Synthesis of Pyrido[2′,3′: 3,4]pyrazolo[1,5‐a]pyrimidine,Pyrido[2′,3′:3,4]pyrazolo[5,1‐c][1,2,4]triazine,and Pyrazolyl Oxadiazolylthieno[2,3‐b]pyridine Derivatives

6‐(2‐Thienyl)‐4‐(trifluoromethyl)‐1H‐pyrazolo[3,4‐b]pyridine‐3‐amine reacted with different active methylene compounds to afford pyridopyrazolopyrimidine derivatives. On the other hand, it reacted with some halo compounds to give the imidazo[1′,2′:1,5]pyrazolo[3,4‐b]pyridine derivatives. Also, it diazotized to give the corresponding diazonium chloride that is coupled with several active methylene compounds to give the corresponding triazine derivatives. Furthermore, compound 3‐amino‐6‐(2(thienyl)‐4‐(trifluoromethyl)thieno[2,3‐b]pyridine‐2‐carbohydrazide reacted with some β‐dicarbonyl compounds and some sulfur‐containing compounds to afford the corresponding pyrazolyl oxadiazolylthieno[2,3‐b]pyridine derivatives.     

Synthesis of Certain 3-Aminopyrazolo[5,4-b]pyridine and 3,4-Substituted Pyrido[2′,3′：3,4]pyrazolo[5,1-c][1,2,4]triazine Derivatives

2-Thioxo-1,2-dihydropyridine derivatives 2a, 2b were reacted with methyl iodide to give 2-methylthiopyridines 3a, 3b, which were reacted with hydrazine hydrate to produce 3-aminopyrazolo[5,4-b]pyridines 4a, 4b. Compounds 4a, 4b were diazotized to afford the corresponding diazonium salts 5a, 5b, which were reacted with some active methylene compounds 6a-6h to give the corresponding pyrido[2′,3′ ： 3,4]pyrazole[5,1-c][1,2,4]triazines 7-14.     

Synthesis of New Pyrimido[4′,5′:3,4]pyrazolo[1,2‐b]phthalazine‐4,7,12‐triones: Derivatives of a New Heterocyclic Ring System

Several derivatives of the new pyrimido[4′,5′:3,4]pyrazolo[1,2‐b]phthalazine‐4,7,12‐trione ring system have been prepared by the reaction of 3‐amino‐1‐aryl‐5,10‐dioxo‐5,10‐dihydro‐1H‐pyrazolo[1,2‐b]phthalazine‐2‐carbonitriles with aliphatic carboxylic acids in the presence of phosphoryl chloride (POCl₃). The synthesized compounds were characterized on the basis of IR, ¹H NMR, and ¹³C NMR spectral and microanalytical data.     

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.     

A new method for the synthesis of novel 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

Novel 3-substituted 4-amino-8-ethoxycarbonylpyrazolo[5,1-c][1,2,4]triazines 7,8 were synthesized by the reactions of malononitrile and ethyl cyanoacetate with the pyrazole-5-diazonium salt 3 . Moreover, compounds 7,8 were converted into the pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzodiazepines 9, 10 .     

[1,3]Thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines – A New Heterocyclic System Accessed via Bromocyclization

A facile access to novel condensed system of [1,3]thiazolo[2′,3′:3,4][1,2,4]triazolo[1,5‐a]pyrimidine is presented. This protocol consists of bromine‐assisted direct electrophilic heterocyclization of 3‐N‐allylamine‐5,6‐dihydro[1,3]thiazolo[2,3‐c][1,2,4]triazole. The bromination took place in acetic acid and gave a good yield of the target product, which was dehydrobrominated by sodium acetate action.     

Synthesis of New Azocompounds and Fused Pyrazolo[5,1‐c][1,2,4]triazines Using Heterocyclic Components

Diazotization of 3‐methyl‐4‐phenyl‐1H‐pyrazol‐5‐amine 1 in hydrochloric acid has been reported to afford the corresponding diazonium salt 2 . The latter underwent azocoupling with a variety of active methylene compounds (barbituric 3a and thiobarbituric 3b acid, 2‐hetarylpyrimidine‐4,6‐dione 6a , 6b , 4‐hydroxy‐6‐methylpyridin‐2(1H)‐one 10a , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one 10b , 4‐hydroxy‐1‐p‐tolyl‐1H‐pyrazole‐3‐carboxylic acid ethyl ester 14 , 1,3‐thiazolidine‐2,4‐dione 16a , 2‐thioxo‐1,3‐thiazolidin‐4‐one 16b ) to yield new pyrazolylazo derivatives. Fused pyrazolo[5,1‐c][1,2,4]triazines 5 , 9a , 9b , 12 , 13 were obtained by heterocyclization reactions. Copyright © 2013 HeteroCorporation     

A convenient synthesis of novel spiro[benzoxazole-2′,4(1H,3′H)-pyrazolo[5,1-c][1,2,4]triazines] by ring transformation of novel pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines

Novel pyrazolo[1′,5′:3,4][1,2,4]triazino[5,6-b][1,5]benzoxazepines 5, 6 and 8 were synthesized, and these compounds were converted into novel spiro[benzoxazole-2′,4(1H,3′H)-pyrazolo[5,1-c][1,2,4]triazines] 7 and 9 by ring transformation.     

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 and Structure of 3,4‐Dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines

A new convenient synthon for heterocyclic chemistry, namely 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine was successfully prepared by selective guanylation of 1H‐pyrazolo[3,4‐b]pyridin‐3‐amine. A series of 3,4‐dihydropyrido[2′,3′:3,4]pyrazolo[1,5‐a][1,3,5]triazin‐2‐amines was synthesized from 1H‐pyrazolo[3,4‐b]pyridin‐3‐ylguanidine using aldehydes or ketones as one‐carbon inserting reagents. The tautomeric preferences of the products were determined using spectroscopic (e.g., 2D NOESY NMR) and single crystal X‐ray diffraction data.     

Synthesis of some novel 3,7‐dimethyl‐4H‐pyrazolo[5,1‐c][1,2,4]triazin‐4‐ones

Some novel 3,7‐dimethyl‐6H‐pyrazolo[5,1‐c][1,2,4]triazin‐4‐ones were prepared (3a‐g) . Compounds 3a,b were treated with hydrazines to afford various products 7a,b, 8a,b, 9 and lla,b depending on the type of hydrazine derivative and reaction conditions. The benzoyloxyimino‐pyrazolo[5,1‐c][1,2,4]triazines (13a,b) were synthesized by refluxing of compounds 3a,b with hydroxylamine hydrochloride to afford the corresponding oxime derivatives followed by treatment with benzoyl chloride.     

Synthesis,structure and some reactions of 4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]‐quinazolines]

2′‐Substituted 5′,6′,7′,8′‐tetrahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 3a‐d were synthesized by condensation of 3‐substituted 5‐amino‐1,2,4‐triazoles 1a‐d with 2‐cyclohexylidene cyclohexanone 2 in DMF. The compounds 3 were hydrogenated with sodium borohydride in ethanol to give 2′‐substituted cis‐4a',5′,6′,7′,8′,8a'‐hexahydro‐4′H‐spiro[cyclohexane‐1,9′‐[1,2,4]triazolo[5,1‐b]quinazolines] 4a‐d in high yields. The reactions of alkylation, acylation and sulfonylation of the compounds 4 were studied. The structure of the synthesized compounds was determined on the basis of NMR measurements including HSQC, HMBC, NOESY techniques and confirmed by the X‐ray analysis of 6 and 11b . The described synthetic protocols provide rapid access to novel and diversely substituted hydrogenated [1,2,4]triazolo[5,1‐b]quinazolines.     

An Efficient Synthesis of 1′,7′,8′,9′‐Tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐b]quinoline]‐2,5′(6′H)‐dione Derivatives in Aqueous Medium

An efficient and green reactions of isatins, 3‐amine‐1H‐pyrazole (5‐methyl‐1H‐pyrazol‐3‐amine) and 1,3‐diketone in aqueous medium for the synthesis of novel 1′,7′,8′,9′‐tetrahydrospiro[indoline‐3,4′‐pyrazolo[3,4‐b]quinoline]‐2,5′(6′H)‐dione derivatives were reported in this research. The advantages of this reaction are simple operation, mild‐reaction conditions, wide scope substrate, high yields, and friendly environment. The products were confirmed by IR, ¹H NMR, ¹³C NMR, and HRMS.     

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.

     

A Convenient Approach to 4,7‐Dihydrotetrazolo [5,1‐c][1,2,4]triazine Synthesis

Azo coupling of 1,3‐dicarbonyl compounds with tetrazolyl‐5‐diazonium chloride is used to develop a convenient one‐step procedure for the synthesis of 4,7‐dihydrotetrazolo[5,1‐c][1,2,4]triazines. In contrast to nonfluorinated analogs, 7‐hydroxy‐7‐polyfluoroalkyl‐4,7‐dihydrotetrazolo[5,1‐c][1,2,4]triazines undergo a ring‐chain isomerism resulting from the cleavage at the C7―N7a bond. A distinctive feature of nonfluorinated 4,7‐dihydrotetrazolo[5,1‐c][1,2,4]triazines is the possibility to dehydration, which is accompanied by an azide rearrangement due to the tetrazole ring cleavage with the formation of tetrazolo[1,5‐b][1,2,4]triazines.     

Regioselective Synthesis of Some New Pyrazolo[1,5‐a]pyrimidines,Pyrazolo[1,5‐a]quinazoline and Pyrimido[4′,5′:3,4]pyrazolo[1,5‐a] pyrimidines Containing Thiazole Moiety

A regioselective synthesis of novel pyrazolo[1,5‐a]pyrimidines, pyrazolo[1,5‐a]quinazoline and pyrimido[4′,5′:3,4]pyrazolo[1,5‐a]pyrimidines incorporating a thiazole moiety was described via the reactions of the versatile, readily accessible 5‐amino‐3‐(phenylamino)‐N‐(4‐phenylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carboxamide 3 with appropriate 1,3‐biselectrophilic reagents namely, β‐diketones, enaminones, and α,β‐unsaturated cyclic ketone. The newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthetic route whenever possible.     

Synthesis and Evaluation of PDE5 Inhibitory Activity of Novel Pyrido[2＇,1＇：5,1]pyrazolo[4,3-d]pyrimidin-4-one Derivatives

Novel pyridopyrazolopyrimidinone derivatives were designed and synthesized as potential PDE5 inhibitors. The target compounds demonstrated significant inhibitory activity against human platelet PDE5, but less potent than sildenafil.     

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.     

Synthesis of some pyrazolo[1,5‐c][1,3]benzoxazines and a new 5H‐pyrazolo[1,5‐c][1,3,2]benzoxazaphosphorine ring system

Condensations of 5‐(2‐hydroxyphenyl)pyrazoline 3a with 4‐carboxybenzaldehyde, glyoxylic acid and N,N‐carbonyldiimidazole leading to pyrazolobenzoxazine derivatives were studied. The observed diastere‐oselectivity is discussed. Reaction of 3a with Lawesson reagent gave rise to a new 5H‐pyrazolo[1,5‐c]‐[1,3,2]benzoxazaphosphorine heterocyclic system.