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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.

A new one-pot strategy for the synthesis of a series of new N-substituted 3-trifluoroacetyl pyrroles is presented. These compounds were obtained by the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with primary amines, which generated 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-alkylaminobut-3-en-2-one intermediates. In most cases these intermediates were not stable enough to be isolated. Thus, in the same reaction vessel they were directly submitted to oxidation with PCC (Corey's reagent) to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-alkylaminobut-3-en-2-ones, which under reflux underwent intramolecular cyclization to give the desired N-substituted 3-trifluoroacetyl pyrroles, in moderate yields. All of these pyrroles were tested against pan-susceptible Mycobacterium tuberculosis H37Rv and clinical isolates INH- and RMP-resistant strain and some of these compounds showed significant in vitro antimicrobial activity.

The synthesis of a series of fourteen 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (2,3) [CX3COC(R2)=C(R1)OMe, where X = Cl, F; R1/R2 = Me/H, Bu/H, i-Bu/H, Ph/H, Thien-2-yl/H, –(CH2)4–, –CH(CH2)4CH(CH2)2–] from the acylation reactions of acetals (1) with trichloroacetyl chloride or trifluoroacetic anhydride in the presence of equimolar amounts of pyridine and imidazolium based ionic liquid ([BMIM][BF4] or [BMIM][PF6]) is reported. The reaction time, yields and IL recyclation are also investigated and this method showed advantages over the methods described in the literature.

The one-pot and regioselective synthesis of a novel series of 3-aryl(heteroaryl)-5trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazolyl-1-carbohydrazides and bis-(3-aryl-5trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)methanones from the cyclocondensation reactions of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones, where aryl substituents are H, Me, Ph, 4-OMePh, 4-ClPh, 4-BrPh, 4,4’-biphenyl and heteroaryl are 2-thienyl and 2furyl, with carbohydrazide is reported.

The antioxidant capacity of a series of six novel synthetic pyrazoline derivatives (i) 5-hydroxy-3-methyl-5- trifluoromethyl-4,5-dihydro-1 H -carbaldehyde-pyrazole, (ii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-acetyl-pyrazole, (iii) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -carboxyamide-pyrazole, (iv) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5- dihydro-1 H -1-benzoyl-pyrazole, (v) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(2-hydroxybenzoyl)-pyrazole and (vi) 5-hydroxy-3-methyl-5-trifluoromethyl-4,5-dihydro-1 H -1-(4-methoxybenzoyl)-pyrazole was evaluated as the capacity of compounds to transfer a hydrogen atom (protection against brain lipid peroxidation and glutathione oxidation) and their capacity to transfer a single electron (ferric-reducing antioxidant power (FRAP) and 1,1-diphenyl-2-picrylhydrazyl radical scavenging (DPPH) assays). Compound 5 had the highest free radical scavenging capacity in the DPPH assay, while compound 2 had the highest FRAP value (P < 0.05). Only compounds 1, 4 and 5 protected against lipid peroxidation in rat brain homogenate. However, compound 5 was the most effective to prevent basal and iron-, sodium nitroprusside- and H 2 O 2 -stimulated lipid peroxidation (IC 50 < 15 μ M) and the only one effective to block glutathione oxidation-mediated by H 2 O 2 (at 150 μ M). Our results indicate that compound 5 has the greatest potential to prevent oxidative damage in brain homogenates.

Pain is the most common complaint in the medical field and the identification of compounds that can effectively treat painful states without induction of side-effects remains a major challenge in biomedical research. The aim of the present study was to investigate the antinociceptive effect of a novel compound, 3-(4-fluorophenyl)-5-trifluoromethyl-1H-1-tosylpyrazole (compound A) in several models of pain in mice and compare with those produced by the known trifluoromethyl-containing pyrazole compound celecoxib. Compound A or celecoxib were administrated by oral (78–780 µmol/kg), intrathecal (9–22.5 nmol/site) or intracerebroventricular (9–22.5 nmol/site) routes. Oral administration of either compound A or celecoxib abolished the mechanical allodynia, but not the oedema caused by intraplantar injection of carrageenan. Similarly, compound A reduced the overt nociception, but not the oedema, produced by bradykinin or capsaicin. However, compound A (500 µmol/kg, orally) did not alter nociception nor oedema caused by intraplantar injection of prostaglandin E2 or glutamate, whereas celecoxib reduced only the nociception induced by the former. Moreover, oral and intrathecal administration of compound A or celecoxib also reduced the nociception induced by acetic acid. However, only celecoxib reduced the acetic acid-induced nociception when it was injected by the intracerebroventricular route. Finally, neither compound A nor celecoxib was able to produce antinociceptive effect in the tail-flick test or to alter the motor performance and the body temperature. Besides, compound A or celecoxib did not induce gastric lesion. Thus, compound A seems to be an interesting prototype for the development of novel analgesic drugs.

The N1-alkylation of 4-(trichloromethyl)pyrimidin-2(1H)-one, 4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin- 2(1H)-one, and 5-bromo-4-methoxy-4-(trichloromethyl)-3,4-dihydropyrimidin-2(1H)-one with selected alkylating agents such as 2-chloroacetamide, diethyl 2-bromomalonate, and 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2-one, is presented. Further reactions of 1-[5,5,5-trichloro-2-methoxy-4-oxo-penten-2-yl]4-trichloromethyl-pyrimidin-2(1H)-one with primary amines and aminoalcohols furnished a series of unexpected new acyclic nucleoside analogues.

The crystal structures of four novel analgesic agents, methyl 5-hydroxy-3- or 4-methyl-5-trichloro[trifluoro]methyl-4,5-dihydro-1 H -pyrazole-1-carboxylate, have been determined by X-ray diffractometry. The data demonstrated that the molecular packing was stabilized mainly by O H⋯O hydrogen bonds of the 5-hydroxy and 1-carboxymethyl groups. The 4,5-dihydro-1 H -pyrazole rings were obtained as almost planar structures showing RMS deviation at a range of 0.0052–0.0805 A. Additionally, computational investigation using semi-empirical AM1 and PM3 methods were performed to find a correlation between experimental and calculated geometrical parameters. The data obtained suggest that the structural data furnished by the AM1 method is in better agreement with those experimentally determined for the above compounds.

A series of sixteen 2-substituted-2-imidazolines (where the substituent R=Ph, Me-4-Ph; MeO-4-Ph; (MeO)(2)-3,4-Ph; (MeO)(3)-3,4,5-Ph; Ph-4-O-C(O)-Ph; Cl-4-Ph; Cl-2-Ph; Cl(2)-2,4-Ph; NO(2)-4-Ph; NO(2)-3-Ph; Naphth-2-yl; Fur-2-yl; Benzofur-2-yl; Pyridin-2-yl; Quinolin-2-yl) has been synthesized from the reaction of the substituted-aldehydes and ethylenediamine by ultrasound irradiation with NBS in an aqueous medium in high yields (80-99%). The 2-imidazoline ability to inhibit the activity of the A and B isoforms of monoamine oxidase (MAO) was investigated and some of them showed potent and selective MAO inhibitory activity especially for the MAO-B isoform and could become promising candidates for future development.

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 synthesis of a series of trifluoromethyl-cycloalka[b]quinolines (5a, 6a, 6c-e) in 15-30% yields, by intramolecular cyclization reactions of the readily available intermediates 2trifluoroacetyl-1-(arylamino)-cycloalkenes (3a-f and 4a-f) using poly-phosphoric acid (PPA) is reported. Compounds 3 and 4 are obtained from the reaction of 2-trifluoroacetyl-1methoxycycloalkenes 1 (n = 1 and 3) with six 4substituted anilines 2, where the 4substituents are Me, OMe, NO2, Cl, Br, I, in acetonitrile under reflux.

The reaction of unsymmetrical enamino diketones [RC(O)C(=CNMe 2 )C(O)CO 2 Et,where R = Ph, 4-MeC 6 H 4 ,4-MeOC 6 H 4 , 4-BrC 6 H 4 ,4-ClC 6 H 4 , 4-FC 6 H 4 , 4-O 2 NC 6 H 4 ,2-thienyl, benzofuran-2-yl, and CF 3 ] with N-C-Ndinucleophiles, such as benzamidine hydrochloride or 1 H-pyrazole-1-carboxamidine monohydrochloride,afforded a series of ethyl 2,5-disubstituted pyrimidine-4-carboxylatesin a chemoselective and highly chemo-selective manner (51-86%).Reaction of these two series of pyrimidines (R = Ph,4-MeOC 6 H 4 , 4-FC 6 H 4 ,and 2-thienyl) with hydrazine monohydrate under mild conditionsled to 2,5-substituted pyrimido[4,5- D]pyridazin-8(7 H)-ones in high yields (81-92%).

Three methods for the regiospecific bromination of 2-pnenyl-3H-pyrimidin-4-ones are presented: bromination or the 5-position of the pyrimidine ring, bromination of the 6-benzylic position and simultaneous bromination of both the 5-position of the pyrimidine ring and 6-benzylic position. Reactions were carried out using simple protocols and the brominated pyrimidines were obtained in good yields.

Twelve novel 3-alkyl[aryl]-1-carboxamides-5-trichloromethyl-5-hydroxy-4,5-dihydro-lH-pyrazole have been synthesized in good yields (72–90%) using environmentally benign microwave-induced techniques. The compounds were synthesized from the cyclocondensation of 4-alkoxy-1,1,1-trichloro-3-alkyl[aryl]-2-ones [Cl3CC(O)C(R2) = C(R1)OR, where R = Me, Et; R1 = H, Me, Et, Pr, i-Pr, i-Bu, t-Bu, Ph, Ph-4-NO2, Ph-4-F, Ph-4-Cl, Ph-4-Br; and R2 = H, Me] with semicarbazide hydrochloride in the presence of pyridine and using methanol/water (3:1 v/v) as the solvent. The advantages of using microwave irradiation, rather than a conventional method, were demonstrated.

The synthesis of eleven 1-cyanoacetyl-5-hydroxy-5-halomethyl-4,5-dihydro-1H-pyrazoles from the reaction of 4-alkoxy-3-alken-2-ones f(R 3C(O)C(R 2) = C(R 1)OR, where R 3 = CF3, CCl3, CHCl2, CO2 Et; R 2/R 1 = H/H, H/Me, H/Et, -(CH2)4-, Me/H, H/Pr, and R = Me, Et) with cyanoacetohydrazide is reported. The reaction was carried out in the ionic liquid ([bmim][BF4]) and molecular solvents. The results showed that when the ionic liquid was used as reaction medium, the reaction time was drastically decreased and the yield was improved.

A series of twelve 5-trihalomethyl-3-arylisoxazoles was synthesized and screened for antibacterial and antifungal activities. The compounds were synthesized from the cyclondensation of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones [CX 3C(O)C(R 2)=C(R 1)OR, where X = Cl and F; R=Me; R 2=H; R 1=H, Me, F, Cl, Br, and NO2] with hydroxylamine hydrochloride through a rapid one-pot reaction via microwave irradiation. Some of the 5-trihalomethyl-3-arylisoxazoles exhibited good in vitro anti-Cryptococcus activity.

A series of twenty halomethylated β-enaminones [RC(O)CH=C(R 1)NR 3 R 4, where R = CF3,CCl3, CHCl2; R 1 = H, Me, Ph; R 3 = H, Me, Bu, Et; R 4 = Me, Et, Bu, allyl, tert-amyl, CH2CH2OH, Bn, Ph] were synthesized using the ionic liquid [bmim]BF4 at room temperature. It is demonstrated that this ionic liquid is a reaction medium suitable for the amination of β-alkoxyvinyl halomethyl ketones. The advantages of this method are the absence of solvents, short reaction times, and good yields.

A series of 4-substituted 1 H-pyrazole-5-carboxylates was prepared from the cyclocondensation reaction of unsymmetrical enaminodiketones [RC(O)C(=CNMe 2 )C(O)CO 2 Et, where R = Ph, 4-MeOC 6 H 4 , 4-ClC 6 H 4 , 4-FC 6 H 4 , 4-O 2 NC 6 H 4 , thien-2-yl, benzofur-2-yl, CCl 3 and CF 3 ] with TERT-butylhydrazine hydrochloride or carboxymethylhydrazine. The compounds were obtained regiospecifically and in good to excellent yields (73-94%). In addition, 5-carboxyethyl-1-(1,1-dimethylethyl)-1 H-pyrazole-4-carboxylic acid was synthesized from regiospecific conversion of ethyl 4-(2,2,2-trichloroacetyl)-1-(1,1-dimethylethyl)-1 H-pyrazole-5-carboxylate. The carbonyl substitution reaction was regiospecific for the trichloroacetyl group and did not affect the ester group.

In this work, we reported the synthesis and evaluation of the analgesic and anti-inflammatory properties of novel 3- or 4-substituted 5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-1-carboxyamidepyrazoles (where 3-/4-substituent = H/H, Me/H, Et/H, Pr/H, i-Pr/H, Bu/H, t-Bu/H, Ph/H, 4-Br-Ph/H and H/Me) designed in the exploration of the bioisosteric replacement of benzene present in salicylamide with a 5-trifluoromethyl-4,5-dihydro-1H-pyrazole scaffold. Target compounds were synthesized from the cyclocondensation of 4-alkoxy-1,1,1-trifluoromethyl-3-alken-2-ones with semicarbazide hydrochloride through a rapid one-pot reaction via microwave irradiation. In addition to spectroscopic data, the structure of the compounds was supported by X-ray diffraction. Subcutaneous administration of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazoles decreased pain-related behavior during neurogenic and inflammatory phases of the formalin test in mice. Moreover, the more active analgesic compounds (3-/4- = Et/H and H/Me) significantly decreased carrageenan-induced paw edema in mice. The data obtained in this work suggest that the synthesized compounds could be promising candidates for the future development of novel analgesic and anti-inflammatory agents.

The regioselective synthesis of 3- and 5-substituted-isoxazoles from the reaction of β-dimethyl-aminovinyl ketones [R-C(O)CHCH-NMe2, where R Ph, MeO-4-C6H4, F-4-C6H4, Cl-4-C6H4, Br-4-C6H4, O2N-4-C6H4, fur-2-yl, thien-2-yl, pyrrol-2-yl, Et and CCl3] and hydroxylamine hydrochloride varying only the reaction conditions (with and without the addition of pyridine) is reported.

The synthesis of a series of 12 β-dimethylaminovinylketones [RC(O)CH CHN(Me) 2 , where X = Ph, Me-4-Ph, F-4-Ph, Cl-4-Ph, Br-4-Ph, NO 2 -4-Ph, fur-2-yl, thien-2-yl, pirrol-2-yl, pyrid-2-yl, CH(OMe) 2 and hexyl] from the condensation reaction of methyl ketones with dimethylformamide dimethylacetal in the presence of equimolar amounts of imidazolium based ionic liquids [BMIM] · BF 4 and [OMIM] · BF 4 is reported. The reaction time and the yields were investigated and this method showed advantages over the methods described in the literature.

This paper describes the synthesis and characterization of a new series of 4-substituted-3-ethoxycarbonyl-6-trifluoromethyl-(1,2,3)-oxathiazinane-S-oxides and 3-(4,6-diphenyl-pyrimidin-2-yl)-6-trifluoromethyl-(1,2,3)oxathiazinane-S-oxides from the cyclization reaction of 4,4,4-trifluoro-3-hydroxybutylcarbamates and 4-(4,6-diphenyl-pyrimidin-2-ylamino)-1,1,1-trifluoro-butan-2-ols with thionyl chloride. The analysis of the NMR data allowed us to define important features of the molecular structure. Significant chemical and structural differences were observed between the trifluoromethylated oxathiazinanes obtained in this work from other analogue compounds reported in the literature.

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 aim of the present study was to evaluate the antinociceptive potential of four novel pyrazoline methyl ester compounds on chemical and thermal models of pain in mice. The following 5-trihalomethylated-4,5-dihydro-1H-pyrazole methyl ester compounds were tested: 3-methyl-5-trifluoromethyl-(MPF3), 4-methyl-5-trifluoromethyl-(MPF4), 3-methyl-5-trichloromethyl-(MPCl3) and 4-methyl-5-trichloromethyl-(MPCl4). MPF3, MPF4, MPCl3 and MPCl4 (0.03-1.0 mmol/kg) given intraperitoneally decreased neurogenic and inflammatory phases of nociception in the formalin test. Moreover, MPF3, MPF4, MPCl3, MPCl4 (0.1-1.0 mmol/kg) and dipyrone (1.5 mmol/kg) also produced a dose-dependent antinociceptive effect in the hot-plate test. However, MPF3, MPF4, MPCl3 and MPCl4 did not impair motor coordination in the rotarod test or spontaneous locomotion in the open field test. The antinociceptive effect of MPF4 (1.0 mmol/kg, i.p.) was reversed by the opioid receptor antagonist naloxone (2 mg/kg, i.p.), but not by the alpha(2)-adrenergic receptor antagonist yohimbine (0.15 mg/kg, i.p.) or by p-chlorophenylalanine ethyl ester (PCPA, 300 mg/kg, i.p.) treatment. In contrast to morphine (5 mg/kg, i.p.), MPF4 given daily for up to 8 days did not generate a tolerance to its antinociceptive effect. However, similar to morphine (11 mg/kg, i.p.), MPF4 reduced gastrointestinal transit in mice. Taken together these results demonstrate that these novel pyrazoline methyl esters tested may be promising prototypes of additional mild analgesics.

Uma nova serie de nove 3-fosfato-(4,4,4-trifluor-butil)-carbamatos de etila (compostos fosfato-carbamato), foram obtidos atraves da reacao de (4,4,4-trifluor-3-hidroxibut-1-il)-etil carbamatos com oxicloreto de fosforo seguido de adicao de alcoois. Os produtos foram caracterizados por espectroscopia de RMN de 1H, 13C, 31P e 19F, CG-EM e analise elementar. Todos os compostos sintetizados foram testados para a inibicao da enzima acetilcolinesterase (AChE) usando o metodo de Ellman. Todos os compostos analisados contendo os grupos carbamato e fosfato em sua estrutura, mostraram inibicao enzimatica, sendo que o composto contendo o grupo dietoxi (2b) apresentou a maior atividade inibitoria. Estudos de modelagem molecular foram realizados para obter informacoes detalhadas entre o sitio ativo da enzima acetilcolinesterase e os compostos candidatos a inibicao, obtendo-se valiosas informacoes estruturais com relacao a inibicao de enzima acetilcolinesterase.

Six novel ω-brominated-2-trichloroacetylcycloalkanones were regiospecifically obtained in reactions from four 2-trichloroacetylcycloalkanones and bromine. 1H and 13C NMR data reveal that ω-brominated β-diketones are predominantly in keto–keto form.

This work describes the synthesis of a novel series of 2-methylsulfanyl-tetrahydropyrimidines, from the cyclocondensation reaction of β-alkoxyvinyl trihalomethyl ketones with 2-methyl-2-thiopseudourea sulfate, in good yields. A detailed 1H- and 13C-NMR study was performed on the 2-methylsulfanyl-tetrahydropyrimidines obtained and 3D structures were proposed based on AM1 calculations supported by 1H NMR coupling constants and NOESY experiments.

The acylation reaction of secondary (R 1 = H) β-enamino ketones [RCOCH=CHNR 1 R 2 , where R = CF 3 , CCl 3 , Ph, 4-FC 6 H 4 , 4-NO 2 C 6 H 4 , thien-2-yl; R 1 = H, Me; R 2 = Me, Bn, Ph, 4-NO 2 C 6 H 4 ] with trifluoroacetic anhydride or ethyl oxalyl chloride in pyridine led regiospecifically to a series of 14 N-acylated enaminones in good yields (72-88%). On the other hand, when tertiary enaminones (R 1 , R 2 = Me) were used, the acylation reaction led to a series of 12 C-acylated enaminones in good to excellent yields (75-92%).

The regiospecific synthesis of a series of twelve 5-trifluoromethyl-4,5-dihydropyrazoles and -pyrazoles from the cyclocondesation reaction of 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [F3CC(O)CH=C(R1)OR, where R1 = Me, Et, Pr, iso-Pr, Bu, iso-Bu, Ph, H; and R = Me, Et] with phenylhydrazine in toluene by environmentally benign microwave induced techniques is reported. It is shown that under appropriated conditions, the variation of microwave irradiation power leads to 4,5-dihydropyrazole or pyrazole derivatives. This paper also includes the use of montmorillonite K-10 as a solid support for the synthesis of pyrazoles under solvent free conditions.

The first synthesis of a series of 2-aryl(heteroaryl)-4-trifluoromethyl-4,5-dihydro-3H-pyrido[2,3-b][1,4]diazepin-4-ols, where aryl = C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4,4′-biphenyl, 1-naphthyl and heteroaryl = 2-thienyl, 2-furyl obtained from the direct cyclocondensation reaction of 4-methoxy-1,1,1-trifluoroalk-3-en-2-ones with 2,3-diaminopyridine in 54–71% yield, is reported. Another alternative and efficient route for the synthesis of a series of 2-aryl(heteroaryl)-3H-pyrido[2,3-b][1,4]diazepin-4(5H)-ones from the reaction 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with 2,3-diaminopyridine, in 54–70% yield, is also reported.

The synthesis of a series of ten 1,1,1-trichloro[fluoro]-3-alken-2-ones [CX3C(O)C(R2) C(R1)OR, where X = Cl and F; R1/R2/R = H/H/Et, Me/H/Me, H/Me/Et, H/ (CH2)2 and H/ (CH2)3 ] from the acylation reactions of enol ethers with trichloroacetyl chloride or trifluoroacetic anhydride in the presence of equimolar amounts of pyridine and 10% mol-equiv. of imidazolium based ionic liquid [BMIM]·BF4 or [BMIM]·PF6 is reported. The reaction time, the ionic liquid recyclation and yields were investigated and this method showed advantages over the methods described in the literature.

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.

The synthesis of a series of 14 new 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2-ones from the 1,3-dipolar cycloaddition reaction of 1-allyl-4-(trihalomethyl)pyrimidin-2(1H)-ones with aryl nitrile oxides is described. Also, the antiproliferative activity of the title compounds was tested against five human tumoral cell lines: MCF-7 breast cancer cell line, ER+ (estrogen receptor positive); HepG-2 (hepatoma); T-24 (bladder cancer); HCT-116 cell (colorectal carcinoma); and CACO-2. The preliminary results are promising, since three compounds presented IC50 values below 2 μM, as well as moderate to high selectivity.

This study reports a facile and controllable synthetic method for the preparation of both 1,3- and 1,5-isomers of 4-(3(5)-aryl-3(5)-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamides, as well as a new series of 4-(3-aryl-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides, from the cyclocondensation reaction of 4-aryl-1,1,1-trifluoro-4-methoxybut-3-en-2-ones or 1-aryl-4,4,4-trifluoro-butane-1,3-diones or their enolic forms with 4-hydrazinylbenzenesulfonamide. All compounds of the new series of 3-substituted 1-(4-benzenesulfonamide)-5-hydroxy-5-(trifluoromethyl)-4,5-dihydropyrazoles were tested for their effect on a pathological pain model in mice. The compounds 3a, 3b, 3c, 3e, and 3f presented anti-hyperalgesic action, while the compounds 3a, 3c, 3d, 3f, and 3g exhibited anti-edematogenic effects, without causing locomotive disorders in animals, thus making them comparable to Celecoxib in an arthritic pain model.

Reaction of trifluoroacetylated Kabbe adducts (IV) with phenylhydrazine or methylhydrazine proceeds with apposite regioselectivity furnishing chromenopyrazoles (VI) or (VIII), respectively.

This paper describes an efficient approach for the synthesis of a novel series of sixteen 2-(5-trifluoromethyl-1H-pyrazol-1-yl)-5-(5-trihalomethyl-1H-pyrazol-1-yl-1-carbonyl) pyridines, for the first time with non-identical substituents in both pyrazole rings, through the cyclocondensation reaction of 4-methoxy-4-alkyl(aryl/heteroaryl-1,1,1-trihaloalk-3-en-2-ones [CX3C(O)CH=CR1OCH3, in which R1 = CH3, C6H5, 4-CH3C6H4, 4-OCH3C6H4, 2-furyl and X = F, Cl] or acetylacetone with some 6-[3-alkyl(aryl)-5-trifluoromethyl-1H-pyrazol-1-yl]nicotinohydrazides. Optimized yields of 67-91% were obtained when the reactions were performed in ethanol (green solvent) at reflux for 16 h. Subsequent antioxidant and antimicrobial evaluation revealed promising 1,1-diphenyl-2-picrylhydrazyl (DPPH) inhibition percentage and exhibited fungiostatic and fungicidal activities against yeasts, dermatophytes and filamentous, especially for the pyridine systems, when the both pyrazole rings attached to a pyridine ring contain CX3 groups (X = H, F, Cl) of different kinds. It is also observed the trichloromethyl substituted compounds presented higher antioxidant activity in comparison to their fluorinated analogous.

An improved procedure to prepare a series of five 5-alkoxy-1,1,1,2,2-pentafluoro-4-alken-3-ones (CF3CF2C(O)C(R 2 )=C(R 1 )OR, where R 2 /R = H/Et, H/Me, Me/Et, -(CH2)2- , -(CH2)3-, and R 1 = H, Me) in good yields (71 - 82%) and in an up to molar scale from the acylation reaction of enol ethers with pentafluoropropionic anhydride is described. These compounds were cyclocondensed with different dinucleophiles, such as hydroxylamine, 1,2-dimethylhydrazine and phenylhydrazine, to obtain a series of pentafluoroethyl substituted 4,5-dihydroisoxazoles, pyrazolium chlorides and pyrazoles, respectively, in one-pot procedures with moderate to very good yields (60 - 95%).

The regiospecific synthesis of a novel series of nine 4-phenyl- and 3-alkyl(aryl)-5-hydroxy-5-trifluoromethyl-4,5-dihydro-1H-1-tosylpyrazoles (pyrazolinyl p-tolyl sulfones), as well as their antimicrobial activity against yeast, such as fungi, bacteria, and alga are reported. The 1-p-tosyl-2-pyrazolines were obtained from the cyclocondensation reaction of 3-phenyl- and 4-alkyl(aryl)-1,1,1-trifluoro-4-alkoxy-3-alken-2-ones, [where alkyl = H, Me and aryl are -C6H5, 4-CH3C6H4, 4-OCH3C6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4,] with p-tosylhydrazine in a yield of 58–92% when toluene was employed as solvent. The best activity was obtained when the structure possessed a 4-fluorophenyl substituent linked at the carbon-3 of the pyrazoline ring. Subsequently, the dehydration reaction of 3-(4-fluorophenyl) substituted 2-pyrazoline with thionyl chloride/pyridine in benzene as solvent furnished the corresponding 1H-pyrazole in only a moderate yield (49%).

The synthesis of some potentially active 2-(trifluoro-methyl)pyrimido[1,2-a]benzimidazoles and pyrimido[1,2-a]benzimidazol-2(1H)-ones by the cyclization of 4-alkoxyvinyl trifluoro(chloro)methyl ketones with 2-aminobenzimidazole is described. The structure of the products was assigned based on 'H and 13 C NMR as well as 2D-NMR experiments. Some of the obtained products exhibited significant DNA-topoisomerase I inhibitory activity.

The present study investigates the antinociceptive effect of the pyrazolyl-thiazole derivative 2-(5-trichloromethyl-5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-bromophenyl)-5-methylthiazole (B50) in mice. Male albino Swiss mice (30-40 g) were used in the acetic acid-induced abdominal writhes and tail-immersion tests. B50 caused dose-dependent antinociception (8, 23 and 80 micromol/kg, s.c.) in the acetic acid writhing assay (number of writhes: vehicle: 27.69 +/- 6.15; B50 (8 micromol/kg): 16.92 +/- 3.84; B50 (23 micromol/kg): 13.85 +/- 3.84; B50 (80 micromol/kg): 9.54 +/- 3.08; data are reported as means +/- SEM for 9 animals per group). On the other hand, B50 did not cause antinociception in the tail immersion assay. Naloxone (2.75 micromol/kg, s.c.) prevented B50-induced antinociception (number of writhes: vehicle-saline: 31.11 +/- 3.15; vehicle-naloxone: 27.41 +/- 3.70; B50 (80 micromol/kg)-saline: 8.70 +/- 3.33; B50 (80 micromol/kg)-naloxone: 31.84 +/- 4.26; morphine-saline: 2.04 +/- 3.52; morphine-naloxone: 21.11 +/- 4.26; 8-9 animals per group). The removal of the methyl group of the thiazole ring of B50 or substitution of the bromo substituent with the methyl at position 4 of the phenyl group, which is attached to the thiazole ring of B50, resulted in loss of activity, suggesting that these substituents are important for antinociceptive activity. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the antinociceptive effect of B50 is not related to nonspecific motor effects. The antinociceptive profile of B50 seems to be closer to nonsteroidal anti-inflammatory drugs than to classic opioid agents, since it had no analgesic effect in a thermally motivated test.

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.