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 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     

Synthesis,Characterisation and Crystal Structures of Two Bi‐oxadiazole Derivatives Featuring the Trifluoromethyl Group

The synthesis, characterisation, and crystal structure determination of the closely related compounds 3,3′‐bi‐(5‐trifluoromethyl‐1,2,4‐oxadiazole) and 5,5′‐bi‐(2‐ trifluoromethyl‐1,3,4‐oxadiazole) are reported. These two compounds are known for their bioactivity; however, in this study they serve as model compounds to evaluate the suitability of the heterocyclic oxadiazole ring system for energetic materials when the fluorine atoms in the exocyclic CF₃ groups are substituted successively by nitro groups. Quantum chemical calculations for the bi‐1,3,4‐ oxadiazole derivatives with difluoronitromethyl, fluorodinitromethyl, and trinitromethyl groups have been carried out and predict promising energetic performances for both explosive and propulsive applications.     

Polycyclic N‐Heterocyclic Compounds. 56 Reaction of N‐(5,6‐Dihydro[1]benzoxepino[5,4‐d]pyrimidin‐4‐yl)amidine or Its Amide Oxime Derivatives with Hydroxylamine Hyrdochloride

The reactions of N‐(5,6‐dihydro[1]benzoxepino[5,4‐ d]pyrimidin‐4‐yl)amidines or its amide oxime derivatives with hydroxylamine hydrochloride gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of [1,2,4]oxadiazole.     

Utility of 4‐Benzylidene‐2‐phenyl‐5(4H)‐oxazolone in Synthesis of Triazine,Oxadiazole and Imidazole Derivatives of Anticipated Biological Activity

Treatment of oxazolone 1 with hydrazine hydrate at room temperature gave the (Z)‐configurated isomer hydrazide (Z)‐ 3 (high yield). However, refluxing 1 with hydrazine hydrate yielded the (E)‐configurated isomer hydrazide (E)‐ 2 (low yield).The hydrazide derivative (Z)‐ 3 has been utilized as synthon for the synthesis of 1,2,4‐triazinone, imidazolone, and oxadiazole derivatives through appropriate routes. The thiosemicarbazide and semicarbazide derivatives are synthesized by different routes. The structures of the new compounds were established on the basis of IR, ¹H‐NMR, mass spectral data, and elemental analysis.     

Model Study of the Photochemical Rearrangement Pathways of 1,2,4‐Oxadiazole

The mechanisms of photochemical isomerization reactions are investigated theoretically by using a model system of 1,2,4‐ oxadiazole with the CAS(14,9)/6‐311G(d) and MP2‐CAS‐(14,9)/ 6‐311++G(3df,3pd)//CAS(14,9)/6‐311G(d) methods. Three reaction pathways are examined, including 1) the direct mechanism, 2) the ring contraction–ring expansion mechanism, and 3) the internal cyclization–isomerization mechanism, which lead to two types of photoisomers. The theoretical findings suggest that conical intersections play a crucial role in the photorearrangement of 1,2,4‐oxadiazoles. These model investigations also indicate that the preferred reaction route for 1,2,4‐oxadiazole, which leads to phototransposition products, is as follows: reactant → Franck‐Condon region → conical intersection → photoproduct. In other words, the direct mechanism is a one‐step process that has no barrier. These theoretical results agree with the available experimental observations.     

(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).     

Water‐Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4‐Oxadiazoles

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water‐assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4–5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five‐ and six‐membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4‐oxadiazole derivatives having a unique hybrid isoxazoline‐oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly‐like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.     

3,3′‐Bi(1,2,4‐oxadiazoles) Featuring the Fluorodinitromethyl and Trinitromethyl Groups

Here we report on the preparation of two hydrogen atom free 3,3′‐bi(1,2,4‐oxadiazole) derivatives. 5,5′‐Bis(fluorodinitromethyl)‐3,3′‐bi(1,2,4‐oxadiazole) was synthesised by fluorination of diammonium 5,5′‐bis(dinitromethanide)‐3,3′‐bi(1,2,4‐oxadiazole). For our previously reported analogue 5,5′‐bis(trinitromethyl)‐3,3′‐bi(1,2,4‐oxadiazole), a new synthetic route starting from new 3,3′‐bi(1,2,4‐oxadiazolyl)‐5,5′‐diacetic acid was developed. In this course also hitherto unknown 5,5′‐dimethyl‐3,3′‐bi(1,2,4‐oxadiazole) was isolated. The compounds were characterised by multinuclear NMR spectroscopy, IR and Raman spectroscopy, elemental analysis as well as mass spectrometry. X‐ray diffraction studies were performed and the crystal structures for the 5,5'‐dimethyl and 5,5'‐(fluorodinitromethyl) derivatives are reported. The energetic 5,5'‐(fluorodinitromethyl) and 5,5'‐(trinitromethyl) compounds do not contain any hydrogen atoms and show remarkable high densities. Furthermore, the thermal stabilities and sensitivities were determined by differential scanning calorimetry (DSC) and standardised impact and friction tests. The heats of formation were calculated by the atomisation method based on CBS‐4M enthalpies. With these values and the room‐temperature X‐ray densities, several detonation and propulsion parameters, such as the detonation velocity and pressure as well as the specific impulse of mixtures with aluminium, were computed using the EXPLO5 code.     

De Sign and Synthesis of 1,2,4‐Oxadiazole Derivatives as Non‐Steroidal 5α‐Reductase Inhibitors

The purpose of this study was to synthesize compounds in which the 1,2,4‐oxadiazole moiety replaced the amide bond of ONO3805 and to evaluate its 5α‐reductase inhibitory activity as a potential benign prostatic hyperplasia therapeutic target. Four 1,2,4‐oxadiazole derivatives, 1,2,8, and 20, were evaluated in vitro against 5α‐reductase of rat liver microsome. The prepared 1 and 2 possessed similar binding affinity (Ki) to that of ONO3805. Therefore, the use of 1,2,4‐oxadiazole ring as surrogate of the amide bond in ONO3805 has a successful result in this study. It leads not only to enhance chemical stability but also to maintain meaningful inhibitory activity. The butyric acid moiety of these inhibitors is considered to play an important role in mimicing the phosphoric acid portion of coenzyme‐NADPH in interacting with the active site of 5α‐reductase.     

Syntheses and Promising Properties of Dense Energetic 5,5′‐Dinitramino‐3,3′‐azo‐1,2,4‐oxadiazole and Its Salts

A planar energetic molecule with high density, 5,5′‐dinitramino‐3,3′‐azo‐1,2,4‐oxadiazole ( 4 ), was obtained by the nitration of 5,5′‐diamino‐3,3′‐azo‐1,2,4‐oxadiazole using 100 % nitric acid. In addition, selected nitrogen‐rich salts were prepared. Of them, the neutral compound 4 and its hydroxylammonium salt, 6 , were further confirmed by single‐crystal X‐ray diffraction. Physicochemical and energetic properties including density, thermal stability, and sensitivity were investigated. The energetic performance from the calculated heats of formation and experimental densities indicates that many of them have potential applications as energetic materials.     

Synthesis and Antibacterial Activity of Some New 2,5‐Disubstituted‐1,3,4‐oxadiazole Derivatives

Synthesis of some new oxadiazole derivatives starting from 1,2,3-benzo[d]triazole-1-acetic hydrazide (1) is described. The target compounds 2-(N-substituted-aminocarbonylmethylthio)-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (4a—4i) and 2-[2-(N-substituted-aminocarbonyl)ethylthio]-5-(1,2,3-benzo[d]triazol-1-ylmethyl)- 1,3,4-oxadiazole (5a—5i) were obtained in good yields via cyclisation of 1 and subjected to antibacterial activity test against pathogenic bacteria. The halogen containing mono- and di-substituted derivatives showed excellent antibacterial activity compared to other analogues.     

Luminescent copoly(aryl ether)s with new electron‐transporting bis(3‐(trifluoromethyl)phenyl)‐1,3,4‐oxadiazole or bis(3‐(trifluoromethyl)phenyl)‐4‐(4‐hexyloxyphenyl)‐4H‐1,2,4‐triazole segments

To investigate the effect of trifluoromethyl groups in enhancing electron affinity of aromatic oxadiazole and triazole chromophores, we prepared four new copoly(aryl ether)s ( P1 – P4 ) consisting of bis(3‐(trifluoromethyl) phenyl)‐1,3,4‐oxadiazole (ETO) or bis(3‐(trifluoromethyl)phenyl)‐4‐(4‐hexyloxyphenyl)‐4H‐1,2,4‐triazole (ETT) segments and hole‐transporting segments [2,5‐distyrylbenzene (HTB) or bis(styryl)fluorine (HTF)]. Molecular spectra (absorption and photoluminescence) and cyclic voltammetry were used to investigate their optical and electrochemical properties. The emissions of P1 – P4 are dominated by the hole‐transporting fluorophores with longer emissive wavelengths around 442–453 nm via efficient excitation energy transfer. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of P1 – P4 , estimated from electrochemical data, are ?5.15, ?5.18, ?5.30, ?5.27, ?3.39, ?3.49, ?3.36, and ?3.48 eV, respectively. The LUMO levels of ETO and ETT segments are significantly reduced to ?3.39～?3.36 eV and ?3.48～?3.49 eV, respectively, as compared with ?2.45 eV of P5 containing a 2,5‐diphenyl‐1,3,4‐oxadiazole segment. Moreover, electron and hole affinity can be enhanced simultaneously by introducing isolated hole‐ and electron‐transporting segments in the backbone. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5900–5910, 2004     

A New Route to Synthesis of 3,6‐Diaryl‐1,2,4‐triazolo[3,4‐b]1,3,4‐oxadiazoles

Five new 3,6‐diaryl‐1,2,4‐triazolo[3,4‐b]1,3,4‐oxadiazole derivatives were synthesized by 9 steps from aromatic acids and evaluated for their activities of anticancer and antibacteria. The structures of all new compounds synthesized were elucidated by MS, IR, ¹HNMR and HRMS.     

Synthesis of New PMB‐Substituted Indoles Containing 1,3,4‐Oxadiazole and 1,2,4‐Triazole Units

A series of new indolyl‐1,3,4‐oxadiazole derivatives 3 , 4 , 5 , 6 , 7 and 10 , indolyl‐1,2,4‐triazole derivatives 14 and 15 was prepared, using 1‐(4‐methoxybenzyl)‐1H‐indole‐3‐carbohydrazide ( 2 ) as a key intermediate. Some of the new compounds were evaluated for their antineoplastic activity.     

Synthesis of New 1,2,4‐ and 1,3,4‐Oxadiazole Derivatives as Potential Nonpeptide Angiotensin II Receptor Antagonists

The synthesis of new 1,2,4‐ and 1,3,4‐oxadiazole derivatives as potential nonpeptide angiotensin II receptor antagonists is described. The quinoxalinone systems used as the “northern moiety” in these compounds were alkylated through a liquid/liquid phase‐transfer catalysis protocol, with good yields and high nitrogen‐ to oxygen‐alkylated product (N/O) ratios.     

Synthesis and antibacterial activity of some novel N2‐hydroxymethyl and N2‐aminomethyl derivatives of 4‐aryl‐5‐(3‐chlorophenyl)‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thione

In this investigation, several novel N2‐hydroxymethyl and N2‐aminomethyl derivatives of 5‐(3‐chlorophenyl)‐4‐(4‐methylphenyl)‐2,4‐dihydro‐ 3H‐1,2,4‐triazole‐3‐thione and 4‐(4‐bromophenyl)‐ 5‐(3‐chlorophenyl)‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐ thione were prepared. All synthesized compounds were screened for their antibacterial activity against six Gram‐positive and four Gram‐negative bacterial strains. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 22:737–743, 2011; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20737     

Novel method for the synthesis of 1,2,4‐oxadiazoles using alumina supported ammonium fluoride under solvent‐free condition

Alumina supported ammonium fluoride was found as an efficient reagent for the synthesis of 1,2,4‐oxadi‐azoles of amidoximes under solvent free conditions using microwave irradiation. This method is a one‐pot, easy, rapid, and high‐yielding reaction for the synthesis of 1,2,4‐oxadiazole derivatives from amidoximes and acyl chlorides. Reaction of amidoximes with acylchlorides in the presence of alumina without ammonium fluoride gave only the corresponding O‐acylamidoximes as major product.     

New synthesis of highly potential efficient bluish‐green electroluminescent materials based on 1,3,4‐oxadiazole–triazolopyridinone–carbazole derivatives for single‐layer devices

New potential bluish‐green electroluminescent materials of 1,3,4‐oxadiazole–triazolopyridin‐ one–carbazole derivatives were synthesized and characterized for single‐layer devices. Carbazole, pyridine, and triazolopyridinone were completely introduced into 1,3,4‐oxadiazole skeletal to play assistant roles in controlling fundamental photolytic process due to the electron‐donating nature, excellent photoconductivity, and flexible structure properties. Following the spectroscopic studies and the measurements of cyclic voltammogram, 1,3,4‐oxadiazole–triazolopyridinone–carbazole derivatives were highly efficient bluish‐green electroluminescent materials. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:160–165, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20201     

Concomitant polymorphic forms of 3‐cyclopropyl‐5‐(2‐hydrazinylpyridin‐3‐yl)‐1,2,4‐oxadiazole

The dipharmacophore compound 3‐cyclopropyl‐5‐(2‐hydrazinylpyridin‐3‐yl)‐1,2,4‐oxadiazole, C₁₀H₁₁N₅O, was studied on the assumption of its potential biological activity. Two concomitant polymorphs were obtained on crystallization from isopropanol solution and these were thoroughly studied. Identical conformations of the molecules are found in both structures despite the low difference in energy between the four possible conformers. The two polymorphs differ crucially with respect to their crystal structures. A centrosymmetric dimer formed due to both stacking interactions of the `head‐to‐tail' type and N—H…N(π) hydrogen bonds is the building unit in the triclinic structure. The dimeric building units form an isotropic packing. In the orthorhombic polymorphic structure, the molecules form stacking interactions of the `head‐to‐head' type, which results in their organization in a column as the primary basic structural motif. The formation of N—H…N(lone pair) hydrogen bonds between two neighbouring columns allows the formation of a double column as the main structural motif. The correct packing motifs in the two polymorphs could not be identified without calculations of the pairwise interaction energies. The triclinic structure has a higher density and a lower (by 0.60 kcal mol^?1) lattice energy according to periodic calculations compared to the orthorhombic structure. This allows us to presume that the triclinic form of 3‐cyclopropyl‐5‐(2‐hydrazinylpyridin‐3‐yl)‐1,2,4‐oxadiazole is the more stable.