Formylation of 4,7‐Dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines Using Vilsmeier–Haack Conditions

Formylation of 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine 1a using Vilsmeier–Haack conditions yields 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidin‐6‐ylcarbaldehyde 3a . 5,7‐Diaryl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines 1b , 1c in this reaction apart from formylation undergo recyclization into 5‐aryl‐1,2,4‐triazolo[1,5‐a]pyrimidin‐6‐ylmethane derivatives 4b , 4c , 5b , 5c , and 6 . The structure of the synthesized compounds was determined on the basis of NMR, IR, and MS spectroscopic data and confirmed by the X‐ray analysis of the 6‐(ethoxy‐phenyl‐methyl)‐5‐phenyl‐[1,2,4]triazolo[1,5‐a]pyrimidine 6 , 5‐phenyl‐6‐(1‐phenyl‐vinyl)‐[1,2,4]triazolo[1,5‐a]pyrimidine 11 , and 7‐phenyl‐6‐(1‐phenyl‐vinyl)‐[1,2,4]triazolo[4,3‐a]pyrimidine 12 .     

Synthesis and tautomerization of 6,7‐dihydro‐(1,2,3)‐triazolo[1,5‐a]pyrimidines

The condensation of 5‐amino‐4‐phenyl‐1,2,3‐triazole ( 1 ) with chalcones 2a‐e or 3‐dimethylamino‐propiophenone ( 4f ) leads to the 6,7‐dihydro‐(1,2,3)‐triazolo[1,5‐a]pyrimidines 3a‐f. The equilibrium of 3 and the tautomeric 4,7‐dihydro‐(1,2,3)‐triazolo[1,5‐a]pyrimidines 3′ is described.     

New 1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidine derivatives II

The 7‐chloro‐3‐(2‐chlorobenzyl)‐ and 7‐chloro‐3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐d]pyrimidines ( 1 and 4 ), by nucleophilic replacement with some hydrazides, gave the corresponding 7‐hydrazidoderivatives ( 2a‐e and 5a‐e ). These, by heating in Dowtherm, underwent an intramolecular cyclization to form the new tricyclic 7‐substituted‐3‐(2‐chlorobenzyl)‐ and 3‐(2‐fluorobenzyl)‐1,2,3‐triazolo[4,5‐e]1,2,4‐triazolo[4,3‐c]pyrimidines ( 3a‐d and 6a‐d ). The 7‐hydrazino‐3‐(2‐chlorobenzyl)‐ and 7‐hydrazino‐3‐(2‐fluorobenzyl)‐triazolo‐pyrimidines ( 9a and 9b ) were also prepared via the corresponding mercapto ( 7a and 7b ) and thiomethyl ( 8a and 8b ) derivatives.     

Synthesis of some novel pyrazolo[1,5‐a]pyrimidine, 1,2,4‐triazolo[1,5‐a]pyrimidine,pyrido[2,3‐d]pyrimidine,pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives incorporating a thiazolo[3,2‐a]benzimidazole moiety

E‐3‐(N,N‐Dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 2 ) was synthesized by the reaction of 1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)ethanone ( 1 ) with dimethylformamide‐dimethylacetal. The reaction of 2 with 5‐amino‐3‐phenyl‐1H‐pyrazole ( 4a ) or 3‐amino‐1,2,4‐(1H)‐triazole ( 4b ) furnished pyrazolo[1,5‐a]pyrimidine and 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives 6a and 6b , while the reaction of enaminone 2 with 6‐aminopyrimidine derivatives 7a,b afforded pyrido[2,3‐d]pyrimidine derivatives 9a,b , respectively. The diazonium salts 11a or 11b coupled with compound 2 to yield the pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives 13a and 13b . Some of the newly synthesized compounds exhibited a moderate effect against some bacterial and fungal species.     

Synthesis of pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]pyrimidines related to zaleplon,a new drug for the treatment of insomnia

This paper describes the preparation of some pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]‐pyrimidines substituted on the pyrimidine moiety by a 4‐[(N‐acetyl‐N‐ethyl)amino]phenyl group. A new synthesis of related benzo[h]pyrazolo[1,5‐a]‐, benzo[h]pyrazolo[5,1‐b]‐ and benzo[h]1,2,4‐triazolo[1,5‐a]‐quinazolines is also reported.     

Reactions of 4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines with α,β‐unsaturated carbonyl compounds

The reaction of 5,7‐diphenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine ( 1 ) with α,β‐unsaturated carbonyl compounds 2a‐f led to the formation of the alkylated heterocycles 3a‐f (Figure 1). However, the reaction of 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine ( 5 ) with 2a‐c yielded under the same conditions the triazolo[5,1‐b]quinazolines 6a‐c (Figure 3). In this case, the alkylation is followed by a cyclocondensation. The structure elucidation of the products is based on ir, ms, ¹H and ¹³C nmr measurements and on an X‐ray diffraction study.     

Utility of (p‐Sulfonamidophenyl)azomalononitrile,and Ethyl Acetoacetate in Synthesis of Fused Azole and Azines Derivatives II

[(p‐Sulfonamidophenyl)azo]malononitrile ( 1a,b ) reacted with N‐cyclohexanemethylidene‐2‐cyanoacetohydrazide, N'‐arylmethylidene‐2‐cyanoacetohydrazide ( 3a‐c ), S‐methylthiourea and hydrazine hydrate to afford [1,2,4]triazolo‐[1,5‐a]pyridinone derivatives ( 2a,b ) & ( 4a‐c ), substituted pyrimidines 5a,b and 6a,b. The corresponding pyridazinones 7a,b were synthesized from the reaction of 1c,d with ethyl cyanoacetate. Compound 7a,b reacted with elemental sulfur to yield 8a,b . Compound 6a underwent cycloaddition with α‐cinnamonitrile 9a‐e to yield 11a‐c, 14 and 15 . Also, compound 6a reacted with β‐ketoester and 1,3‐diketones to give 16, 17 and 18 .     

Synthesis of New [1,2,4]Triazolo[1,5‐a]pyrimidine Derivatives: Reactivity of 3‐Amino[1,2,4]triazole towards Enaminonitriles and Enaminones

A diversity of new 7 ‐substituted[1,2,4]triazolo[1,5‐a]pyrimidine and 6‐substituted[1,2,4]triazolo[1,5‐a]pyrimidine‐7‐amine derivatives has been synthesized via reaction of 3‐amino‐[1,2,4]triazole with enaminonitriles and enaminones. The regio orientation and the structure of the products were confirmed by spectral and analytical data and synthesis via an alternative route. The procedure proved to be simple, efficient, and high yielding, and diversities of [1,2,4]triazolo[1,5‐a]pyrimidines were obtained.     

On triazoles XLIV [1]. synthesis of new ring systems containing imidazo[2′,1′:3,4] [1,2,4] triazolo [1,5‐a]pyrimidine and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrimidine skeleton

Dedicated to Dr. János Császár on the occasion of his 70^th birthday Ring transformation of 2‐cyanoimido‐3‐methyl‐1,3‐oxazolidine ( 10 ) yielded 5‐amino‐3‐[N‐(2‐hydrox‐yethyl)‐N‐methyl]amino‐1H‐1,2,4‐triazole ( 6 ) that was ring closed with different β‐keto esters to 2‐[N‐(2‐hydroxyethyl)‐N‐methyl]amino‐1,2,4‐triazolo[1,5‐a]pyrimidinones ( 4 ). Cyclisation of derivatives 4 led to imidazo[2′,1′:3,4][1,2,4]triazolo[1,5‐a]pyrimidines ( 2 ) and imidazo[1′,2′:2,3][1,2,4]triazolo[1,5‐a]pyrim‐idines ( 3 ) representing 10 novel ring systems. Besides spectroscopical evidence of structure of derivatives 2 and 3 X‐ray diffraction analysis of derivative 2b was also performed.     

Efficient Routes for the Synthesis of Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines)

Bis(triazolo[3,4‐b]thiadiazine) 4 in which the fused system is linked directly to the benzene core can be synthesized in 75% yield by, firstly, preparation of bis(s‐triazole) 2 followed by reaction with phenacyl bromide 3 in refluxing EtOH/DMF mixture containing piperidine. Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 8 and 11 in which the triazolothiadiazines are linked to benzene core via alkyl or ether linkage were synthesized in 70 and 72% yields, respectively, starting from dicarboxylic acids 5 and 9 upon treatment with two moles of thiocarbohydrazide 6 to give the corresponding bis(4‐amino‐5‐mercapto‐s‐triazolo‐3‐y1) derivatives 7 and 10 and subsequent reaction with two equivalents of phenacyl bromide. Bis(6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines) 15a , 15b , 15c , 15d , 15e , 15f , which are linked to arene cores via sulfanylmethylene spacers, were prepared by the reaction of 4‐amino‐4H‐1,2,4‐triazole‐3,5‐dithiol 12 with the appropriate bis(bromomethyl)benzenes 13a , 13b , 13c , 13d , 13e , 13f to give bis(4‐amino‐5‐mercapto‐4H‐3‐sulfanylmethyl)arenes 14a , 14b , 14c , 14d , 14e , 14f and subsequent reaction with phenacyl bromide. Compounds 15a , 15b , 15c , 15d , 15e , 15f were alternatively obtained in 60–70% yields by twofold substitution of 13a , 13b , 13c , 13d , 13e , 13f with two equivalents of 6‐phenyl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine‐3‐thiol 16 in refluxing EtOH/DMF mixture containing KOH. Bis(triazolothiadiazine) 22 attached to the benzene core through the thiadiazine ring via an amine linkage was prepared in 70% yield starting from p‐phenylenediamine 19 by, firstly, acylation with chloroacetyl chloride 18 followed by bis‐alkylation with 1,2,4‐triazole 20 and subsequent intramolecular ring closure upon treatment with phosphorus oxychloride.     

Green One‐Pot Solvent‐Free Synthesis of Pyrazolo[1,5‐a]pyrimidines,Azolo[3,4‐d]pyridiazines,and Thieno[2,3‐b]pyridines Containing Triazole Moiety

Synthesis of pyrazolo[1,5‐a]pyrimidines, [1,2,4]triazolo[1,5‐a]pyrimidine, 8,10‐dimethyl‐2‐(5‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐1,2,3‐triazol‐4‐yl)pyrido[2′,3′:3,4]‐pyrazolo[1,5‐a]pyrimidine, benzo[4,5]imidazo[1,2‐a]pyrimidine via heterocyclic amines, and sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one were carried out. Also, synthesis of isoxazoles, and pyrazoles from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one and hydroxymoyl chlorides and hydrazonoyl halides, respectively, were made. Analogously, (1,2,3‐triazol‐4‐yl)thieno[2,3‐b]pyridine derivatives were obtained from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐ triazole‐4‐yl)prop‐2‐en‐1‐one and cyanothioacetamide followed by its reacting with active methylene compounds. In addition to full characterization of all synthesized compounds, they were tested to evaluate their antimicrobial activities, and some compounds showed competitive activities to those of tetracycline, the typical antibacterial drug, and clotrimazole, the typical antifungal drug.     

Regioselective synthesis and characterization of new 3‐aryl‐7‐trifluoromethyl‐[1,2,4]triazolo[4,3–a]pyrimidines

The regioselective synthesis and characterization of a new series of 3‐aryl‐7‐trifluoromethyl[1,2,4]triazolo[4,3–a]pyrimidines from the oxidative heterocyclization of 2‐(N′‐benzylidenehydrazino)‐4‐trifluoromethylpyrimidines with copper dichloride is described. J. Heterocyclic Chem., (2011).     

Synthesis and reactivity of some imidazo‐, triazolo‐ and tetrazolo‐isoquinoline derivatives

1‐Acetylirrüno‐3‐methyl‐1H‐isochromene‐4‐carbonitrile, 1 , reacts with glycine ethyl ester under basic conditions to give an imidazo[2,1‐a]isoquinoline derivative, while reaction with hydrazine hydrate in 1,4‐dioxane, with further chemistry, provides access to [1,2,4]triazolo[5,1‐a]isoquinoline, [1,2,4]triazolo[3,4‐a]isoquinoline and tetrazolo[5,1‐a]isoquinoline analogs. Benzene ring nitration and radical bromination of substituent methyl groups were investigated in the four tricycles, with some different positional reactivities being found. Two bromomethyl derivatives so produced were oxidised; ethyl 2‐bromomethyl‐6‐cyano‐5‐methylimidazo[2,1‐a]isoquinoline‐3‐carboxylate gave the anticipated ethyl 6‐cyano‐2‐formyl‐5‐methylimidazo[2,1‐a]isoquinoline‐3‐carboxylate (which reacted further with hydrazine to form a new system, 8,9‐dihydro‐6‐methyl‐8‐oxopyridazino[4′,5′:4,5]imidazo[2,1‐a]isoquinoline‐5‐carbonitrile), while 5‐bromomethyl‐2‐methyl[1,2,4]triazolo[5,1‐a]isoquinoline‐6‐carbonitrile unexpectedly gave directly another new system, 5,6‐dihydro‐5‐hydroxy‐2‐methyl‐7H‐pyrrolo[3,4‐c][1,2,4]triazolo[5,1‐a]isoquinolin‐7‐one.     

Bis(enaminones) as Versatile Precursors for Novel Bis([1,2,4]triazolo[1,5‐a]pyrimidines) and Bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones)

Novel bis([1,2,4]triazolo[1,5‐a]pyrimidines) and bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones) were prepared utilizing bis(enaminones) as precursors. The structures of the prepared compounds were elucidated by several spectral tools as well as elemental analyses.     

Utility of 2‐[4‐(3‐oxobenzo[f]‐2H‐chromen‐2‐yl)‐1,3‐thiazol‐2‐yl]ethanenitrile in heterocyclic synthesis

Pyrazolo[4,3‐d]pyrimidines, pyrazolo[4,3‐d]triazolino[4,3‐a]pyrimidines, 3‐(2‐thiazolyl)thiophenes, thiazolo[3,2‐a]pyridine and pyrazolo[1,5‐a]pyrimidines were synthesized from 2‐[4‐(3‐oxobenzo[f]‐2H‐chromen‐2‐yl)‐1,3‐thiazol‐2‐yl]ethanenitrile. The newly synthesized compounds were elucidated by elemental analysis, spectral data, chemical transformation and alternative synthesis route whenever possible.     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

Studies with enaminones: The reaction of enaminones with aminoheterocycles. A route to azolopyrimidines,azolopyridines and quinolines

The enaminones 1b,d,f react with 4‐phenyl‐3‐methyl‐5‐pyrazoleamine 3a to yield the pyrazole derivatives 4a‐c that cyclised readily on reflux in pyridine solution in presence of hydrochloric acid to yield the pyrazolo[1,5‐a]pyrimidines 5a‐c. Similarly 3(5)‐amino‐1H‐triazole (3b) reacted with 1b,d,f to yield the triazolo[1,5‐a]pyrimidines 5d‐f. In contrast attempted condensation of the 5‐tetrazoloamine (3c) with 1a,d,e resulted in its trimerisation and only triaroylbenzene 8a,d,e was isolated. The reaction of 1a,b,d with anthranilonitrile 9a and the reaction of 1a‐c with the 2‐aminocyclohexene thiophene‐3‐nitrile 10a afforded the cis enaminones 11a‐c and 12a‐c. Similarly, reaction of 1a‐c with the methylanthranilate 9b and reaction of 1b,e with ethyl 2‐aminocyclohexene thiophene‐3‐carboxylate 10b afforded the cis enaminones 11d‐f and 12d,e respectively. Attempted cyclization of 11a‐c into quinoline failed. Successful cyclization of 11d into the quinolinone 13 could be affected, on heating for five minutes in a domestic microwave oven at full power. The reaction of 1a‐c,f with piperidine afforded the trans enaminones 14a‐d. Similarly, trans 14e was formed from the reaction of 1b with morpholine. The coupling reaction of 1b with excess of benzene diazonium chloride afforded the formazane 16. The enaminone 2 reacted with heterocyclic amines to yield the pyridones 17,18.     

New [g]-fused [1,2,4]triazolo[1,5-c]pyrimidines: Synthesis of pyrido[3,2-e] and [4,3-e][1,2,4]triazolo[1,5-c]pyrimidine,pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-c]pteridine derivatives

A number of 2-aryl-substituted pyrido[3,2-e] and [4,3-e][1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-c]pteridines 11,12a,b,e , their corresponding 5-carbonyl derivatives 7,8a,b,e and some pyrimido[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ones 7,8c,d have been synthesized, according to different pathways. The new tricyclic heterocycles were prepared with the aim of studying their possible benzodiazepine receptors affinity.     

Isolation and structural data of the opened ring derivative of a 1,2,4‐triazolothieno‐1,4‐diazepine

The preparation of the trihydrochloride form of 2‐[3‐(aminomethyl)‐5‐methyl‐1,2,4‐triazol‐4‐yl]‐3‐(2‐chlorobenzoyl) thieno[2,3‐c]‐4,5,6,7‐tetrahydropyridine ( 2 ) the ring opened derivative of a 1,2,4‐triazolo‐thieno‐1,4‐diazepine is described. Its structural properties are given, and are compared with those of the corresponding closed form 4H‐6‐(2‐chlorophenyl)‐1‐methyl‐7,8,9,10‐tetrahydropyrido[4′,3′:4,5]thieno[3,2‐f]‐[1,2,4]triazolo[4,3‐a][1,4]diazepine ( 1 ).     

A new approach for the synthesis of some pyrazolo[5,1‐c]triazines and pyrazolo[1,5‐a]pyrimidines containing naphtofuran moiety

Naphtho[2,1‐b]furan‐2‐yl)(8‐phenylpyrazolo[5,1‐c][1,2,4]triazin‐3‐yl)methanone, ([1,2,4]triazolo[3,4‐c][1,2,4]triazin‐6‐yl)(naphtho[2,1‐b]furan‐2‐yl)methanone, benzo[4,5]imidazo[2,1‐c][1,2,4]triazin‐3‐yl‐naphtho[2,1‐b]furan‐2‐yl‐methanone, 5‐(naphtho[2,1‐b]furan‐2‐yl)pyrazolo[1,5‐a]pyrimidine, 7‐(naphtho[2,1‐b]furan‐2‐yl)‐[1,2,4]triazolo[4,3‐a]pyrimidine, 2‐naphtho[2,1‐b]furan‐2‐yl‐benzo[4,5]imidazo[1,2‐a]pyrimidine, pyridine, and pyrazole derivatives are synthesized from sodium salt of 5‐hydroxy‐1‐naphtho[2,1‐b]furan‐2‐ylpropenone and various reagents. The newly synthesized compounds were elucidated by elemental analysis, spectral data, chemical transformation, and alternative synthetic route whenever possible. J. Heterocyclic Chem., (2012).