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,Antimicrobial, and Antioxidant Screening of Aryl Acetic Acid Incorporated 1,2,4‐Triazolo‐1,3,4‐Thiadiazole Derivatives

Some novel [1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole derivatives were synthesized from aryl acetic acids. All the synthesized derivatives were selected for the screening of antibacterial potential against Gram‐positive bacteria [Staphylococcus aureus (MTCC 3160) and Micrococcus luteus (MTCC 1538)] and Gram‐negative bacteria [Escherichia coli (MTCC 1652) and Pseudomonas aeruginosa (MTCC 424)] and antifungal potential against Aspergillus niger (MTCC 8652) and Candida albicans (MTCC 227), and free radical scavenging activity through 2,2‐diphenyl‐2‐picrylhydrazyl hydrate method. The compounds TH‐4 , TH‐13 , and TH‐19 were found to be more potent antimicrobial agents compared to standard drugs. The compounds TH‐3 , TH‐9 , and TH‐18 also showed significant antimicrobial activity. The compound TH‐13 showed antioxidant activity with IC₅₀ value better than the standard compound. The structures of all the synthesized compounds were confirmed by Fourier transform infrared, ¹H‐NMR, liquid chromatography–mass spectrometry, and CHN analyzer.     

Synthesis of chiral fused heterocyclic compounds containing 1,2,4‐triazole ring

A series of new chiral (S)‐3‐ary1‐6‐pyrrolidin‐2‐yl‐[1,2,4]triazolo[3,4‐b]thiadiazole (II_1‐5), (S)‐1‐(3‐aryl‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐ethylamine (II_6‐8) and (S)‐1,2‐bis(3‐aryl‐[1,2,4]triazolo‐[3,4‐b][1,3,4]thiadiazol‐6‐yl)‐ethylamine (II_9‐11) were prepared by the condensation of 3‐aryl‐4‐amino‐5‐mercapto‐1,2,4‐triazoles with different L‐amino acids in the presence of phosphorus oxychloride and evaluated for their antibacterial activity.     

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.     

Interaction of 7-Chloro-9-methylthio-3-phenylpyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine with Some Nucleophiles

The reactions of 7-chloro-9-methylthio-3-phenylpyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine (1) with some nucleophiles have been studied. Substitution of the chlorine atom with hydrogen occurs with ammonia in DMSO to give 9-methylthio-3-phenylpyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepin-7(8H)-one. With a methanolic solution of ammonia the 7-methoxy derivative is formed. Reaction of compound 1 with an excess of sodium methoxide in methanol gave 6,7-dimethoxy-9-methylthio-3-phenyl-5,6-dihydropyrimido[5,4-f][1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. The corresponding 7-substituted derivatives were obtained when compound 1 was heated with morpholine or 2-(dimethylamino)ethylamine. The azomethine bond of the thiadiazepine ring is reduced by sodium borohydride to give the corresponding 5,6-dihydro derivatives.     

Facile synthesis of 6-hetaryl[1,2,4]triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>][1,3,4]thiadiazoles and 7-hetaryl[1,3,4]thiadiazolo[2,3-<Emphasis Type="Italic">c</Emphasis>][1,2,4]triazines with fungicidal activity

Condensation of 4-amino-4H-1,2,4-triazole-3-thiol and 4-amino-6-methyl-3-sulfanyl-1,2,4-triazin-5(4H)-one with ethyl cyanoacetate gave ethyl [1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylacetate and ethyl 3-methyl-4-oxo-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-7-ylacetate, respectively. Reactions of the condensation products with 1,3-diphenylprop-2-en-1-one, aromatic aldehydes, and carbon disulfide or N,N-dimethylformamide dimethyl acetal (followed by treatment with hydrazine hydrate) gave the corresponding 6-hetaryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles and 7-hetaryl-3-methyl-4H-[1,3,4]thiadiazolo[2,3-c][1,2,4]triazin-4-ones. Preliminary tests revealed fungicidal activity of the pyrazolyl-substituted derivatives. Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 12, pp. 1813–1818. The text was submitted by the authors in English.     

Synthesis of Thienotriazolopyrimidine Derivatives Containing Triazolothiadiazole Moiety

A series of diheterocyclic compounds 15 and 16 was synthesized by the introduction of 6‐aryl or 6‐benzyl‐1,2,4‐triazolo[3,4‐b][1,3,4]thiadiazole moiety to thieno[1,2,4]triazolo[4,3‐c]pyrimidine ring through a sulfur linkage.     

Synthesis and in vitro Biological Evaluation of Some Novel Triazole‐Based Heterocycles as Potential Antimicrobial Agents

A series of novel 6‐{5‐aryl‐4H‐1,2,4‐triazol‐3‐ylthio}methyl‐3‐substituted‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles and 2‐{(5‐aryl‐4H‐1,2,4‐triazol‐3‐ylthio)‐N‐4‐aryl}acetamides containing 1,2,4‐triazole moiety were synthesized and characterized by ¹H, ¹³C, DEPT, and D₂O. The synthesized compounds were evaluated for their antibacterial activity against three strains of bacteria along with antifungal activity against five fungal species. It has been found that tested compounds showed moderate activity.     

Synthesis of Coumarin Substituted Triazolothiadiazine Derivatives via Ring Transformation Reaction

A novel ring transformation reaction for the synthesis of 3‐(3‐aryl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)‐2H‐chromen‐2‐ones has been described. Reaction of 3‐(2‐bromoacetyl)coumarins ( 1 ) with 5‐aryl‐1,3,4‐oxadiazole‐2‐thiol ( 2 ) gave ketones ( 4a–h ). The in situ formed ketones ( 4a–h ) were reacted with hydrazine hydrate to give 3‐(3‐aryl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)‐2H‐chromen‐2‐ones ( 3a–h ) and not 5 or 6 . The compounds ( 3a–h ) can also be prepared by the reaction of 3‐(2‐bromoacetyl)coumarins ( 1 ) with 5‐aryl‐1,3,4‐oxadiazole‐2‐thiol ( 2 ) in anhydrous ethanol to give corresponding 3‐(2‐(5‐aryl‐1,3,4‐oxadiazol‐2‐ylthio)acetyl)‐2H‐chromen‐2‐ones ( 4a–h ). These on reaction with hydrazine hydrate in acetic acid gave corresponding 3‐(3‐aryl‐7H‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazin‐6‐yl)‐2H‐chromen‐2‐ones ( 3a–h ).     

6-Arylamino-3-methyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines: Novel N-Arylamidine Structures

We propose a method for obtaining derivatives of 7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine by alkylation of 4-amino-5-methyl-4H-1,2,4-triazole-3-thiol by substituted -chloroacetanilides, followed by cyclization of the intermediate by phosphorus oxychloride.     

Synthesis and Biological Activity Test of Some New Five Membered Heterocycles

A new series of 1,3,4‐oxadiazoles, 1,2,4‐triazoles, 1,3,4‐thiadiazoles were synthesized using alkylhydrazides as the starting materials, and then 1,2,4‐triazoles were used to synthesize [1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles. All the compounds were evaluated for in vitro antibacterial activity and antitumor activity.     

Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives embedded with benzimidazole moiety as potent antioxidants

Fourteen novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives bearing benzimidazole moiety ( 7a-n ) have been synthesized using the one-pot nitro reductive cyclization method. All the synthesized compounds were confirmed by ¹H nuclear magnetic resonance (¹H NMR), ¹³C NMR, fourier-transform infrared (FT-IR), mass spectrum, and elemental analyses. All the title compounds were subjected to in vitro antioxidant activity. The free radical scavenging activity of the compounds was examined using DPPH, nitric oxide, and superoxide radical scavenging methods. The results demonstrated that compound 3-(2-(3,4-dimethoxyphenyl)-1-propyl-1H-benzo[d]imidazol-5-yl)-6-4-tolyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine ( 7c ) was potent in scavenging both DPPH and nitric oxide radical with IC₅₀ values of 13.57 and 18.55 μg/ml when compared to the standard with IC₅₀ values of 23.75 and 23.14 μg/ml, respectively, which was due to the presence of electron-donating groups. The activity was found to decline when electron-donating groups were replaced by electron-withdrawing groups. Moderate scavenging activity was observed for the superoxide radical. Structure activity relationship and physiochemical properties were studied for all the derivatives.     

Synthesis of 3-Alkyl-6-aryl(arylamino)-7H-[1,2,4]triazolo- [3,4-b][1,3,4]thiadiazines

Starting from 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols and substituted chloroacetanilides, the corresponding (5-alkyl-4-amino-4H-1,2,4-triazol-3-ylsulfanyl)acetanilides were synthesized. The products underwent intramolecular cyclization in boiling phosphoryl chloride to afford 3-alkyl-6-arylamino-7H-[1,2,4]-triazolo[3,4-b][1,3,4]thiadiazines. 3-Alkyl-6-aryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine hydrobromides were obtained by reaction of 5-alkyl-4-amino-4H-1,2,4-triazole-3-thiols with substituted 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.     

Synthesis of Triazoles,Oxadiazoles and Condensed Heterocyclic Compounds Containing Cinchopheny and Studies on Biological Activity of Representative Compounds

Compounds 2‐arylamino‐5‐cinchophenyl‐1,3,4‐oxadiazoline ( 7 ) and 3‐thio‐4‐amino‐5‐cinchophenyl‐1,2,4‐triazole ( 3 ) have been synthesized utilizing cinchophen as the starting material. The compound 3‐cinchopheny‐s‐triazolo[3,4‐b]‐1,2,3,4‐thiatriazole ( 4 ) was prepared from compound 3 . Condensation of 3 with aromatic acid in the presence of POCl₃ gave 10 new 6‐aryl‐3‐cinchopheny‐1,2,4‐triazolo[3,4‐b]‐1,3,4‐thiadiazoles ( 5 ). Some of the representative compounds were screened for antibacterial activity. The structures of these new compounds have been confirmed by means of elemental analysis, IR, ¹H NMR and MS.     

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.     

Cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine with hydroxylamine and hydrazine

The cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (3) with hydroxylamine or hydrazine leads to 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenylisoxazolo-[5,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4a ) and 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenyl-1H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4b ), respectively. In the presence of methanolic hydrogen chloride, 4b undergoes a cleavage of the pyrimidine ring to yield (5-amino-1,2,4-triazol-1-yl)(3,5-dimethylpyrazol-4-yl)phenylmethane ( 5 ). The structure determination of the compounds obtained is based on ¹H and ¹³C nmr spectra including NOE measurements.     

Microwave‐Promoted Efficient Synthesis of 3‐(5‐Arylfuran‐2‐yl)‐6‐aryl/aryloxymethylene‐1,2,4‐s‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles

A simple, rapid, and efficient method for the synthesis of substituted 1,2,4‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazoles under microwave irradiation conditions is reported, and a series of 3‐(5′‐aryl‐2′‐furyl)‐6‐aryl/aryloxymethylene‐1,2,4‐s‐triazolo[3,4‐b]‐1,3,4‐thiadiazoles was synthesized via this method.     

Synthesis and antitumor activity of new 1,2,4‐triazine and [1,2,4]triazolo[4,3‐b][1,2,4]triazine derivatives and their thioglycoside and acyclic C‐nucleoside analogs

New 1,2,4‐triazine and their derived 1,2,4‐triazolo[3,4‐b][1,2,4]triazine derivatives were synthesized starting from 5,6‐diphenyl‐1,2,4‐triazine‐3‐thiol. Furthermore, the corresponding 1,2,4‐triazolo[3,4‐b][1,2,4]‐triazine thioglycosides and acyclic C‐nucleoside analogs were synthesized. The newly synthesized compounds were evaluated for their antitumor activity and some of them showed high inhibition activities. J. Heterocyclic Chem., 2011.     

Synthesis of spiro[indole-3,3′-[1,3,4]thiadiazino[3,2-a]benzimidazoles] and spiro[indole-3,6′-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines]

A method for annulation of the tetrahydrothiadiazine ring to benzimidazoles and 1,2,4-tri-azoles was developed. A number of earlier unknown [1,3,4]thiadiazino[3,2-a]benzimidazoles and triazolo[3,4-b][1,3,4]thiadiazines were obtained as spiro compounds with the oxindole fragment. According to NMR and X-ray diffraction data, the formation of the tetrahydrothiadiazine ring is a diastereospecific process.