in human leukocytes at high concentrations (200 μM).

A convenient and environmentally benign procedure for the synthesis of a new series of trifluoromethyl-substituted N-(pyrimidin-2-yl)benzo[d]thiazol-2-amines by the cyclocondensation reaction of (benzo[d]thiazolyl)guanidine with either 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones or 2,2,2-trifluoro-1-(2-methoxycyclohexen-1-en-1-yl)ethanone is described. The main reactions were performed in refluxing water as the solvent (8–24 h), without catalysts, and the corresponding new N-(pyrimidinyl)-1H-(benzo[d]thiazolyl)amines were obtained at a 60–88 % yield. Subsequently, some di(hetero)arylamines were derivatized to the respective tertiary amines via easy N-alkylation and N-alkenylation reactions at 55–82 % yields. Finally, the Lipinski parameters and the total antioxidant activity of the new series of secondary arylamines were also evaluated.

A simple and regioselectively controlled method for the preparation of both 1,4- and 1,6-regioisomers of 1-substituted 4(6)-trifluoromethyl-pyrimidin-2(1H)-ones is described. Both regioisomers were synthesized from the cyclocondensation reaction of 4-substituted 1,1,1-trifluoro-4-methoxybut-3-en-2-ones: with nonsymmetric ureas for the 1-substituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones (1,4-isomer) and with nonsymmetric 1-substituted 2-methylisothiourea sulfates for the synthesis of 1-substituted 6-(trifluoromethyl)pyrimidin-2(1H)-ones (1,6-isomer). Each method furnished only the respective isomer in very good yields. The structure of the products was assigned based on the (1)H and (13)C NMR as well as 2D HMBC spectral analysis.

A mild and efficient protocol for the assembly of tetra-substituted 5-trifluoromethylpyrazoles is presented, involving halogenation at the 4-position of readily prepared tri-substituted 5-trifluoromethylpyrazoles to give 4-halo-1-phenyl-5-trifluoromethyl pyrazoles, and subsequent palladium-catalyzed Negishi or Buchwald-Hartwig cross-couplings to install carbon or nitrogen-based 4-substituents. Key to the success of these challenging cross-couplings is the use of XPhos and JosiPhos CyPF-tBu ligands, respectively.

The synthesis, crystallization, and theoretical calculations (energetic dimers and QTAIM analyses) of three polymorphs of 3,12-dihydrotetrabenzo[d,h,m,q]-[1–3, 10–12]hexaazacyclooctadeca-1,10-dien-5,14-diyne are reported. The supramolecular cluster approach is proposed for understanding the formation and stabilization of crystal arrangements of the polymorphs. The results show that the π⋯π-interactions were responsible for the crystal packing of the three polymorphs and that they are in a determined energetic region. The energetic difference between the more stable and less stable polymorphs is around 8 kcal mol−1, indicating that if, probably other polymorphs will be formed, all of them will be in the same energetic region. The results confirmed that the first molecular coordination sphere (supramolecular cluster) is the smallest portion of the crystal that represents all necessary energy information for understanding the intermolecular interactions in the entire crystal.

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.

This short study reports firstly the synthesis of a new series of six 1-substituted 6-((4,4,4-trihalo-3-oxo-alk-1-en-1-yl)amino)-2H-chromen-2-ones (4 and 5) and three 4- substituted 2,2-difluoro-3-(2-oxo-2H-chromen-6-yl)-6-(trichloromethyl)-2H-1,3,2-oxazaborinin-3-ium-2-uides (7), in which the selected 1- and 4-substituents are Me, Ph, and thien-2-yl. Both series (4 and 5) were synthesized from the reaction of 6-aminecoumarin (3) with (Z)-1,1,1-trihaloalk-3-en-2-ones (1 and 2), at 50–95 % yields. Subsequently, reactions of the coumarins 4 and 5 with boron (BF3·OEt2) gave only the corresponding 6-trichlorometylated heterocycles (7), at 65–78 % yields. Absorption and emission properties were investigated for the new coumarin derivatives. The results for UV–vis, emission fluorescence, quantum yield, and Stokes shift analysis indicated important relationships between the β-enaminone skeletons and their substituents.

Dicationic ionic liquids have been attracting attention due to their high thermal storage density, which is attributed to an increase in the number of cations. However, there is no information about the effect that the dianionic structure has on the thermophysical properties of dicationic ionic liquids. Thus in this study, imidazolium-based dicationic dicarboxylate ionic liquids (Cn (MIM)2[Cm(CO2)2], n = 4, 6, 8, 10 and m = 0, 1, 2, 3, 4, 5) were synthesized and their thermal properties were determined. The results showed that the dicarboxylate's spacer length has no effect on the melting point; however, a trend in which the heat of fusion of ionic liquids increases with the increase in the spacer chain length of the dication and dianions was observed. Moreover, dicationic dicarboxylate ionic liquids have a greater heat capacity than monocationic ionic liquids, but a smaller heat capacity than analogous dicationic ionic liquids with bromine. Our results also showed that the anion has a strong effect on the heat capacity of dicationic ionic liquids. In terms of thermal storage, [C6(MIM)2][C2] and [C6(MIM)2][C5] were the most promising ionic liquids, because they have thermal storage higher than monocationic ILs and mineral oil and compared with analogues ILs with bromine, they are potentially less toxic. All of the ionic liquids were soluble in protic polar solvents and DMSO, and were insoluble in aprotic and nonpolar–polar solvents. The study and determination of these properties is extremely important for future applications.

The synthesis of 4-ethoxy-5-hydroxypyrrolidin-2-ones and 6-hydroxyhexahydro-4H-furo[2,3-c]pyrrol-4-ones — through the regio- and stereoselective reduction of the corresponding 3-alkoxysuccinimides — is described. The reaction used NaBH4 at low temperatures and short reaction times, providing products with yields of up to 77%. The stereoselectivity was highly influenced by both alkoxy and the N-moiety in the starting succinimide.

Supramolecular gels present several applications in which the gelator properties are closely dependent on their structure and solvent. Despite this, there are few studies on the effect of the gelation ability of gelators with slight molecular changes. Therefore, N-arylestearamides (in which aryl = phenyl (1), 4-tolyl (2) and 4-acetylphenyl (3)) were evaluated in different solvents. The critical gelefication concentration (CGC) values indicated that the substituents can significantly affect the concentration at which the supramolecular gels are formed, mainly in non-aromatic solvents (e.g. cyclohexane, acetonitrile and DMSO). From UV-Vis and DSC data, we verified that the gel-sol and sol-gel transitions (Tgel-sol and Tsol-gel) increase in the order of 123. Organogel strength was evaluated for 1-3 as a function of concentration and solvent type using rheology data. Gel strength is concentration-dependent and a strength order was found in acetonitrile, cyclohexane and DMSO, in which: 1 ∼ 23. Dynamic viscoelastic measurements as a function of temperature sweeps indicate a predominantly enthalpic contribution to the elasticity of the organogels formed from 1-3. Temperature-dependent 1H NMR indicates that NHO interactions may be responsible for the molecular association of molecules into 1D fibers, while 3D fibers were formed from van der Waals interactions.

This Letter reports the first series of seven examples of novel 7-amine-spiro[chromeno[4,3-b]quinoline- 6,1′-cycloalkanes], where cycloalkane is cyclopentane, cyclohexane, cycloheptane, 2-methyl-, 3-methyl-, 4-methyl-, and 4-t-butyl-cyclohexane. These new compounds were synthesized at yields of 30–65% by a one-pot cyclocondensation reaction of 2-aminobenzonitrile and seven examples of spiro[chroman-2,1′-cycloalkan]-4-ones, using AlCl3 as the catalyst, without solvent and under conventional thermal heating. Subsequently, these spirochromeno-quinolines were subjected to AChE and cytotoxicity activity, and molecular docking studies. Both results for these new tacrine analogues were correlated with the structural features and showed the best results for the tacrine hybrid that possesses the spirocyclopentane moiety.

A concise method to synthesize 1-substituted 4-amino-2-(trifluoromethyl)-1H-pyrroles from the heterocyclization reaction of 5-bromo-4-methoxy-1,1,1-trifluoropent-3-en-2-ones with amines is described. This method has the following advantages: it uses a wide range of primary amines, starting materials are easily available, it is simple to perform, the reaction conditions are mild, it is environmentally friendly, and it furnishes yields of up to 98%.

The results of the chemical behavior of three substituted cyanoacetylazoles and some salicylic aldehydes used to obtain new trifluoromethylated azolecarbonyl-2H-chromen-2-ones through Knoevenagel condensation reactions, are reported. First, a new series of four 3-(5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1H-pyrazole-1-carbonyl)-2-imino-2H-chromenes were efficiently synthesized, in yields of 50–78%, using 0.4 M NaOH/EtOH as the catalyst. They were then subjected to an acid hydrolysis reaction, which produced the respective trifluoromethyl-substituted pyrazolinecarbonyl coumarins in good yields (80–91%). In order to study the influence of the CF3 substituent, reactions involving 1-cyanoacetyl-3,5-dimethyl-5-hydroxy-4,5-dihydro-1H-pyrazole were also performed, but they did not provide the desired coumarins. On the other hand, attempts to synthesize some pyrrolecarbonyl coumarins not containing trifluoromethyl groups, but using the same methodology, directly resulted in a new series of five 3-(1-methyl-1H-pyrrol-2-carbonyl)-2H-chromen-2-ones in good yields (40–60%).

This study reports a simple and highly regioselective synthesis of a new series of 3,6-disubstituted 2-(methylsulfanyl)pyrimidin-4(3H)-ones, in which the 6-substituents are methyl or aryl groups and the 3-substituents are alkyl, allyl, phenyl, benzyl, or 2-phenylethyl groups. The products are obtained in good yields by cyclocondensation of the appropriate 4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with nonsymmetric 1-substituted 2-methylisothiourea sulfates under mild basic conditions.

A new one-pot method, for the synthesis of polysubstituted pyrrolo[3,4- d ]pyridazinones, is presented. The protocol consists in cascade reactions performed in the same media: (i) the thermal in situ pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds, via the 1,2-addition of 1,3-dicarbonyl compounds to 2 H -azirine intermediates; (ii) the nucleophilic addition of hydrazines to the ketone group present in the pyrroles previously formed, followed by intramolecular cyclization with the bordering ester, which furnishes the respective pyrrolo[3,4- d ]pyridazinones, substituted at the pyrrole and/or pyridazinone rings. All transformations occur in a two-step one-pot methodology, and a series of ten new compounds were obtained at yields of 42–87%.

Metal-free electrophilic fluorination, promoted by Selectfluor, of pyrazoles with methylene groups (CH2X), in which X = OH, OMe, F, N3, and NHMe at the C-4 position furnished the 4-fluoro-pyrazole products from unexpected C–C bond cleavage, at moderate to good yields. Otherwise, under the same reaction conditions, when X = NEt2 or SPr, the oxidation product 4-formyl-pyrazole was obtained.

This study describes a simple, efficient, and environmentally benign procedure for synthesizing a novel series of 13 N-(pyrimidinyl)-N-(1H-benzo[d]imidazolyl)amines, from the cyclocondensation reaction of (benzo[d]imidazolyl)guanidine with 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones or 2,2,2-trifluoro-1-(2-methoxycyclohexen-1-en-1-yl)ethanone. The (benzo[d]imidazolyl)guanidine precursor was earlier obtained from the reactions of cyanoguanidine with o-phenylenediamine. The trifluoroacetylated enol ethers were synthesized from the trifluoroacetylation reaction of enol ethers or acetals with trifluoroacetic anhydride. The main reactions were performed in pure refluxing water as the solvent (1–24 h), without catalysts, and the corresponding new N-(pyrimidinyl)-N-(1H-benzo[d]imidazolyl)amines were obtained at good to excellent yields (60–90 %). Subsequently, N-alkylation reactions were performed to obtain tertiary amines and to increase the solubility of the amines.

This paper reports a synthetic and NMR spectroscopic studies of two new series of 4-fluorinated 1,3,5-substituted 1H-pyrazoles. Firstly, an efficient synthesis of new series of 3-aryl-4-(di)fluoromethyl-1H-1-phenylpyrazoles, where [aryl = Ph, 4-NO2C6H4, 4-CH3OC6H4] is described, from fluorination reactions of 4-(formyl)- and 4-(hydroxymethyl)-1H-1-phenylpyrazoles in dichloromethane as solvent at room temperature, employing diethylaminosulfur trifluoride (DAST) as fluorinating agent in 41 to 73% yield. The 4-formyl-pyrazoles are obtained in 54–58% yield by Vilsmeier–Haack reaction using a mixture of POCl3/DMF with arylhydrazones, which were derived from the respective aryl methyl ketones and phenylhydrazine. The 4-hydroxymethyl-pyrazole precursors were easily obtained from the reduction of 4-formyl-pyrazoles by sodium borohydride (NaBH4) in 52–87% yield. Subsequently, the present work also discusses the 1H, 13C and 19F NMR spectroscopic data.

A simple and efficient procedure for the synthesis of ethyl 2-methylthio- and ethyl 2-benzylthio-6-methyl(aryl)-pyrimidine-4-carboxylates and their corresponding acid derivatives is reported. The products are obtained in good yields via the cyclocondensation reaction of ethyl 4-alkoxy-2-oxo-4-methyl(aryl)-but-3-enoates with 2-meth­ylisothiourea sulfate or 2-benzylisothiourea hydrochloride, under mild, basic, aqueous conditions.

The supramolecular structure of 3-amino-4-halo-5-methylisoxazoles (halo = Cl, Br, and I) was investigated in order to suggest a route for crystallization of small molecules. The hierarchy of intermolecular interactions during the growth of the crystal was established by X-ray diffraction, 1H NMR titration, QTAIM analysis and quantum mechanical calculations. The relationship between QTAIM and energetic data was the fundamental innovation in this work. It allowed partitioning of the dimer interaction energy between interacting atoms. The partitioning shows the cooperation of the intermolecular interactions in the stabilization of the dimers and led to observation of the energetic consequences that small changes in the molecular structure of each compound may have on the crystal packing. The proposed route for the crystallization of the supramolecular cluster was based on the energetic hierarchy, in which the hydrogen bond is the strongest interaction and the first to form, and the π-interactions are weaker than the hydrogen bond and cannot compete with it. However, the π-interactions are responsible for the growth of the crystal, connecting the rising layers of the hydrogen bond dimers. The other interaction formed, the halogen bond, is too weak to compete with the other two interactions, but it is fundamental for linking the layer that leads to the final three-dimensional arrangement. Finally, a new way of understanding the crystallization process and the design of new materials is presented.

This work presents a new synthesis of the antiepileptic drug rufinamide—1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide) in chemical form—and some analogue compounds, through a one-pot reaction employing a solventless, metal-free catalysis and without any reducing reagent. The great novelty presented is the synthesis of 4-trichloroacetyl-1-(2,6-difluorobenzyl/benzyl/4-methoxybenzyl)-5-methyl(phenyl)-1H-1,2,3-triazoles as new precursors from a regioselective 1,3-dipolar cycloaddition reaction between 1,1,1-trichloro-4-alkoxyalk-3-en-2-ones and some benzyl azides, which are converted into rufinamide and the analogues by an addition–elimination reaction with an aqueous solution of NH4OH in good yields (42–52%).

This study reports a simple, fast, and efficient method for the synthesis of a new series of 1-arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and related compounds from the reaction of 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans with 2-arylethanamines and related 2-ethanamines. The desired tetrahydropyridines were obtained in excellent yields (90–98%), through a reaction that can be described as an AAB′ three-component reaction protocol following an ANRORC-type mechanism.

This paper firstly describes an efficient and regioselective method for the synthesis of a new series of 2,2,2-trifluoro-1-[4-methoxy-spiro(2 H -chromen-2,1′-cycloalkane)-3-yl]ethanones from spiro[chroman-2,1′-cycloalkan]-4-ones (Kabbe's adduct). Yields of 38–61% were obtained when trifluoroacetylation reactions of mixtures of enolethers and/or acetals derived from four spiro ketones (Kabbe's adduct) were performed at a temperature of 45 °C, employing anhydrous chloroform as the solvent. Subsequently, when the respective trifluoroacetylated Kabbe adducts reacted with phenylhydrazine and methylhydrazine at a 1:1 molar ratio in refluxing ethanol for 24 h, a new series of seven examples of a new spiro-condensed heterocyclic system, namely 1(2)-methyl(phenyl)-3-(trifluoromethyl)-1,4(2,4)-dihydro-spiro(chromen[4,3- c ]pyrazole-4, n ′-cycloalkanes) – where cycloalkanes are cyclopentane, cyclohexane, and cycloheptane for n = 1; and tetrahydro-2 H -pyran for n = 2 – were isolated at yields of between 35% and 51%. Finally, the structures of new spiro heterocycles were determined with the aid and simultaneous application of 1 H, 13 C and 19 F one-dimensional and gHMBC NMR experiments, X-ray monocrystal diffraction, and mass spectrometry techniques.

Pain is the most common complaint in the medical field and the identification of novel compounds that can effectively treat painful states without causing side effects remains a major challenge in biomedical research. The aim of the present study is to investigate the antinociceptive effect of 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (FTosPz) in models of pathological pain in mice and compare these effects with those produced by Celecoxib. FTosPz (100-500 μmol/kg) or Celecoxib (26-260 μmol/kg) was administrated orally. The administration of either FTosPz or Celecoxib reduced the hyperalgesia but not the edema or leukocyte infiltration that was caused by Complete Freund's Adjuvant (CFA), used as an arthritis model. Oral administration of both FTosPz and Celecoxib also attenuated the postoperative hyperalgesia as well as the hyperalgesia caused by partial sciatic nerve ligation, used as a neuropathic pain model. FTosPz and Celecoxib produced antinociceptive effects without altering the locomotor activity of animals. Furthermore, FTosPz neither altered AST/ALT enzyme activity nor the urea/creatinine levels. Still, the FTosPz did not alter the COX-1 and COX-2 enzyme activities. Thus, FTosPz is an interesting prototype for the development of novel analgesic drugs.

Acute lymphoblastic leukemia (ALL) is a malignant disorder caused by the proliferation of lymphoid progenitor cells and is the most common cancer in children. Cytotoxic nucleoside analogues are important chemotherapeutic agents, which are used in many cancers, including leukemias. In this study, we investigated the effects of the synthetic nucleoside analogue 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one, named compound 3 or C3, on leukemia cell lines. The compound stimulated cell death by apoptosis, evidenced by DNA fragmentation, phosphatidylserine externalization, and caspase-3 activation. Compound 3 seemed to trigger several cell death pathways. The mitochondrial pathway was evidenced through a disturbance of mitochondrial membrane potential, strong cytochrome c liberation, decrease of antiapoptotic Bcl-2 protein expression, and caspase-9 activation. The C3 also induced caspase-8 and -12 activation, an increase in the intracellular calcium level, and an overproduction of reactive oxygen species. Increased caspase 8 activity suggests that the extrinsic pathway was activated and that the ROS production and enzyme activity alteration (glutathione S-transferase, glutathione peroxidase, catalase, and glutathione reductase) might be related to oxidative stress. Finally, the increase in calcium release, CHOP expression, and caspase-12 activity might characterize endoplasmic reticulum stress. Compound 3 was likewise cytotoxic to leukemic and melanoma human cell lines. Taken together, the results contribute to further understanding the new pyrimidine analogue as a potential chemotherapeutic drug or lead molecule.

This work investigated the chemical and mechanical factors that affect cyclocondensation reactions in a ball mill. Chemical characteristics such as the use or non-use of a catalyst, amount of catalyst and reactants, and product formation, as well as the yield and mechanical factors such as rotation frequency and the number, diameter, and material of the milling balls were evaluated. It was found that a rotation frequency of 450 rpm is efficient for energy transfer to the reactants because the conversion is higher at this rotation. The reaction was highly dependent on the time (3 min) and amount of p-TSA (p-toluenesulfonic acid) utilized as catalyst (10 mol %). Five steel balls of 10 mm were considered to be the ideal number for the efficient mixing of the particles. For this work, the ideal conditions determined were used for the green synthesis of a series of 1H-pyrazoles.

Ultrasonic irradiation was used in the synthesis of a series of novel 1,2,4-triazolo[1,5-a]pyrimidines. The products were synthetized from the cyclocondensation reaction of 1,1,1-trifluoro-4-metoxy-3-alken-2-one [CF3C(O)CH C(R)OMe, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, Thien-2-yl, Biphen-4-yl] or β-enaminones [RC(O)CH CHNMe2, where R = Ph, 4-F-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, 4-CH3O-C6H4, 4-NO2-C6H4, Thien-2-yl, Biphen-4-yl, Naphth-2-yl, Pyrrol-2-yl, CCl3] with 5-amino-1,2,4-triazole in acetic acid at 99 °C with 5–17 min of ultrasound irradiation. This methodology has shown several advantages, such as shorter reaction times, mild conditions, high regioselectivity, and excellent yields, when compared with conventional thermal heating (oil bath).

This paper reports a facile and convenient access by a conventional thermal procedure in ethanol as solvent to a new examples of (E)-6-[2-ferrocenylalkylidenehydrazino]nicotinic hydrazides (3) (53–72%) from the quimioselective reactions of 6-hydrazinonicotinc hydrazide (1) with acylferrocenes (2), where acyl = formyl and acetyl. Subsequently, cyclocondensation reactions of ferrocenylalkylidene hydrazones (3) with 4-R1-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (4), where R1 = Me, Ph, 2-Furyl, to obtain new six heterocyclic derivatives as (E)-pyrazolyl-pyridinohydrazones (5) (58–63%), are also presented. The structures of these new heterocyclic compounds 5 containing an organometallic unit were characterized and studied by NMR, ESI–MS/MS techniques. DFT calculations were also employed to assign the E configuration for compounds 3 and 5.

4-(Trifluoromethyl)-2(1H)-pyrimidinones were synthesized from the reaction between 1,1,1-trifluoro-4-methoxy-3-buten-2-ones [CF3C(O)C(R2)C(R1)(OCH3) where R1 = Ph, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C6H4, 4-CH3-C6H4, naphth-2-yl, 4-OCH3-C6H4, thien-2-yl and R2 = H, CH3] and urea in the presence of ionic liquid [BMIM][BF4] combined with HCl. The results demonstrate that [BMIM][BF4]/HCl catalyzed the reaction in the absence of molecular solvents. Use of ionic liquid combined with HCl allowed the reaction temperatures to be increased to 100 °C and decreased the reaction times from 48–72 to 3–6 h. The products were obtained in good yields (70–97 %).

In this work, an approach is proposed for understanding the crystal arrangements of organic compounds. The crystals are studied taking into account the stabilization energy and the topological properties like contact surfaces of a molecule (M1) due to the presence of neighboring Mn (cluster). The molecular system models chosen were five heterocycles and one β-enaminone. The cluster of compounds had a Molecular Coordination Number (MCN) of 14, except for one compound that had an MCN of 16. Our study showed that intermolecular interactions can be divided into four main types: type I, with large energy values and a small contact surface; type II, involving a large value for both the energy and the contact surface; type III, with small and medium energy values, and a medium-sized contact surface; and type IV, with small energy values and a relatively large contact surface. Additionally, from this approach we show that only from the supramolecular cluster is it possible to observe the participation of the topological component during the formation of the crystal. This is demonstrated by the fact that the fragility of the electrostatic interaction between M1 and one Mn in the same plane is compensated by a strong interaction of M1 with a molecule in another plane.

The synthetic versatility of ethyl 2-(2-ethoxy-3,4-dihydro-2H-pyran-5-yl)-2-oxoacetate for the synthesis of ethyl 2-oxo-2-(1-alkyl/aryl-6-(amino/ethoxy)-1,4,5,6-tetrahydropyridin-3-yl)acetates, from the reaction with primary amines, is presented. The methodology proposed herein is highly chemoselective, and twenty products were obtained in moderate to good yields (up to 87%).

This work reports the synthesis of a new series of 2-aryl-6-(phenylethynyl)-4-(trifluoromethyl) quinolines (2), where aryl = 4-(phenylethynyl)phenyl (2a), Ph (2b), 4-MeC6H4 (2c), 4-FC6H4 (2d). These were obtained by the Sonogashira coupling reaction producing 42–88% yield, utilizing 6-bromoquinolines and phenylacetylene as precursors in the presence of catalyst systems of Pd(OAc)2 and PPh3. The precursor 6-bromoquinolines were obtained from an intramolecular cyclisation reaction of (Z)-4-[(4-bromophenyl)amino]-1,1,1-trifluorobut-3-en-2-ones, which were previously prepared though the reaction of 4-methoxy-4-aryl-1,1,1-trifluoroalk-3-en-2-ones with 4-bromoaniline. Liquid crystal (LCs) properties were evaluated using thermal data and mesophase texture. Only compound 2a displayed monotropic nematic mesophase with very narrow liquid crystal window. Compounds 2b, 2c and 2d only displayed transition between the crystal phase to a liquid state. Nematic behavior was mainly dependent on the molecular length, as proved for 2a, which has the longest molecular length. Torsional angles between quinoline and aryl moieties at the 2-position were significant on hysteresis observed during the crystallization process.

This paper describes an efficient approach for the synthesis of a new series of 6-[3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinic acids (where alkyl = CH3; aryl = Ph, 4-OCH3Ph, 4,4′-BiPh; and heteroaryl = 2-Furyl) from the hydrolysis reaction of alkyl(aryl/heteroaryl)substituted 2-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-5-(5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carbonylpyrazol-1-yl)pyridines, under basic conditions and at 70–95% yields. In a subsequent step, the esterification reaction of pyrazolyl-nicotinic acids done in thionyl chloride and methanol led to the isolation of a series of methyl 6-[alkyl(aryl/heteroaryl)-5-trifluoromethyl-1H-pyrazol-1-yl] nicotinates as stable hydrochloride salts at 64–84% yields, which could be easily converted to hydrazides to give new oxadiazolyl-pyrazolyl-pyridine tricyclic scaffolds at good yields from a [4 + 1] cyclocondensation reaction with 1,1,1-triethoxyethane and 1-(triethoxymethyl)benzene as the reagent/solvent.

This paper describes an efficient method for synthesis of rufinamide analogs from the 1,3-dipolar cycloaddition and/or electrocyclization reactions under conventional thermal conditions of 4-alkyl(aryl/heteroaryl)-4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones (1) with 2,6-difluorobenzyl azide, where 4-alkyl = H, Me; 4-aryl = Ph, 4-NO2C6H4, 4-OCH3C6H4, 4-FC6H4, 4,4′-BiPh; and 4-heteroaryl = 2-thienyl; for the efficient preparation of a series of ten new trifluoroacetyl(trifluoromethyl) substituted 1H-1,2,3-triazoles. Yields in the range of 30–71% were obtained when the reactions were performed at high temperatures (130–150 °C) under solvent-free conditions. The pure regioisomers or mixtures of triazoles could be isolate with dependency of the 4-substituent of the enones 1. Finally, two mechanisms are proposed and the results are discussed in accordance with the X-ray diffraction results and FMO theory, which describes the possible HOMO/LUMO interactions via DFT calculations for both precursors.

This paper describes easy access to twelve examples of five- and six-membered heterocycles (monocyclic and fused) containing a dimethyl acetal aldehyde function and/or a trifluoromethyl substituent, in good to excellent yields (72-98%). The dimethyl acetal-protected heterocycles were obtained in one-step via regioselective cyclocondensation reactions of 4,6,6-trimethoxy- 1,1,1-trifluorohex-3-en-2-one with 1,2-, 1,3- and 1,5-dinucleophiles (hydrazines, hydrazides, hydroxylamine, 1-acetylguanidine and 1,8-diaminonaphthalene). Subsequently, to demonstrate a potential synthetic application, some pyrazole rings containing dimethyl acetal moiety were converted to the respective secondary homoallylic alcohols by efficient allylation reactions employing allylaluminum reagent in 84 to 90% yields.

Pyrazolo[1,5-a]pyrimidines were synthesized via the ultrasonic sonochemical method using the cyclocondensation reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH = C(R)(OMe) – where R = Me, Bu, i-Bu, Ph, 4-Me–C6H4, 4-F–C6H4, 4-Cl–C6H4, 4-Br–C6H4, naphth-2-yl and biphen-4-yl] – with 3-amino-5-methyl-1H-pyrazole in the presence of EtOH for 5 min. This methodology has several advantages, for example, it is a simple procedure, it has an easy work-up, mild conditions, short reaction times (5 min) and produces satisfactory yields (61–98%).