One-pot,microwave-assisted synthesis of polymethylene-bridged bis(1H-1,2,4-triazol-5(3)-amines) and their tautomerism

A highly selective and efficient method for the synthesis of 3,3′(5,5′)-polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) was developed using the reaction of dicarboxylic acids and aminoguanidine in an aqueous medium. This one-pot, microwave-promoted method was proved to be scalable affording the desired products in good yields and purity. The scope of the method was successfully explored by the preparation of a small library of polymethylene-bis(1H-1,2,4-triazol-5(3)-amines) with different alkyl chain linkers. The annular prototropic tautomerism in the prepared compounds was studied using NMR spectroscopy and X-ray crystallography.     

Multicomponent cyclocondensation reactions of aminoazoles, arylpyruvic acids and aldehydes with controlled chemoselectivity

The multicomponent reactions of 3-amino-1,2,4-triazoles/5-aminotetrazole with phenylpyruvic acids and aromatic aldehydes were studied using conventional thermal heating, ultrasonification and microwave dielectric heating. Two different reaction pathways for these cyclocondensations occurring under either kinetic or thermodynamic control were established depending on the temperature regime and building block selection. In case of aminotriazoles, an unprecedented reaction pathway leading to 5-aryl-7-hydroxy-6-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidine-7-carboxylic acids was found and discussed.     

Monodentate phosphorus-coordinated palladium(Ⅱ)complexes as new catalyst for Mizoroki-Heck reaction of aryl halides with electron-deficient olefins

Four novel monodentate phosphorus-coordinated palladium(Ⅱ) complexes derived from 3,5-disubstituted-1H-1,2,4-diazaphospholes were developed as efficient catalyst for Mizoroki-Heck reactions of aryl halides with electron-deficient olefins. The role of these monophosphine ligands in catalysis was illustrated by control experiments using Pd salt and ligands as combined catalyst.     

Solution-phase parallel synthesis of new 2H-pyrimido-[4,5-e][1,2,4]triazin-3-ylidenecyanamides

A practical synthesis of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides has been developed. The key step is the coupling reaction of an aryldiazonium salt with 1-cyano-3-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-ylamino)-2-methylisothiourea followed by intramolecular cyclization. A library of 2H-pyrimido[4,5-e][1,2,4]triazin-3-ylidenecyanamides was prepared in two steps from 6-aminouracils using this method.     

A mild synthesis of [1,2,4]triazolo[4,3-a]pyridines

The reaction between 2-hydrazinopyridines and ethyl imidates was examined as a one-pot method for rapidly preparing [1,2,4]triazolo[4,3-a]pyridines. A diverse set of 2-hydrazinopyridines were cyclized with a variety of alkyl- and aryl-substituted ethyl imidates in good yields. The reaction proceeds optimally under mild conditions (50−70 °C) using 1.5 equiv of acetic acid. The electronic and steric properties of the hydrazine and imidate strongly impact the rate of the reaction. When highly electron deficient 2-hydrazinopyridines were used, the products rearranged to [1,2,4]triazolo[1,5-a]pyridines.     

NBS-mediated practical cyclization of N-acyl amidines to 1,2,4-oxadiazoles via oxidative N‒O bond formation

A reaction involving an efficient NBS-mediated oxidative N?O bond formation has been established for the synthesis of 1,2,4-oxadiazoles from readily accessible N-acyl amidines. The features of this synthetic method include simplicity of operation, mild reaction conditions, short reaction times, high yields, and eco-friendliness. The reaction also works well with crude N-acyl amidines obtained by amidation of simple benzoic acids and amidines to produce biologically relevant 1,2,4-oxadiazoles in a scalable fashion.     

Boric acid in aqueous micellar medium: an effective and recyclable catalytic system for the synthesis of aryl-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitriles

A simple, green, and efficient protocol is reported for the preparation of aryl-7,8-dihydro[1,2,4]triazolo[4,3-a]-pyrimidine-6-carbonitriles through one-pot multi component reaction using substituted aromatic aldehydes, malononitrile, and 3-amino[1,2,4]triazole. The reaction is catalyzed by boric acid in aqueous micellar condition. Present protocol incorporates environmentally non-hazardous reaction condition, easy work-up, and use of recyclable catalytic system with associated benefits like excellent yield (84–96%) and shorter reaction time (20 min). Proposed methodology offers rapid access to substituted aryl-7,8-dihydro[1,2,4]triazolo[4,3-a]pyrimidine-6-carbonitriles with high atom-economy and catalytic efficiency.     

Condensation of Vilsmeier salts,derived from tetraalkylureas,with amidoximes: a novel approach to access N,N-dialkyl-1,2,4-oxadiazol-5-amines

A novel approach, condensation of Vilsmeier salts and amidoximes, to access N,N-dialkyl-1,2,4-oxadiazol-5-amines has been developed. By this approach, a broad range of N,N-dialkyl-1,2,4-oxadiazol-5-amines, including aromatic, heteroaromatic, and aliphatic substituents, can be synthesized in good to high yields (up to 82%) under mild reaction conditions.     

A study of chiral oxazoline ligands with a 1,2,4-triazine and other six-membered aza-heteroaromatic rings and their application in Cu-catalysed asymmetric nitroaldol reactions

Enantiomerically pure oxazoline ligands with variously substituted 1,2,4-triazine rings have been synthesized using the Pd-catalysed cross-coupling amination of 3-halo-1,2,4-triazines. The catalytic efficiency of the ligands was studied in the asymmetric Henry reaction of nitromethane with several aldehydes. The appropriate β-nitro alcohols were formed in good yields (up to 93%) and with up to 78% ee. The impact of the substitution of the 1,2,4-triazine ring on the nitroaldol reaction is discussed. In order to investigate the influence of the 1,2,4-triazine ring on the catalytic activity of the ligands, ligands where the 1,2,4-triazine ring was replaced by a pyridine, pyrimidine, pyrazine or pyridine N-oxide ring were synthesized and applied to asymmetric nitroaldol reactions.     

Air-oxidized products of multi-component reactions between 3-amino-1,2,4-triazole, aromatic aldehydes and isonitriles

The Groebke-type multi-component reaction (MCR) between 3-amino-1,2,4-triazole, aromatic aldehydes and isonitriles has been studied from the viewpoint of convenient generation of combinatorial arrays of imidazo[1,2-b][1,2,4]triazoles. However, it was established that the desired heterocyclic structures can be produced in moderate to good yields in an oxidized form, when benzylic isonitriles are used. Oxidation occurred at the benzylic position to produce N-alkylidene-4H-imidazo[1,2-b][1,2,4]triazol-6-amines that proved to be unusually stable towards acid hydrolysis and reduction. The presence of an easily oxidized benzylic position in the target structures is thought to be the prerequisite for successful Groebke-type MCR of 3-amino-1,2,4-triazole.     

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines via microwave-activated inverse electron demand Diels-Alder reactions

Polysubstituted 2,3-dihydrofuro[2,3-b]pyridines and 3,4-dihydro-2H-pyrano[2,3-b]pyridines have been synthesized from 1,2,4-triazines using the inverse electron Diels-Alder reaction. For this purpose, 3-methylsulfanyl-1,2,4-triazines were reacted with several nucleophiles allowing the formation of appropriately substituted alkynes to undergo the intramolecular inverse electron demand Diels-Alder reaction. Sealed-tube microwave activation of the cycloaddition reaction has proved to be very efficient and allowed shorter reaction times. This strategy enabled an efficient synthesis of 3-hydroxy-2,3-dihydrofuro[2,3-b]pyridines and 4-hydroxy-3,4-dihydro-2H-pyrano[2,3-b]pyridines with several points of diversity on the bicyclic scaffold.     

Pd-catalyzed Suzuki/Sonogashira cross-coupling reaction and the direct sp3 arylation of 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine

A rapid and efficient method is reported for the synthesis of the [1,2,4]triazolo[1,5-a]pyrimidine motif. Palladium catalyzed Suzuki and Sonogashira cross coupling reactions on 7-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrimidine were performed. The direct sp³ arylation of compounds resulting from the Suzuki reaction was then carried out.     

Synthesis, structure, and photoluminescence of 5-phenyl-2-pyridyl-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolines

The reactions of salicylaldehyde and benzoic aldehyde with 5-(2-aminophenyl)-3-pyridyl-1H-1,2,4-triazoles were studied. The reaction products are 5-phenyl-2-pyridyl-5,6-dihydro[1,2,4]triazolo[1,5-c]quinazolines. The structures of the synthesized compounds were determined by IR spectroscopy and ¹H and ¹³C NMR spectroscopy. The luminescence properties of solutions and solid samples were studied.     

Oxidative azacyclization of 1-monosubstituted thioureas in reaction with [bis(acyloxy)iodo]arenes to form 1,2,4-thiadiazole derivatives

For the first time, derivatives of 1,2,4-thiadiazoles have been obtained by the reaction of [bis(acyloxy)iodo]arenes with 1-monosubstituted thioureas. 1-Acetylthiourea is subject to intermolecular azacyclization to form 3,5-bis-(acetylamino)-1,2,4-thiadiazole in reaction with [bis(acyloxy)iodo]benzene. 1-Phenylthiourea forms 3,5-bis-(phenylamino)-1,2,4-thiadiazole in a single-stage reaction with (diacetoxyiodo)benzene. The reaction of 1-phenylthiourea with [bis(trifluoroacetoxy)iodo]benzene leads to the formation of 5-imino-4-phenyl-3-phenylamino-4H-1,2,4-thiadiazoline.     

Tandem synthesis of [1,2,4]-triazoles mediated by iodine—a regioselective approach

A tandem regioselective one-pot synthesis of 3-amino-[1,2,4]-triazoles has been achieved from 1,3-disubstituted thioureas using molecular iodine. In this one-pot strategy, the intermediate carbodiimide generated in situ from thiourea upon reaction with HCONHNH₂ gives diaryl/alkylhydrazinecarboximidamide or acylureidrazone, which then undergoes an intramolecular cyclodehydration to afford the corresponding 3-amino-[1,2,4]-triazole. The product regioselectivity for unsymmetrical 1,3-disubstituted thioureas correlate well with the pK_as of the parent amines attached, in which the amine having higher pK_a goes to the ring nitrogen while the other nitrogen remains flanked as an exocyclic nitrogen of the triazole core. This method is milder and environmentally sustainable giving good to excellent yields of the desired products.     

Nano nickel [1,2,4]-triazole-3-thiones complex: Design,sonochemical synthesis,and antimicrobial evaluation

A series of new 1,2,4-triazole-3-thiones were synthesized by calm, benign, no risk, eco-friendly, and energy efficient sequential reaction methodology like grinding and ultrasonic (US). In addition, 1,2,4-triazoles were prepared under conventional method and comparative study was done. The synthesized 1,2,4-triazoles were complexed with Ni(II) to produce nanoparticles complexes (NPC's) with average particle size vary from 55 to 100 nm (using scanning electron microscope technique) with good yields via both US and conventional techniques. X-ray diffraction technique and spectra analysis techniques were used to confirm the square planer geometry of the synthesized NPC's. Antimicrobial activity of the prepared 1,2,4-triazoles and their nickel complexes were studied which evaluated a high activity with complexes instead their triazoles.     

Aerobic oxidation of trimethylbenzenes catalyzed by N,N′,N″-trihydroxyisocyanuric acid (THICA) as a key catalyst

The oxidation of trimethylbenzenes was examined with air or O₂ using N,N′,N″-trihydroxyisocyanuric acid (THICA) as a key catalyst. Thus, 1,2,3-, 1,2,4-, and 1,3,5-trimethylbenzenes under air (20 atm) in the presence of THICA (5 mol %), Co(OAc)₂ (0.5 mol %), Mn(OAc)₂, and ZrO(OAc)₂ at 150 °C were oxidized to the corresponding benzenetricarboxylic acids in good yields (81-97%). In the aerobic oxidation of 1,2,4-trimethylbenzene by the THICA/Co(II)/Mn(II) system, remarkable acceleration was observed by adding a very small amount of ZrO(OAc)₂ to the reaction system to form 1,2,4-benzenetricarboxylic acid in excellent yield (97%). In contrast, no considerable addition effect was observed in the oxidation of 1,3,5-trimethylbenzene. This aerobic oxidation by the present catalytic system provides an economical and environmentally benign direct method to benzenetricarboxylic acids, which are very important polymer materials.     

Azo-coupling of pyrazole-3(5)-diazonium chlorides with cyanothioacetamide: a convenient synthesis of pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides

Cyanothioacetamide reacts with pyrazole-3(5)-diazonium chlorides to afford pyrazolo[5,1-c][1,2,4]triazine-3-carbothioamides 5. The latter can be oxidized with H₂O₂ to give either pyrazolo[5,1-c][1,2,4]triazine-3-carboxamides or 1,2,4-thiadiazole derivatives, depending on the reaction conditions. The Hantzsch-type reaction of thioamides 5 with α-bromo ketones leads to 3-(thiazol-2-yl)pyrazolo[5,1-c][1,2,4]triazines.     

Reductions of (1R,3R,4R)-3-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and their analogues

Reductions of (1R,3R,4R)-3-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones and their lactone analogues, prepared from (1R)-(+)-camphor, were studied. Catalytic hydrogenation selectively led to partial saturation of the [1,2,4]triazolo[4,3-x]azine residue, while in reactions with borane–methylsulfide coordination of borane to the 1-position of [1,2,4]triazolo[4,3-x]azine system took place. On the other hand, activation of the carbonyl group in (1R,3R,4R)-3-([1,2,4]triazolo[4,3-x]azin-3-yl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ones with boron trifluoride etherate followed by reaction with borane–methylsulfide furnished the corresponding isoborneols, stereoselectively. The structures of all representative compounds were confirmed by X-ray diffraction.     

Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety

An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.