6085-94-5

We report the metalation of the 1,3,4-oxadiazole and 1,2,4-triazole scaffolds via regioselective zincation or magnesiation using the TMP bases (TMP = 2,2,6,6-tetramethylpiperidyl) TMP2Zn·2LiCl, TMP2Zn·2MgCl2·2LiCl, TMPMgCl

The invention discloses an N-difluoromethylazole sulfur (selenium) urea derivative and a preparation method thereof. The N-difluoromethylazole sulfur (selenium) urea derivative comprises N-difluoromethyl benzimidazole sulfourea, N-difluoromethyl imidazole sulfourea, N-difluoromethyl triazole sulfourea and an relevant N-difluoromethyl selenourea derivative; and a benzimidazole derivative, an imidazole derivative or a triazole derivative, elemental sulfur powder or selenium powder, and a catalyst are added into a reaction tube, an organic solvent is added into the reaction tube, halohydrocarbonis injected into the reaction tube, and reacting is carried out under a heating condition to obtain the N-difluoromethylazole sulfur (selenium) urea derivative. The preparation method is simple and easy to operate, the condition is mild, the cheap and economical effects are achieved, and the provided compounds have important potential application value in pesticides, medicines and organic functional materials.

Molecules labeled with fluorine-18 (18F) are used in positron emission tomography to visualize, characterize and measure biological processes in the body. Despite recent advances in the incorporation of 18F onto arenes, the development of general and efficient approaches to label radioligands necessary for drug discovery programs remains a significant task. This full account describes a derisking approach toward the radiosynthesis of heterocyclic positron emission tomography (PET) radioligands using the copper-mediated 18F-fluorination of aryl boron reagents with 18F-fluoride as a model reaction. This approach is based on a study examining how the presence of heterocycles commonly used in drug development affects the efficiency of 18F-fluorination for a representative aryl boron reagent, and on the labeling of more than 50 (hetero)aryl boronic esters. This set of data allows for the application of this derisking strategy to the successful radiosynthesis of seven structurally complex pharmaceutically relevant heterocycle-containing molecules.

A series of highly luminescent, heteroleptic copper(I) complexes has been synthesized using a modular approach based on easily accessible P^N ligands, triphenylphosphine, and copper(I) halides, allowing for an independent tuning of the emission wavelength

Direct N-alkylation of amines with alcohols was successfully performed by using nanosized zeolite beta, which showed the highest catalytic activity among other conventional zeolites. This method has several advantages, such as eco-friendliness, moderate to high yields, and simple work-up procedure. The catalyst was successfully recovered and reused without significant loss of activity and only water is produced as co-product. In addition, imines were also efficiently prepared from the tandem reactions of amines with 2-, 3- and 4-nitrobenzyl alcohols using nanosized zeolite beta.

A series of bis- and mono-benzonitrile or phenyl analogues of letrozole 1, bearing (1,2,3 and 1,2,5)-triazole or imidazole, were synthesized and screened for their anti-aromatase activities. The unsubstituted 1,2,3-triazole 10a derivative displayed inhibitory activity comparable with that of the aromatase inhibitor, letrozole 1. Compound 10a, bearing a 1,2,3-triazole, is also 10000-times more tightly binding than the corresponding analogue 25 bearing a 1,2,5-triazole, which confirms the importance of a nitrogen atom at position 3 or 4 of the 5-membered ring needed for high activity. The effect on human epithelial adrenocortical carcinoma cell line (H295R) proliferation was also evaluated. The compound 10j (IC50 = 4.64 μM), a letrozole 1 analogue bearing para-cyanophenoxymethylene-1,2,3-triazole decreased proliferation rates of H295R cells by 76 and 99% in 24 and 72 h respectively. Computer calculations, using quantum ab initio structures, suggest a possible correlation between anti-aromatase activity and the distance between the nitrogen in position 3 or 4 of triazole nitrogen and the cyano group nitrogen.

Two series of bistriazolium dibromides with different alkyl bridged length (n = 2-4) were synthesised through a simple solvent-free method. Six of these compounds were prepared from the reaction of 1-R-1H-1,2,4-triazole with dibromoalkane in moderate to excellent yield (45-98%). However, the other six compounds were prepared from the reaction of alkyl bridged bistriazole with bromoalkane in 55-99% yield. All compounds are new and were fully characterised by IR, NMR and elemental analyses.

The rate constants for the reactions of a variety of nucleophiles reacting with substituted benzyl chlorides in liquid ammonia (LNH3) have been determined. To fully interpret the associated linear free-energy relationships, the ionization constants of phenols ions in liquid ammonia were obtained using UV spectra. These equilibrium constants are the product of those for ion-pair formation and dissociation to the free ions, which can be separated by evaluating the effect of added ammonium ions. There is a linear relationship between the pKa of phenols in liquid ammonia and those in water of slope 1.68. Aminium ions exist in their unprotonated free base form in liquid ammonia and their ionization constants could not be determined by NMR. The rates of solvolysis of substituted benzyl chlorides in liquid ammonia at 25 °C show a Hammett ρ of zero, having little or no dependence upon ring substituents, which is in stark contrast with the hydrolysis rates of substituted benzyl halides in water, which vary 107 fold. The rate of substitution of benzyl chloride by substituted phenoxide ions is first order in the concentration of the nucleophile indicative of a SN2 process, and the dependence of the rate constants on the pKa of the phenol in liquid ammonia generates a Bronsted βnuc = 0.40. Contrary to the solvolysis reaction, the reaction of phenoxide ion with 4-substituted benzyl chlorides gives a Hammett ρ = 1.1, excluding the 4-methoxy derivative, which shows the normal positive deviation. The second order rate constants for the substitution of benzyl chlorides by neutral and anionic amines show a single Bronsted βnuc = 0.21 (based on the aqueous pKa of amine), but their dependence on the substituent in substituted benzyl chlorides varies with a Hammett ρ of 0 for neutral amines, similar to that seen for solvolysis, whereas that for amine anions is 0.93, similar to that seen for phenoxide ion.(Figure Presented)

γ-Secretase inhibitors have been shown to reduce the production of β-amyloid, a component of the plaques that are found in brains of patients with Alzheimer's disease. A novel series of heterocyclic sulfonamide γ-secretase inhibitors that reduce β-amyloid levels in cells is reported. Several examples of compounds within this series demonstrate a higher propensity to inhibit the processing of amyloid precursor protein compared to Notch, an alternative γ-secretase substrate.

Enantiomerically pure 3,5-bis[(1S)-1-methoxyethyl]-4H-1,2,4-triazol-4-amine 14a and 3,5-bis[(1S)-1-ethoxyethyl]-4H-1,2,4-triazol-4-amine 14b were used as chiral auxiliaries to obtain enantiomerically enriched α-aminoacetals, primary alkyl and arylalkyl amines (ee ranging from 40% to 90%). The different stages of the process were imine formation from the corresponding aldehydes, diastereoselective addition of a Grignard reagent, quaternization of the triazole auxiliary and cleavage of the N4-Nexocyclic bond by LiBH4. The mechanism of the cleavage of the N4-Nexocyclic bond is supported by the use of deuterated metal hydride. The absolute configurations of the new stereogenic centres were established by X-ray analyses of the enantiomerically pure stereomers isolated by semi-preparative liquid chromatography on a chiral support.

It has been found that the N-alkylation of aniline, carboxamides and heterocyclic compounds bearing an acidic hydrogen atom attached to nitrogen can be accomplished with alkyl halides in acetonitrile and cesium fluoride-celite employed as a solid base. In this manner, pyrrole, indole, pyrazole, imidazole, benzimidazole, carbazole, phthalimide, indazole, indoline, 2-pyrrolidinone, piperidine and 1,2,4-triazole can be successfully alkylated. The procedure is convenient, efficient and generally gives rise to the N-alkylated product exclusively.

The syntheses and characterization of 4-substituted 4H-[1,2,4]triazol-1-ium phenylmethylides 8c-e and the new 5-aryl-1-phenacyl-1H-[1,2,4]triazolo[5,1-a]isoindole core 13 are reported for the first time. Treatment of triazolium salts 6c-e with triethylami

The alkylation of 1,2,4-triazole with 4-nitrobenzyl halides and a variety of bases afforded the 1- and 4-alkylated isomers with a consistent regioselectivity of 90:10. Previously reported regiospecific alkylations of 1,2,4-triazole were re-examined and the quoted isomer ratios were shown to depend on the isolation procedure. The use of DBU as base in the alkylation of 1,2,4-triazole allows for a convenient and high yielding synthesis of 1- substituted-1,2,4-triazoles. (C) 2000 Elsevier Science Ltd.

Novel 1,2,3-benzothiadiazole derivatives of the formula STR1 in which Het has the meanings set forth in the specification, and addition products thereof with an acid or metal salt are very effective for the control of undesired microorganisms. Novel intermediates of the formulae STR2 in which Het1 and R5 have the meanings given in the specification.

The reaction of 1,2,4-triazolium salt (7) with polarized olefins (2,3a,b) in the presence of K2CO3 in CHCl3-EtOH gave the corresponding triazolium N-allylides (8a-c).Thermolyses of N-allylides (8a,c) afforded the mesomeric betaine (9a) and the 8-amino-1,2,4-triazolopyridine derivative (10).Similar treatment of the salt (7) with polarized olefins (3c,d,4a) directly yielded mesomeric betaines (9c-e), while the reaction of the salt (7) with polarized olefin (4b) gave the pyrrolo-1,2,4-triazine derivative (11).The formation of mesomeric betaines is suggested to proceed via back-donated 1,6-cyclization.

Alkylation of 1,2,4-triazole and benzotriazole has been performed either in basic media under solvent free phase transfer catalysis conditions or in the absence of base by conventional and microwave heating.Several parameters affecting the selectivity have been studied.In the case of triazole alkylation, microwave irradiation produces specific (non thermal) effects both on reactivity and selectivity.

The lithiation chemistry of 1-alkyl-1H-1,2,4-triazol-5-yl phosphonic acid esters 3 has been investigated.Lithiation occurs exclusively on the 1-alkyl group, α to nitrogen, to give carbanioninc intermediates 10.No evidence was found for any lithiation at the 3-position of the triazole ring.On warming, intermediates 10 undergo an unusual anion-mediated phosphonate migration, giving rise to 1H-1,2,4-triazol-1-yl-methylphosphonates 14.

On heating with a catalytic quantity of the corresponding alkyl or phenacyl halides, 4-alkyl- or 4-phenacyl-1,2,4-triazoles isomerize via quaternary salts to their 1-substituted isomers.Thus, the 1-substituted compounds can now be obtained regiospecifical

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Performing alkylation, acylation and silylation reactions in separate deprotonation and nucleophilic displacement steps allows for better control of reaction conditions and facilitates problem handling in these processes.In the alkylation of azoles the alkylating agents and solvents possess individual reaction capabilities which seem to be approximately additive.Monoalkylation occurs if the sum of the normalized reaction potentials is equal or larger than the pKa value of the azole.Dialkylation is avoided by keeping the sum of the normalized reaction potentials below the pKa value of the alkylazole.The applicability of these principles is demonstrated by the development of effective procedures for the methylation, benzylation, acetylation, methoxycarbonylation and trimethylsilylation of azoles.

A therapeutically effective class of low toxicity aldoxime-substituted trazolium derivatives is disclosed which is effective in the treatment of living species poisoned by organophosphorus chemicals which inactivate the enzyme acetylcholinesterase. In vivo administration of therapeutically effective amounts of these low toxicity aldoxime-substituted triazolium derivatives has been found to save mice having inhibited acetylcholinesterase due to injection with lethal dosages of Soman.

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Quaternary 1,2,4-triazolium salts 1 couple easily with p-N,N-dimethylamino-benzenediazonium salts to form azodyes 3 (5-N,N-dimethylaminophenylazo-1,2,4-triazolium salts), preferably under solid-liquid phase transfer conditions using chloroform or methylene chloride and triethylamine or DABCO.Zwitterionic 1,2,4-triazolium salts (anhydro mercapto hydroxide, anhydro hydroxy hydroxide, and anhydro anilido hydroxide ("nitron")) couple as well.The azodyes - as also well known from industrially used types - absorb in the region of 500 nm and have high extinction coefficients.Substituents in 1-, 3- or 4-position of the triazolium ring exert no clear substituent effects.The quaternary 1,2,4-triazolium salts were synthesized according to standard procedures.

The electrochemical reduction of some N-acylamino-, N-amino-, N-benzyl- and N-phenacyl-substituted pyridinium and triazolium ions is investigated in acetonitrile by voltammetric methods and potentiostatic electrolyses.The acylaminopyridinium ions 1 and the arylaminopyridinium ions 3 are cathodically cleaved into the pyridine derivative and the carboxylic amide or the aromatic amine.In the case of the 1-benzyl-4-acylaminotriazolium ions 5 the reductive formation of hydrogen from the acidic N-acylamino group is preferred and the corresponding ylide is formed, which reacts at more negative potential by splitting off the benzyl group.The reduction of the N-phenacylpyridinium ion 7d occurs with splitting off the phenacyl radical, which dimerizes to 1,2-dibenzoylethane in a good yield.In the case of N-benzyl- and N-p-cyanobenzylpyridinium ions the cathodic dimerization to the corresponding bisdihydropyridines was found, whereas the electrolysis of the N-nitrobenzylpyridinium ions occurs with cleavage of the N-substituent-bond, which is initiated by the primary formation of the nitrophenyl anion radical.It follows from electrogenerated chemiluminescence experiments that the cleavage of the cations 1 and 5 occurs with the uptake of one electron.

Pyrazole, imidazole, 1,2,4-triazole, indazole and benzotriazole were alkylated under phase transfer catalysis (PTC) with benzyl-, diphenylmethyl- and trityl chloride.Alkylation occured only at the ring nitrogen atoms of the heterocycle, except for indazole in which substitution took also place at position 3.A systematic study of the N- and C-substituted derivatives by proton NMR and chromatographic techniques has been done.

Insecticidal agents containing insecticidal active ingredients selected from the group consisting of carbamates, phosphoric (phosphonic) (di)(thio) acid esters, pyrethrins, pyrethroids, α-alkylphenyl acetates, α-cyclopropyl-phenyl acetates and chlorinated

The reactivity of organosilylamines of imidazole, pyrazole, 1,2,4-triazole and benzotriazole towards alkyl halides, acidic chlorides and halogenated ketones has been studied.Except for 1-trimethylsilylimidazole, which gives a mixed quaternary salt, reactions with primary halides lead to the corresponding 1-alkylated heterocyclic compounds in high yields; in each case only one isomer is obtained (1-alkyl-1,2,4-triazole and 1-alkylbenzotriazole).Similarly acidic chlorides give 1-acylated derivatives in quantitative yields.Finally α- or β-halogenated ketones show different behaviour and give the addition or substitution products.