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 and Antifungal Activities of ω‐[4‐Aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thio]‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenones

New 4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thiones 3 have been synthesized by the intramolecular cyclization of 4‐aryl‐1‐(1‐phenyl‐5‐methyl‐1,2,4‐triazol‐4‐formyl)thiosemicarbazides 2 with an 8% NaOH solution, and then 3 reacted with ω‐bromo‐ω‐(1H‐1,2,4‐triazol‐1‐yl)acetophenone to afford ω‐[4‐aryl‐5‐(1‐phenyl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,2,4‐triazol‐3‐thio]‐ω‐(1H‐1,2,4‐triazol‐1‐yl)‐acetophenones 4 . The preliminary biological test showed that the representative compounds possess some anti fungal activities.     

Synthesis of 1,3,4‐Oxadiazole Acyclo C‐Nucleosides Bearing 5‐Methylthio{7‐substituted‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}moieties

Oxidative cyclization of the sugar hydrazones ( 3_a‐f ) derived from {7H‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐ylsulfanyl}acetic acid hydrazide ( 1 ) and aldopentoses 2_a‐c or aldohexoses 2_d‐f with bromine in acetic acid in the presence of anhydrous sodium acetate, followed by acetylation with acetic anhydride gave the corresponding 2‐(per‐O‐acetyl‐alditol‐l‐yl)‐5‐methylthio{7H‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}‐1,3,4‐oxadiazoles ( 5_a‐f ). Condensative cyclization of the sugar hydrazones ( 3_a‐f ) by heating with acetic anhydride gave the corresponding 3‐acetyl‐2‐(per‐O‐acetyl‐alditol‐1‐yl)‐2,3‐dihydro‐5‐methylthio{7‐acetyl‐1,2,4‐triazolo[1,5‐d]tetrazol‐6‐yl}‐1,3,4‐oxadiazoles ( 11_a‐f ). De‐O‐acetylation of the acyclo C‐nucleoside peracetates ( 5 and 11 ) with methanolic ammonia afforded the hydrazono lactones ( 7 ) and the acyclo C‐nucleosides ( 12 ), respectively. The structures of new oxadiazole derivatives were confirmed by analytical and spectral data.     

Synthesis and Molecular Structure of New S‐Nucleosides of 5‐(4‐Pyridyl)‐4‐Aryl‐4H‐1,2,4‐Triazole‐3‐Thiols

The synthesis of some new S‐nucleosides of 5‐(4‐pyridyl)‐4‐aryl‐4H‐1,2,4‐triazole‐3‐thiols ( 4a‐n ) is described. Direct glycosylation of ( 4a‐n ) with tetra‐O‐acetyl‐α‐D‐glucopyranosyl bromide in the presence of potassium hydroxide followed by deacetylation using dry ammonia in methanol gave the corresponding 3‐S‐(ñ‐D‐glucopyranosyl)‐5‐(4‐pyridyl)‐4‐aryl‐4H‐1,2,4‐triazoles ( 6a‐n ) in good yields. All the compounds were fully characterized by means of ¹HNMR, ¹³C NMR spectra and elemental analyses. To assist in the interpretation of the spectroscopic data, the crystal structure of 3‐S‐(2′,3′,4′,6′‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl)‐5‐(4‐pyridyl)‐4‐phenyl‐4H‐1,2,4‐triazole ( 5a ) was determined by X‐ray diffraction.     

Microwave‐assisted synthesis of some 1,2,4‐triazol‐5‐one derivatives

A series of 3‐alkyl(aryl)‐4‐(p‐hydroxy‐phenyl)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 2 were obtained from the reaction of alkyl (aryl) ester ethoxycarbonyl hydrazones 1 with p‐hydroxy aniline. The reaction of 1 with 1,4‐diamino benzene (1:1) to afford 3‐alkyl(aryl)‐4‐(p‐aminophenyl)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 3 . The reaction of 3 with benzaldehyde gave 3‐alkyl(aryl)‐4‐(4′‐benzilidenamino)‐4,5‐dihydro‐1H‐1,2,4‐triazol‐5‐ones 4 . All of the above reactions occurred under microwave heating and conventional methods. Their structures were confirmed by ¹H NMR, ¹³C NMR, IR, and elemental analyses. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:38–42, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20381     

Behavior of 3‐benzylamino‐5‐aryl‐2(3H)‐furanones towards some nitrogen nucleophiles

Ring closure of 2‐N‐benzylamino‐3‐aroylpropionic acids ( 3 ) with acetic anhydride afforded 3‐N‐benzylamino‐5‐aryl‐2(3H)‐furanones ( 4 ). The reaction of the furanones ( 4 ) with benzylamine in benzene was found to be time dependent. Thus refluxing the reaction mixture for 1 h only afforded the open‐chain amides ( 5a‐c ). When the reaction was conducted for 3 h the 2(3H)‐pyrrolones ( 6 ) were obtained. Hydrazine hydrate affected ring opening of the furanones to give the hydrazides ( 5d‐f ). Also, semicarbazide converted ( 4 ) into the corresponding semicarbazide derivatives ( 5g‐i ). The hydrazides ( 5d‐f ) were reacted with benzoyl chloride to give the corresponding diaroylhydrazines ( 5j‐l ). The open‐chain derivatives ( 5 ) were converted into a variety of heterocycles: isothiazolones ( 7 ), dihydropyridazinones ( 8 ), 1,3,4‐oxadiazoles ( 9 ) and 1,2,4‐triazole derivatives ( 10 ) via cyclization reactions.     

TiO2‐Nanoparticles Catalyzed Synthesis of New Trifluoromethyl‐4,5‐dihydro‐1,2,4‐oxadiazoles and Trifluoromethyl‐1,2,4‐oxadiazoles

Synthesis of a new series of trifluoromethyl‐4,5‐dihydro‐1,2,4‐oxadiazoles and trifluoromethyl‐1,2,4‐oxadiazoles have been described by utilizing the reactions between amidoximes and trifluoroacetimidoyl chlorides. Trifluoromethyl‐4,5‐dihydro‐1,2,4‐oxadiazoles have been synthesized under mild conditions such as Na₂CO₃, THF‐H₂O, and titanium dioxide nanoparticles as catalyst in good to excellent yields. Also, trifluoromethyl‐1,2,4‐oxadiazoles have been synthesized directly from reaction of amidoximes and trifluoroacetimidoyl chlorides in a one‐pot manner in present of NaH, THF, and titanium dioxide nanoparticle as catalyst.     

Synthesis of 6‐Aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐Aryl‐thiazolo[3,2‐b][1,2,4]triazoles

The cyclization of the derivatives of 3‐aminotriazole, 2‐(5‐substituted 4H‐1,2,4‐triazol‐3‐ylamino)‐1‐arylethanones and 2‐(4H‐1,2,4‐triazol‐3‐ylthio)‐1‐arylethanones to yield 6‐aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐aryl‐thiazolo[3,2‐b][1,2,4]triazoles has been described.     

Basicity of Phenyl‐ and Methyl‐Substituted 1,2,4‐Oxadiazoles

The basicity of a series of 3,5‐disubstituted 1,2,4‐oxadiazoles in aqueous H₂SO₄ was examined by means of UV and ¹H‐NMR spectroscopy. The experimental data were analyzed by the modified Yates–McClelland method to yield the following pK values: 3,5‐dimethyl‐1,2,4‐oxadiazole, −1.66±0.06; 3‐methyl‐5‐phenyl‐1,2,4‐oxadiazole, −2.61±0.02; 3‐phenyl‐5‐methyl‐1,2,4‐oxadiazole, −2.95±0.01; 3,5‐diphenyl‐1,2,4‐oxadiazole, −3.55±0.06. A pK value of ca. −3.7 was estimated for the parent unsubstituted 1,2,4‐oxadiazole based on substituents' additivity increments. Possible protonation sites of the compounds were discussed in terms of both experimental data and theoretical calculations (HF/6‐31G**). Generally, protonation is most likely to occur at N(4) of the 1,2,4‐oxadiazole ring. However, concurrent formation of both N(4)‐ and N(2)‐protonated species in comparable amounts is possible in the case of 3‐phenyl‐1,2,4‐oxadiazoles.     

Synthesis of Novel 3‐Aryl‐5‐dichloromethyl‐Δ2‐1,2,4‐oxadiazolines

The first synthetic approach to hitherto unknown 3‐aryl‐5‐dichloromethyl‐Δ²‐1,2,4‐oxadiazolines, of synthetic and biological interest, has been developed involving high‐yield reactions between N‐(2,2‐dichlorovinyl)benzimidoyl chlorides and hydroxylamine. The molecular structure of one member of this new family of compounds—5‐dichloromethyl‐3‐(4‐fluorophenyl)‐1,2,4‐oxadiazoline—has been determined by X‐ray crystallography. Density functional theory calculations supporting the proposed reaction pathway for the formation of these products have been carried out.     

Microwave‐assisted Synthesis of 6‐{(5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)methyl}‐6H‐indolo[2,3‐b]quinoxalines

An efficient and convenient synthesis of a new series of 2‐{(6H‐indolo[2,3‐b]quinoxalin‐6‐yl)methyl}‐5‐aryl‐1,3,4‐oxadiazoles from readily available 1,2‐diaminobenzene and isatins under microwave irradiation conditions was disclosed. The 6‐{(5‐aryl‐1,3,4‐oxadiazol‐2‐yl)methyl}‐6H‐indolo[2,3‐b]quinoxalines were also prepared by the thermal cyclo‐condensation reaction of 2‐(6H‐indolo[2,3‐b]quinoxalin‐6‐yl)acetohydrazides with carboxylic acids in refluxing POCl₃. The microwave‐assisted synthesis was rapid and resulted in higher yield of the products at lower operating temperature with reduced waste generation in comparison with the thermal reaction protocol.     

(3+2) Annulation of Amidinothioureas with Binucleophile: Synthesis and Antimicrobial Activity of 3‐Phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole Derivatives

Herein, we report an efficient method for preparation of 3‐phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole by (3+2) annulation of amidinothioureas with binucleophilic hydroxylamine hydrochloride in the presence of mercury (II) chloride. Desired 3‐phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole was prepared in good to moderate yields. On the basis of the literature precedence, the mechanism for the formation of 3‐phenylamino‐5‐aryl/alkyl‐1,2,4‐oxadiazole is proposed. The synthesized compounds were tested for their antimicrobial activity and showed promising inhibition of Gram‐positive bacteria (Staphylococcus aureus) and fungi (Candida albicans).     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 5‐Amino‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐selones

The reaction of S‐methylisothiosemicarbazide hydroiodide (=S‐methyl hydrazinecarboximidothioate hydroiodide; 1 ), prepared from thiosemicarbazide by treatment with MeI in EtOH, and aryl isoselenocyanates 5 in CH₂Cl₂ affords 3H‐1,2,4‐triazole‐3‐selone derivatives 7 in good yield (Scheme 2, Table 1). During attempted crystallization, these products undergo an oxidative dimerization to give the corresponding bis(4H‐1,2,4‐triazol‐3‐yl) diselenides 11 (Scheme 3). The structure of 11a was established by X‐ray crystallography.     

Synthesis,Characterization, and Herbicidal Activities of New 1,3,4‐Oxadiazoles, 1,3,4‐Thiadiazoles,and 1,2,4‐Triazoles Derivatives Bearing (R)‐5‐Chloro‐3‐fluoro‐2‐phenoxypyridine

Synthesis of some novel 1,2,4‐triazoles, 1,3,4‐oxadiazoles and 1,3,4‐thiadiazoles bearing a (R) 5‐(1‐(4‐(5‐chloro‐3‐fluoropyridin‐2‐yloxy)phenoxy)ethyl) unit, as a moiety of commercial herbicide, using their thiosemicarbazides in an alkaline, iodine and acidic media is reported, respectively. The structure of the synthesized compounds was characterized by IR, ¹H, ¹³C NMR spectroscopic data, and elemental analyses. The herbicidal activities of synthesized compounds were evaluated against Echinochloa cruss‐galli, Avena fatua, and Sorgum halepense weeds. Compounds 7 and 12a showed potential herbicidal activity against gramineous weeds. Our results may provide some guidance for synthesis development of some novel oxa or thiadiazole and triazole‐based herbicidal lead structures.     

Synthesis and Fungicidal Activity of 5‐Aryl‐1‐(aryloxyacetyl)‐3‐(tert‐butyl or phenyl)‐4‐(1H‐1,2,4‐triazol‐1‐yl)‐4,5‐dihydropyrazole

A series of novel 5‐aryl‐1‐(aryloxyacetyl)‐3‐(tert‐butyl or phenyl)‐4‐(1H‐1,2,4‐triazol‐1‐yl)‐4,5‐dihydropyrazole 3a – 3n were synthesized by the annulation of 2‐aryloxyacetohydrazides with 3‐aryl‐1‐t‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)prop‐2‐en‐1‐ones ( 2 ) in the presence of a catalytic amount of acetic acid. Compounds 2 were obtained by the Knoevenagel reactions of 1‐t‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethanone ( 1 ) with aromatic aldehydes in the presence of piperidine. Their structures were confirmed by IR, ¹H‐NMR, ESI‐MS, and elemental analyses. The preliminary bioassay indicated that some compounds displayed moderate to excellent fungicidal activity. For example, compounds 3l , 3m , and 3n possessed 100% inhibition against Cercospora arachidicola Hori at the concentration of 50 mg/L.     

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 .     

Syntheses of 4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones from Sydnone Derivatives and Their Fragments

4‐(5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 11 and 4‐(4‐arylamino‐5‐oxo‐1,2,4‐triazol‐3‐yl)‐sydnones 13 have been obtained from a‐chloroformylarylhydrazine hydrochloride 2 . Moreover, the intermediates, including 3, 4 , 9 and 10 , in this study are synthetically informative and valuable. It is also noteworthy that three reactants, 1, 2 and sydnonecarbaldehydes, were prepared from sydnone derivatives and their fragments. The oxidative cyclizations of sydnonecarbaldehyde semicarbazones 9 and carbazones 10 with two different oxidizing agents (Cu(ClO₄)₂ and Fe(ClO₄)₃) have been extensively examined. The reaction time and the yields of cyclizations were affected by the substituents of semicarbazones 9 and carbazones 10.     

Synthesis of heterocyclic nitrogen derivatives from aryl‐1,4‐benzoquinones

Treatment of 2‐aryl‐3,6‐bis(arylamino)‐1,4‐benzoquinones 2a‐h with different acid chlorides, namely acetyl, phenylacetyl and chloroacetyl chloride yields 3a,7a‐dihydropyrrolo[2,3‐f]indole‐2,6‐dione 3, 5‐(N‐phenylacetylarylamino)‐3‐phenylindole‐2,6‐dione 4 and 3‐chloro‐5‐(N‐chloroacetylarylamino)indole‐2,6‐dione 5 respectively. Stirring 2‐aryl‐1,4‐benzoquinones ( 1 ) with ethylenediamine and/or o‐phenyl‐enediamine in methylene chloride gives pyrazino[2,3‐g]quinoxalines derivative 6 and/or tetrapentacene derivative 7 respectively. The products 5‐aryl‐ and 6‐aryl‐1/H‐indazole‐4,7‐diones 8 and 9 were obtained in the 1,3‐dipolar cycloaddition of diazomethane to ( 1 ).     

Synthesis of (3,5‐Aryl/methyl‐1H‐Pyrazol‐1‐yl)‐(5‐Arylamino‐2H‐1,2,3‐Triazol‐4‐yl)Methanone

Some new (3,5‐aryl/methyl‐1H‐pyrazol‐1‐yl)‐(5‐arylamino‐2H‐1,2,3‐triazol‐4‐yl)methanones were synthesized and characterized by ¹HNMR, ¹³C NMR, MS, IR spectra data and elemental analyses or high resolution mass spectra (HRMS). During the procedure, Dimroth rearrangement was used in this synthesis.     

Synthesis of Bis{(S‐methyl)azolespoly(ethylene oxide)} from 3,6‐dioxa‐1,8‐octanedithiol

Bis(1,3,4‐oxadiazoles) 4 , 5 and bis(1,2,4‐triazoles) 6a , 6b have been prepared from 3,6‐dioxa‐1,8‐octanedithiol 1 through a multistep reaction sequence. Compound 4 reacted with the appropriate alkyl halide in the presence of potassium carbonate in refluxing acetone to give the corresponding bis(S‐alkylated‐1,3,4‐oxadiazoles) 7a , 7b . The title compound 8 was prepared by condensing 4 with benzoyl bromide in the presence of triethylamine. Further, 6,9‐dioxa‐3,12‐dithiotetradecanedihydrazide 3 was converted to bis{N′‐(phenylaminocarbonyl) hydrazides} and bis{N′‐(phenylaminocarbonothioyl)hydrazides} 9a , 9b using phenylisocyanate and phenylthioisocyanate, respectively, which underwent cyclization in alkaline medium to produce 6,9‐dioxa‐3,12‐dithiotetradecane bis(4‐phenyl‐2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐one) and their 3‐thio analogs 10a , 10b . The new compounds 4 , 5 , 6 , 7 , 8 , 9 , 10 were characterized by their IR, ¹H‐NMR, ¹³C‐NMR, MS, and elemental analyses.