Synthesis of novel 3-(α-arylhydrazono-1,3,4-oxadiazol-2-ylmethyl)-2-oxo-1,2-dihydroquinoxalines and their characteristic tautomerism between the hydrazone imine and diazenyl enamine forms

The reactions of 3-(α-arylhydrazono)hydrazinocarbonylmethyl-2-oxo-1,2-dihydroquinoxalines 1a,b with triethyl orthoesters resulted in the intramolecular cyclization to give the 3-(α-arylhydrazono-1,3,4-oxadiazol-2-ylmethyl)-2-oxo-1,2-dihydroquinoxalines 4a–d , but not the 1,2,4,5-tetrazepinylquinoxalines 5a–d . The cyclization mode into the 1,3,4-oxadiazole ring was confirmed by the alternate syntheses of 4a,c from the reactions of 3-(1,3,4-oxadiazol-2-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines 6a,b with o-chlorophenyl diazonium salts, respectively. Moreover, 4a–d exhibited an interesting tautomerism between the hydrazone imine form A and diazenyl enamine form B.     

Synthesis of 3-(α-chlorophenylhydrazono)heteroarylmethyl-2-oxo-1,2-dihydroquinoxalines with antimicrobial activity

The reactions of 3-(α-chlorophenylhydrazono)hydrazinocarbonylmethyl-2-oxo-1,2-dihydroquinoxalines 4a,c with triethyl orthoesters resulted in the intramolecular cyclization to give the 3-(α-chlorophenylhydrazono-1,3,4-oxadiazol-2-ylmethyl)-2-oxo-1,2-dihydroquinoxalines 5a-d , but not the 1,2,4,5-tetrazepinylquinoxalines 6a-d . The cyclization mode into the 1,3,4-oxadiazole ring was confirmed by the alternate syntheses of 5a,c from the reactions of the 3-(1,3,4-oxadiazol-2-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines 7a,b with o-chlorobenzenediazonium chloride. Moreover, the reactions of 3-(benzimidazol-2-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline hydrochloride 8 with o-, m- and p-chlorobenzenediazonium chlorides afforded the 3-(α-chlorophenylhydrazonobenzimidazol-2-ylmethy])-2-oxo-1,2-dihydroquinoxa]ine hydrochlorides 9a-c , respectively. Compounds 5a-d and 9a-c were found to exhibit antimicrobial activities.     

Poly(1,3,4-oxadiazole-imide)s containing dimethylsilane groups

New poly(1,3,4-oxadiazole-imide)s containing dimethylsilane units have been prepared by solution polycondensation reaction of an aromatic dianhydride incorporating dimethylsilane group, namely bis(3,4-dicarboxyphenyl)dimethylsilane dianhydride, with different aromatic diamines having preformed 1,3,4-oxadiazole ring, such as 2,5-bis(p-aminophenyl)-1,3,4-oxadiazole, 2,5-bis[p-(4-aminophenoxy)phenyl]-1,3,4-oxadiazole, 2,5-bis[p-(3-aminophenoxy)phenyl]-1,3,4-oxadiazole, 2-(4-fluorophenyl)-5-(3,5-diaminophenyl)-1,3,4-oxadiazole, and 2-(4-dimethylaminophenyl)-5-(3,5-diaminophenyl)-1,3,4-oxadiazole. The polymers were easily soluble in polar organic solvents, such as N-methylpyrrolidinone, N,N-dimethylformamide, and pyridine, as well as in less polar organic solvents, such as tetrahydrofuran and chloroform. Very thin coatings deposited on silicon wafers exhibited smooth, pinhole-free surface in atomic force microscopy investigations. The polymers showed high thermal stability with decomposition temperature being above 415 °C.They exhibited a glass transition in the temperature range of 202-282 °C, with reasonable interval between glass transition and decomposition temperature. Solutions of the polymers in N,N-dimethylformamide exhibited fluorescence, having maximum emission wavelength in the range of 353-428 nm.     

Poly(1,3,4-oxadiazole-ether-imide)s and their polydimethylsiloxane-containing copolymers

Poly(1,3,4-oxadiazole-ether-imide)s were prepared by thermal imidization of poly(amic-acid) intermediates resulting from the solution polycondensation reaction of a bis(ether-anhydride), namely 2,2′-bis-[(3,4-dicarboxyphenoxy)phenyl]-1,4-phenylenediisopropylidene dianhydride, with different aromatic diamines containing 1,3,4-oxadiazole ring, such as 2,5-bis(p-aminophenyl)-1,3,4-oxadiazole, 2,5-bis[p-(4-aminophenoxy)phenyl]-1,3,4-oxadiazole, 2-(4-dimethylaminophenyl)-5-(3,5-diaminophenyl)-1,3,4-oxadiazole. Poly(1,3,4-oxadiazole-ether-imide)-polydimethylsiloxane copolymers were prepared by polycondensation reaction of the same bis(ether-anhydride) with equimolar quantities of an aromatic diamine having 1,3,4-oxadiazole ring and a bis(aminopropyl)polydimethylsiloxane oligomer of controlled molecular weight. A solution imidization procedure was used to convert quantitatively the poly(amic-acid) intermediates to the corresponding polyimides. All the polymers were easily soluble in polar organic solvents such as N-methylpyrrolidone and N,N-dimethylacetamide. The polymers showed good thermal stability with decomposition temperature being above 400 °C. Solutions of some polymers in N-methylpyrrolidone exhibited blue fluorescence, having maximum emission wavelength in the range of 370-412 nm.     

Ethynyl pi-extended 2,5-diphenyl-1,3,4-oxadiazoles and 2-phenyl 5-(2-thienyl)-1,3,4-oxadiazoles: synthesis, X-ray crystal structures and optical properties

2-(4-tert-Butylphenyl)-5-(4-ethynylphenyl)-1,3,4-oxadiazole reacts with a series of heteroaryl iodides under standard Sonogashira cross-coupling conditions (Pd[PPh(3)](2)Cl(2), CuI, triethylamine, THF) to yield products 2a-g in 40-79% yields (heteroaryl = 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazyl, 5-bromo-2-pyrimidyl, 2-thienyl and 3-thienyl, respectively). Compound 2f was lithiated followed by electrophilic iodination (BuLi, perfluorohexyl iodide) to give 3, which by a two-step sequence gave the terminal ethynylthienyl derivative 5. Conversion of 5 into the terminal ethynylaldehyde derivative 7, via acetal derivative 6, proceeded in high yield. Starting from 2-iodo-5-methoxycarbonylthiophene, a five-step sequence afforded 2-(4-tert-butylphenyl)-5-(4-ethynylthienyl)-1,3,4-oxadiazole 13 (13% overall yield). Reactions of 13 gave terminal pyridyl, pyrazyl, pyrimidyl and thienyl derivatives, analogous to those obtained from 1. Two-fold reaction of 13 with 2,5-diiodothiophene gave the bis(ethynylthienyl)thiophene derivative 15 (30% yield). Solution UV-Vis absorption and photoluminescence spectra establish that replacement of the phenyl ring in the 2,5-diphenyl-1,3,4-oxadiazole series 2a-g by a thienyl ring [i.e. the 2-phenyl-5-(2-thienyl)-1,3,4-oxadiazole series 14a-g] leads to a red shift in the lowest energy band in both the absorption spectra and emission spectra. The X-ray crystal structures of compounds 2d, 2g, 5 and 14d.CHCl(3) reveal that the molecular structures are approximately planar although there are substantial differences in the conformations.     

Design and synthesis of new 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles as anticonvulsant agents

A new series of 2-substituted-5-[2-(2-halobenzyloxy)phenyl]-1,3,4-oxadiazoles was designed and synthesized as anticonvulsant agents. Electroshock and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group at position 2 of 1,3,4-oxadiazole ring and a fluoro substituent at ortho position of benzyloxy moiety had the best anticonvulsant activity. Our results showed that this effect is mediated through benzodiazepine receptors mechanism.     

2-(4-Biphenylyl)-1,3,4-oxadiazoles: synthesis and mesogenic studies

A series of 2-(4-biphenylyl)-1,3,4-oxadiazoles bearing alkyl or alkoxy substituents at the 4? position, and a hydrogen, or alkyl substituent (linear, branched, fluorinated or functionalised) at the 5 position were synthesised and characterised (51 compounds). Their mesogenic properties were evaluated using differential scanning calorimetry and polarising optical microscopy. Results show that substitution of the 1,3,4-oxadiazole ring for a terminal benzene ring in a conventional p-terphenyl enriched the mesogenic properties. Most of the new oxadiazole compounds exhibit either monotropic or enantiotropic smectic A mesophases with widths ranging from 3 to 50°C. A few compounds (short tailed) exhibit nematic phases and some compounds with branched or fluorinated alkyl substituents at the 5 position are also mesogenic.     

2-Phenyl-5-(4-Biphenylyl)-1,3,4-Oxadiazole and 2-(4'-tert-Butylphenyl-5)-(4'biphenylyl)-1,3,4-Oxadiazole in a Polymethyl Methacrylate Based Plastic Scintillator

The fluorescence intensity was studied for the scintillation formulation including 1,1,3-trimethyl-3-phenylindan and 2-phenyl-5-(4-biphenylyl)-1,3,4-oxadiazole, 2-(4'-tert-butylphenyl-5-(4"-biphenylyl)-1,3,4-oxadiazole, and 1,4-di(5-phenyl-2-oxazolyl)benzene. The scintillation efficiency was determined for the polymethyl methacrylate based plastic scintillator containing the above-listed compounds as luminescent additives.     

Research on the fluorescence spectra of 2-(ω-biphenylylpolymethylene)-5-biphenylyl-1,3,4-oxadiazole

The fluorescence spectra of bichromophore compounds 2-(ω-biphenylylpolymethylene)-5-biphenylyl-1,3,4-oxadiazole ( 1—4 ) and its corresponding model compounds 2-methyl-5-biphenylyl-1,3,4-oxadiazole ( 5 ) and 2,5-dibiphenylyl-1,3,4-oxadiazole ( 6 ) have been determined. The formation of intra- and intermolecular excimers and exciplexes have been studied. The relationship between the molecular configuration and the formation of intra exciplex have been discussed. From the experimental results, it can be seen that when the number of the carbon atoms of the methylene bridge is odd, intra exciplex is readily formed.     

Synthesis of Novel 3-(5-(Alkyl/arylthio)-1,3,4-Oxadiazol-2-yl)-8-Phenylquinolin-4(1H)-One Derivatives as Anti-HIV Agents

Novel quinolone derivatives featuring an 1,3,4-oxadiazole ring as a metal-chelating component and a benzyl group base on HIV-1 integrase inhibitors pharmacophore were designed and synthesized. An antiviral assay revealed that most analogues inhibited HIV-1 replication in the cell culture. Our results showed that compounds bearing small alkyl groups as R group were inactive in anti-HIV-1 assay, whereas compounds possessing benzyl or substituted benzyl at the same position showed good anti-HIV activity with the range of 20–57% at 100 μM concentration. Among them, 3-(5-((2-fluorobenzyl)thio)-1,3,4-oxadiazol-2-yl)-8-phenylquinolin-4-(1H)-one (compound 13) showed reasonable cell-based antiviral activity (EC₅₀ = 50 μM) with no considerable cytotoxicity (CC₅₀ > 100 μM) in the cell viability assay, suggesting that it may be amenable to further development for identifying new anti-HIV-1 agents. Docking studies using the later crystallographic data available for PFV integrase corroborate favorable binding to the active site of HIV integrase, providing a basis for the design of more potent analogues.     

Ringtransformationen von 3-substituiertem 5-Trifluormethyl-1,3,4-thiadiazol-2(3H)-on mit Nucleophilen

Ring Transformations of 3-Substituted 5-Trifluoromethyl-1,3,4-thiadiazol-2(3H)-one with Nucleophiles The 3-chlormethyl-5-trifluoromethyl-1,3,4-thiadiazolone 3 undergoes a ring transformation to 3-acylated 2,3-dihydro-1,3,4-thiadiazoles 4 with many nucleophiles. Upon formal replacement of the chloromethyl group in the 3-position of 3 by an extended bromoalkyl chain (→9a-c) , the reaction with nucleophiles yields 4-acylated 5,6-dihydro-4H-1,3,4-thiadiazines 10 (from 9a ), 4,5,6,7-tetrahydrothiadiazepines 13 (from 9b ) and 5,6,7,8-tetrahydro-4H-1,3,4-thiadiazocines 14 (from 9c ) by ring enlargement. The 3-propargyl-thiadiazolone 17 rearranges with nucleophiles to 4-acylated 6-methylidene-5,6-dihydro-4H-1,3,4-thiadiazines 18 . The structures of the new compounds were elucidated by ¹H- and ¹³C-NMR spectroscopy.     

The synthesis and structure of a new type of aromatic heterocyclic macrocycle. IV. Synthesis of a 1,3,4-oxadiazole-containing azomacrocycle

A novel azomacrocycle containing the 1,3,4-oxadiazole ring has been prepared from 2,5-bis[3-(4-hydroxyphenylazo)phenyl]-1,3,4-oxadiazole 5 and 2,5-bis(2-chloromethlylphenyl)-1,3,4-oxadiazole 8 . The coupling reaction between the diazonium salt 4 and bisphenol A has been reported.     

Synthesis and Crystal Structure of 2-（ 4-Decarboxydehydroabietyl）- 5-p-tolyl-[ 1,3,4 ]-oxadiazole

2-（4-Decarboxydehydroabietyl）-5-p-toyl-[1,3,4]-oxadiazole, C28H34N2O, has been synthesized and characterized by IR, NMR, elemental analysis and single-crystal X-ray diffraction method. The crystal belongs to the orthorhombic system, space group P212121 with a = 6.1351（5）, b = 14.8495（19）, c = 25.9050（2） A, V = 2360.0（4） A3, Z = 4, Mr = 414.57, Dc = 1.167 Mg/m^3, 2 = 0.71073 A,μ（MoKa） = 0.070 mm^-1, F（000） = 896, the final R = 0.0452 and wR = 0.1076 for 1647 observed reflections with I 〉 2σ（I）. There are five rings in the crystal structure of the title compound, but the oxadiazole ring is non-coplanar with the benzene ring D.     

Synthesis,spectroscopic and crystal structure investigation of [Cu(bzsmp)2Cl2];{bzsmp = 2-benzylsulfanyl-5-(2-methoxyphenyl)-1,3,4-oxadiazole}: cyclization of N-[bis(benzylsulfanyl)methylene]-2-methoxybenzohydrazide to 2-benzylsulfanyl-5-(2-methoxyphenyl)-1,3,4 -oxadiazole during complexation

The ligand N²-[bis(benzylsulfanyl)methylene]-2-methoxybenzohydrazide (N²-bmbh) (1) on reaction with CuCl₂.2H₂O yielded the mononuclear complex [Cu(bzsmp)₂Cl₂] (2) (2-benzylsulfanyl-5-(2-methoxyphenyl)-1,3,4-oxadiazole, bzsmp). Complex 2 has been characterized by analytical, spectroscopic and X-ray data. X-ray study of 2 reveals that the cyclized ligand 2-benzylsulfanyl-5-(2-methoxyphenyl)-1,3,4-oxadiazole (bzsmp) acts as neutral bidentate ligand to form six membered chelate ring and the presence of C–H?π (face to edge) and C–H?S and two type of C–H?Cl weak interactions.     

Synthesis and characterization of poly(1-benzoylsemicarbazide) and poly(1,3,4-oxadiazole amine) from 2-(p-aminophenyl)-1,3,4-oxadizolin-5-one via ring-opening

A novel thermally stable and semiconducting polyheterocycle, poly(1,3,4-oxadiazole amine), was synthesized from 2-(p-aminophenyl)-1,3,4-oxadiazolin-5-one via ring-opening. The polymer is a new class of ordered alternating copoly(aniline) containing 1,3,4-oxadiazole heterocyclic units. The polymer is highly thermally stable and exhibits no weight loss up to 370°C in air. Its electric conductivity is less than 10⁻¹⁰ S · cm⁻¹ at ambient temperature, but markedly increases to 6,5 · 10⁻⁷ S · cm⁻¹ upon doping with iodine.     

Synthesis and biological activity of 1,3,4-oxa(thia)diazole, 1,2,4-triazole-5-(thio)one and S-substituted derivatives of 3-((2-carboxyethyl)phenylamino)propanoic acid

Research on Chemical Intermediates - A series of novel derivatives of 3-((2-carboxyethyl)phenylamino)propanoic acid bearing two identical substituted 1,3,4-oxadiazole, 1,3,4-thiadiazole, or...     

Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents

Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl₃-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl₃ was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC₅₀ values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.     

2-Phenyl-5-(trichloromethyl)-1,3,4-oxadiazoles,A new class of antimalarial substances

An investigation of hybrids of 2,5-dimethyl-1,3,4-oxadiazole (I) and α,α,α,α',α',α'-hexachloro-p-xylene (Hetol®) (II) as potential antimalarial agents led to the synthesis of representative 2-phenyI-5-(trichloromethyl)-1,3,4-oxadiazoles (VIa-f, VIII-X) and related trichloromethyl 1,2,4-oxadiazole, 1,3,4-oxadiazoles, and 1,3,4-thiadiazole (VII, XIII-XV). Treatment of the appropriately substituted benzoic: acid hydrazides (IVa-f) with trichloroacetic anhydride afforded the intermediate 1-benzoyl-2-(triehloroacetyl)hydrazines (Va-f) which were cyclized to the desired 5-(chlorophenyl, tolyl, or α,α,α-trifluorotolyl)-2-(trichloromethyl)-1,3,4-oxadiazoles (VIa-f) (44–66%) in situ utilizing phosphorous oxychloride. Chlorination of the 5-tolyl-2-(trichloromethyl)-1,3,4-oxadiazoles (VId-f) afforded 2-(trichloromethyl)-5-(α,α,α-trichloro-m- and p-tolyl)-1,3,4-oxadiazole (VIII and IX) and 2-(α,α,α,α',α',α'-hexachloro-3,5-xylyl)-5-(trichloromethyl)-1,3,4-oxadiazole (X) in 23–56% yield. Each of the 2-phenyl-5-(trichloromethyl)-1,3,4-oxadiazoles (VIa-f, VIII-X) was active against Plasmodium berghei in mice when administered in single 160 or 640 mg./kg. subcutaneous doses or given orally by drug-diet for 6 days at doses of 29–336 mg./kg./day. The 2-(trichloromethyl)-5-(α,α,α-trichlorotolyl)-1,3,4-oxadiazoles (VIII-X) were the most active compounds prepared and exhibited activity against P. berghei comparable with Hetol®. Structure-activity relationships are discussed.     

Synthesis of Novel Chiral C2-Symmetric Bisoxazoline Ligands Containing 2,5-Di( m -substituted)phenyl-1,3,4-oxadiazole

Abstract

Seven novel chiral C₂-symmetric substituted bisoxazoline ligands containing 2,5-di(m-substituted)phenyl-1,3,4-oxadiazole have been synthesized from 2,5-di-(m-carboxylphenyl)-1,3,4-oxadiazole and aminoalcohol by NaOH or Et₃N cyclization method via halogenated amide intermediate.     

A facile retro-ene reaction of 5-(methoxyamino)-3-aryl-1,3,4-oxadiazol-2(3H)-ones

5-(N-Methoxy-N-methyl)amino-3-aryl-1,3,4-oxadiazol-2(3H)-ones 3 undergo a heteroretro-ene reaction in refluxing methanol in which the leaving enophile is formaldehyde. The resulting 5-(methylimino)-3-aryl-1,3,4-oxadiazolidin-2-one 4 may be viewed as a kinetic product which tautomerizes to the more stable 5-(methylamino)-3-aryl-1,3,4-oxadiazol-2(3H)-one 5 as the thermodynamic product. Comparison of calculated reaction energies reveals that the presence of the heterocyclic ring facilitates the retro-ene reaction, but the expulsion of formaldehyde is predicted to be highly exothermic even in its absence.