Alkylating nucleosides. 3. The reaction of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide

Bromination of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide gave the corresponding 4-bromo-3,5-dimethylpyrazole, 3-methyl-5-(bromomethyl)pyrazole and 4-bromo-3-methyl-5-(bromomethyl)pyrazole nucleosides. Structural assignments were made on basis of analytical and ¹ H nmr spectral data. All of the bromomethylpyrazole nucleosides described showed cytostatic activity against HeLa cell sultures.     

Hetarylpyrazoles. II. Reactions of pyrazol-l'-ylpyridines

Pyrazol-l'-ylpyridines undergo electrophilic substitution reactions (bromination, chlorination, and nitration) preferentially in the pyrazole ring. There is some evidence of the mutual influence of the pyrazole and the pyridine ring on the reactivity of the system. Some modifications of the substituents were also carried out. A dihydro derivative of a new ring system, pyrazolo[1′,2′-a]pyrido[2,1-c][l,2,4]triazine was also obtained.     

Acetylenic ketones. Part IV. Reaction of p-nitrobenzoylphenylacetylene with nucleophilic nitrogen compounds

p-Nitrobenzoylphenylacetylene (I) reacted with acylhydrazines (IIa-d) to give the corresponding hydrazones (VIa-d), which when treated with acetic anhydride, gave the same substituted pyrazole (VII). Hydrolysis of the latter with methanolic potassium hydroxide gave the pyrazole derivative (IX). The reaction of I with ethyl and phenyl hydrazinecarboxylates (IIe,f) led to the formation of the hydrazones (VIe) and (VIf), respectively, whereas with methyl- and phenylhydrazines it produced the pyrazoles (X) and (XI), respectively. However, guanidine hydrochloride gave with acetylenic ketone (I), the pyrimidine (XV).     

Electron density distribution in heterocyclic systems with two vicinal nitrogen atoms. III. Dipole moments of some alkyl,aryl, and nitro pyrazole derivatives

Dipole moments of 13 alkyl and aryl derivatives of pyrazole are determined. It is found that fundamentally it is the pyrazole ring that determines the values of these dipole moments. The phenyl group behaves as a weak electron donor with respect to the pyrazole ring. It is shown that under the action of powerful electron-accepting substituents, such as the nitro group, the electron cloud of the pyrazole ring is polarized toward the electron acceptor.For Part II see [1].     

Nitropyrazoles 22. On reactivity of 3,5-dinitro-4-(phenylsulfonyl)pyrazole and its N-methyl derivative

3,5-Dinitro-4-(phenylsulfonyl)pyrazole (5) obtained by oxidation of 3,5-dinitro-4-(phenylthio)pyrazole with 30% H₂O₂ in AcOH was involved into nucleophilic substitution reaction with thiophenol, which proceeded with substitution of the phenylsulfonyl group at position 4. N-Methyl-3,5-dinitro-4-(phenylsulfonyl)pyrazole obtained by methylation of 5 with dimethyl sulfate was involved into nucleophilic substitution reaction with thiophenol, p-bromophenol, and morpholine with the regioselective substitution of the nitro group at position 5 to form 5-R-3-nitro-4-(phenylsulfonyl)pyrazoles.     

Research on nitrogen heterocyclic compounds. XV. Synthesis of 1H,4H-pyrazolo[4,3f]pyrrolo[1,2-a][1,4]diazepine derivatives

The synthesis of derivatives of 1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine, a new tricyclic nitrogen-containing nucleus is reported. Condensation of arylaldehydes with 4-aminomethyl-1-phenyl-5-(1-pyrryl)pyrazole afforded the title compounds. Bischler-Napieralski intramolecular cyclization of 4-acetamidomethyl-1-phenyl-5-(1-pyrryl)pyrazole was also studied. The reaction led to 6-methyl-1-phenyl-1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepine or alternatively to 4-chloromethyl-1-phenyl-5-(1-pyrryl)pyrazole depending on the solvent used.     

Oxidation of pyrazoles containing the 2-hydroxyethyl group on a NiO(OH) electrode in aqueous alkali

The electrooxidation of pyrazoles containing hydroxyethyl group bound with the pyrazole ring at its N and C atoms (1-(2-hydroxyethyl)pyrazole and (4-(2-hydroxyethyl)pyrazole, respectively) in an undivided cell on a NiO(OH) electrode in aqueous alkali is studied. The oxidation of 1-(2-hydroxyethyl)pyrazole is shown to result in the formation of pyrazole-1-acetic acid with a yield of 80.0%. In the case of 4-(2-hydroxyethyl)pyrazole the process proceeds more exhaustively, leading to the formation of pyrazole-4-carboxylic acid as the major product with a yield of 57.0%. The regularities of these processes are discussed.     

Thermodynamique de composes azotes. VII. Etude thermochimique du pyrazole et de l'imidazole

Enthalpies of sublimation for pyrazole and imidazole have been obtained by calorimetry at 298.15K. The ΔH⁰_sub (298.15 K) values for these two compounds are, respectively, 69.16 ± 0.32 and 74.50 ± 0.40 kJ mole^?1. From literature data obtained by combustion calorimetry for ΔH⁰_f (c, 298.15 K), the enthalpies of formation of these compounds in the gaseous state (pyrazole: 185.1 ± 2.3 kJ mole^?, imidazole: 133.0 ± 1.7 kJ mole^?1) have been derived. Several energy values related to the molecular structure of these two compounds (as resonance energy, enthalpy of isomerization, …) have been determined. The study of pyrazole has enabled us to contribute to the evaluation of some characteristics of the NN bond.     

Ruthenium-catalyzed C-H/CO/Olefin coupling reaction of N-arylpyrazoles. Extraordinary reactivity of N-arylpyrazoles toward carbonylation at C-H bonds

The reaction of 1-arylpyrazoles with CO and ethylene in the presence of Ru(3)(CO)(12) resulted in regioselective carbonylation at the ortho C-H bonds. While it is found that the pyrazole ring also functions as the directing group for C-H bond cleavage, the efficiency of the reaction depends on the position of the pyrazole ring.     

Chemistry of Modified Flavonoids. 24. Synthesis of 4- Aryloxy-3-(2-hydroxy-4-hydroxy/alkoxyphenyl)pyrazoles

3-Aryloxychromones are recyclized under the action of hydrazine into derivatives of 4-aryloxy-3-(2,4-dihydroxyphenyl)pyrazole.     

Pyridazines. XLV . on the mechanism of an unusual 1,2-diazine → 1,2-diazole ring contraction

Starting with succinic acid-2,3-13C, phenyl(4-pyridazinyl)methanol-4,5-¹³C was prepared in order to gain insight into the mechanism of an unusual pyridazine into pyrazole rearrangement reported previously. According to the ¹³C-nmr spectrum of labeled 1-phenyl-2(4-pyrazolyl)ethanone obtained upon p-toluenesulfonic acid mediated ring contraction, the methylene and the pyrazole C-4 carbon atoms of the reaction product originate from the pyridazine carbon atoms 4 and 5 of the educt. Thus, a mechanism for this ring-transformation is proposed involving well stabilized carbocations as intermediates.     

Pyrazoles. 5. Novel pyrazole analogues of flavanone,flavone and flavane

The synthesis of the new pyrano[2,3-c]pyrazole derivatives 4, 5 , and 7 starting from (E)-(1,3-dimethyl-5-hydroxy-4-pyrazolyl)-3-phenyl-2-propen-1-one ( 2 ) is reported.     

Condensation of methylhydrazine with 4‐ethoxy‐1,1,1‐trifluoro‐3‐buten‐2‐one. A reinvestigation

In contrast to previous reports, 4‐ethoxy‐1,1,1‐trifluoro‐3‐buten‐2‐one ( 1 ) was observed to react with methylhydrazine ( 2 ) in refluxing ethanol to yield 1‐methyl‐3‐(trifluoromethyl)pyrazole ( 6 ) and 4,5‐dihydro‐1‐methyl‐5‐(trifluoromethyl)pyrazol‐5‐ol ( 4 ). The later compound undergoes acid catalyzed dehydration to 1‐methyl‐5‐(trifluoromethyl)pyrazole ( 3 ).     

Study of the spectroscopic characteristics of methyl (ligand) cobaloximes and their antibacterial activity

Spectroscopic characterization (IR, NMR and electronic spectra) of methyl (ligand) cobaloxime was done, where ligand = pyrazole, dimethyl pyrazole, alanine and alanine methyl ester. The frequency changes in the IR spectra and shifts in the NMR were explained on the basis of basicity of the ligand, steric hindrance, HSAB principle and dπ-pπ back-bonding from metal to ligand. Alanine and alanine methyl ester form more stable complexes than pyrazole and dimethyl pyrazole. Based on their IR and ¹H NMR spectra it is inferred that pyrazole and dimethylpyrazole bind to Co (III) via N-2 ring nitrogen, i.e. monodentate coordination.     

Dopamine interaction in the absence and in the presence of Cu2+ ions with macrocyclic and macrobicyclic polyamines containing pyrazole units. Crystal structures of [Cu2(L1)(H2O)2](ClO4)4 and [Cu2(H-1L3)](ClO4)3*2H2O.

The interaction with Cu2+ and dopamine of three polyazacyclophanes containing pyrazole fragments as spacers is described. Formation of mixed complexes Cu2+-macrocycle-dopamine has been studied by potentiometric methods in aqueous solution. The crystal structures of the complexes [Cu2(L1)(H2O)2](ClO4)4*2H2O (4) (L1 = 13,26-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.1(11,14)]octacosa-1(27),11,14(28),24-tetraene) and [Cu2(H-1L3)](HClO4)(ClO4)2*2H2O (6) (L3 = 1,4,7,8,11,14,17,20,21,24,29,32,33,36-tetradecaazapentacyclo[12.12.12.1(6,9).1(19,22).1(31,34)]hentetraconta-6,9(41),19(40),21,31,34(39)-hexaene) are presented. In the first one (4), each Cu2+ coordination site is made up by the three nitrogens of the polyamine bridge, a sp2 pyrazole nitrogen and one water molecule that occupies the axial position of a square pyramid. The distance between the copper ions is 6.788(2) A. In the crystal structure of 6, the coordination geometry around each Cu2+ is square pyramidal with its base being formed by two secondary nitrogens of the bridge and two nitrogen atoms of two different pyrazolate units which act as exobidentate ligands. The axial positions are occupied by the bridgehead nitrogen atoms; the elongation is more pronounced in one of the two sites [Cu(1)-N(1), 2.29(2) A; Cu(2)-N(6), 2.40(1) A]. The Cu-N distances involving the deprotonated pyrazole moieties are significantly shorter than those of the secondary nitrogens. The Cu(1)...Cu(2) distance is 3.960(3) A. The pyrazole in the noncoordinating bridge does not deprotonate and lies to one side of the macrocyclic cavity. One of the aliphatic nitrogens of this bridge is protonated and hydrogen bonded to a water molecule, which is further connected to the sp2 nitrogen of the pyrazole moiety through a hydrogen bond. The solution studies reveal a ready deprotonation of the pyrazole units induced by coordination to Cu2+. In the case of L2 (L2 = 3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.1(11,14)]octacosa-1(27),11,14(28),24-tetraene), deprotonation of both pyrazole subunits is already observed at pH ca. 4 for 2:1 Cu2+:L2 molar ratios. All three free receptors interact with dopamine in aqueous solution. L3 is a receptor particularly interesting with respect to the values of the interaction constants over five logarithmic units at neutral pH, which might suggest an encapsulation of dopamine in the macrocyclic cage. All three receptors form mixed complexes Cu2+-L-dopamine. The affinity for the formation of ternary dopamine complexes is particularly high in the case of the binuclear Cu2+ complexes of the 1-benzyl derivative L1.     

Novel anionic annelation tactics for construction of fused heteroaromatic frameworks. 1. Synthesis of 4-substituted pyrazolo[3,4-c]quinolines, 9-substituted pyrazolo[3,4-c]quinolines, and 1,4-dihydrochromeno[4,3-c]pyrazoles

4-Substituted pyrazolo[4,3-c]quinolines 4a-i and 6a-b were prepared from pyrazole 3 whereas 9-substituted pyrazolo[3,4-c]quinolines 9a-d and 17 were prepared from pyrazole 13 utilizing anionic annelation techniques. 1,4-dihydrochromeno[4,3-c]pyrazoles 7a-c were accessed from pyrazole 3, extending the method for the synthesis of 4a-i.     

Synthesis and properties of pyrazole carbaldehyde bis(2-hydroxyethyl)-dithioacetal hydrochlorides*

A simple method has been developed for the synthesis of water-soluble pyrazole derivatives, namely 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazoles hydrochlorides, by the reaction of a series of pyrazole carbaldehydes with 2-mercaptoethanol in the presence of trimethylchlorosilane. When treated with aqueous ammonia solution the pyrazole-4-carbaldehydes bis(2-hydroxyethyl)dithioacetal hydro-chlorides are converted to the 4-[bis(2-hydroxyethylsulfanyl)methyl]pyrazole free bases.     

Design, synthesis, and biological evaluation of novel alkenylthiophenes as potent and selective CB1 cannabinoid receptor antagonists

A novel class of (5-(pent-1-enyl)thiophen-2-yl)pyrazole antagonists was discovered, many of which exhibited potent CB1 activity and good CB1/2 selectivity, suggesting that along with a 1,3-transposition of the carbonyl of the pyrazole 3-carboxamide, bioisosteric replacement of the conventional pyrazole 5-aryl group with a thienyl ring substituted with an appropriate alkenyl moiety is viable.     

Sequential functionalization of pyrazole 1-oxides via regioselective metalation: synthesis of 3,4,5-trisubstituted 1-hydroxypyrazoles

A range of 3,5-diarylated and 3,4,5-triarylated 2-(4-methoxybenzyl)pyrazole 1-oxides have been prepared by regioselective deprotonation at C-5 or bromine-magnesium exchange at C-3 or C-4 followed by transmetalation with ZnCl(2) and palladium(0)-catalyzed cross-coupling. Furthermore, the metalated pyrazole 1-oxides could be trapped with electrophiles. The sequential metalation/functionalization of the pyrazole 1-oxides may follow the order C-5, C-3, C-4, or alternatively the order C-3, C-5, C-4. The 4-methoxybenzyl group of the functionalized 2-(4-methoxybenzyl)pyrazole 1-oxides could be removed by treatment with TFA and i-Pr(3)SiH in CH(2)Cl(2), providing the corresponding functionalized 1-hydroxypyrazoles.