Search

This study reports a simple, fast, and efficient method for the synthesis of a new series of 1-arylethyl-2-arylethylamino-5-trifluoroacetyl-1,2,3,4-tetrahydropyridines and related compounds from the reaction of 2-alkoxy-5-trifluoroacetyl-3,4-dihydro-2H-pyrans with 2-arylethanamines and related 2-ethanamines. The desired tetrahydropyridines were obtained in excellent yields (90–98%), through a reaction that can be described as an AAB′ three-component reaction protocol following an ANRORC-type mechanism.

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.

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.

A simple procedure for the synthesis and characterization of new 3-alkoxy-3-(1H-tetrazol-5-yl)propionic acids and 2-(1H-tetrazol-5-yl)tetrahydrofuran- and -(1H-tetrazol-5-yl)-2H-pyran-3-carboxylic acids from the [2 + 3] cycloaddition reactions between the nitrile group of β-cyanocarboxylic acids with sodium azide in the presence of zinc chloride is described. The tetrazolic acids were isolated in moderate to good yields and are structurally analogous to succinic acid.

This article reports a convenient and general method for the regioselective synthesis of a new series of 2-alkyl(aryl)-8-methyl-4-trifluoromethyl-7-aminoquinolines in 86–93% yields, from cycloaromatization reactions of N-(oxotrifluoroalkenyl)-2,6-diaminotoluenes in a strongly acidic medium polyphosphoric acid and absence of solvent. The enaminoketone intermediates were easily isolated from the reaction of 4-alkoxy-4-alkyl(aryl)-1,1,1-trifluoroalk-3-en-2-ones [CF3C(O)CH═C(R)OR1, where R = H, Me, Ph, 4-FPh, 4-BrPh, 4-MePh, and R1 = Me, Et] with 2,6-diaminotoluene (2,6-DAT) in methanol under mild conditions, in 46–70% yields. Another synthetic route also allowed the regioselective synthesis of 2-aryl(heteroaryl)-4-methyl-4-trifluoromethyl-7-aminoquinolines from direct cyclocondensation reactions of 4-alkoxy-4-aryl(heteroaryl)-1,1,1-trifluoroalk-3-en-2-ones with 2,6-diaminotoluene in methanol under mild conditions, in 21–36% yields.

5-Bromo[5,5-dibromo]-1,1,1-trihalo-4-methoxy-3-penten[hexen]-2-ones are explored as precursors to the synthesis of 3-ethoxymethyl-5-trifluoromethyl-1H-pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3-Ethoxymethyl-carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3-acetal-pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3-azidomethyl-5-ethoxycarbonyl-1H-pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3-[4(5)-phenyl-1,2,3-triazolyl]5- ethoxycarbonyl-1H-pyrazoles and to reduction conditions resulting in 3-aminomethyl-1H-pyrazole-5-carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.

The regioselective synthesis and characterization of a new series of 3-aryl-7-trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines from the oxidative heterocyclization of 2-(N′-benzylidenehydrazino)-4-trifluoromethylpyrimidines with copper dichloride is described. J. Heterocyclic Chem., (2011).

The facile and convenient access by a conventional procedure in ethanol as solvent to a new series of succinyl-spaced pyrazoles including 1,4-bis[5-(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones (64–82%) and the respective dehydrated derivatives as 1,4-bis[5-(trichloromethyl)-1H-pyrazol-1-yl]butane-1,4-diones in 57–82% yields, from the regioselective cyclocondensation reactions of 4-substituted 4-methoxy-1,1,1-trichloroalk-3-en-2-ones with succinic acid dihydrazide, where the 4-substituents are Me, Ph, 4-FC6H4, 4-ClC6H4, 4-NO2C6H4, 2-furyl, and 2-thienyl, is reported. J. Heterocyclic Chem., 2011.

Reactions of trihalomethylated enones with dimethylisothiourea sulfate furnish chemoselectivity 2-methylthiotetrahydropyrimidine or -dihydropyrimidine derivatives depending on the reaction conditions and electronic effects of the substituents on the enones.

A simple, convenient and regioselective one-pot condensation reaction is used for the preparation of the title pyrazoles, e.g. (III).

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.

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.

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 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.

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.

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 study of the regiochemistry of the cyclo-condensation reaction of s-alkoxyvinyl trihalomethyl ketones with an unsymmetric dinucleophile N-methyl thiourea to afford a series of 1-methyl-3-(4,4,4-trifluoro[chloro]-3-oxo-1-butenyl)thioureas and the corresponding N-methyl pyrimidinethione derivatives is reported. The absolute assignment of the position of the N-methyl group in the pyrimidine ring was obtained through a nmr study based on two dimensional HMBC and NOESY experiments.

The reaction of a series of β-methoxyvinyl trifluoromethyl ketones [CF3COC(R2)C(OMe)R1, where R1 = Me, -(CH2)3-C3, -CH2)4-C3, Ph and R2 = H, Me, -(CH2)3-C4, -(CH2)4-C4] with N-methylhydroxylamine is reported. The regiochemistry of the reaction are explained by MO calculation data.

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.

The synthesis and isolation of the intermediates N-[1-aryl(alkyl)-3-oxo-4,4,4-trichloro-1-buten-1-yl]-o-phenylenediamines 2a-f and the corresponding 2-trichloromethyl-4-aryl-3H-1,5-benzodiazepines 3c-g or benzimidazoles 4a-b derivatives obtained from the intramolecular cyclization of 2a-f or from direct cyclo-condensation reaction of β-alkoxyvinyl trichloromethyl ketones 1a-g with o-phenylenediamine, is reported. Depending of the structure of the β-alkoxyvinyl trichloromethyl ketones or the N-[1-aryl(alkyl)-3-oxo-4,4,4-trichloro-buten-1-yl]-o-phenylenediamines and the reactions conditions, benzimidazoles or 3H-1,5-benzodiazepines were obtained.

The synthesis of 4-trifluoromethyl-2-methyl[phenyl]pyrimidines and the corresponding tetrahydro derivatives from the cyclo-condensation reaction of β-alkoxyvinyl trifluoromethyl ketones 1a-d with acetamidine or benzamidine hydrochloride, is reported. For the cyclo-condensation of 1a-d with acetamidine and benzamidine hydrochloride, two methods were tested: 1 M solution of sodium hydroxide (method A) and sodium alkoxide/alcohol (method B). Depending on the structure of the β-alkoxyvinyl trifluoromethyl ketones and the reactions conditions, pyrimidines or tetrahydropyrimidines or a mixture of both compounds were obtained.

In this work the results of the reaction of β-alkoxyvinyl trihalomethyl ketones 1, 2a-e, with guanidine hydrochloride are reported. Depending on the ketone 1 or 2 and the conditions under which the reactions were carried out, 4-trihalomethyl-2-amino pyrimidines, β-alkoxyvinyl carboxylic acids, or β-acetal carboxylic esters were obtained.

β-Aryl-β-methoxyvinyl trihalomethyl ketones 1a-g, 2a-g [aryl = p-YC6H4 where Y= H, Me, OMe, F, Cl, Br, NO2] are cyclocondensed with hydroxylamine hydrochloride to afford the 3-aryl-5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazoles 3a-g, 4a-f in good yield. The dehydratation of compounds 3a-g with concentrated sulfuric acid, led the corresponding 3-aryl-5-trichloromethylisoxazoles 5a-g. An alternative one-pot procedure yields 3-aryl-5-trihalomethylisoxazoles 5,6a-g directly by cyclocondesation of 1,2a-g with hydroxylamine hydrochloride in the presence of an excess of concentrated hydrochloric acid.

The investigation of the effect of the cyclopentane ring on the regiochemistry of the reactions of 2-acetylcyclopentanones 1a-d and β-methoxyvinyl trifluoromethyl ketone derivative 2a with hydroxylamine hydrochloride is reported. The reactions give regiospecifically the 4,5-trimethylene-4,5-dihydroisoxazoles 3a-d in good yields.

The mechanism for the dehydration and unexpected loss of the methyl carboxylate group at higher temperatures is discussed.

The β-alkoxyvinyl dichloromethyl ketones 1a-d are cyclocondensed with hydroxylamine hydrochloride in pyridine to afford the 5-hydroxy-5-dichloromethyl-4,5-dihydroisoxazoles 2a-d in good yield. The cyclo-condensation of compound 1c gave, together with 2c, 3-cyano-2-hydroxy-2-dichloromethyltetrahydrofuran 5c. The dehydratation of compounds 2a,b, derived from acyclic enol ethers, with concentrated sulfuric acid at 30°, led the corresponding 5-dichloromethylisoxazoles 3a,b. The dehydratation of compounds 2c,d, derived from cyclic enol ethers, with concentrated sulfuric acid at 30°, led the bicyclic 4,5-dihydroisoxazoles 4c,d, and at 55°, a competitive rearrangement reaction gives the 3-cyano-2-hydroxy-2-dichloromethyl-2H-pyran 5d.

The investigation of the halomethyl group effect on the regiochemistry of the reaction of 2-acetylcyclo-hexanones 1a-d and β-methoxyvinyl trifluoro methyl ketone derivative 2a with hydroxylamine to afford 3,3a,4,5,6,7-hexahydro-3-halomethyl-3-hydroxy[2,1]benzoisoxazoles 3a-c, and the respective dehydrated compounds 4a-c, is reported. Compounds 1a-c, 2a proved to be versatile building blocks for the regiospecific synthesis of isoxazole derivatives having a 3-halomethyl substituent, in good yields.