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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.

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

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.

This work reports the synthesis of a series of (1H-1,2,3-triazol-4-yl)carbohydrazides (2), which were obtained from 4-trichloroacetyl-1H-1,2,3-triazoles (1). Triazoles 1 were synthesized by 1,3-dipolar cycloaddition reaction, starting from 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones and benzyl azides and easily (15 min) converted to 2 by reaction with hydrazine hydrate (73–82% yield). Carbohydrazides 2 proved to be a versatile building block for constructing a series of fluorinated heterocycles analogous to rufinamide, i.e., 1H-1,2,3-triazol-4-yl-1,3,4-oxadiazoles, a pyrrole derivative, and a 2-pyrazoline, through [4+1]–, [1+4]–, and [3+2]–cyclocondensation reactions, respectively. Finally, and according to the Lipinski’s rule of five, 2,6-difluorobenzylated 1,2,3-triazoles can be considered as potential candidates for further biological activity assays.

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.

A facile and regioselective synthesis of a series of new methyl 3-ferrocenyl-1H-pyrrole-2-carboxylates obtained from methyl ferrocenyl azido acrylate and symmetrical or non-symmetrical 1,3-dicarbonyl compounds under microwave-assisted conditions is reported. 3-Ferrocenyl substituted pyrroles, which are normally difficult to obtain via the known reported methods, can now be regioselectively prepared by this protocol. Compared to already known acidic, basic, or metal-catalyzed methodologies for polysubstituted pyrrole synthesis, the present synthetic route is mild, quick, simple, and it furnishes new functionalized tetrasubstituted-pyrroles in short reaction times (30 min) and at satisfactory to good yields (32–75%).

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.

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%.

This work presents a new synthesis of the antiepileptic drug rufinamide—1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide) in chemical form—and some analogue compounds, through a one-pot reaction employing a solventless, metal-free catalysis and without any reducing reagent. The great novelty presented is the synthesis of 4-trichloroacetyl-1-(2,6-difluorobenzyl/benzyl/4-methoxybenzyl)-5-methyl(phenyl)-1H-1,2,3-triazoles as new precursors from a regioselective 1,3-dipolar cycloaddition reaction between 1,1,1-trichloro-4-alkoxyalk-3-en-2-ones and some benzyl azides, which are converted into rufinamide and the analogues by an addition–elimination reaction with an aqueous solution of NH4OH in good yields (42–52%).

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%).

A microwave-assisted synthesis of a series of 1-aryl-4-dimethylaminomethylene pyrrolidine-2,3,5-triones from the cyclocondensation reaction of ethyl 5,5,5-trichloro-3-dimethylamino methylene-2,4-dioxopentanoate with aniline, 3- or 4-substituted anilines [where the substituents = 3-Me, 3-OMe, 3-OH, 4-Me, 4-F, 4-Cl, 4-Br, 4-NO 2 , and 4-COMe] is reported. This process is an efficient alternative to the conventional thermal heating and furnishes the products in a short reaction time (ca. 13 min), under mild conditions and in moderate to good yields (50–76%).

The unexpected results of the cyclization reactions of N,N′-bis(oxotrifluoroalkenyl)-1,3-phenylenediamines [1,3-C6H4-(NHCR CHC(O)CF3)2], where R = H, Me, and Ph, in a strongly acidic medium (PPA), allowing the synthesis of new trifluoromethylated heterocycles containing the 1,7-phenanthroline nucleus in 32–40% yields and 7-aminoquinolines (38–40% yields), is reported. The bis-enaminoketone intermediates were easily isolated from the reactions of 4-alkoxy-4-alkyl(aryl)-1,1,1-trifluoroalk-3-en-2-ones with 1,3-phenylenediamine in ethanol under mild conditions (68–86% yields).

A series of NH-pyrazoles was efficiently synthesized from the reaction of b-dimethylaminovinylketones ([R 1 C(O)C(R 2 )@CHN(Me2)], where R

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.

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.

This work reports a two-step synthetic strategy to obtain a series of 6-methylenesubstituted-4-trichloromethyl-2-methylsulfanylpyrimidines from the cyclization of 5-bromo-4-methoxy-1,1,1-trichloro-pent-3-en-2-ones with 2-methyl-2-pseudothiourea sulfate, followed by nucleophilic substitution of 6-bromomethyl-4-trichloromethyl-2-methylsulfanylpyrimidine with a series of nucleophiles. Alternative strategies to obtain 6-halomethyl-4-trichloro[fluoro]methyl-2-methylsulfanyl pyrimidines have been addressed.

One-pot condensation of ethyl trichloroacetoacetate 1 with p -substituted aromatic aldehydes (Ph, 4-Me–C 6 H 4 , 4-Cl–C 6 H 4 , 4-MeO–C 6 H 4 ) or furfural, and urea or thiourea catalyzed by indium(III) bromide affords eight trichloromethylated tetrahydropyrimidinones, in high yields.

A simple and convenient synthesis of a series of 3-aminomethylenedihydrofuran-2-ones from the reaction of 3-trichloroacetyl-4,5-dihydrofuran with amines, is presented.

Synthesis of 4-alkoxy-1,1-dichloro-3-alken-2-ones [CHCl 2 C(O)C(R 2 ) C(R 1 )-OR, where R, R 1 , R 2 = Et, H, H; Me, Me, H; Et, H, Me; Me, –(CH 2 ) 2 –; Me, –(CH 2 ) 3 –; Et, Et, H; Et, Bu, H; Et, i -Pr, H; Et, i -Bu, H; Me, Ph, H; Me, thien-2-yl, H] from acylation of enol ethers and acetals with dichloroacetyl chloride, in ionic liquid ([BMIM][BF 4 ] or [BMIM][PF 6 ]) is reported. The synthesis of alkenones [R 3 –C(O)C(R 2 ) C(R 1 )-OR], where R/R 1 /R 2 /R 3 = Et/H/H/Ph, t -Bu/H/H/Ph, Me/-(CH 2 ) 4 /Ph, Me/-(CH 2 ) 4 /Me] from the reaction of enol ethers with benzoyl chloride or acetyl chloride, in ionic liquid [BMIM][BF 4 ], is also reported. Last products are described for the first time.

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%).

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.

In this study, diethylaminosulfur trifluoride (DAST) was successfully applied in monofluorination reactions of some trifluoromethyl substituted 2-hydroxy-2H-chromenones, employing a general, mild, and efficient methodology. The fluorinated compounds (2-fluoro-2H-chromenones) were synthesized as unique products by a chemoselective reaction in 63–81% yield despite the presence of different reactive sites subjected to reactions with DAST.

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.

The one-pot synthesis of ten 5-carboxyisoxazoles from the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones [CCl3C(O)C(R2)C(R1)OR, where R1, R2=H, Me and R=Me, Et] and 2-trichloroacetyl cyclohexanone with hydroxylamine is reported. This work shows that the trichloromethyl group attached to β-alkoxyvinyl trichloromethyl ketones (a heterocyclic CCC building block) is an excellent carboxyl group precursor.

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 regiochemistry of the acylation of enol ethers, generated in situ, from acetals of unsymmetrical ketones is reported. These results demonstrate a convenient one-pot method to obtain a series of β-methoxyvinyl trichloromethyl ketones [CCl3COCHC(OMe)R, where R=Et, n-Bu, i-Pr, (CH2)2C(OMe)CHC(O)CCl3 and (CH2)5CO2CH3)] in high yields.

A convenient method to obtain a new series of 2-trichloromethyl-4-aryl-3H-1,5-benzodiazepines from the reaction of β-methoxyvinyl trichloromethyl ketones derived from acetals and o-phenylenediamine is reported.

An efficient and regioselective procedure for the synthesis of a series of alkyl(aryl/heteroaryl) substituted 3-trifluoromethyl-1 H -1-phenylpyrazoles and alkyl 3-carboxylate analogs, from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones [CX 3 C(O)CR 2 =CR 1 (OMe/OEt), where R 1 = H, Me, Ph, 2-Furyl; R 2 = H; R 1 -R 2 = -C 4 H 8 - and X = F, Cl] and 1-phenylsemicarbazide in an acidified alcoholic medium (R 3 OH/H 2 SO 4 ), where R 3 = Me, Et, Pr i was successfully applied and is described here in detail.

A regioselective synthesis of 3-trifluoromethyl-1-phenyl-1H-pyrazoles (1,3-isomers) as well as their 1,5-isomers (5-trifluoromethyl-1-phenyl-1H-pyrazoles), is described. The 1,3-isomers were obtained from the reaction of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with arylhydrazones followed by deprotective hydrolysis while the 1,5-isomer was obtained by direct cyclocondensation of 4-alkoxy-1,1,1-trifluoroalk-3-en-2-ones with phenylhydrazine. An unequivocal assignment of the 1,3- and 1,5-isomers of the pyrazole products is given.

The efficient synthesis of 1,2-dihydropyridine from the intramolecular cyclization reaction of N -propargylic β-enaminones [R 2 C(O)CH C(R 1 )(N(R)CH 2 C CH), where R = Pr, Bn, Ph, 4-Me-C 6 H 4 , R 1 = Me, Et, Pr, R 2 = CF 3 , CO 2 Et] using AgNO 3 as a catalyst (12 h at 25 °C) is reported. The products were obtained at good yields (70–90%). In particular, when the reaction of N -propargylic β-enaminone with R = Me was performed over a 24 h period, the intramolecular cyclization resulted in the formation of a pyrrole with 80% yield.