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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.

This paper covers the synthesis of a series of eleven examples of new 7-(1H-pyrrol-1-yl)spiro[chromeno[4,3-b]quinoline-6,1′-cycloalkanes] (3), where cycloalkanes are cyclopentane, cyclohexane, and cycloheptane. Heterocyclic system 3 was successfully obtained in 53–78% yields by the Clauson–Kaas reaction, in which 7-amino-spiro[chromeno[4,3-b]quinoline-6,1′-cycloalkanes] (1) were reacted with 2,5-dimethoxytetrahydrofuran (2) in an acetic acid medium at 90 °C for 48 h. Then, to demonstrate synthetic applicability, the 9-bromoquinoline-substituted derivative 3h was selected and successfully employed in traditional CC and CN cross-coupling reactions, yielding three new modified tacrine scaffolds (4–6). Photophysical studies of π → π* and n → π* transitions corroborated the aromatic structures of the heterocycle molecules and showed high emission properties, good Φf values, and moderate to large Stokes shifts (SS).

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%.

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.

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.

The synthesis and structural elucidation of a new series of six 6-amino-2-alkyl(aryl/heteroaryl)-4-(trifluoromethyl) quinolines are reported, yielding 22 to 87% isolated products. This was achieved through a regioselective intramolecular cyclization reaction of novel (Z)-4-((4-aminophenyl)amino)-1,1,1-trifluoro-but-3-en-2-ones in an acidic solvent-free medium, in which alkyl/aryl/heteroaryl = methyl, phenyl, 4-MeC6H4, 4-FC6H4, 4-NO2C6H4, and 2-furyl. The novel compounds were fully characterized by 1H-, 13C- and 19F-NMR spectroscopy, GC-MS and single-crystal X-ray diffraction. In addition, the preliminary investigation of photophysical properties of the 6-aminoquinolines (UV-Vis, fluorescence, quantum yield calculations, Stokes shifts, and TD-DFT analysis) and inhibitory activity against M. tuberculosis H37Rv strain was also presented. Thermal analyses were carried out to assess their properties as new materials.

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.

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 of up to 91% from the reactions between 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. The compounds are fully characterized by 1H-, 13C-, and 19F-NMR spectroscopy and SC-XRD. Complementarily, the photophysical, photostability, and reactive oxygen species (ROS) generation properties of these novel trifluoromethylated Schiff bases are evaluated.

The synthesis, antimicrobial activity evaluations, biomolecule-binding properties (DNA), and absorption The synthesis, antimicrobial activity evaluations, biomolecule-binding properties (DNA), and absorption and emission properties of a new series of (Z)-1,1,1-trichloro-4-alkyl(aryl)amino-4-arylbut-3-en-2-ones (4,5) and 2,2-difluoro-3-alkyl(aryl)amino-4-aryl-6-(trichloromethyl)-2H-1,3,2-oxazaborinin-3-ium-2-uides (6,7) in which 3(4)-alkyl(aryl) = H, Me, iso-propyl, n-butyl, C6H5, 4-CH3C6H4, 4-CH3OC6H4, 4-NO2C6H4, 4-FC6H4, 4-BrC6H4, 2-naphthyl, is reported. A series of β-enaminoketones (4,5) is synthesized from the O,N-exchange reaction of some amines (3) with (Z)-1,1,1-trichloro-4-methoxy-4-aryl-but-3-en-2-ones (1,2) at 61–90% yields. Subsequently, reactions of the resulting β-enaminoketones with an appropriate source of boron (BF3.OEt2) gave the corresponding oxazaborinine derivatives (6,7) at 50-91% yields. UV-Vis and emission properties of biomolecule-binding properties for the DNA of these new BF2-β-enamino containing CCl3 units were also evaluated. Some compounds from the present series also exhibited potent antimicrobial effects on various pathogenic microorganisms at concentrations below those that showed cytotoxic effects. Compounds 4d, 4e, 6e, and 6f showed the best results and are very significant against P. zopfii, which causes diseases in humans and animals.

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 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 work reports a successful synthesis of two new series of 2-(aryl/heteroaryl)-6-(morpholin-4-yl/pyrrolidin-1-yl)-(4-trifluoromethyl)quinolines via the Buchwald–Hartwig amination, at 60–88% yields, starting from 2-(aryl/heteroaryl)-6-bromo-4-trifluoromethyl-quinolines and heteroarylamines (morpholine and pyrrolidine). The 6-bromoquinoline precursors were obtained from an easy intramolecular cyclization reaction of (Z)-4-((4-bromophenyl)amino)-1,1,1-trifluoro-but-3-en-2-ones, which were previously prepared through the reaction of 4-methoxy-(aryl/heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones with 4-bromoaniline. Photophysical analyses indicated intraligand and charge-transfer type transitions, in agreement with the aromatic structures of the heterocycle moieties. In the case of ct-DNA titrations (via the absorption and emission method), morpholinyl- and pyrrolydinyl-substituted quinolines had strong interactions with ct-DNA, which could be attributed to π-stacking and/or hydrogen-bonding interactions.

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.

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).

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.

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.

The nickel-catalyzed cyclization of in situ generated ortho-chlorobenzophenone hydrazone derivatives, to afford 3-(hetero)aryl-1H-indazoles, is documented for the first time. The product 1H-indazoles can be transformed subsequently in a one-pot procedure into 1,3-di(hetero)aryl-1H-indazoles via copper-catalyzed N-arylation with (hetero)aryl bromides.

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%.

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 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.

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.

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.

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.

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.

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 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.

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.

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 paper describes firstly the synthesis of a new series of 3-hydroxy-2-[(3(5)-(methyl/phenyl)-5(3)-(trifluoromethyl)-1 H -pyrazol-4-yl)arylmethyl]-cyclohex-2-en-1-ones (2), where aryl = C 6 H 5 , 4-NO 2 C 6 H 4 , 4-OCH 3 C 6 H 4 , from an ANRORC ring transformation reaction of 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2 H -chromen-5(6 H )-ones (1), where acyl = acetyl and benzoyl, in the presence of hydrazine hydrate, at 63–90% yields. In subsequent steps, an oxidative aromatization reaction from 2 was done in an iodine/methanol medium for the preparation of 3(5)-trifluoromethyl-5(3)-methyl-4-[(2,6-dimethoxyphenyl)-(4-methoxyphenylmethyl)]-1 H -pyrazole (3) at 72% yields. Also, the alkylation reaction using benzyl chloride easily converted a pyrazole like 2 to its N -benzyl derivative (4), at 69% yield. Finally, the structural assignment of compounds 2–4 was deduced by mass spectrometry, X-ray crystal diffraction and density functional theory (DFT) calculations, which clearly and unambiguously furnished values very close to those determined from 1 H, 13 C and 19 F NMR data.

1-(Pentafluorophenyl)-4,5-dihydro-1H-pyrazoles were synthesized from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (CX3C(O)CH=C(R1)OR, where X = F, Cl; R = Me, Et; R1 = H, Me, Et, n-Pr, i-Pr, n-Bu, i-Pent, Ph, 4-Cl-C6H4, 4-Br-C6H4, 4-F-C6H4) with pentafluorophenyl hydrazine. Pyrazoles were obtained under microwave irradiation in solvent-free conditions or under conventional heating in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [BMIM][BF4]. These procedures furnished products in moderate to good yields in a short reaction time. Atom economy, reaction mass efficiency (RME), and environmental factor (E-factor) were determined for the cyclocondensation reaction performed under microwave (MW)/solvent-free and under conventional thermal heating/[BMIM][BF4] conditions. RME and E-factor indicated that the solvent-free procedure is invariably less green than [BMIM][BF4] when the isolated product was considered.

This paper describes a mild method for regioselective reduction of 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2 H -chromen-5(6 H )-ones, where acyl = Ac, Bz, 2-thenoyl; and aryl = Ph, 4-NO 2 C 6 H 4 , 4-OCH 3 C 6 H 4; employing sodium borohydride as the reducing reagent for successful preparation of a series of nine new 3-acyl-4-aryl-2-(trifluoromethyl)-8a-hydroxy-octahydrochromen-5-ones. Yields in the range of 25–63% were obtained when the reduction reactions were performed at room temperature using ethanol as the solvent. When 3-acetyl-2-hydroxy-5-methoxy-4-phenyl-2-(trifluoromethyl)chromane was also tested under similar conditions, the 3-(1-hydroxyethyl)-3,4-dihydro-2 H -chromane derivative was obtained at 83% yield. A representative X-ray diffraction ORTEP for an example of 2-(trifluoromethyl)-octahydrochromen-5-one is shown and the reduction mechanisms discussed.

An efficient one-pot transition metal-free procedure for the synthesis of new pyrazolo[1,5-a]quinoxalin-4(5H)-ones from easily prepared 1-(2-chlorophenyl-5-ethylcarboxylate)pyrazoles and various primary alkylamines is described. The key steps involved in the synthesis of the new 5,6-fused ring system are the formation of an amide intermediate followed by an intramolecular N-arylation reaction via nucleophilic aromatic substitution.

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 1H and 13C NMR as well as 2D HMBC spectral analysis.

The title pyrimidinones are highly regioselectively obtained by cyclocondensation of trichloro-alkenones with non-symmetric substituted isothiourea sulfates under mild basic conditions.

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.

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.

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%.

A study is presented for the synthesis of a series of 1-tert-butyl-3(5)-(trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Et and R1 = H or R = Me and R1 = Me, Ph, 4-Me-C6H4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)-trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H-pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, followed by cyclization in [BMIM][BF4] and pyridine.

This paper describes the one-pot simple and efficient oxidative aromatization reaction employing an iodine/alcohol medium for the preparation of a series of 11 new 3-acyl-2-hydroxy-5-alkoxy-4-aryl-2-(trifluoromethyl)chromanes, where acyl = Ac, Bz, furan-2-oyl; aryl = Ph, 4-NO 2 C 6 H 4 , 4-OCH 3 C 6 H 4 and alkoxy = OMe, O-Pr n , EtO and OBn from the respective 3-acyl-4-aryl-2-(trifluoromethyl)-2-hydroxy-3,4,7,8-tetrahydro-2 H -chromen-5(6 H )-ones. Yields in the range of 50–89% were obtained when the oxidative reactions were performed using both conventional thermal heating (CTH) and microwave (MW) procedures. In general, the MW method produced similar yields with shorter reaction times and easier reaction workups. As an example, a representative X-ray diffraction ORTEP for 3-benzoyl-2-hydroxy-5-methoxy-4-methoxyphenyl-2-(trifluoromethyl)chromane is also shown.