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A protocol for synthesizing triazole-containing pyrazolines and pyrazoles selectively using trifluoromethylated 5-(1,2,3-triazol-1-yl)enones as starting materials, is reported. The selectivity of the reaction was controlled by the nature of the hydrazine or derivative used: free hydrazines furnished the 1,5-regiosiomer exclusively in yields up to 98%, whereas protected hydrazines provided the 1,3-regioisomer in yields up to 77%. To demonstrate the synthetic versatility of the triazole-based enone, reactions with other unsymmetrical dinucleophiles (hydroxylamine hydrochloride and S-methyl isothiourea sulfates) allowed the selective preparation of triazole-containing isoxazoline and pyrimidine rings.

In this work, the reactivity of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one toward primary aliphatic amines was studied. The reaction was found to be extremely selective to synthesize a series of 1-alkyl-4-(aminoalkyl)-2-(trifluoromethyl)-1H-pyrroles (13 examples, up to 90% yield) and a series of highly functionalized β-enaminones (6 examples, up to 78% yield), with only the amount of amine and the reaction conditions needing to be controlled. The structure of the products was unambiguously determined by single crystal X-ray diffraction and 2D NMR experiments.

A convenient synthesis of a broad series of thirteen examples of alkyne-spacer derivatives 2 from the well-known Sonogashira cross-coupling reaction on diazenyl-pyrazolo[1,5-a]pyrimidin-2-amine compounds 1 is reported. The reactivity of heterocycles 1 due the presence of selected electron-donor (EDG) and electron-withdrawing (EWG) groups attached to different alkynes was evaluated. Also, the reactional versatility due the position variation of the bromo atom at the scaffolds 1 was also investigated. In general, derivatives presented strong absorption bands at the 250-500 nm optical window and UV to cyan emission properties. Also, the redox analysis was recorded by electrochemical cyclic voltammetry technique. For HSA biomacromolecule assays, spectroscopic studies by UV-Vis, steady-state and time-resolved emission fluorescence, and molecular docking calculations evidenced the ability of each compound to establish interactions with human serum albumin (HSA). Finally, the behavior presented for this new class of heterocycles makes them a promising tool as optical sensors for albumins.

The regioselective synthesis of twenty novel [3-substituted 5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl][6-aryl-(2-methylthio)pyrimidin-4-yl]methanones from the cyclocondensation reactions of new 6-aryl-2-(methylthio)pyrimidine-4-carbohydrazides with 4-substituted 1,1,1-trifluorobut-3-en-2-ones is reported. Human acetylcholinesterase (HsAChE) and butyrylcholinesterase (HsBChE) inhibition tests were performed on selected products in order to explore the possible pharmacological applications of these compounds. Two compounds showed significant and selective inhibitory activity for BChE.

The 1,4-dicarbonyl scaffold ethyl 3-formyl-4,5-dihydrofuran-2-carboxylate was obtained through the rearrangement of the parent ethyl 2-(4,5-dihydrofuran-3-yl)-2-oxoacetate and applied to the synthesis of a series of 7-alkoxy-2,3-dihydrofuro[2,3-d]pyridazines. Twelve pyridazines­ were obtained in yields of up to 70%.

5-Bromo- and 5,5-dibromo-1,1,1-trihalo-4-methoxypent-3-en-2-ones (brominated enones) have proven to be attractive building blocks for the construction of heterocyclic and polyheterocyclic compounds bearing a trihalomethyl moiety through interesting cyclocondensation, alkylation, and cycloaddition reactions. This review compiles all of the reactions conducted with these brominated enones since they were first disclosed in 2001.1 Introduction2 Synthesis and Initial Applications3 Synthesis Using First-Generation Intermediates4 Synthesis Using Second-Generation Intermediates5 Synthesis Using Third-Generation Intermediates6 Conclusions

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 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.

A series of seven 5-aryl-1-(1,1-dimethylethyl)-3-trifluoromethyl-1H-pyrazoles [in which aryl: C6H5 (1); C6H4-4-F (2); C6H4-4-Cl (3); C6H4-4-Br (4); C6H4-4-I (5); C6H4-4-CH3 (6), C6H4-4-OCH3 (7)] and 5-aryl-1-(1,1-dimethylethyl)-1H-pyrazole [C6H4-4-NO2 (8)] was studied at the molecular and supramolecular level. X-ray diffraction, thermal analysis, sublimation enthalpy data, NMR spectroscopy, and DFT calculations were used in this systematic study. The supramolecular cluster was used as demarcation and furnished energetic and contact area data of each compound, which allowed proposals of crystallization mechanisms. Two different mechanisms were observed: (i) compounds 1–4 had 2 stages, where initially the monomers formed a 2-D block, followed by the formation of the 3-D block; (ii) compounds 5–8 also had 2 stages, where initially the monomers formed a 1-D block, followed by formation of the 3-D block. The packing observed in the crystal was corroborated by data from 1H NMR experiments. The types of interactions observed were evaluated using Hirshfeld surface and QTAIM analysis and showed slight differences in both methods. Lastly, energetic and topologic data obtained from the clusters were correlated with crystal properties such as crystal packing efficiency, sphericity, and sublimation enthalpy and presented good trends between data.

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%.

This paper describes the synthesis of a novel series of 2-aryl-6-(1H-indol-1-yl)-4-(trifluoromethyl)quinolines, in which aryl = C6H5, 4-CH3C6H4, 4-FC6H4, 4-CF3C6H4 and heteroaryl = 2-thienyl, by an Ullmann-type cooper-catalyzed amination cross-coupling reaction. Photophysical properties of indolyl-quinolines were investigated using absorption and emission analysis. The emission fluorescence analysis showed a blue to cyan region emission in the 400–650 nm range. Large Stokes shifts values were observed for all new quinolines and attributed to the ICT state and to the electron-substituent properties. The ability to generate 1O2 species after being exposed to white light and biomolecule-binding DNA / HSA properties were also investigated.

An efficient protocol for the assembly of a new series of 1,3-disubstituted 4,5-bis(trifluoromethyl)-1H-pyrazoles – through a concise sequential iodination-trifluoromethylation reaction at the C-4 position of an initial series of 1-aryl-3-(alkyl/aryl)-5-trifluoromethyl-1H-pyrazoles (electronically deactivated heterocycles), using NIS and MFSDA, at good conversion yields and in short reaction times – is reported.

The use of β-enamino diketones as an easy entry to the regioselective synthesis of [1,2,4]triazolo[1,5-a]pyrimidines is reported. These ketones reacted with 3-amino-1H-1,2,4-triazoles to furnish exclusively 6-substituted 5-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidines in yields of up to 95%. The regioselectivity of the reactions performed was maintained regardless of the substituent in the starting ketone or aminoazole.

Reaction of 5-bromo enones with pyrazoles provided a series of unexpected N,O-aminal derivatives, through a 1,4-conjugated addition at the β-carbon of the 5-bromo enones instead of the expected nucleophilic substitution of the bromine. This reaction also furnished the 1,3-regioisomer of the pyrazole. A similar reaction of pyrazoles using 5-bromo enaminones furnished only N-alkylated pyrazoles-with high regioselectivity and at good yields-through nucleophilic substitution of the bromine.

The synthetic versatility of 4-alkoxy-4-alkyl/aryl-1,1,1-trichloroalk-3-en-2-ones (enones) for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidines, in which the trichloromethyl group is either maintained or eliminated from the product by simply controlling the reaction medium, is reported. These enones react with 3-amino-1H-1,2,4-triazoles under acidic conditions to furnish exclusively 7-(trichloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidines, whereas under basic conditions [1,2,4]triazolo[1,5-a]pyrimidin-5/7(1H)-ones are obtained with elimination of the trichloromethyl group. The regioselectivity of the reactions performed under basic conditions is highly influenced by the substituents present in the starting enones. Twenty-one examples are synthesized using these two methodologies, with yields of up to 86%.

The present paper describes first an efficient methodology for an easy O -functionalization (alkylation) of tetracyclic hydroxyisoxazolines 1 applied to the synthesis of eight examples of new 3-(alkoxy)-3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno [4,3- c ]isoxazole-4,1′-cycloalkanes] ( 6-9 ) at 61–84% yields, in which the alkoxy substituents were methoxy, benzyloxy, allyloxy, or prop-2-yn-1-yloxy; while the cycloalkanes were 5-, 6-, and 7-membered carbocycles, as well as 4′-methyl- and 4′- t -butyl-cyclohexane. The reaction medium used 1 , four alkyl halides ( 2 - 5 ), K 2 CO 3 , and KI in DMF at room temperature. The selected 3-(prop-2-yn-1-yloxy)-substituted isoxazolines 6 were successfully used as a CC -fragment in the construction of another series of five examples of 3-((1-benzyl-1 H -1,2,3-triazol-4-yl)methoxy)-3-(trifluoromethyl)-3,3a-dihydrospiro[chromeno[4,3- c ]isoxazole-4,1′-cycloalkanes] ( 10 ), at 36–84% yields, through a regioselective 1,3 dipolar cycloaddition reaction catalyzed by copper iodide (CuAAC), using benzyl azide as an NNN -building block (Click Chemistry).

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.

This paper firstly describes the synthesis of a series of (Z)-4-((3-chloro-4-fluorophenyl)amino)-1,1,1-trifluorobut-3-en-2-ones (3a–f) as well as 1-(1-((3-chloro-4-fluorophenyl)amino)-3,4-dihydronaphthalen-2-yl)-2,2,2-trifluoroethanone (3g), from the O,N-exchange reaction of some 4-methoxy-4-alkyl(aryl)-1,1,1-trifluoroalk-3-en-2-ones (1) with 3-chloro-4-fluoroaniline (2), at 70–90% yields. Subsequently, in concentrated sulfuric acid, the enaminoketones 3 underwent a successful and regioselective intramolecular cyclocondensation reaction, which furnished a novel series of 2-alkyl(aryl)-7-chloro-6-fluoro-4-(trifluoromethyl)-quinolines (4) at 70–85% yields. To demonstrate synthetic applicability through the Sonogashira coupling reaction for obtaining quinolines with potential antimicrobial activity, the synthesis of a novel series of 2-alkyl(aryl)-6-fluoro-7-(phenylethynyl)-4-(trifluoromethyl)-quinolines (5) was performed, using quinolines 4 and phenylacetylene, via a regioselective Sonogashira coupling reaction (25–50% yield). Unfortunately, the new series of heterocycles 4 and 5 did not produce significant results against bacteria and fungi at the concentrations of 80–0.31 μg/mL.

This paper reports the results of the synthesis and structural elucidation by multinuclear NMR spectroscopy and single crystal X-ray diffraction of a new series of four examples of 1,1-difluoro-3-methyl-9-(aryl/heteroaryl)-7-(trifluoromethyl)-1H-[1,3,5,2]oxadiazaborinino[3,4-a][1,8]naphthyridin-11-ium-1-uides, which were obtained, at good yields (60–66%), from the reaction of 7-substituted N-(5-(trifluoromethyl)-1,8-naphthyridin-2-yl)acetamides — in which the 7-substituents are C6H5, 4-CH3C6H4, 4-FC6H4, and 2-Thienyl — with BF3·Et2O solution. One-dimensional multinuclear NMR spectroscopy (1H, 13C, 19F, and 11B) and two-dimensional 1H–15N HMBC are presented as powerful tools for an easy and secure NMR chemical shift assignments and structural characterization of fluorinated 1,8-naphthyridine-based boron complexes. Additionally, investigations of photophysical, electrochemical and DNA-binding properties were done.

A series of seven novel scaffolds of 2-substituted 4-trifluoromehyl-5H-chromeno[4,3-b]pyridin-5-ones (3a-g), where R (2-substituents) = Me, Ph, 4-tolyl, 4-NO2C6H4, 4-FC6H4, 4-BrC6H4, and 2-thienyl, were easily and regioselectively synthesized by employing a [3 + 3] cyclocondensation reaction of 4-methyl(aryl/thienyl)-4‑methoxy-1,1,1-trifluoroalk-3-en-2-ones (1) with 4-aminocoumarin (2) in up to 66% yields. The photophysical and electrochemical analysis of 3a-g revealed large Stokes shifts (30 to 130 nm) due to the ICT state and low redox oxidation processes. Additionally, the antioxidant activity evaluated by DPPH assays (aided by cyclic voltammetry) showed that compounds 3b (R = Ph, EC50 (µM) = 19.6) and 3e (R = 4-FC6H4, EC50 (µM) = 19.1) had the most significant radical scavenging capacity (ref. ascorbic acid = 10.9 µM).

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.

A new, simple, and efficient method for the synthesis a novel series of 1-substituted 4-(trifluoromethyl)-5-(alkan-1-ol)-pyridin-2(1 H )-imines from the reaction of 3-(5,6-dihydro-4 H -pyran-3-yl)-4,4,4-trifluorobut-2-enenitrile and 3-(4,5-dihydrofuran-3-yl)-4,4,4-trifluorobut-2-enenitrile with primary amines – is described. The products were obtained in 29–82% yield.