A Facile Synthesis of Aryl‐Substituted Hydrazono‐Pyrazolyl[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin Derivatives

Some inimitable and therapeutic coumarin‐substituted fused[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadizole derivatives were synthesized by the cyclocondensation reaction of 2‐oxo‐2H‐chromene‐3‐carboxylic acid ( 1 ) and 4‐amino‐5‐hydrazinyl‐4H‐[1,2,4]‐triazole‐3‐thiol ( 2 ) by using phosphorous oxychloride as a cyclizing agent. This cyclized intermediate 3‐(3‐hydrazino‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐chromen‐2‐one ( 3 ) later condensation with various ethyl 2‐(2‐arylhydrazono)‐3‐oxobutanoates ( 4 ) in NaOAc/MeOH under reflux conditions afforded the corresponding new series of aryl‐substituted hydrazono‐pyrazolyl‐[1,2,4]triazolo[3,4‐b][1,3,4][thiadiazol]‐coumarin derivatives ( 5 ) in good to excellent yields. The structures of newly synthesized compounds were established on the basis of elemental analysis, IR, ¹H NMR and mass spectroscopic studies.     

Synthesis of Imidazo[2,1‐b][2H‐1,3,4]thiadiazines and 1,2,4‐Triazolo[3,4‐b][2H‐1,3,4]thiadiazines

Imidazo[2,1‐b][2H‐1,3,4]thiadiazines were prepared by cyclization of 2‐amino‐5‐(4‐chlorophenyl)‐6H‐1,3,4‐thiadiazine with α‐haloketones. 1,2,4‐Triazolo[3,4‐b][2H‐1,3,4]thiadiazines were prepared by cyclization of 4‐amino‐5‐sulfanyl‐l,2,4‐triazoles with phenacyl bromides.     

Synthesis of New Pyrimido[4,5‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine Derivatives via S/N Smiles Rearrangement

Several new pyrimido[4,5‐e ][1,2,4]triazolo[3,4‐b ][1,3,4]thiadiazine derivatives ( 5a , 5b , 5c , 5d , 5e , 5f , 5g ) were synthesized through the condensation reaction of 5‐bromo‐4,6‐dichloropyrimidine ( 1 ) and 4‐amino‐5‐methyl‐4H‐1,2,4‐triazole‐3‐thiol ( 2 ). The single crystal X‐ray data of one of the derivatives confirmed the occurrence of the S/N type Smiles rearrangement during the course of the reaction.     

Bis(α‐bromo ketones): Versatile Precursors for Novel Bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) and Bis(as‐triazino[3,4‐b][1,3,4]thiadiazines)

A synthesis of bis(α‐bromo ketones) 5a‐c and 6b,c was accomplished by the reaction of bis(acetophenones) 3a‐c and 4b,c with N‐bromosuccinimide in the presence of p‐toluenesulfonic acid (p‐TsOH). Treatment of 5a‐c and 6b,c with each of 4‐amino‐3‐mercapto‐1,2,4‐triazoles 9a,b and 4‐amino‐6‐phenyl‐3‐mercapto‐1,2,4‐triazin‐5(4H)‐ones 13 in refluxing ethanol afforded the novel bis(s‐triazolo[3,4‐b][1,3,4]thiadiazines) 10a‐d and 11a‐c as well as bis(as‐triazino[3,4‐b][1,3,4]thiadiazines) 14a‐c and 15 , respectively, in good yields. Compounds 11b and 11c underwent NaBH₄ reduction in methanol to give the target 1,ω‐bis{4‐(6,7‐dihydro‐3‐substituted‐5H‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)phenoxy}butanes 12a and 12b in 42 and 46% yields, respectively.     

A Facile Synthesis of Novel Dihydroindeno[1,2‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines Using HTIB

The synthesis of a series of 21 novel 3‐alkyl/aryl‐7/9‐methyl‐10,10a‐dihydroindeno[1,2‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines ( 4 ) has been achieved by the cyclocondensation between 4/6‐methyl‐2‐tosyloxy‐1‐indanones ( 2 ) and 3‐alkyl/aryl‐4‐amino‐5‐mercapto‐1,2,4‐s‐triazoles ( 3 ). 4/6‐Methyl‐2‐tosyloxy‐1‐indanones ( 2 ) were readily accessible through hypervalent iodine oxidation of 4/6‐methyl‐1‐indanones using [(hydroxy)tosyloxyiodo]benzene (HTIB, Koser's reagent) in acetonitrile.     

Facile routes to 1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines and 1,2,4‐triazino[3,4‐b][1,3,4]thiadiazine by heteropolyacides

Cyclization of 4‐amino‐6‐methyl‐3‐propargylmercapto‐1,2,4‐triazine‐5‐one 3 and 4‐amino‐3‐propargyl mercapto‐1,2,4‐triazole derivatives 6 were afforded 1,2,4‐triazino[3,4‐b][1,3,4]thiadiazines 4 and 1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazines 7 in presence of heteropolyacids, H₁₄[NaP₅W₂₉MoO₁₁₀] and H₆P₂W₁₈O₆₀ in high yields. Among used heteropoly acids, the yields were higher with H₁₄‐P₅Mo, caused to their high acid strengths.     

Synthesis,Acidity Constants and Tautomeric Structure of 7‐Arylhydrazono[1,2,4]Triazolo[3,4‐b][1,3,4]thiadiazines in Ground and Excited States

7‐Arylhydrazono[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 4 were synthesized from the reactions of 4‐amino‐5‐phenyl‐4H‐[1,2,4]triazole‐3‐thiol 2 and 2‐(2‐naphthyl)‐2‐oxoethanehydrazonoyl bromides 1 and their acid dissociation constants pK and pK*, in the ground and excited states, respectively, were determined. Both pK and pK* constants were correlated by Hammett equation. The pK and the spectral data presented indicate that the title compounds exist predominantly in the hydrazone tautomeric form.     

Synthesis and Biological Activities of 7‐Arylazo‐7H‐pyrazolo[5,1‐c][1,2,4] Triazol‐6(5H)‐Ones and 7‐Arylhydrazono‐7H‐[1,2,4]triazolo[3,4‐b] [1,3,4]thiadiazines

Two series of 7‐arylazo‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)pyrazolo[5,1‐c][1,2,4]triazol‐6(5H)‐ones 4 and 7‐arylhydrazono‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 7 were prepared via reactions of 4‐amino‐3‐mercapto‐5‐(2‐methyl‐1H‐indol‐3‐yl)‐1,2,4‐triazole 1 with ethyl arylhydrazono‐chloroacetate 2 and N‐aryl‐2‐oxoalkanehydrazonoyl halides 5 , respectively. A possible mechanism is proposed to account for the formation of the products. The biological activity of some of these products was also evaluated.     

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.     

Part 1: Synthesis of Polyfused Heterocyclic Systems Derived From 3-Phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione

3-Phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione ( 1 ) was condensed with o -aminothiophenol, 2-amino-ethanol or cystamine to afford compounds 2-4 respectively. Treatment of compound 1 with dimethylthiomethylenemalononitrile yielded the corresponding pyrano[3,2- f ][1,2,4]triazolo[3,4- b ]-[1,3,4]thiadiazepine derivative 5 . 7-[5-Amino-1,3-dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6,8-dione ( 6 ) was obtained by treating compound 1 with CS 2 and chloroacetonitrile. Thiation of compound 1 gave the corresponding thioanalog 7 , which in turn was condensed with malononitrile to give 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazepine-6-one-8-ylidenemalononitrile ( 8 ). On treating compound 8 with benzaldehyde or p -nitrobenzaldehyde, pyrano[1,2,4]triazolo[1,3,4]thiadiazepin derivatives 9a , b , respectively, were obtained. Compound 8 was treated with CS 2 and methyl iodid to give the corresponding dithiomethylmethylene derivative 10 which was subjected to react with aniline to give pyrido[1,2,4]triazolo[1,3,4]thiadiazepine derivative 11 . Compound 8 was treated with 3-aminopyridine, o -aminothiophenol, or o -phenylenediamene to yield compounds 12 and 13a , b respectively. Finally, tertiary amines or activated phenols were condensed with compound 8 to yield compounds 14 and 15a , b respectively.     

Synthesis and antimicrobial evaluation of some 1,2,4‐triazole, 1,3,4‐oxa(thia)diazole,and 1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazine derivatives

3‐Methyl‐2‐benzofurancarboxylic acid hydrazide ( 2 ) reacts with carbon disulfide and pota‐ ssium hydroxide to give the corresponding potassium carbodithioate salt 3 . Treatment of the latter salt with hydrochloric acid, hydrazine hydrate, and with phen‐ acyl bromide afforded the corresponding 1,3,4‐oxadia‐ zole‐5‐thione 4 , 4‐amino‐1,2,4‐triazole‐5‐thione 5 , and thiazolidine‐2‐thione 9 derivatives, respectively. The reaction of either 1,3,4‐oxadiazole‐5‐thione 4 or 4‐amino‐1,2,4‐triazole‐5‐thione 5 with phenacyl bromide resulted in the formation of 1,2,4‐triazolo[3, 4‐b]‐1,3,4‐thiadiazine derivative 8 . Treatment of compounds 3 or 4 with hydrazonoyl halides 10a–d furn‐ ished the same 1,3,4‐thiadiazol‐2‐ylidene derivatives 11a–d . The 7‐arylhydrazono‐1,2,4‐triazolo[3,4‐ b ]‐1, 3,4‐thiadiazine derivatives 12a–d were obtained either by treatment of 4‐amino‐1,2,4‐triazole‐5‐thione 5 with hydrazonoyl halides 10a–d or by coupling of the 1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazine derivative 8 with diazonium salts. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:621–627, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20162     

C5‐Alkyl‐1,3,4‐Oxadiazol‐2‐ones Undergo Dealkylation upon Nitrogen Insertion to Form 2H‐1,2,4‐Triazol‐3‐ones: Synthesis of 1,2,4‐Triazol‐3‐one Hybrids with Triazolothiadiazoles and Triazolothiadiazines

The present study emphasizes on the dealklylation of 3‐aryl‐5‐alkyl‐2‐oxo‐Δ⁴‐1,3,4‐oxadiazoles when reacted with formamide resulting in the formation of 2‐aryl‐2H‐1,2,4‐triazol‐3(4H )‐ones as major product. Subsequent reactions of 2‐aryl‐2H‐1,2,4‐triazol‐3(4H )‐one gave triazolo[3,4‐b ][1,3,4]thiadiazoles and triazolo[3,4‐b ][1,3,4]thiadiazines derivatives incorporated with 1,2,4‐triazol‐3‐one.     

Synthesis of 1,2,4-triazole, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazine derivatives of benzotriazole

A novel series of 1-(1-carbonylmethyl-1H-benzotriazole) thiosemicarbazides 3a-e was synthesized and then cyclized with sodium hydroxide to afford 1-(4-substituted-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazoles 4a-e , which were alkylated with ethyl iodide to l-(3-ethylthio-4-substituted-4H-1,2,4-triazol-5-yl)-methyl-1H-benzotriazoles 5b-e . The reaction of 1H-benzotriazol-1-acetic acid hydrazide ( 2 ) with carbon disulphide and potassium hydroxide followed by hydrazine hydrate gave 1-(4-amino-4H-1,2,4-triazole-3-thion-5-yl)methyl-1H-benzotriazole ( 6 ). Its subsequent condensation with carboxylic acids in the presence of phosphorus oxychloride or with phenacyl bromides afforded two series of fused heterocycles namely; 6-substituted-3-[1-(1H-benzotriazole)methyl]-1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 7a-e and 6-substituted phenyl-3-[1-(1H-benzotriazole)methyl]-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 8a-e respectively. The structure of the newly synthesized compounds was elucidated by elemental analyses, ir and nmr spectra.     

Stereospecific synthesis of 6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines

The reaction of 3-mercapto-4-arylideneamino-1,2,4-triazoles 2b-d , 3a-d with ethyl bromoacetate and/or phenacyl bromide in hot DMF and triethylamine affords the stereochemically pure 7-acyl-6-aryl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 4b-d , 5a-d , 6b , d in which the consecutive hydrogen atoms N(5)H-C(6)H-C(7)H are cis to each other. This stereochemistry was determined by ¹H NMR spectroscopy and confirmed by comparison with the spectrum of 3,6-diphenyl-6,7-dihydro-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine 10 . The latter was prepared by NaBH₄ reduction of 3,6-diphenyl-5H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazine 9 . The reported reactions offer two interesting stereospecific syntheses of the condensed heterocyclic compounds.     

Synthesis and antibacterial studies of 6‐aryl‐2,2a‐dihydro‐naphtho‐[2′,1′‐5,6]pyrano[4,3‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine and its derivatives

Chemoselective synthesis of novel hetero cyclopenta[b]chrysene derivatives, namely, 6‐Aryl‐2,2a‐dihydro‐naphtho[2′,1′‐5,6]pyrao[4,3‐e][1,2,4]triazolo[3,4‐b][1,3,4]thiadiazine ( 4a‐j ) under neutral condition has been described. These molecules exhibited good to excellent anti‐bacterial activities.     

Synthesis of 6‐(5‐Methylisoxazol‐3yl)‐3‐alkyl Sulfanyl‐[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadiazoles

A new series of isoxazole substituted fused triazolo‐thiadiazoles have been synthesized by the cyclocondensation of 5‐methylisoxazole‐3‐craboxylic acid and 4‐amino 1,2‐4‐triazole‐ 3,5‐dithiol using phosphorous oxychloride. The cyclised intermediate 6‐(5‐methylisoxazol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole‐3‐thiol later on S‐alkylated with different alkyl halides in ethanol to give the title products in good to excellent yields.     

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 and Biological Evaluation of Novel Bis[1,2,4]triazolo[3,4‐b] [1,3,4]oxadiazoles

A series of novel 6‐2‐methoxy‐5‐[4‐methoxy‐3‐(3‐aryl[1,2,4]triazolo[3,4‐b][1,3,4]oxadiazol‐6‐yl)benzyl]phenyl‐3‐aryl[1,2,4]triazolo[3,4‐b][1,3,4]oxadiazoles 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j has been synthesized and characterized via IR, ¹H NMR, ¹³C NMR, MS, and elemental analyses. Compounds 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j were also screened for their antibacterial activity against Gram‐positive bacteria viz. Bacillus subtilis (MTCC 441), Bacillus sphaericus (MTCC 11), and Staphylococcus aureus (MTCC 96), and Gram‐negative bacteria viz. Pseudomonas aeruginosa (MTCC 741), Klobsinella aerogenes (MTCC 39), and Chromobacterium violaceum (MTCC 2656). The antibacterial screening reveal that the presence of 2,4‐difluorophenyl ( 7e ) or 4‐nitrophenyl ( 7f ) of 2‐pyrazyl ( 7i ), or 2‐furyl ( 7j ) on the triazole moiety exhibited potent inhibitory activity comparable with the standard drug streptomycin, at the tested concentrations, and emerged as potential molecules for further development.     

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine Derivatives: Synthesis,Anti-Viral In Vitro Study and Target Validation Activity

This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level.     

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.