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This paper describes the photophysical properties of a series of seven selected examples of 5-(alkyl/aryl/heteroaryl)-2-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidines (3), which contain alkyl, aryl, and heteroaryl substituents attached to the scaffolds of 3. Given the electron-donor groups and -withdrawing groups, the optical absorption and emission in the solid state and solution showed interesting results. Absorption UV–Vis and fluorescence properties in several solvents of a pyrazolo[1,5-a]pyrimidines series were investigated, and all derivatives were absorbed in the ultraviolet region despite presenting higher quantum emission fluorescence yields in solution and moderate emission in the solid state. Moreover, the solid-state thermal stability of compounds 3a–g was assessed using thermogravimetric analysis. The thermal decomposition profile showed a single step with almost 100% mass loss for all compounds 3. Additionally, the values of T0.05 are considerably low (72–187 °C), especially for compound 3a (72 °C), indicating low thermal stability for this series of pyrazolo[1,5-a]pyrimidines.

This study reports two strategies for preparing

The selective

Graphical abstract, Highlights • Ultrasound is a powerful tool in the synthesis of pyrimidines. • Selectivity in the synthesis of pyrimidines under ultrasound is demonstrated. • Synergic effects of US combined with other methods are presented., The pyrimidine scaffold is present in many bioactive drugs; therefore, efficient synthetic routes that provide shorter reaction times, higher yields, and site-selective reactions are constantly being sought. Ultrasound (US) irradiation has emerged as an alternative energy source in the synthesis of these heterocyclic scaffolds, and over the last ten years there has been a significant increase in the number of publications mentioning US in either the construction or derivatization of the pyrimidine core. This review presents a detailed summary (with 140 references) of the effects of US (synergic or not) on the construction and derivatization of the pyrimidine core through classical reactions (e.g., multicomponent, cyclocondensation, cycloaddition, and alkylation reactions). The main points that were taken into consideration are as follows: chemo- and regioselectivity issues, and the results of conventional heating methods compared to US and mechanistic insights that are also presented and discussed for key reactions.

A new series of ten examples of (E)-2-(((2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenols (Schiff bases), was easy synthesized at yields up to 91% from the reactions involving a series of 2-(R-substituted) 6-amino-4-(trifluoromethyl)quinolines and 4(5)-R1-substituted salicylaldehydes – in which alkyl/aryl/heteroaryl for 2-(R)-substituents are Me, Ph, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl, and (R1)-substituents are 5-NEt2, 5-OCH3, 4-Br, and 4-NO2. Complementarily, the Schiff bases showed low to good quantum fluorescence yield values both in CHCl3 (Φf = 0.12-0.80), DMSO (Φf = 0.20-0.75) and MeOH (Φf = 0.13-0.85). Higher values of Stokes shifts (SS) ​​were observed in more polar solvents (DMSO; 65-150 nm and MeOH; 65-130 nm) than in CHCl3 (59-85 nm). Also, compounds 3 confirmed to present good stability under white-LED irradiation conditions and moderate ROS generation properties were observed.

A new series of ten examples of Schiff bases, namely (E)-2-(((2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl)quinolin-6-yl)imino)methyl)phenols 3, was easily synthesized with yields of up to 91% from the reactions involving a series of 2-(R-substituted) 6-amino-4-(trifluoromethyl)quinolines 1 and 4(5)-R1-substituted salicylaldehydes 2 – in which alkyl/aryl/heteroaryl for 2-R-substituents are Me, Ph, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl, and R1-substituents are 5-NEt2, 5-OCH3, 4-Br, and 4-NO2. Complementarily, the Schiff bases showed low to good quantum fluorescence yield values in CHCl3 (Φf = 0.12–0.80), DMSO (Φf = 0.20–0.75) and MeOH (Φf = 0.13–0.85). Higher values of Stokes shifts (SS) were observed in more polar solvents (DMSO; 65–150 nm and MeOH; 65–130 nm) than in CHCl3 (59–85 nm). Compounds 3 presented good stability under white-LED irradiation conditions and moderate ROS generation properties were observed.

Herein, we explore the synthetic potential of tetrazolo[1,5-a]pyrimidines to obtain new pyrimidine derivatives by click chemistry and hydrogenation. Click chemistry reactions of the trifluoromethyltetrazolo[1,5-a]pyrimidines with terminal acetylenes produced unprecedented trifluoromethylated triazolylpyrimidines in excellent yields (84-98 %) in which one of them was active against all tested microorganisms, presenting moderate MIC values (62.5-15.62 mg/ml). Hydrogenation was carried out using Pd/C-H2 in MeOH under conventional, photochemical, and pressure (5 bar) conditions. The hydrogenation was an excellent method to obtain 2-amino-6-aryl-4-trifluoromethyl pyrimidines and/or 2-amino-6-aryl-4-trifluoro methyltetrahydro pyrimidines with a preference for 2-aminopyrimidine formation. The photochemical hydrogenation was the fastest and only pathway to reduce aryl-brominated substrate for the product without dehalogenation. Trifluoromethyl-substituted tetrazolo[1,5-a]pyrimidines reacted to 2-amino-6-aryl-4-trifluoromethyl pyrimidine formation in preference to the formation of the corresponding tethaydropyrimidines. However, the hydrogenation of non-trifluoromethylated tetrazolo[1,5-a]pyrimidines showed a preference for tetrahydropyrimidine formation.

The synthetic potential of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one toward the catalyst-free synthesis of N-pyrrolyl(furanyl)-piperazines, 1,4-diazepanes, and 1,4-diazocanes through a telescoped protocol is reported. This three-component one-pot method provided 23 examples with high chemo- and regioselectivity at yields up to 96%.

A systematic investigation to assess the degree of similarity between polymorphs was carried out. A similarity indices (IX) approach was applied in ten series of polymorphs with different characteristics and number of molecules in the asymmetric unit. Geometric (ID), contact area (IC), and stabilization energy (IG) parameters were used. It was possible to situate each comparison in different regions of similarity within the polymorphism phenomenon and determine the boundaries between quasi-isostructural polymorphs and polymorphs of low similarity. The multiparameter IDCG index was used as a robust tool to determine the total similarity within the polymorphism phenomenon. The highest contribution of the stabilization energy parameter (45%) toward the final value of similarity (IDCG) was observed, followed by the contact area index (32%). The geometric index contributed approximately 23% to the final value of IDCG. This information reinforces the importance of the contact area and stabilization energy in assessing the degree of similarity between crystalline structures. A new descriptor (IQ) based on the comparison of the energetic contribution of intermolecular interaction types present in each crystal structure is presented. IQ can be a versatile tool and applicable even for systems that do not share any similarity.

A series of seven N-phenylamides [R–C(O)NHPh, in which R: CH3, C(CH3)3, Ph, CF3, CCl3, CBr3, and H] were used as models in this study. Molecular packing and intermolecular interactions were evaluated by theoretical calculations, solution NMR, and quantum theory of atoms in molecules analyses. Crystallization mechanisms were proposed based on the energetic and topological parameters using the supramolecular cluster as demarcation. Concentration-dependent 1H NMR experiments corroborated the proposed interactions between molecules. For all compounds (except for R: H, which initially formed tetramers), layers (two-dimensional) or chains (one-dimensional) were formed in the first stage of the proposed crystallization mechanisms. The presence of strong intermolecular NH···O═C interactions promoted the first stages. The study in solution provided different values of association constant (Kass) governed by the hydrogen bond NH···O═C, showing that the stronger interactions are directly influenced by the substituen...

This study reports a comparison between conventional methods, ionic liquids, microwave (MW) irradiation, and combinations thereof for the synthesis of a series of fourteen 1-aryl-2-arylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines. In all of the reactions tested, the products were obtained at very good yields (87–97%), but the reaction times were very different, depending on the method used. Comparing to other methods, the time decreased to 1 min when [BMIM]BF 4 under MW irradiation was used, thus evidencing a synergic effect.

The quest for concepts of isostructurality in organic crystals has been long and mostly based on geometric data, even with the development of modern software. This field of study is of great interest to the pharmaceutical industry and for the prediction of crystal structures. Despite this, there is still no methodology that provides broad quantitative and comparable similarity data between two complete crystalline structures. The present study demonstrated that the similarity between two crystalline structures could be estimated from the similarity between the two "supramolecular clusters". Quantitative indexes for similarity comparisons of crystal structures were shown using nine 5-aryl-1-(1,1-dimethylethyl)-1H-pyrazoles as a model. This proposal includes the quantitative data of a geometric parameter (ID), a contact area parameter (IC), and an energetic parameter (IG). The proposed indexes exhibited good perspective regarding the similarity data and distinct regions of similarity. The range of similarity was set at IX ≥ 0.80, 0.80 > IX > 0.60, and IX ≤ 0.60 (X = D, C, or G). Indexes with a value near 1.0 indicate systems with isostructural, isocontact, and isoenergetic behavior. The results indicated that supramolecular structures with high similarity must have high values for all three indexes (ID, IC, and IG).

Electrospray ionization mass spectrometry with variable collision-induced dissociation (CID) was used to conduct a comprehensive study of cation-anion interaction strength in dicationic ionic liquids (ILs). This investigation reports the influence of anion structure (Cl−, Br−, NO3−, BF4−, and SCN−) and spacer chain length (n = 4, 6, 8, and 10) on the interaction strength of dicationic ILs derived from 1,n-bis(3-methylimidazolim-1-yl)alkane. The anion-cation interaction strength was determined from the binary mixture of ILs and from the center-of-mass energy (Ecm). Moreover, two novel models were proposed, based on the extended first order and zero order equations, which allow determining the order of stability from the constant dissociation (Kd) and decay rate (k0), respectively. Additionally, quantum chemical calculations of cation-anion energy were done in order to support experimental results. The order of energy of the anion-cation interaction determined by both Ecm,1/2 and Kd followed the same trend, while the order of the cation-anion interaction strength observed in the binary mixtures was in accordance with quantum chemical calculations. The model based on zero order process did not show good agreement with either the Ecm,1/2 or Kd, thus indicating that it is a very simplified model that does not result in an appropriate order for the cation-anion energy interaction. Orders were not comparable; however, it was the first time that binary mixture experiments and Ecm were used with the same set of ILs.

An efficient synthesis methodology for a series of tetrazolo[1,5-a]pyrimidines substituted at the 5- and 7-positions from the cyclocondensation reaction [CCC + NCN] was developed. The NCN corresponds to 5-aminotetrazole and CCC to β-enaminone. Two distinct products were observed in accordance with the β-enaminone substituent. When observed in solution, the compounds can be divided into two groups: (a) precursor compounds with R = CF3 or CCl3, which leads to tetrazolo[1,5-a]pyrimidines in high regioselectivity with R at the 7-position of the heterocyclic ring; and (b) precursor compounds with R = aryl or methyl, which leads to a mixture of compounds, tetrazolo[1,5-a] pyrimidines (R in the 5-position of the ring) and 2-azidopyrimidines (R in the 4-position of the ring), which was attributed to an equilibrium of azide–tetrazole. In the solid state, all compounds were found as 2-azidopyrimidines. The regiochemistry of the reaction and the stability of the products are discussed on the basis of the data obtained by density functional theory (DFT) for energetic and molecular orbital (MO) calculations.

The objectives of this study were to evaluate tetrahydropyridine derivatives as efflux inhibitors and to understand the mechanism of action of the compounds by in silico studies. Minimum inhibitory concentration (MIC) determination, fluorometric methods and docking simulations were performed. The compounds NUNL02, NUNL09 and NUNL10 inhibited efflux, and NUNL02 is very likely a substrate of the transporter protein AcrB. Docking studies suggested that the mechanism of action could be by competition with substrate for binding sites and protein residues. We showed for the first time the potential of tetrahydropyridines as efflux inhibitors and highlighted compound NUNL02 as an AcrB-specific inhibitor. Docking studies suggested that competition is the putative mechanism of action of these compounds.

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.

This work reports a successful one-pot three-step protocol for the synthesis of a new series of 15 examples of polysubstituted 4-(5-(trifluoromethyl)-1H-pyrazol-4-yl)-1H-1,2,3-triazoles, in which sequential Sonogashira cross-coupling, desilylation, and a copper(I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC) with an overall yield of up to 72% were used. The presence of a trifluoromethyl substituent attached to the pyrazole moiety made the Sonogashira cross-coupling reaction challenging. Additionally, the selection of the ancillary ligand XPhos was essential and indispensable for the desired heterocyclic construction.

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

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.

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.

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 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.

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.