A one-pot,three-component,microwave-promoted synthesis of 2-amino-substituted 7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines

A new, efficient, catalyst-free, one-pot, three-component method for the synthesis of 2-amino-substituted 7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines using 3,5-diamino-1,2,4-triazoles, cyanamide, and triethyl orthoformate is developed. The reaction proceeds smoothly under microwave-assisted heating. Advantages of the method include using easily available reagents, short reaction times, and operational simplicity.     

Reactions of 4-oxobenz[1,3-e]oxazinium perchlorates with α-aminoazoles

Reactions of 4-oxo benz[1,3-e]oxazinium perchlorates with 1-R¹-3-R²-5-aminopyrazoles lead to the formation of derivatives of pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]1,3,5]triazine series, and with 3-amino-1,2,4-triazole, to [1,2,4]triazolo[1,5-a][1,3,5]triazines.     

Reaction of 1-Aryl-1,3,4,4-tetrachloro-2-azabuta-1,3-dienes with aminoazoles

Reactions of polychlorinated 2-aza-1,3-dienes of the general formuls ArCCl=NCCl=CCl₂ with 3(5)-aminopyrazoles, 3(5)-amino-1,2,4-triazoles, and 5-aminotetrazole led to the formation of substituted pyrazolo[1,5-a][1,3,5]triazines, [1,2,4]triazolo[1,5-a][1,3,5]triazines, and 2-azido-1,3,5-triazine derivatives whose structure was reliably established by spectral methods and X-ray analysis.     

4-Amino-substituted pyrazolo[1,5-a][1,3,5]triazin-2-amines: a new practical synthesis and biological activity

The trichloromethyl moiety was successfully employed as a leaving group in nucleophilic substitutions with various amines for the synthesis of 4-amino-substituted pyrazolo[1,5-a][1,3,5]triazin-2-amines. The key precursor for this reaction, 4-trichloromethylpyrazolo[1,5-a][1,3,5]triazin-2-amine, was prepared via the solvent-dependent condensation of 5-guanidino-3-phenylpyrazole with trichloroacetonitrile. In a broad biological activity screening, some of the prepared compounds were identified as CGRP receptor antagonists.     

Synthesis of nitrogen-containing heterocycles. 5. A new route to 5-amino-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives

Treatment of certain diaminomethylenehydrazones 1 of aromatic carbonyl compounds with ethyl N-cyanoimidate ( 2 ) in acetonitrile in the presence of a tertiary amine at room temperature gives the corresponding amino(N-cyanoiminomethyl)aminomethylenehydrazones 3 in high yields. The intermediate 3 can readily be cyclized to the corresponding 5-amino-2,3-dihydro[1,2,4]triazolo[1,5-a][1,3,5]triazines 4 in moderate to good yields by brief heating in acetonitrile. When the reaction of diaminomethylenehydrazones 1 with ethyl N-cyanoimidate ( 2 ) is performed at reflux temperature in the presence of a tertiary amine, 5-amino-2,3-dihydro[1,2,4]triazolo[1,5-a]1,3,5]triazines 4 can be directly obtained in moderate yields. The yields of triazolotriazine produced by the one-step synthesis are generally comparable or even higher than the overall yields from the two-step procedure.     

A convenient method for the synthesis of 7-amino-substituted 1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amines

A new practical synthesis of 7-amino-substituted 1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amines is developed. The triazine ring closure of 5-guanidino-3-phenyl-1,2,4-triazole with trichloroacetonitrile proceeds chemo- and regioselectively depending on the nature of the solvent. Conducting the reaction in toluene provided 7-trichloromethyl-1,2,4-triazolo[1,5-a][1,3,5]triazin-5-amine as the product, which can be further aminated efficiently with replacement of the trichloromethyl group.     

A facile synthesis of novel pyrazolo[5′,1′:3, 4]-[1, 2, 4]triazino[6, 5-f][1, 3, 4]thiadiazepines

The reaction of the 3-substituted 4-aminopyrazolo[5, 1-c][1, 2, 4]triazines 1a-d with thiosemicarbazide hydrochloride in acetic acid gave new pyrazolo[5′,1′:3, 4][1, 2, 4]triazino[6, 5-f][1, 3, 4]thiadiazepines 3, 4 and 6 , which were converted into the 5-oxo derivatives 5 and 7 by hydrolysis in hydrochloric acid/acetic acid.     

Synthesis of unsymmetrical 2,4-dialkylpyrazolo[1,5-a]-1,3,5-triazines

The reaction of 3-aminopyrazole with imidate esters such as ethyl acetimidate, gave N-(pyrazol-3-yl)acetamidine (1) rather than the isomeric 2-acetamidoyl-3-aminopyrazole. Ring closure of 1 with orthoesters such as ethyl propionimidate, afforded unsymmetrically substituted 2.4-dialkylpyrazolo[1,5-a]-1,3,5-triazines such as 4-ethyl-2-methylpyrazolo[1,5-a]-1,3,5-triazine (3). The structure of 1 was confirmed by several alternate syntheses. The unique feature of this two-step synthetic approach to the synthesis of pyrazolo[1,5-a]-1,3,5-triazines is that it is a convenient method of preparing fused triazines based on available pyrazoles rather than the less accessible dialkyltriazines.     

Direct access to 2-aminopyrazolo[1,5-a]pyridines via N-amination/cyclization reactions of 2-pyridineacetonitriles

We describe the straightforward synthesis of 6-substituted-2-aminopyrazolo[1,5-a]pyridines from 2-pyridineacetonitriles by N-amination with O-(mesitylsulfonyl)hydroxylamine and subsequent base-promoted cyclization. This N-amination/intramolecular cyclization reaction allows access to a variety of 6-substituted-2-aminopyrazolo[1,5-a]pyridines in a one-pot procedure, in moderate to good yields.     

Synthesis of nitrogen‐containing heterocycles 9. Preparation and carbon‐carbon bond cleavage of spiro[cycloalkane[1′,2′,4′]‐triazolo[1′,5′‐a][1′,3′,5′]triazine] derivatives and related compounds

Diaminomethylenehydrazones of cyclic ketones 1–5 reacted with ethyl N‐cyanoimidate (I) at room temperature or with bis(methylthio)methylenecyanamide (II) under brief heating to give directly the corresponding spiro[cycloalkane[1′,2′,4′]triazolo[1′,5′,‐a][1′,3′‐5′]triazine] derivatives 7–12 in moderate to high yields. Ring‐opening reaction of the spiro[cycloalkanetriazolotriazine] derivatives occurred at the cycloalkane moiety upon heating in solution to give 2‐alkyl‐5‐amino[1,2,4]triazolotriazines 13–16. Diaminomethylenehydrazones 17–19, of hindered acyclic ketones, gave 2‐methyl‐7‐methylthio[1,2,4]‐triazolo[1,5‐a][1,3,5]triazines 21–23 by the reaction with II as the main products with apparent loss of 2‐methylpropane from the potential precursor, 2‐tert‐butyl‐2‐methyl‐7‐methylthio[1,2,4]triazolo[1,5‐a]‐[1,3,5]triazines 20, in good yields. In general, bis(methylthio)methylenecyanamide II was found to be a favorable reagent to the one‐step synthesis of the spiro[cycloalkanetriazolotriazine] derivatives from the diaminomethylenehydrazones. The spectral data and structural assignments of the fused triazine products are discussed.     

Synthesis of novel 3-carboethoxy-6-methyl-4-oxo-4H-pyrimido[1′,2′:5,6]-[1,3,5]triazino[1,2-a]benzimidazoles

Reaction of 4-amino-2-methylbenzimidazo[1,2-a][1,3,5]triazines 2 with diethyl ethoxymethylenemalonate afforded 3-carboethoxy-6-methyl-4-oxo-4H-pyrimido[1′,2′:5,6][1,3,5]triazino[1,2-a]benzimidazoles 3 , a new ring system.     

An expedient approach to substituted triazolo[1,5-a][1,4]benzodiazepines via Cu-catalyzed tandem Ullmann C–N coupling/azide-alkyne cycloaddition

An approach to the synthesis of triazolo[1,5-a][1,4]benzodiazepines comprising copper catalyzed tandem Ullmann C–N coupling followed by azide-alkyne cycloaddition has been described. The reaction of o-azidobenzylbromide and N-propargylated aniline derivatives in the presence of CuI and base leads to the formation of triazolo[1,5-a][1,4]benzodiazepines. The reaction has been successfully generalized by synthesizing a number of triazolo[1,5-a][1,4]benzodiazepine derivatives in good to excellent yields.     

Synthesis of 1,3-dialkylpyrazolo [1,5-a]-1,3,5-triazine-2,4-diones isomers of 1,3-dialkylxanthines

The synthesis of a new series of alkylxanthine analogs containing a bridgehead nitrogen atom is reported. 1,3-Dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones, were prepared by the treatment of 3-methylpyrazolo[1,5-a]-1,3,5-triazine-2,4-dione (3) with the corresponding alkyl iodide. Similarly, the reaction of 3-methyl-7-phenylpyrazolo[1,5-a]-1,3,5-dialkyl-7-phenylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones. The starting materials, 3 and 17 , were prepared via the reaction of an appropriate 3-aminopyrazole with ethoxycarbonyl isothiocyanate. Several 8-bromo derivatives were prepared by direct bromination of the 1,3-dialkylpyrazolo[1,5-a]-1,3,5-triazine-2,4-diones.     

Microwave-Assisted Sequential One-Pot Synthesis of 8-Substituted Pyrazolo[1,5-a][1,3,5]triazines

This paper reports a convenient sequential one-pot approach for the synthesis of an array of 14 pyrazolo[1,5-a][1,3,5]triazines, substituted in C8 by halogen (Br), various functions (CN and CO₂Et) and alkyl or (het)aryl groups. This study confirms the interest of combining the efficient heating obtained under dielectric microwave heating and the achievement of sequential one-pot reactions, avoiding the tedious work-up and purification of intermediate compounds, achieving sustainable synthesis processes. Considering usual conventional methods, this microwave protocol is featured by advantages in terms of yields, reaction times, and convenient gram scale synthesis.     

Synthesis of Condensed and Uncondensed Tetrazolo[1,5-<Emphasis Type="Italic">b</Emphasis>][1,2,4]triazines as Potential Antimicrobial Agents

Summary. Reactions of two cyclic amidrazones, the 6-methyl and 6-phenyl derivatives of 7-hydrazinotetrazolo[1,5-b][1,2,4]triazines with mono- and dicarbonyl compounds afforded various heterocyclic systems. Thus, acetic acid, benzoyl chloride, or ethyl chloroformate reacted with the former cyclic amidrazones to yield the corresponding [1,2,4]triazolo[4,3-d]tetrazolo[1,5-b][1,2,4]triazines. With pyruvic acid or ethyl pyruvate the corresponding hydrazone derivatives were obtained, which then cyclized to tetrazolo[1′,5′:2,3][1,2,4]triazino[5,4-c][1,2,4]triazines. The 9,10-dioxotetrazolo-triazinotriazine structures were synthesized by condensative cyclization of the cyclic amidrazones with diethyl oxalate, whereas the reaction of these amidrazones with acetylacetone or ethyl acetoacetate furnished pyrazolyltetrazolo[1,5-b][1,2,4]triazines through the isolable hydrazone intermediates. Some of the representative members of the prepared compounds were screened for antimicrobial activity.     

Synthesis of 5H-benzimidazo[1,2-a][1,3,4]thiadiazolo[2,3-d][1,3,5]triazin-5-one and 12H-benzimidazo[1,2-a]pyrimido[6,1-d][1,3,5]triazin-12-one,two new heterocyclic ring systems

2-(2,6-Dimethylpyrimidin-4-ylaminobenzimidazole) (VIIa) and 2-(1,3,4-thiadiazol-2-ylamino)benzimidazole (VIIb) underwent a ring-closure reaction with phosgene giving 1,3-dimethyl-12H-benzirnidazo[1,2-a]pyrirnido[6,1][-d][1,3,5]triazin-12-one (IIa) and 5H-benzimidazo[1,2-a][1,3,4]thiadiazolo[2,3-d][1,3,5]triazin-5-one (IIb) two hitherto unknown heterocyclic systems. A convenient synthesis of 2,6-dimethyl-4-aminopyrimidine is described.     

A general approach toward the synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines

An expedient synthesis of 8-acylamidopyrazolo[1,5-a]-1,3,5-triazines was developed by treating 8-amino-4-[N-(4-aminophenyl)-N-(methyl)amino]pyrazolo[1,5-a]-1,3,5-triazine with various acyl chlorides following by the displacement of the so-formed N-(methyl)-N-[4-(acylamido)phenyl]amino leaving group with various amines. Applications to high-throughput synthesis are suggested.     

Cobalt-catalyzed isocyanide insertion cyclization to dihydrobenzoimidazotriazins

We have developed an isocyanide insertion reaction for the synthesis of dihydrobenzo[4,5]imidazo[1,2-a][1,3,5]triazins and imidazol-quinoxaline-5-carboxamides utilizing cobalt catalyst. Cobalt-catalyzed system is inexpensive and more acceptable from industrial point of view.     

Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo[4,5-d][1,2,3]triazines

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedländer reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.     

Structural characterization of 1,3,4-thiadiazolo[3,2-a][1,3,5]triazines by electron impact mass spectrometry

The electron-impact-induced fragmentation of eleven 1,3,4-thiadiazolo[3,2-a][1,3,5]triazines was investigated with the aid of exact mass measurements, B/E and B²/E linked scans, and deuterated compounds. The dominating breakdown process in the electron impact mass spectra of 2-substituted 6-phenyl-1,3,4-thiadiazolo[3,2-a]-[1,3,5]triazine-5,7-diones (1–5) is a retro-Diels-Alder reaction. This process gives rise to the base peak, whereas the molecular ions are of very low intensity. In the mass spectra of 2-substituted 7-methylthio-1,3,4-thiadiazolo-[3,2-a][1,3,5]triazine-5-ones (6–11) in which this fragmentation cannot occur because of the two conjugated double bonds in the triazine ring, the molecular ions are very intense. The mass spectral data permits an unequivocal structure assignment to these compounds, which are otherwise difficult to characterize.