Synthesis and X-ray single crystal structure of first aromatic ortho-di-tert-butyl azolo[1,2,4]triazine

Oxidation of 3,4-di-tert-butyl-8-methyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine with NBS/K₂CO₃ furnished 3,4-di-tert-butyl-8-methylpyrazolo[5,1-c][1,2,4]triazine, a mildly strained heteroaromatic compound. X-Ray single crystal diffraction analysis indicated that the conjugated 1,2,4-triazine ring adopts a twist-boat configuration, while the two t-Bu substituents are located on the opposite sides of the azole plane. The related 3-tert-butyl-4-(o-C-carboranyl)-8-methyl-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine was also synthesized, however, its oxidative aromatization was unsuccessful.     

Reactivity of 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbonitrile

By reaction of carbonyl compounds with 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c]-[1,2,4]triazine-8-carbonitrile 3-tert-butyl-8-R-4,6,9,10-tetrahydropyrimido[4′,5′:3,4]pyrazolo[5,1-c][1,2,4]-triazine-4,10-diones and (3-tert-butyl-4-oxo-8-cyano-4,6-dihydropyrazolo[5,1-c][1,2,4]triazin-7-yl)acetamide were obtained.     

The first stable examples of compounds containing both diazonium and acyl azide,and synthesis of a new pyrazino[2′,3′:3,4]pyrazolo[5,1-c][1,2,4]triazin-4(6H)-one heterocyclic system

The first stable compound containing both N₂⁺BF₄^? and CON₃ functional groups – 8-azidocarbonyl-3-(tert-butyl)-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-7-diazonium tetrafluoroborate was synthesized, and its stability and reactivity discussed. The Curtius rearrangement of 7-azido-3-(tert-butyl)-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbonylazide was investigated, and the synthesis of a novel heterocyclic system –pyrazino[2′,3′:3,4]pyrazolo[5,1-c][1,2,4]triazin-4(6H)-one is described.     

Synthesis and reactivity of ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate

Treatment of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate with P₂S₅ in pyridine gave ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate which was subjected to acylation, decarboxylation, and hydrazinolysis.     

Synthesis of new halo-substituted pyrazolo[5,1-c][1,2,4]triazines

Ethyl 3-tert-butyl-4-oxo-7-X-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylates (X = H, Cl, Br) were synthesized for the first time by diazotization of 7-amino-3-tert-butyl-4oxo-8-ethoxycarbonyl-6H-pyrazolo[5,1-c][1,2,4]triazines with tert-butyl nitrite in the presence of trimethylsilyl halides. A new method was developed: a reaction between 7-amino-3-tert-butyl-4-oxo-6H-pyrazolo[5,1-c][1,2,4]triazine-8-carboxylic acid and I₂/TEA followed by treatment with NaBH₄ led to a mild decarboxylation. The acid reacts with N-halosuccinimides to give novel 8-halo-substituted derivatives. The amino groups of the latter were acylated by treatment with trifluoroacetic anhydride to give monoacylation products.

     

Synthesis of 8-alkylthio- and 8-selanyl-3-tert-butylpyrazolo[5,1-c][1,2,4]triazines

Abstract

Interaction of 8-lithio-3-tert-butyl-4-oxopyrazolo[5,1-c][1,2,4]triazin-1-ide with elemental sulfur or selenium in THF with further in situ alkylation at –97?°C followed by warming to room temperature furnished a series of 3-tert-butyl-8-X-pyrazolo[5,1-c][1,2,4]triazin-4(6H)-ones (X?=?n-BuS, n-BuSe, MeSe, PhCH₂S) in good yields. 8,8'-Diselanediylbis(3-tert-butylpyrazolo[5,1-c][1,2,4]triazin-4(1H)-one) was also isolated as a by-product in these reactions. One-pot interaction of the n-BuSe substituted derivative with diborane/boron trifluoride led to reduction of the 1,2,4-triazine core and partial elimination of the alkylselanyl moiety. The structures of the synthesized products were established on the basis of IR, ¹H, 13C, 2D HMBC ¹H–⁷⁷Se NMR and high resolution mass spectra, as well as X-ray single crystal diffraction analyses. Two of the prepared compounds were also tested for antimicrobial and antifungal activities.     

Facile synthesis and antifungal activity of 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines and pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines

The reactions of the pyrazole-5-diazonium salt 3 with malononitrile and ethyl cyanoacetate gave 4-amino-3-cyano-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazine 7 and 4-amino-3,8-bisethoxycarbonylpyrazolo[5,1-c]-[1,2,4]triazine 8 , whose reactions with p-chloroaniline hydrochloride afforded 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)amidinopyrazolo[5,1-c][1,2,4]triazine 9 and 4-amino-8-ethoxycarbonyl-3-(p-chlorophenyl)car-bamoylpyrazolo[5,1-c][1,2,4]triazine 10 , respectively. The reactions of 7 and 8 with o-phenylenediamine di-hydrochloride provided 9-ethoxycarbonyl-13H-spiro[benzimidazole-2′(3′H),6(5H)-pyrazolo[1,5′:3,4][1,2,4]tri-azino[5,6-b][1,5]benzodiazepine] hydrochloride 11a and 9-ethoxycarbonyl-6-oxo-13H-5,6-dihydropyrazolo-[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepine 12 , respectively. The antifungal activity of the above compounds was described.     

Reduction and diazotization of ethyl 7-amino-3-<Emphasis Type="Italic">tert</Emphasis>-butyl-4-oxo-4,6-dihydropyrazolo[5,1-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazine-8-carboxylate

The ester group in ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate was converted for the first time to methyl by the action of lithium tetrahydridoborate in the presence of boron trifluoride–diethyl ether complex. This reaction has almost no analogies among other classes of organic compounds. New difficultly accessible 7-chloro and 7-azido derivatives were synthesized via diazotization of the reduction product, and treatment of the latter with acetic anhydride afforded the exhaustively acetylated derivative. Diazotization of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo-[5,1-c][1,2,4]triazine-8-carboxylate, followed by reaction with sodium azide, gave the corresponding azide, and the product of azo coupling with ethyl acetoacetate failed to undergo intramolecular cyclization to tricyclic pyrazolo[3,2-c: 5,1-c′]bis[1,2,4]triazine system.     

Unexpected Direction of Iodocyclization of 3-Allylthio-5-phenyl-4H-1,2,4-triazole

The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, and 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of the products obtained was established using ¹H NMR spectroscopy of their dehydriodination products.     

Regioselective alkylation of 1H-7-ethoxycarbonyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole and 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole

Alkylation of 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole and 1H-7-ethoxycarbonyl-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole using different alkylating agents leads regioselectively to 1-N-alkylated products. The hydrolysis-decarboxylation of 1,6-dimethyl-7-ethoxycarbonyl-pyrazolo[5,1-c][1,2,4]triazole yields a compound identical with that obtained by the direct methylation of 1H-6-methyl-3-phenyl-pyrazolo[5,1-c][1,2,4]triazole. The 1-N-alkylation is confirmed by NMR spectroscopy and mass spectrometry.     

Pyrolytic desulfurization ring contraction of condensed thiadiazines as a general route towards pyrazoloazines and pyrazoloazoles with a bridgehead (ring junction) nitrogen atom

Pyrolytic conversion of [1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, [1,3,4]thiadiazino[2,3-b]quinazolin-10-ones and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines into their corresponding pyrazolo[5,1-c][1,2,4]triazin-4-ones, pyrazolo[4,3-b]quinazolin-9-ones and pyrazolo[5,1-b][1,2,4]triazoles via desulfurization ring contraction is described. The starting condensed 1,3,4-thiadiazines were prepared from the corresponding readily available 4-amino-3-thioxo-1,2,4-triazin-5(4H)-ones, 3-amino-2,3-dihydro-2-thioxoquinazolin-4(1H)-one and 4-amino-3(2H)-thioxo-1,2,4-triazoles upon reaction with the appropriate α-haloketones in two steps, or directly in one step in ethylpyridinium tetrafluoroborate (ionic liquid, IL).     

Pyrazoles as building blocks in heterocyclic synthesis: Synthesis of pyrazolo [3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo [3,4-d][1,2,3]triazine and pyrolo [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives

Several new pyrazolo[3,4-d]pyrimidine, pyrazolo[3,4-e][1,4]diazepine, pyrazolo[3,4-d][1,2,3]triazine and pyrolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives were prepared by the reaction of the corresponding 5-amino-pyrazole-4-carbonitrile derivative with different organic reagents under different reaction conditions. Using IR, ¹H NMR, and mass spectra we have characterized all new compounds.     

Stereoselective synthesis of dihydrothiadiazinoazines and dihydrothiadiazinoazoles and their pyrolytic desulfurization ring contraction

Intramolecular base catalyzed C-C bond formation led to exclusive stereoselective syntheses of trans-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, trans-7,8-dihydro-6H-[1,2,4]triazino[3,4-b][1,3,4]thiadiazin-4-ones, and trans-3,4-dihydro-2H-[1,3,4]thiadiazino[2,3-b]quinazolin-10-one. trans-6,7-Dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines isomerize slowly in CDCl₃ and more rapidly in DMSO-d₆ into the corresponding cis-stereoisomers. The other trans-6,7-dihydro-[1,3,4]thiadiazines isomerize also in DMSO-d₆ into the corresponding cis-stereoisomers. Pyrolytic conversion of these heterocyclic condensed dihydrothiadiazines into their corresponding pyrazolo[5,1-b][1,2,4]triazoles, pyrazolo[5,1-c][1,2,4]triazin-4-ones and pyrazolo[4,3-b]quinazolin-9-ones via desulfurization ring contraction is described.     

Ring transformation of 1,5-benzoxazepines into spirobenzoxazoles. Synthesis of pyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines and spiro[benzoxazole-2′(3′H),4(1H)-pyrazolo[5,1-c][1,2,4]triazines]

The reactions of the 3-substituted 4-amino-8-ethoxycarbonyl[5,1-c][1,2,4]triazines 1 and 2 with o-amino-phenol hydrochloride gave the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5 and 8 . The alkylation of 5 with methyl iodide and isopropyl iodide afforded the 6-alkoxylpyrazolo[1′,5′:3,4][1,2,4]triazino-[5,6-b][1,5]benzoxazepines 6a and 6b , respectively. Refluxing of 5, 6a, 6b and 8 in hydrochloric acid/acetic acid resulted in ring transformation to produce the spiro[benzoxazole-2′(3′H),4(1H)pyrazolo[5,1-c][1,2,4]-triazines] 7a, 7b and 9 . The screening data of the above compounds was described.     

Synthesis of 8-tert-Butyl-9-oxo-1,2,4-triazolo[4,5-b]-1,2,4-triazolo[3,4-c]-1,2,4-triazine

8-tert-Butyl-9-oxo-1,2,4-triazolo[4,5-b]-1,2,4-triazolo[3,4-c]-1,2,4-triazine has been synthesized by the interaction of 6-tert-butyl-3-hydrazino-1,2,4-triazolo[3,4-c]-1,2,4-triazin-5-one with formic acid. The conditions of carrying out the reaction are discussed. Spectral characteristics are given.     

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.     

Interaction of 4‐Oxo‐4H‐pyrazolo[5,1‐c][1,2,4]triazin‐1‐ides with Grignard Reagents

Reactions of magnesium 3‐tert‐butyl‐8‐R‐4‐oxo‐4H‐pyrazolo[5,1‐c][1,2,4]triazin‐1‐ides (R = CN, CO₂Et) with AlkMgBr led to nucleophilic additions to either side chain or triazine core, with selectivity being dependent on the nature of substituents, as well as on the solvents used. Previously inaccessible C⁸‐functionalized and C⁴‐functionalized pyrazolo[5,1‐c][1,2,4]triazines and 3‐tert‐butyl‐3‐ethyl‐4‐oxo‐1,2,3,4‐tetrahydropyrazolo[5,1‐c][1,2,4]triazine were synthesized, and their reactivity and spectral data discussed.     

A new method for the synthesis of novel 6-quinoxalinylpyrazolo[5,1-c][1,2,4]triazines

The reaction of the quinoxaline 1 with 4-ethoxycarbonyl-1H-pyrazole-5-diazonium chloride 7 at room temperature gave 3-[α-(4-ethoxycarbonyl-1H-pyrazol-5-ylhydrazono)methoxycarbonylmethyl]-2-oxo-1,2-dihydroquinoxaline 8. The pmr spectrum of 8 in deuteriodimethylsulfoxide supported the presence of two tautomers 8-I and 8-II. Refluxing of 8 in N,N-dimethylformamide or acetic acid resulted in cyclization to afford 8-ethoxycarbonyl-4-oxo-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,4-dihydropyrazolo[5,1-c][1,2,4]triazine 9. Compound 9 was also obtained directly by the reaction of 1 with 7 under reflux in better yield. The reaction of 9 with hydrazine hydrate provided the hydrazinium salt 10 , while the reactions of 9 with triethyl and trimethyl orthoformates in the presence of 1,8-diazabicyclo[5,4,0]-7-undecene produced 8-ethoxycarbonyl-4-ethoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11a and 8-ethoxycarbonyl-4-methoxyl-3-(3-oxo-3,4-dihydroquinoxalin-2-yl)pyrazolo[5,1-c][1,2,4]triazine 11b , respectively. The chlorination of 11a with phosphoryl chloride gave 3-(3-chloroquinoxalin-2-yl)-8-ethoxycarbonyl-4-ethoxylpyrazolo[5,1-c]-[1,2,4]triazine 12 , whose reaction with morpholine afforded 8-ethoxycarbonyl-4-ethoxyl-3-[3-(morpholin-4-yl)-quinoxalin-2-yl]pyrazolo[5,1-c][1,2,4]triazine 13.     

4-Aryl-3-(methanesulfonyl)pyrazolo[5,1-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazines and their transformations

Coupling of 3-alkyl-4-aryl-1H-pyrazole-5-diazonium chlorides with methylene-active methyl phenacyl sulfones afforded new pyrazolo[5,1-c][1,2,4]triazine derivatives via cyclization of the corresponding intermediate 1-aryl-2-(hetarylhydrazinylidene)-2-(methanesulfonyl)ethanones. The reactivity of the methanesulfonyl group on C³ of pyrazolo[5,1-c][1,2,4]triazines toward some nucleophiles was studied.     

Synthesis of new heterocyclic systems fused at pyrazolo[3,4-c]-2,7-naphthyridine core

Efficient syntheses of new heterocyclic systems comprising pyrimido[1',2':1,5]pyrazolo[3,4-c]-2,7-naphthyridine, pyrazolo[3,4-c][1,2,4]triazolo[3,4-a]-2,7-naphthyridine and pyrazolo[3,4-c]tetrazolo[5,1-a]-2,7-naphthyridine cores were performed in two simple steps. In the first step, pyrazole ring was fused at the 2-chloro-3-cyanopyridine moiety by treatment with hydrazine. In the second step, pyrimidine part was fused at the thus formed 3-aminopyrazole moiety by heterocyclization with acetylacetone.