Search

The present work reports the biological assays between synthetic BF2-naphtyridine complexes and four proteins: human serum albumin (HSA), calf-thymus DNA (CT-DNA), tyrosinase and acetylcholinesterase enzymes via spectroscopic analysis at physiological conditions, combined with molecular docking simulations. The BF2-complexes presented spontaneous and moderate binding ability to HSA through the ground-state association (static fluorescence quenching mechanism). The main binding site is Sudlow's site I (subdomain IIA) and the binding does not perturb significantly both secondary and surface structure of HSA. Despite BF2-complexes showed good binding ability with HSA, these compounds presented weak intercalative ability with CT-DNA (the most conventional and simple model to preliminary studies), except in the case of 1 h, which suggested that the presence of electronic donor groups in both aromatic ring moieties of BF2-complex structure can increase the intercalative ability for DNA strands. Competitive binding displacement assays in the presence of methyl green and molecular docking calculations indicated that the studied compounds interact preferentially in the major groove of DNA. In addition, the assayed compounds presented the ability to activate or inhibit both tyrosinase (the decontrolled activity can induce melanoma carcinoma) or AChE (involved in reactions related to the function of neurotransmitters) enzymes.

The crystallization mechanisms of a series of fourteen 7-chloro-4-substituted-quinolines (substituents: (1) OCH3, (2) OCH2CH3, (3) OCH2CHCH2, (4) O(CH2)2OH, (5) O(CH2)3OH, (6) NH(CH2)2CH3, (7) NH(CH2)3CH3, (8) NH(CH2)2OH, (9) NHCH(CH2CH3)CH2OH, (10) NH(CH2)2Cl, (11) NHNCH(C6H5), (12) NHNCH(2-FC6H4), (13) NHNCH(3-FC6H4), and (14) NHNCH(4-FC6H4)) were proposed based on a retrocrystallization approach using the supramolecular cluster as demarcation. Crystallization mechanism stage parameters – NCG% and NG/NC – were determined. The 4-substituents present in quinolines caused six different mechanisms, starting from the monomers in solution to dimers, 1D nuclei, and 2D nuclei (6, 11, 12); 2D nucleus formation (5); 1D nuclei to 2D nuclei (7, 9); concomitant dimers and 1D nuclei to a 3D crystal (8); 1D nuclei directly to a 3D crystal lattice (1–4, 10, 14), and dimers to 2D nuclei and then to a 3D crystal (13). Analysis of GAI showed atom⋯atom intermolecular interactions in the proposed first nuclei for compounds 4 and 5. The nucleation process inferred in the solid state was partially confirmed during the formation of the proto-crystal in solution due to the changes of the hydrogen chemical shift in variable-concentration 1H-NMR experiments. Results revealed that the size of the alkyl chain and the presence of different functional groups in the 4-substituents influenced the crystallization process.

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.

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.

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.

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.

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.

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.

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%).

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%.

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.

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 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 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.

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%.

In this work, 3-haloacetyl-4-methylquinolines were synthesized from the reaction of 4-alkoxy-3-alken-2-ones [R¹C(O)CH=C(R²)OCH3, where R¹ = CF3, CCl3, CHCl2, CF2Cl, CF2CF3 and R² = Me, Et, Pr, Bu, i-Bu and i-Pe] and 2-aminoacetophenone. The reaction was performed in ionic liquid and 4-toluene sulfonic acid under microwave irradiation. Results showed that the catalytic method was effective. Products were formed in a short time (10-20 min) and presented good yields (70-91%). Neste trabalho, 3-haloacetil-4-metilquinolinas foram sintetizadas a partir da reação de 4-alcóxi-3-alquen-2-onas [R¹C(O)CH=C(R²)OCH3, onde R¹ = CF3, CCl3, CHCl2, CF2Cl e CF2CF3 e R² = Me, Et, Pr, Bu, i-Bu e i-Pe] e 2-aminoacetofenona. A reação foi realizada em líquido iônico e ácido 4-toluenosolfônico sob irradiação de micro-ondas. Os resultados mostraram que o método catalítico foi efetivo e os produtos foram formados em tempos de reação curtos (10-20 min) e com bons rendimentos (70-91%).

A new series of twenty-one trifluoromethyl-containing ( E )- N ′-arylidene-1 H -pyrazole-1-carbohydrazides ( 4 ) was synthesized by the cyclocondensation reactions of six 3-alkyl(aryl/heteroaryl)-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1 H -pyrazole-1-carbohydrazides ( 2 ) with eleven aryl/heteroaryl aldehydes and acetophenone ( 3 ) in 52–97% yields and six new carbohydrazides 2 were easily obtained from the reaction of 1,1,1-trifluoro-4-alkyl(aryl/heteroaryl)-4-methoxy-3-alken-2-ones ( 1 ) with carbohydrazide. Subsequently, four examples of carbohydrazides 4 were fully studied by X-ray diffraction and the twenty-seven pyrazolyl-carbohydrazides 2 and 4 screened for their antioxidant and antimicrobial proprieties and evaluated by DPPH and MIC methods, respectively. Both series 2 and 4 showed ability to capture DPPH free radical for IC 50 from 47.57 to 487 μg/mL. Most of the compounds presented fungistatic and bacteriostatic activity only for high MIC levels ranging from 0.25 mg/mL to 0.5 mg/mL.

This work describes the regioselective synthesis of two new series of 1,1′-oxalylbis[3-(alkyl/aryl/heteroaryl)-4,5-dihydro-5-hydroxy-5-(trihalomethyl)-1H-pyrazoles], where the 3-substituents are H, Me, C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-NO2C6H4, 4,4′-BiPh, and 2-furyl, in a one-pot methodology with ethanol as solvent, from the reaction of 4-alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-trihaloalk-3-en-2-ones with oxalyldihydrazide (51–89%). Complementarily, the dehydration reactions of five examples of the described oxalylbispyrazolines are also reported, which furnished the respective 1,1′-oxalylbis[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles] in 53–78% yields without the two C(O)–N bond cleavages. .

A simple one-pot procedure to obtain a series of five- and six-membered heterocycles, in three different ionic liquids ([BMIM][BF4], [BMIM][OH] and [HMIM][HSO4]) is described. The synthetic protocol involves the reaction between β-enamino ketone derived from 1,4-diacetylbenzene and hydroxylamine, hydrazines (R1NHNH2, where R1 = H, Ph, 4-O2N-Ph, 2,4-(O2N)2-Ph, C6F5, CO2Me, CONH2, CH2CH2OH, t-Bu) or amidines (R2C(NH)NH2, where R2 = NH2, Ph), furnishing bis-isoxazoles, bis-pyrazoles and bis-pyrimidines in good yields and short reaction times.

The efficacy of ionic liquids was evaluated in the N-alkylation reaction of 3,5-dimethyl- and 5-trifluoromethyl-3-methyl-1H-pyrazoles, from the reaction of N–H pyrazoles with alkyl halides (R1–X, where R1 = Bu, octyl, allyl, benzyl, –CH2CH2CONEt2, –CH2C(O)Ph, CH2CH2C(O)Ph and X = Cl, Br, I). Novel trifluoromethylated pyrazoles are among the compounds obtained. The reaction was chemoselective for trifluoromethylpyrazoles and 1-alkyl-3-trifluoromethyl-5-methyl-1H-pyrazoles were preferentially formed. The reaction time and yields were investigated and this method showed shorter reaction times and better yields in comparison with the reaction performed in molecular solvents.

This paper reports a comparative study of the chemoselectivity and yields of the synthesis of N-alkyl-4-(trihalomethyl)-1H-pyrimidin-2-ones carried out by the cyclocondensation of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (enones) with methyl- and allylureas with the N-alkylation of 4-(trihalomethyl)-1H-pyrimidin-2-ones with methyl iodide and allyl bromide. To determine the chemoselectivity of the products obtained, all compounds were fully analyzed by 1H and 13C NMR and 2D HMBC spectroscopy. This study has demonstrated that the cyclocondensation reactions give better yields and furnish either N1- or N3-alkylated products depending on both the reaction conditions and the substituents on the enones, whereas the alkylation of pyrimidin-2-ones gives lower overall yields and either an N1-alkylated product or a mixture of N1- and O-alkylated products.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The one-pot synthesis of a novel series of amino-protected 6-alkyl-, 6-aryl-, 6-heteroaryl- and 5,6-fused-cycloalkane 4-trifluoromethyl-2-acetylaminopyrimidines, where alkyl = Me; aryl = Ph, 4-CH3Ph, 4-FPh, 4-ClPh, 4-BrPh, 4-OCH3Ph, 4-NO2Ph, 4,4′-biphenyl, 1-naphthyl; heteroaryl = 2-thienyl, 2-furyl and cycloalkyl = c-C6H4, c-C7H5 from the reaction of substituted 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 1-acetylguanidine in acetonitrile or propan-2-ol as solvent, is reported. The acetylamino group of 2-acetylaminopyrimidines was hydrolyzed under three different conditions to afford the corresponding free 2-aminopyrimidines.

The heating profile for 25 solvents was determined in ultrasonic probe equipment at amplitudes of 20%, 25%, and 30%. Each solvent was heated in accordance with its boiling point. The effect of vapor pressure, surface tension, and viscosity of the solvents in dissipated ultrasonic power (U p ) was evaluated. Multiple regression analysis of these solvent properties and dissipated U p reveals that solvent viscosity is the property that most strongly affected dissipated U p . Experimentation involving acetonitrile doped with [BMIM][BF 4 ] indicated faster heating than MeCN. Aprotic polar solvents such as DMSO, DMF, and MeCN were tested in the N -alkylation of pyrazoles under ultrasonic conditions. After 5 min at 90 °C, the reactants had been totally converted into product in these solvents. Solvents, with low dissipated U p (e.g., toluene) were tested. Conversions were lower compared to those of aprotic polar solvents. When the reactions were done in hexane, no conversion to product was observed. To check the effect of doping in solvents with low U p , [BMIM][BF 4 ], DMSO, and DMF were selected. The conversions for toluene doped with [BMIM][BF 4 ], DMSO, and DMF were 100%, 59%, and 25%, respectively. These conversions were greater than when done in just toluene (46%). Thus, [BMIM][BF 4 ] was the best polar doping solvent, followed by DMSO. DMF was not considered to be a satisfactory doping solvent. No conversion was observed for reactions in the absence of base performed in DMSO, DMF, and MeCN doped with [BMIM][BF 4 ].

The simple preparation of the title compounds succeeds in moderate to good yields via cyclocondensation of 4-substituted ethyl 4-alkoxy-2-oxobut-3-eneoates with 2-methyl or 2-benzylisothiourea.

This work presents a three-step synthesis of a new series of 4-substituted 2-oxo-6-trihalomethyl-[1,3]oxazinane-3-carboxylic acid ethyl esters, from β-alkoxyvinyl trihalomethyl ketones of general formula X 3 C–C(O)–CH C(R)–OR 1 , where R = H, Me, Ph, and 4-Me-Ph; R 1 = Me and Et; and X = F and Cl. The Michael addition–substitution of the ethyl carbamate on β-alkoxyvinyl trihalomethyl ketones furnished the corresponding (4,4,4-trihalo-3-oxo-but-1-enyl)-carbamic acid ethyl esters. These compounds underwent reduction with NaBH 4 leading to the respective (4,4,4-trihalo-3-hydroxy-butyl)-carbamic acid ethyl esters. The 3-hydroxy-butyl carbamates were submitted to cyclization reaction with triphosgene to give a series of 4-substituted 2-oxo-6-trihalomethyl-[1,3]oxazinane-3-carboxylic acid ethyl esters. The in vitro antimicrobial activity, of some of the three new series of the title compounds, was assessed against a panel of microorganisms including yeast like fungi, bacteria, and algae, and their minimal inhibitory concentration and minimal fungicidal, bactericidal, and algacidal concentrations were determined. Some of the analyzed carbamates exhibited significant in vitro antimicrobial activity.

A convenient method for the preparation of 5-hydroxy-5-trihalo-4,5-dihydroisoxazoles and beta-enamino trihalomethyl ketones, from the reaction of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones with hydroxylamine and anilines, respectively, using water as solvent and under ultrasound irradiation is reported.

A new, efficient and easy route for the preparation of a series of 2-alkyl(aryl) substituted 4-oxo-4H-pyrido-[1,2-a]pyrimidines, where alkyl = CH3; aryl = C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4-NO2C6H4 in 45–80 % yield from the reaction of β-alkoxyvinyl trichloromethyl ketones with 2-aminopyridine under mild conditions, is then reported.

A convenient method for the synthesis of eight alkyl 6-[4,5-dihydroisoxazol-3-yl(-pyrazol-3(5)-yl)]hexanoates from the cyclocondensation of methyl 10,10,10-trifluoro[chloro]-9-oxo-7-methoxydec-7-enoates and hydroxylamine hydrochloride or hydrazine hydrochloride, respectively, in ethanol as solvent is reported. The reaction of methyl 10,10,10-trichloro-9-oxo-7-methoxydec-7-enoates with hydrazines furnished the pyrazole derivatives with the simultaneous transformation of trichloromethyl to carboxyl group.

In this study, a new series of trihalomethyl-substituted pyrimidines and dihydropyrimidines were synthesized and tested as potential NTPDase inhibitors. For this purpose, synaptosomes from rat cerebral cortex were used as the enzyme source and ATP and ADP were used as the substrate. Among the new compounds, 4-methyl-2-methylsulfanyl-6-trichloromethylpyrimidine (2b) was found to be the most effective noncompetitive inhibitor, with an estimated K(i) value of 0.18 and 0.55 mM for ATP and ADP, respectively. Other pyrimidines inhibited NTPDase activity with the following rank order of inhibitory potency: 3,6-dimethyl-2-methylsulfanyl-4-trifluoromethyl-3,4-dihydro-pyrimidin-4-ol (3a) > 5-methyl-2-(4-methyl-6-trifluoromethyl-pyrimidin-2-yl)-3-trifluoromethyl-3,4-dihydro-2H-3-pyrazol-3-ol (6a) > 5-bromo-4,6-dimethoxy-4-trichloromethyl-1,2,3,4-tetrahydro-2-pyrimidin-2-one (9) for ATP and 6a > 9 > 3a for ADP. Our results demonstrate that a novel group of pyrimidines compounds can act as inhibitors of ATP and ADP hydrolysis in synaptosomes from rat cerebral cortex. These results can contribute for the understanding of the NTPDase activity and for further studies involving new compounds that can enlist as it inhibitors.

The synthesis of a novel series of eleven 6-aryl(5-methyl)-4-trifluoromethyl-2(1H)-pyrimidinones, where aryl ¼ Ph, 4-CH3Ph, 4-FPh, 4ClPh, 4-BrPh, 4-OCH3Ph and alkyl ¼ H, CH3, from the reaction of 4-aryl-4-methoxy-1,1,1-trifluoro-3-buten-2-ones with urea in the presence of hydrochloric acid, is reported. Trifluoroacetylation of acetophenone- and propiophenone-dimethylacetals derived from phenones, was employed to obtain the precursors. # 2002 Elsevier Science B.V. All rights reserved.

Using trichloromethyl substituent as convenient leaving group for the synthesis of interesting bi-heterocyclic compounds, a series of 6-methyl- and 7-alkyl(aryl)-5 H -thiazolo[3,2- a ]pyrimidin-5-ones, where alkyl=methyl, n -propyl, isopropyl, isobutyl, n -hexyl, isopentyl and aryl=phenyl, 4-toluyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl was obtained from a simple and regiospecific reaction of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones with 2-aminothiazole in good yield (45–89%).

The synthesis of a novel series of twelve 4-(trihalomethyl)dipyrimidin-2-ylamines, from the cyclo-condensation reaction of 4-(trichloromethyl)-2-guanidinopyrimidine, with β-alkoxyvinyl trihalomethyl ketones, of general formula: X3C-C(O)-C(R2)=C(R1)-OR, where: X = F, Cl; R = Me, Et, -(CH2)2-, -(CH2)3-; R1 = H, Me; R2 = H, Me, -(CH2)2-, -(CH2)3-, is reported. The reactions were carried out in acetonitrile under reflux for 16 hours, leading to the dipyrimidin-2-ylamines in 65-90% yield. Depending on the substituents of the vinyl ketone, tetrahydropyrimidines or aromatic pyrimidine rings were obtained from the cyclization reaction. When X = Cl, elimination of the trichloromethyl group was observed during the cyclization step. The structure of 4-(trihalomethyl)dipyrimidin-2-ylamines was studied in detail by 1H-, 13C- and 2D-nmr spectroscopy.

A series of 13 5-hydroxy-5-trichloromethyl-4,5-dihydroisoxazoles have been synthesized in 78–96% yield by environmentally benign microwave induced techniques involving the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alken-2-ones [CCl 3 C(O)C(R 2 )=C(R 1 )OR, where R 2 =H, alkyl; R 1 =H, alkyl, aryl and R=H, alkyl] with hydroxylamine using toluene as solvent. The advantages obtained by the use of microwave irradiation in relation to a classical method were demonstrated.

A convenient selective protection of the u-amino carboxyl group of amino acids bearing reactive side chain groups such as arginine, asparagine, glutamine, cysteine, histidine, serine and lysine, using 4-alkoxy-1,1,1-trifluoro[chloro]alk-3-en-2-ones is reported. The reactions were performed without esterification of the carboxyl group and N-deprotection was carried out using a six molar solution of hydrochloric acid.

The synthesis of a novel series of N-[1-alkyl(aryl)-3-oxo-4,4,4-trichloro(trifluoro)-1-buten-1-yl]-o-aminophenols and the analogous o-phenylenediamine derivatives [X3CC(O)CH=CR(o-NHC6H4Y), where X = F, Cl; R = H, Me, Et, aryl; and Y = NH2, OH] is reported.

A quantitative relationship between the 17O substituent chemical shifts (SCS) of γ-alkyl substituents and the torsion angles calculated by the AM1 method is reported. A series of 3-alkyl substituted 5-trichloromethyl-5-hydroxy-4,5-dihydroisoxazoles and 5-trichloromethyl isoxazoles [where 3-alkyl substituents are Me, Et, n-Pr, iso-Bu, BrCH2, iso-Pr, Br2CH and tert-Bu] as model compounds were used. †For Parts 1–6, see References 14-15a, 15b-16, [19a], [19b].

In this study, the versatile diethylaminosulfur trifluoride (DAST), a well-known fluorinating agent, was applied in the dehydration, intramolecular cyclization, and mono- and difluorination reactions of some 5-trifluoromethyl-1H-pyrazoles and 2-pyrazolines employing a general, mild, and efficient methodology. The azole precursors were synthesized from the reactions of acyclic and cyclic trifluoroacetylated enol ethers with hydrazines [NH2NHR, where R = C6H5, C6F5, 2-Furanoyl] and showed a differentiated chemical behavior in the presence of DAST.

This study examines the effect of new 1,5 benzodiazepines on acetylcholinesterase (AChE) and ATPDase (apyrase) activities from cerebral cortex of adult rats. Simultaneously, the effects of the classical 1,4-benzodiazepine on these enzymes were also studied for comparative purpose. The compounds 2-trichloromethyl-4-phenyl-3H-1,5-benzodiazepin and 2-trichloromethyl-4-(p-methyl-phenyl)-3H-1,5-benzodiazepin significantly inhibited acetylcholinesterase activity (p < 0.01) when tested in the range of 0.18–0.35 mM. The inhibition caused by these two new benzodiazepines was noncompetitive in nature. Similarly, at concentrations ranging from 0.063 to 0.25 mM, the 1,5 benzodiazepines inhibited ATP and ADP hydrolysis by synaptosomes from cerebral cortex (p < 0.01). However, the inhibition of nucleotide hydrolysis was uncompetitive in nature. Our results suggest that, although diazepam and the new benzodiazepines have chemical differences, they both presented an inhibitory effect on acetylcholinesterase and ATPDase activities.

This study describes, firstly, the synthesis of a new precursor, 4,6,6-trimethoxy-1,1,1-trifluorohex-3-en-2-one ( 1 ), from the trifluoroacetylation reaction of 1,1,3,3-tetramethoxybutane, in 65% yields. Afterwards, the reaction of 1 with two hydrazines (NH 2 NHR, where R = 2-furanoyl, C 6 F 5 ) led to a new series of 4,5-dihydro-1 H -pyrazoles, containing an acetal-protected aldehyde function as substituent, in 90–97% yields. In a subsequent step, the dehydration reactions of these 4,5-dihydro-1 H -pyrazoles gave the respective aromatic 1 H -pyrazoles. Finally, we report the results of the deprotection reactions of the acetals to obtain the respective aldehyde function, as well as, the subsequent fluorination reaction using DAST, leading to new difluorinated derivatives in 55–60% yields.

The 17O chemical shifts of simple aliphatic ethers were studied, and the additivity substituent increments for carbon atoms in the alkyl groups were determined. The additivity parameters were used to establish a linear correlation with experimental data for a series of aliphatic ethers, alcohols, vinyl ethers, trichloroacetyl vinyl ethers, alkyl phenyl ethers, alkyl formates, alkyl acetates and alkyl trichloroacetates. The use of correlation to estimate the 17O chemical shifts allows the calculation of data with an accuracy better than ±2.5 ppm. Copyright © 1999 John Wiley & Sons, Ltd.

A convenient method to obtain β-alkyl-β-methoxyvinyl trifluoromethyl ketones [CF 3 COCHC(OMe)R, where R = Et, n -Pr, i -Pr, i -Bu, t-Bu, –(CH 2 ) 2 OMe] from the regiospecific acylation of kinetic enol ether generated in situ is reported. The unsymmetrical ketone dimethyl acetals react with trifluoroacetic anhydride in the presence of pyridine using dry chloroform as solvent with a temperature range of 25–60°C. These acetals [R–C(OMe) 2 Me] are obtained from the reaction of alkyl methyl ketones with trimethyl orthoformate in the presence of p -toluenesulfonic acid as catalyst in pure methanol as solvent. The new acetylated enol ethers proved to be versatile building blocks for the construction of interesting alkyl trifluoromethyl substituted heterocycles. Thus, examples of isoxazoline, pyrazoline, pyrazole and pyrimidinone have been obtained in good yields (62–79%).

The regiospecific synthesis and structural elucidation by NMR spectroscopy, AM1 semiempirical MO calculations and X-ray diffraction of a novel series of twelve 3-aryl[alkyl]-5-hydroxy-5-trichloromethyl-4, 5-dihydro-1H-pyrazole-1-carboxyamides and analogous 1-thiocarboxy-amides, is reported.

A one-pot synthesis of 1-methyl- and 1-phenylpyrazole-3(5)-ethyl esters 2,3a-e by the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones 1a-e with methyl and phenyl hydrazine hydrochloride under mild conditions, is reported. A study using compounds 1a-e with different substituents proved that these are versatile building blocks for the synthesis of pyrazole derivatives, having a 3(5)-ethoxycarbonyl substituent in good yields (60–89%). The hydrazine and β-alkoxyvinyl trichloromethyl ketone substituent effects on the reaction regiochemistry on the formation of the 1,3- and 1,5-isomer were observed.