Synthesis and spectral analysis of (±)-cis-N-[1-(2-hydroxy-2-phenyl-ethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide

Treatment of (±)-cis-N-(3-methyl-4-piperidyl)-N-phenylpropanamide (2) with styrene oxide (1) yielded a mixture of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (3) and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (4) . The structure of compound 3 was confirmed by an unambiguous synthesis via (±)-cis-N-[1-(2-oxo-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (6) . The proton and carbon-13 resonances of compounds 3 and 4 were assigned with the aid of two-dimensional heteronuclear correlation experiments.     

4-Functionally Substituted 3-Heterylpyrazoles: IV. 1-Phenyl-3-aryl(heteryl)-5-(4-pyrazolyl)-2-pyrazolines

3-Aryl(heteryl)-4-formylpyrazoles in condensation with methyl aryl(heteryl) ketones afforded 1-aryl(heteryl)-3-[3-aryl(heteryl)-4-pyrazolyl]propenones. The latter reacted with phenylhydrazine yielding 1-phenyl-3-aryl(heteryl)-5-(4-pyrazolyl)-2-pyrazolines.     

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1353–1358, September, 2007.     

Metallacycles of iron, zinc, and cadmium assembled by polytopic bis(pyrazolyl)methane ligands and fluoride abstraction from BF4-

Reactions of the arene-linked bis(pyrazolyl)methane ligands m-bis[bis(1-pyrazolyl)methyl]benzene (m-[CH(pz)2]2C6H4, Lm) and 1,3,5-tris[bis(1-pyrazolyl)methyl]benzene (1,3,5-[CH(pz)2]3C6H3, L3) with BF4- salts of divalent iron, zinc, and cadmium result in fluoride abstraction from BF4- and formation of fluoride-bridged metallacyclic complexes. Treatment of Fe(BF4)2.6H2O and Zn(BF4)2.5H2O with Lm leads to the complexes [Fe2(mu-F)(mu-Lm)2](BF4)3 (1) and [Zn2(mu-F)(mu-Lm)2](BF4)3 (2), in which a single fluoride ligand and two Lm molecules bridge the two metal centers. The reaction of [Cd2(thf)5](BF4)4 with Lm results in the complex [Cd2(mu-F)2(mu-Lm)2](BF4)2 (3), which contains dimeric cations in which two fluoride and two Lm ligands bridge the cadmium centers. Equimolar amounts of the tritopic ligand L3 and Zn(BF4)2.5H2O react to give the related monofluoride-bridged complex [Zn2(mu-F)(mu-L3)2](BF4)3 (4), in which one bis(pyrazolyl)methane unit on each ligand remains unbound. NMR spectroscopic studies show that in acetonitrile the zinc metallacycles observed in the solid-state remain intact in solution.     

Microwave-assisted synthesis of 1-{2-[(1-benzyl-1<Emphasis Type="Italic">H</Emphasis>-1,2,3-triazol-4-yl)methoxy]phenyl}-3-(3-aryl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)prop-2-en-1-ones and their antimicrobial activity

A series of new (E)-1-{2-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3i) has been synthesized via copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction (CuAAC) of benzyl azide with substituted (E)-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-[2-(prop-2-ynyloxy)phenyl]prop-2-en-1-ones (2a–2i). The synthesized compounds have been characterized by their IR, ^lH, ¹³C NMR spectra, and mass spectroscopy data. All the compounds have been screened for antimicrobial activity.     

Polyfunctional pyrazoles. 4. Synthesis of 3-[3-aryl-1-(2-ethoxycarbonyl)-4-pyrazolyl]acrylic and-propionic acids

3-(3-Aryl-4-formyl-1-pyrazolyl)propionic acids are converted by Knoevenagel condensation under conditions of microwave activation into 3-[3-aryl-1-(2-ethoxycarbonyl)-4-pyrazolyl]acrylic acids. Reduction of the latter with hydrazine hydrate in the presence of Raney nickel gives 3-[3-aryl-1-(2-ethoxycarbonyl)-4-pyrazolyl]propionic acids. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 686–690, May, 2006.     

Roles of two basic nitrogen atoms in 1-substituted 4-(1,2-diphenylethyl)piperazine derivatives in production of opioid agonist and antagonist activities

To ascertain roles of the two basic nitrogen atoms in 1-substituted 4-[2,(3-hydroxyphenyl)-1-phenylethyl]-piperazine derivatives (1) in the expression of opioid agonist and antagonist activities, a methine group (CH) was isosterically substituted for nitrogen atom at the 1-position (N-1) in compound 1 to obtain 4-substituted 1-[2-(3-hydroxyphenyl)-1-phenylethyl]piperidine derivatives (2). Their analgesic action and ability to produce physical dependence (jump-producing activity) as the mu-opioid receptor specific in vivo actions, and narcotic antagonist action in mice were compared with those of compound 1. Results of this study showed that, in cases of the racemate and the (S)-(+) enantiomer, opioid agonist activities (analgesic and jump-producing activities) were not greatly affected by the methine-substitution for N-1 in compound 1, but that the narcotic antagonist activity of the (R)-(-) enatiomer was abolished by this substitution. It thus appears that N-1 in compound 1 contributes to the expression of narcotic antagonist activity, whereas the nitrogen atom at the 4-position corresponds to the tyramine moiety necessary for the expression of mu-opioid agonist activity.     

Synthesis of 7-azabicyclo[2.2.1]heptane and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives by base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides, investigating the effect of the nitrogen protecting group and the relative configuration of the leaving group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11, 13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been carried out to rationalize the formation of the different adducts.     

Synthesis of 4,4-disubstituted piperidine analogs of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide

Condensation of (±)-1-benzyl-3-methyl-4-piperidone ( 1 ) with aniline followed by trapping of the intermediate imine with cyanide generated a mixture of isomeric nitriles 2A and 2B , the structures of which were established unambiguously by obtaining an X-ray crystal structure on nitrile 2B . Subsequent elaboration of the nitrile intermediates provided analogs of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide having a second substituent (carbomethoxyl, carboethoxyl, methoxymethyl) at the piper-idine 4-position. The conversion of the carboxamide intermediates 3A and 3B to the carboalkoxyl intermediates 5A, 5B and 6A was accomplished utilizing a modified esterification procedure. Proton nmr data are presented for both the final products and the key synthetic intermediates.     

Unprecedented long-range 1,7-bromination in gold complexes of N-(aryl)imino functionalized N-heterocyclic carbenes

An unique long-range 1,7-bromination reaction is observed in gold(iii) complexes of N-(aryl)imino functionalized N-heterocyclic carbene with the bromination occurring at two different carbon (sp(2) and sp(3)) centers spatially separated by ca. 6.4 A but existing in extended conjugation to each other. In particular, the unusual distant 1,7-brominated gold(iii) complexes [1-R-3-{N-(p-bromo-2,6-di-i-propylphenylimino)-2-phenyl-1-bromoethyl}imidazol-2-ylidene]AuBr(3) [R = Me (), i-Pr (), t-Bu (), -CH(2)Ph ()] were synthesized cleanly at room temperature under ambient conditions from the reactions of molecular bromine with the gold(i) complexes [1-R-3-{N-(2,6-di-i-propylphenylimino)-2-phenylethyl}imidazol-2-ylidene]AuCl [R = Me (), i-Pr (), t-Bu (), -CH(2)Ph ()]. All of the 1,7-bromination products (, , and ) have been structurally verified by X-ray diffraction studies.     

Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. II. Optimization of the phenylpiperazine moiety of 1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-3-phenylpiperazinyl-1-trans-propenes

A series of novel 3-substituted-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes in order to improve the in vitro and in vivo activity of our prototype 3-[4-(3-chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propene (2) were synthesized and evaluated by assays of growth inhibition against several tumor cell lines in vitro and antitumor activity against some tumor models when dosed both intraperitoneally and orally in vivo. Compounds 7a and 7e, the 3,5-difluorophenyl and 3,5-dichlorophenyl analogues of 2, respectively, showed significantly more potent cytotoxicity than 2 in vitro and potent antitumor activities without causing decrease of body temperature related to side effects.     

Synthesis and antimicrobial study of linked heterocyclics containing Pyrazole-pyrimidine-thiazolidin-4-one

A new series of linked heterocyclics, 3-[4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-pyrimidinyl]-2-(aryl/heteryl)-1,3-thiazolan-4-ones (6a-j), has been synthesized by the one-pot cyclo-condensation of 4-(4-chlorophenyl)-6-(3,5-dimethyl-1-phenyl-1H-4-pyrazolyl)-2-pyrimidinamine (5), aryl/heteroaryl aldehyde and thioglycolic acid. The structures of the synthesized compounds have been confirmed via IR, (1)H-NMR, (13)C-NMR, MS and elemental analyses. Further, all the newly synthesized compounds 6a-j have been assayed for their antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi. The compounds containing moieties like 4-nitrophenyl (6c), 3-nitrophenyl (6d), 4-dimethylaminophenyl (6g), 2-furyl (6i) and 1,3-benzodioxole (6j), at 2-position of thiazolidin-4-one ring exhibited good inhibitory activity against all the tested organisms.     

Heteroatomic derivatives of aziridine. 14. Reactions of 1-(carbomethoxyethyl)-, 1-[1,2-bis(carbethoxy)ethyl]-, and 1-[1,2-bis(carbomethoxy)vinyl]aziridine with thiols, 1,2-ethanedithiol,and thiolcarboxylic acids

The reactions of 1-(carbomethoxyethyl)-, 1-[1,2-bis(carbethoxy)-ethyl]-, and 1-[1,2-bis(carbomethoxy)vinyl]aziridine with thiols and thiolcarboxylic acids produce the corresponding sulfides and esters of S-substituted N-(2-mercaptoethyl) amino acids. The reaction of 1-[1,2-bis(carbethoxy)ethyl]aziridine with 1,2-ethane-dithiol results in the formation of {1,8-bis[1,2-bis(carbethoxy)-ethyl]amino}-3,6-dithiaoctane. Cyclization of the latter by condensation with phthaloyl chloride gives 9,10-benzo-8,11-dioxo-1,4-dithia-7,12-bis[1,2-bis(carbethoxy)ethyl]-7,12-diazacyclotetradec-9-ene.For report 13 see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1340–1342, October, 1984.     

Synthesis and pharmacological evaluation of 2-(1-alkylpiperidin-4-yl)-n-[(1r)-1-(4-fluorophenyl)-2-methylpropyl]acetamide Derivatives as Novel Antihypertensive Agents

We synthesized and evaluated the inhibitory activity of a series of 2-(1-alkylpiperidin-4-yl)-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]acetamide derivatives against T-type Ca(2+) channels. Structure-activity relationship studies revealed that the position of the amide structure was important for the potent inhibitory activity toward T-type Ca(2+) channels. In addition, the introduction of an appropriate substituent on the pendant benzene ring played a crucial role for the selectivity towards T-type Ca(2+) channels over L-type Ca(2+) channels and the potent bradycardic activity of these derivatives. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-2-(1-{2-[2-(2-methoxyethoxy)phenyl]ethyl}piperidin-4-yl)acetamide (4f), which had superior selectivity for T-type Ca(2+) channels over L-type Ca(2+) channels, lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.     

Synthesis and reactions of 3-(3-ethoxycarbonyl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)propenic acid

The reaction of ethyl 4-formyl-1-phenyl-1H-pyrazole-3-carboxylate with the malonic acid led to the formation (2E)-3-(3-ethoxycarbonyl-1-phenyl-1H-pyrazol-4-yl)propenic acid. In reactions of this acid chloride with 4-amino-5-aryl(hetaryl)-4H-1,2,4-triazole-3-thiols were obtained ethyl 4-[(E)-2-{3-aryl(hetaryl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl}ethenyl]-1-phenyl-1H-pyrazoe-3-carboxylates, with 5-aryltetrazoles, ethyl 4-[(E)-2-(5-aryl-1,3,4-oxadiazol-2-yl)-ethenyl]-1-phenyl-1H-pyrazole-3-carboxylates, with 1-(2-hydroxy-3,5-dimethylphenyl) followed by the Baker-Venkataraman rearrangement and the cyclization, ethyl 4-[(E)-2-(6,8-dimethyl-4-oxo-4Hchromen-2-yl)ethenyl]-1-phenyl-1H-pyrazole-3-carboxylate.     

Synthesis and properties of ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1<Emphasis Type="Italic">H</Emphasis>-pyrazole-3-carboxylates

Ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates reacted with phenylhydrazine to give the corresponding hydrazones, ethyl 1-aryl-5-methyl-4-[1-(phenylhydrazinylidene)ethyl]-1H-pyrazole-3-carboxylates, which were converted to ethyl 1′-aryl-4-formyl-5′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazole-3′-carboxylates by treatment with the Vilsmeier–Haack reagent. No indole derivatives were formed from the same hydrazones under the Fischer reaction conditions, but cyclization to 2-aryl-3,4-dimethyl-6-phenyl-2,6-dihydro-7H-pyrazolo[3,4-d]pyridazin-7-ones was observed.     

Synthesis, Crystal Structure and Herbicidal Activity of N-（7-Chloro-5-ethoxy-2H-[1,2,4] thiadiazolo [2,3-a] pyrimidin-2-ylidene）-2-（2,4-dichlorophenoxy）propanamide

The title compound N-(7-chloro-5-ethoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin- 2-ylidene)- 2-(2,4-dichlorophenoxy)propanamide 3 has been synthesized through using bromine as cyclic reagent in 63% isolated yield. Suitable single crystals for X-ray diffraction were obtained by recrystallization from the mixture solvents at room temperature. Crystallographic data of 3: C16H13- Cl3O3S, Mr = 447.71, triclinic, space group P, a = 8.7461(8), b = 9.9560(10), c = 11.8572(11) , α = 94.341(2), β = 94.683(2), γ = 112.929(2)o, Z = 2, V = 941.21(15) 3, Dc = 1.580 g/cm3, F(000) = 456, R = 0.0794, wR = 0.2056 and μ(MoKα) = 0.623 mm-1. The title compound 3 was found to be effective in herbicidal activity.     

Some reactions of 1-methyl-(2-phenylethyl)-1,2,3,4-tetrahydropyridines with organic azides. Synthesis of 1-methyl-(2-phenylethyl)piperidylidene-2-sulfonamides

The 1,3-dipolar cycloaddition reaction of 1-methyl- and 1-(2-phenylethyl)-1,2,3,4-tetrahydropyridines 7 with organic azides 8 afforded the respective 1-substituted-piperidylidene-2-sulfon(cyan)amides 9. Nitration of the 1-(2-phenylethyl) analogue 9o yielded the 1-[2-(4-nitrophenyl)ethyl] derivative 9r which on reduction with palladium-on-charcoal and hydrazine gave the 1-[2-(4-aminophenyl)ethyl] analogue 9s.     

Nucleophilic substitution in 4-bromo-5-nitrophthalodinitrile: VIII. Synthesis of 4-(benzotriazol-1-yl)-5-[4-(1-methyl-1-phenylethyl)phenoxy]phthalodinitrile and phthalocyanines on its basis

Nucleophilic aromatic substitution of the bromine atom in 4-bromo-5-nitrophthalodinitrile by a 2-aminophenylamine residue followed by conversion of the resulting compound to 4-(1-benzothiazol-1-yl)-5-nitrophthalodinitrile and nucleophilic substitution of the nitro group by a 4-(1-methyl-1-phenylethyl)-phenoxy group gave 4-(benzotriazol-1-yl)-5-[4-(1-methyl-1-phenylethyl)phenoxy]phthalodinitrile. The latter product was reacted with certain metal acetates and chlorides to obtain the corresponding metal complexes of octasubstituted phthalocyanines. Spectral properties of the complexes were studied.     

The solvent extraction and spectrophotometric determination of vanadium (V) with 4-(2-thiazolylazo)resorcinol and tetrazolium salts

The formation and extraction of ion-associate complexes between the vanadium(V)-4-(2-thiazolylazo)resorcinol (TAR) anionic chelate and the cations of some mono-and ditetrazolium salts {3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (Thiazolyl blue, MTT), 3-(2-naphtyl)-2,5-diphenyl-2H-tetrazolium chloride (Tetrazolium violet), 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-phenyl-2H-tetrazolium chloride (Iodonitrotetrazolium chloride), 3,3′-[3,3′-dimetoxy(1,1′-biphenyl)-4,4′-diyl]-bis[2,5-diphenyl-2H-tetrazolium] chloride (Tetrazolium blue chloride) and 3,3′-(3,3′-dimetoxy-4,4′-biphenylene)bis[2-(4-nitrophenyl)-5-phenyl-2H-tetrazolium chloride] (Nitro blue tetrazolium chloride)} have been studied. The optimum extraction conditions have been found. The composition of the V-TAR-monotetrazolium and V-TAR-ditetrazolium complexes extracted into chloroform has been determined to be 1:2:3 and 2:4:3 respectively. The extraction, distribution and association constants, and the recovery factors have been calculated. The relationship between the molecular weight of tetrazolium cations, and the association constants of their complexes has been discussed. The special behavior of the tetrazolium cations, containing-NO₂ groups has been noticed. The effects of foreign ions and reagents on the extraction of vanadium with TAR and the best tetrazolium salt-MTT have been studied. A sensitive, selective, simple and fast method for the determination of vanadium has been developed.