Reaction of 4,5-Dihydro-1H-pyrazole-3,5,5-tricarboxylic Acids Esters with Halogens

Esters of 4-R-4,5-dihydro-1H-pyrazole-3,5,5-tricarboxylic acids with chlorine yield esters of 4-R-5-chloro-4,5-dihydro-3H-pyrazole-3,3,5-tricarboxylic acids that at thermolysis provide the esters of the corresponding 2-chlorocyclopropanetricarboxylic acid. The same esters react with bromine in dichloromethane at room temperature to give a mixture of esters of the corresponding 1H-pyrazole-3,5-dicarboxylic acids and 5-bromo-4,5-dihydro-3,3,5-tricarboxylic acids. From 5,5-diethyl 3-methyl 4,5-dihydro-1Hpyrazole-3,5,5-tricarboxylate and N-iodosuccinimide or a system iodine-silver trifluoroacetate we obtained 1,1-diethyl 2-methyl 2-iodocyclopropane-1,1,2-tricarboxylate.     

An unexpected aromatization during the N-alkylation reaction of 3,4-dihydro-1H-pyrazole derivatives: insight into the reaction mechanism

In this letter we describe the unexpected aromatization that takes place during the N-alkylation reaction performed on several 3-(2-nitrobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid methyl esters, giving rise to a mixture of 1-alkyl-3-(2-nitrobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid methyl esters and 1-alkyl-3-(2-nitrobenzoyl)-1H-pyrazole-5-carboxylic acid methyl esters.     

Reactions of Aliphatic Diazo Compounds: III. Reaction of Ethyl Diazoacetate with 1,3-Diarylpropenones

Ethyl diazoacetate adds to 1,3-diarylpropenones in a regioselective fashion to give intermediate 4,5-dihydro-3H-pyrazole derivative; 1,3-hydride shift in the latter leads to formation of isomeric ethyl 4-aryl- 5-aroyl-4,5-dihydro-1H-pyrazole-3-carboxylate and ethyl 4-aryl-3-aroyl-4,5-dihydro-1H-pyrazole-5-carboxylate at a ratio of 5:1. Thermolysis of these products is not stereospecific; as a result, three isomeric substituted ethyl cyclopropanecarboxylates and 2-pyranone derivative are formed.     

Synthesis and in-vitro-antibacterial activity of [5-(furan-2-yl)-phenyl]-4,5-carbothioamide-pyrazolines

Cyclization of various different alkoxy [1-[2-(alkoxy)phenyl]-5-(furan-2-yl)-prop-2-en-1-one] chalcone with thiosemicarbazide in the presence of NaOH in ethanol afforded a series of novel 1-N-substituted cyclized pyrazoline analogues [5-(furan-2-yl)-3-[2-(alkoxy) phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2a–2d. The structures of these compounds were elucidated by IR, ¹H NMR, ¹³C NMR, Fab mass spectrometry and their purities were confirmed by elemental analyses. In vitro antibacterial activity of these compounds were evaluated by the disk diffusion assay and then the minimum inhibitory concentration (MIC) strain of two Gram-positive and two Gram-negative bacteria like Aeromonas hydrophila, Yersinia enterocolitica, Listeria monocytogenes, and Staphylococcus aureus, among all the compounds, alkoxy [5-(furan-2-yl)-2-(benzyloxy)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2b and 5-(furan-2-yl)-1-[2-(naphthalen-2-ylmethoxy) phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2d showed the most promising antibacterial agent when compared to gentamicin and tetracycline.     

Reaction of methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrrole-2-carboxylates with arylhydrazines. synthesis of isomeric 5-arylcarbamoyl-4-aroyl- and 5-aryl-4-aryloxamoyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazoles

Methyl 3-aroyl-1-aryl-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylates reacted with arylhydrazines to give methyl 3-aroyl-1-aryl-2-(2-arylhydrazinyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylates which underwent thermal recyclization into isomeric methyl 1-aryl-5-(arylcarbamoyl)-4-aroyl-1H-pyrazole- 3-carboxylates and methyl 1,5-diaryl-4-[2-oxo-2-(arylamino)acetyl]-1H-pyrazole-3-carboxylates.     

Regioselectivity of the thermal van Alphen–Hüttel rearrangement of 4- and 5-mono- and 4,5-disubstituted 3,3-diphenyl-3<Emphasis Type="Italic">H</Emphasis>-pyrazoles

Thermal van Alphen–Hüttel rearrangement of methyl 3,3-diphenyl-3H-pyrazole-4-carboxylate, 3,3-diphenyl-3H-pyrazole-4-carbonitrile, and methyl 5-methyl-3,3-diphenyl-3H-pyrazole-4-carboxylate involves completely regioselective migration of one phenyl group from the 3-position to N² with formation of aromatic 1H-pyrazole system. Thermal rearrangement of methyl 3,3-diphenyl-3H-pyrazole-5-carboxylate leads to the formation of methyl 4,5-diphenyl-1H-pyrazole-3-carboxylate as a result of migration of the 3-phenyl group exclusively to the C⁴ atom and subsequent prototropic isomerization. Under analogous conditions, methyl 4-methyl-3,3-diphenyl-3H-pyrazole-5-carboxylate, methyl 5-(methanesulfonyl)-3,3-diphenyl-3H-pyrazole-4-carboxylate, methyl 5-(benzenesulfonyl)-3,3-diphenyl-3H-pyrazole-4-carboxylate, and dimethyl 3,3-diphenyl-3H-pyrazole-4,5-dicarboxylate have been regioselectively converted into the corresponding 4H-pyrazoles. Thermolysis of 5-(4-methylbenzenesulfonyl)-3,3-diphenyl-3H-pyrazole-4-carbonitrile gives rise to a mixture of 1H- and 4H-pyrazoles, the former considerably prevailing, whereas the corresponding 1H-pyrazoles are formed as the only product from 5-(methanesulfonyl)- and 5-(benzenesulfonyl)-3,3-diphenyl-3H-pyrazole-4-carbonitriles.     

Quantum-chemical study of the structure and reactivity of 4,5-dihydropyrazol-5-ones and their thio and seleno analogs: VIII. Solvation effects and tautomerism of 4,5-dihydropyrazol-5-ones and their thio and seleno analogs

The effect of hydration on the stability of tautomeric forms of 1-methyl-4,5-dihydro-1H-pyrazol-5-one, 1-methyl-4,5-dihydro-1H-pyrazole-5-thione, and 1-methyl-4,5-dihydro-1H-pyrazole-5-selone was analyzed by nonempirical quantum-chemical methods at different theory levels. The results of calculations by all these methods, including density functional theory, with two types of models (continuum and discrete) showed stronger stabilization of the NH tautomers of all the examined heteropyrazolones in water, as compared to their CH and XH tautomers. The strongest stabilization effect is reached in the calculation of discrete complexes in terms of the self-consistent reaction field model. The degree of differentiation of the stability of tautomeric forms considerably decreases when electronic correlation is taken into account, whereas the use of polarization functions on hydrogen atoms in addition to polarization functions on heavy atoms almost does not affect the position of the tautomeric equilibrium.     

Interaction of a lithiated nitronyl nitroxide with polyfluorinated 1,4-naphthoquinones

A 4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl lithium derivative was found to react with 2-methoxypentafluoro-1,4-naphthoquinone to form a product of addition at the carbonyl function: radical 2-(3,5,6,7,8-pentafluoro-1-hydroxy-2-methoxy-4-oxo-1,4-dihydronaphthalen-1-yl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazole-3-oxide-1-oxyl. The yield of the addition product increased with temperature and reached 84% at 0?°C. The reaction of the lithium derivative with hexafluoro-1,4-naphthoquinone gave rise to a product of addition at both carbonyl groups, namely, nitronyl nitroxide diradical 2,3,5,6,7,8-hexafluoro-1,4-bis(4,4,5,5-tetramethyl-3-oxide-1-oxyl-4,5-dihydro-1H-imidazole-2-yl)-1,4-dihydronaphthalene-1,4-diol in a 16% yield. The structures of both mono- and diradical were solved by X-ray diffraction analysis, which revealed formation of an intramolecular H-bond between the OH group and nitroxide oxygen. According to electron paramagnetic resonance (EPR) spectroscopy, the obtained mono- and dinitroxide are prone to spontaneous deoxygenation in a toluene solution to give corresponding iminonitroxides. In water, they are much more stable.     

Reaction of acetylenedicarboxylic acids esters with 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-1-carbothioamides and 3,4,5,6-tetrahydro-2<Emphasis Type="Italic">H</Emphasis>-1,2,4-triazepine-3-thiones

The reactions of dimethyl acetylenecarboxylate with 3,4,5,6-tetrahydro-2H-1,2,4-triazepine-3-thiones and 4,5-dihydro-1H-pyrazole-1-carbothioamides are convenient methods for the synthesis of 7,8-dihydrothiazolo[3,2-b][1,2,4]triazepin-3-ones derivatives and methyl esters of (2Z)-[2-(4,5-dihydro-1H-pyrazol-1-yl)-4-oxo-1,3-thiazol-5(4H)-ylidene]acetic acids, respectively. The reaction of methyl propynoates with 4,5-dihydro-1H-pyrazole-1-carbothioamides or with 5,5,7-trimethyl-2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thione gives 2-(4,5-dihydro-1H-pyrazol-1-yl)-4H-1,3-thiazin-4-ones.     

Fused isoquinolines: 3-aryl-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-1,5-dione-2-spiro-4′-(1′-alkyl-1′,4′-dihydropyridine)s

Previously unknown 3-arylamino-1,2-dihydro-1-isoquinolones were obtained by condensation of 2-cyanomethylbenzoic acid with arylamines. Isonicotinoylation of the compounds was shown to proceed at the carbon atom in the 4-position to give 3-arylamino-4-isonicotinoyl-1,2-dihydro-1-isoquinolones which were quaternized with alkylating agents and formed the corresponding pyridinium salts. Deprotonation of the latter induced intramolecular conjugated addition with the pyrrole ring closure and formation of spiro compounds. The structure of the products was confirmed by NMR, IR and UV spectroscopy and by synthesis of the model compound, 3-(4-tolyl)-2,3,4,5-tetrahydro-1H-pyrrolo[2,3-c]isoquinoline-1,5-dione.     

Reversible Migrations of Nitro Group in a Methyltetramethoxycarbonylcyclopentadiene System

Quantum chemical calculations by the density functional theory method at the B3LYP/6-311++G** level have shown that 5-nitro-5-methyl-1,2,3,4-tetramethoxycarbonylcyclopentadiene (1) and 5-nitro-2-methyl- 1,3,4,5-tetramethoxycarbonylcyclopentadiene (2) undergo interconversion by consecutive 1,5-sigmatropic shifts via the formation of an unstable isomer, 5-nitro-1-methyl-2,3,4,5- tetramethoxycarbonylcyclopentadiene (3), rather than through the NMR-detected 1,3-shift of the nitro group over the cyclopentadiene ring perimeter. According to calculations in the gas phase, isomer 3 is by ΔE _ZPE of 3.6 kcal/mol less stable than isomer 1, while the activation barrier of the stepwise 1 → 2 process is 24.5 kcal/mol, which agrees well with NMR data (ΔG_25C^≠, chlorobenzene, 26.5 kcal/mol).     

Electrophilic cyclization of <Emphasis Type="Italic">N</Emphasis>-allyl(propargyl)-5-amino-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-4-carboxamides. Synthesis of 4-[(dihydro)oxazol-2-yl]-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-5-amines

N-Allyl-5-amino-1H-pyrazole-4-carboxamides in reactions with polyphosphoric acid, with N-halosuccinimides in chloroform, and with (chlorosulfanyl)benzenes in nitromethane in the presence of lithium perchlorate underwent cyclization involving the N-allylamide fragment to give 4-[5-methyl(halomethyl)-4,5-dihydrooxazol-2-yl]-1H-pyrazol-5-amines and 2-(5-amino-1H-pyrazol-4-yl)-5-[(arylsulfanyl)methyl]-4,5-dihydro-1,3-oxazolium perchlorates, respectively. Analogous reactions of N-propargyl-5-amino-1H-pyrazole-4-carboxamides with polyphosphoric acid afforded 4-(5-methyloxazol-2-yl)-1H-pyrazol-5-amines, and with (chlorosulfanyl) benzenes, 2-(5-amino-1H-pyrazol-4-yl)-5-[(arylsulfanyl)methylidene]-4,5-dihydro-1,3-oxazolium perchlorates.     

Convenient Synthesis of Pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazoles via Intramolecular Nitrile Oxide Cycloaddition

A simple and efficient synthetic route to the novel 3a,4-dihydro-3H,7H- and 4H,7H-pyrazolo[4′,3′:5,6]pyrano[4,3-c][1,2]oxazole ring systems from 3-(prop-2-en-1-yloxy)- or 3-(prop-2-yn-1-yloxy)-1H-pyrazole-4-carbaldehyde oximes has been developed by employing the intramolecular nitrile oxide cycloaddition (INOC) reaction as the key step. The configuration of intermediate aldoximes was unambiguously determined using NOESY experimental data and comparison of the magnitudes of ¹J_CH coupling constants of the iminyl moiety, which were greater by approximately 13 Hz for the predominant syn isomer. The structures of the obtained heterocyclic products were confirmed by detailed ¹H, ¹³C and ¹⁵N NMR spectroscopic experiments and HRMS measurements.     

New derivatives of 4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-pyrazole, 4,5-dihydro-1,2-oxazole,and pyrimidine prepared proceeding from (<Emphasis Type="Italic">E</Emphasis>)-3-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-one

Condensation of acetylferrocene with 5-phenyl(4-methylphenyl)-1,2-oxazole-3-carbaldehydes afforded (Е)-3-[5-phenyl(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-ones. Reactions of (Е)-3-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-one with semicarbazide, thiosemicarbazide, and hydroxylamine led to the formation of 5-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-3-ferrocenyl-4,5-dihydro-1H-pyrazole- 1-carboxamide, 5-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-3-ferrocenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide, and 5-(4-methylphenyl)-3'-ferrocenyl-4',5'-dihydro-3,5'-bi-1,2-oxazole respectively. Reactions of (Е)-3-[5-(4-methylphenyl)-1,2-oxazol-3-yl]-1-ferrocenylprop-2-en-1-one with guanidine and thiourea result in 4-[5-(4-methyl-phenyl)-1,2-oxazol-3-yl]-6-ferrocenylpyrimidin-2-amine and -2-thione respectively.     

Derivatives of α,β-dehydro amino acids: III. Reaction of 4-arylmethylidene-4,5-dihydro-1,3-oxazol-5-ones with hexamethyldisilazane

4-Arylmethylidene-4,5-dihydro-1,3-oxazol-5-ones reacted with hexamethyldisilazane in ethyl acetate, acetonitrile, or DMF at room temperature to give mainly 2-acylamino-3-arylmethylideneprop-2-enamides, whereas in boiling DMF the corresponding 4-arylmethylidene-4,5-dihydro-1H-imidazol-5-ones were formed. The reaction of 2-benzoylamino-3-phenylprop-2-enamide with hexamethyldisilazane also led to the formation of 4-benzylidene-2-phenyl-4,5-dihydro-1H-imidazol-5-one, while its reaction with chlorotrimethylsilane afforded either a 1:1 mixture of 4-benzylidene-2-phenyl-4,5-dihydro-1,3-oxazol-5-one and 4-benzylidene-2-phenyl-4,5-dihydro-1H-imidazol-5-one or only the latter, depending on the solvent.     

Thermally induced opening of the diaziridine ring in 6-aryl-2-methyl-1,5-diazabicyclo[3.1.0]hexanes

Thermally induced opening of the diaziridine ring in 6-aryl-2-methyl-1,5-diazabicyclo[3.1.0]-hexanes at the carbon-nitrogen bond is characterized by low regioselectivity; isomerization of unstable intermediate azomethine imines leads to mixtures of the corresponding 1-arylmethyl-5-methyl-4,5-dihydro-1H-pyrazoles and 1-arylmethyl-3-methyl-4,5-dihydro-1H-pyrazoles at a ratio of ～6:5. Analogous regioselectivity in opening of the three-membered ring is observed in the presence of phenyl isocyanate. In this case, adducts with cis arrangement of the aryl and methyl groups are formed as the major products (cis/trans ratio ～3:1).     

Synthesis of Azaheterocyclic Cymantrene Derivatives

The reduction of acetylcymantrene with sodium tetrahydridoborate gave cymantrenylethanol which was acylated with 4,5-dichloroisothiazole- and 5-(4-methylphenyl)isoxazole-3-carbonyl chlorides to obtain esters containing a 1,2-thia(oxa)zole fragment. The condensation of acetylcymantrene with 5-arylisoxazole-3- carbaldehydes, (5-arylisoxazol-3-yl)methoxybenzaldehydes (Ar = Ph, 4-Tol), and 4,5-dichloroisothiazole-3- carbaldehyde afforded the corresponding (E)-3-(azol-3-yl)-1-cymantrenylprop-2-en-1-ones. The resulting α,β- unsaturated ketones reacted with semicarbazide hydrochloride and thiosemicarbazide to produce substituted 4,5-dihydro-1H-pyrazole-1-carboxamides and -1-carbothioamides, and their reaction with hydroxylamine hydrochloride led to the formation of 4,5-dihydroisoxazoles containing cymantrene and 1,2-azole fragments. Heterocyclization of azolylcymantrenylpropenones with guanidine gave 2-aminopyrimidine derivatives, and dihydropyrimidine-2-thiones were obtained by their reaction with thiourea.     

Azines and azoles: CXXV. New regioselective synthesis of 1-amino-6-methyluracils

Readily accessible 5-acetyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione reacts with substituted hydrazines and carboxylic acid hydrazides under mild conditions to give the corresponding hydrazones. Under severe conditions (heating in boiling dimethylformamide) the reaction is accompanied by extrusion of COS with formation of substituted 1-amino-6-methyluracils. Reactions of 5-acetyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione with monosubstituted alkyl-and arylhydrazines take different pathways, depending on the conditions. Heating of equimolar mixtures of the reactants in ethanol or propan-1-ol leads to the formation of 2-substituted 5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamides rather than 1-amino-6-methyluracil derivatives.     

Five-membered 2,3-dioxo heterocycles: LXXXII. Recyclization of dimethyl 4,5-Dioxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates in reaction with monosubstituted hydrazines. crystalline and molecular structure of dimethyl 1-benzyl-5-(4-methylphenylcarbamoyl)-1H-pyrazole-3,4-dicarboxylate

Dimethyl 1-aryl(benzyl)-4,5-dioxo-4,5-dihydro-1H-pyrrole-2,3-dicarboxylates reacted with phenylhydrazine and benzylhydrazine to give dimethyl 1-aryl(benzyl)-5-[(aryl or benzyl)carbamoyl]-1H-pyrazole-3,4-dicarboxylates.     

Regioselective cyclocondensation of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates with thiazolylhydrazines

Ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates reacted in a regioselective fashion with thiazolylhydrazines to give the corresponding ethyl 1-thiazolyl-5-fluoroalkyl-1H-pyrazole-4-carboxylates. The product structure was determined on the basis of NMR and X-ray diffraction data.