A novel one-pot synthesis of 2-alkylthio-1,3,4-oxadiazoles in water

A facile and one-pot protocol for the synthesis of 2-alkylthio-1,3,4-oxadiazoles is reported. This green method relies on the reaction of acid hydrazides with CS₂ and an alkyl halide. The reaction is carried out under mild and environmentally friendly procedure in water with high to excellent yields. Thirteen different valuable alkylthio-1,3,4-oxadiazoles are synthesized from cheap and easily available CS₂ with this method. This is the first report for the synthesis of 1,3,4-oxadiazoles in water.     

Reactions of α-mercaptocarboxylic acid hydrazides with triethyl orthoesters: synthesis of 1,3,4-thiadiazin-5(6H)-ones and 1,3,4-oxadiazoles

Reactions of α-mercapto-β-phenylpropionic and α-mercaptophenylacetic acid hydrazides with triethyl orthoesters were conducted under N₂ in glacial acetic acid and resulted in the formation of two groups of products, derivatives of 1,3,4-thiadiazin-5(6H)-ones and 2-(1-mercaptomethyl)-1,3,4-oxadiazoles. When conducting the same transformations on α-mercaptophenylacetic acid hydrazide in the presence of air, two different products from the 1,3,4-oxadiazole family, the appropriate bis(1,3,4-oxadiazol-2-yl-phenylmethyl) disulfides and 2-benzyl-1,3,4-oxadiazoles, were formed with the liberation of free sulfur. The oxygenated bis(1,3,4-oxadiazol-2-yl-phenylmethyl) disulfides were reduced to the corresponding 2-(1-mercaptomethyl)-1,3,4-oxadiazoles with the use of zinc powder under mild conditions.     

Greener and rapid access to bio-active heterocycles: one-pot solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles

A novel one-pot solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles by condensation of acid hydrazide and triethyl orthoalkanates under microwave irradiations is reported. This green protocol was catalyzed efficiently by solid supported Nafion^®NR50 and phosphorus pentasulfide in alumina (P₄S₁₀/Al₂O₃) with excellent yields.     

Two reaction routes for the preparation of aromatic polyoxadiazoles and polytriazoles: Syntheses and properties

Two reaction routes for the preparation of aromatic poly-1,3,4-oxadiazoles and poly-1,2,4-triazoles are studied and their influence on the physical properties, i.e., inherent viscosity, glass transition, degradation temperature, and film integrity of the final products are discussed. Aromatic poly-1,3,4-oxadiazoles are prepared by means of a polycondensation reaction of terephthaloyl chloride and isophthalic dihydrazide yielding a precursor polymer, poly(p, m-phenylene) hydrazide, which is converted into the corresponding poly-1,3,4-oxadiazole by means of a cyclodehydration reaction. Poly-1,3,4-oxadiazoles are also prepared by means of a polycondensation reaction between terephthalic and isophthalic acid and hydrazine yielding poly-1,3,4-oxadiazoles with higher inherent viscosities. Flexible poly-1,3,4-oxadiazole films are obtained only if the inherent viscosities of the polymers used are higher than 2.7 dL/g. The thermal stability is found to increase with increasing content of p-phenylene groups in the polymer backbone. Aromatic poly-1,2,4-triazoles are prepared using polyhydrazides with alternating para- and meta-phenylene groups and poly-1,3,4-oxadiazoles with a random incorporation of para- and meta-phenylene groups in the main chain as precursor polymers. The glass transition temperatures are found to increase with increasing content of p-phenylene groups in the main chain of these polymers. Cold crystallization is observed only for the alternating polymer. © 1994 John Wiley & Sons, Inc.     

A simple and efficient one step synthesis of 1,3,4-oxadiazoles utilizing polymer-supported reagents and microwave heating

1,3,4-Oxadiazoles can be rapidly and efficiently synthesized from a variety of carboxylic acids and acid hydrazides in one simple step. The use of commercially available PS-PPh₃ resin combined with microwave heating delivered the product 1,3,4-oxadiazoles in high yields and purities.     

Halogen effects in Robinson-Gabriel type reaction of cyclopropanecarboxylic acid N′-substituted-hydrazides with PPh3/CX4

We found that the reaction of cyclopropanecarboxylic acid N′-substituted-hydrazides with PPh₃/CCl₄ proceeded smoothly to give the corresponding normal Robinson-Gabriel type product 2-cyclopropyl-5-substituted-[1,3,4]-oxadiazoles in good yields. Using CBr₄ or CI₄ instead of CCl₄ in the above system, the ring opening of cyclopropane occurred after dehydration to give the corresponding 2-(3-halopropyl)-5-substituted-[1,3,4]-oxadiazoles (4 or 5) in good yields.     

The synthesis of bis(1,3,4-oxadiazol-2-yl-phenylmethyl) sulfides and other related 1,3,4-oxadiazoles from 1,1′-diphenylthiodiacetic acid dihydrazide and triethyl orthoesters

Reactions of symmetrical 1,1′-diphenylthiodiacetic acid dihydrazide and triethyl orthoesters in the presence of catalytic amount of glacial acetic acid resulted in the formation of three heterocyclic products: the appropriate bis(1,3,4-oxadiazol-2-yl-phenylmethyl) sulfides, 2-benzyl-1,3,4-oxadiazoles and 2-benzoyl-1,3,4-oxadiazoles. The presence of the latter two compounds is connected with carbon-sulfur fission in the molecule of the starting hydrazide. The identity of the unexpected fission products was confirmed by parallel syntheses of the model 1,3,4-oxadiazoles from phenylacetic acid hydrazide and 2-hydroxymethyl-1,3,4-oxadiazole derivatives.     

Synthesis of di- and trisubstituted 1,2,4-triazoles containing indole fragments

The reaction of imino esters of indole-series acids with acid hydrazides gave N₍₁₎-acylamidrazones, which, during heating, were converted to 3,5-disubstituted 1H-1,2,4-triazoles containing indole fragments. Compounds of this type were also synthesized by the reaction of indolyl-containing 2,5-disubstituted 1,3,4-oxadiazoles with formamide. Condensation of 2,5-disubstituted 1,3,4-oxadiazoles with aniline gave 3,4,5-trisubstituted 4H-1,2,4-triazoles containing indolyl radicals. Cyclocondensation of N₍₁₎-phenylamidrazones of indole-series acids with benzoyl chloride gave 1,3,5-trisubstituted 1H-1,2,4-triazoles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 189–196, February, 1993.     

含2-三氟甲基苯并咪唑的双噁二唑硫醚及其亚砜衍生物的合成

芳甲酰肼和氯乙酸在二甲苯中反应生成了一系列的2-芳基-5-氯甲基-1,3,4-噁二唑(1a～1j), 继而与2-(2-三氟甲基苯并咪唑-1-亚甲基)-5-巯基-1,3,4-噁二唑(2)在乙醇-水的溶液中反应得到了一系列的含2-三氟甲基苯并咪唑的双噁二唑硫醚3a～3j, 再用硝酸氧化得到相应的亚砜衍生物4a～4j. 化合物的结构经元素分析, IR, ¹H NMR确证.     

General synthesis of tetrasubstituted alkenyl-1,3,4-oxadiazoles

Tetrasubstituted alkenyl-1,3,4-oxadiazoles were synthesized in moderate to excellent yield, under mild conditions and in the presence of sensitive functional groups, via the cyclization of diacylhydrazides using PPh₃ and hexachloroethane in the presence of Hünig’s base. An efficient one-pot acylation/cyclization approach for the conversion of acylhydrazides to 1,3,4-oxadiazoles is also described. The complexity of our substrate as well as the wide range of functional groups incorporated substantially broadens the scope of this methodology.     

Hypervalent iodine(V) mediated mild and convenient synthesis of substituted 2-amino-1,3,4-oxadiazoles

A simple protocol for the synthesis of 2-amino-1,3,4-oxadiazoles starting from the corresponding acylhydrazides by cyclodesulfurization of intermediate acylthiosemicarbazides mediated by o-iodoxybenzoic acid in good yields has been described. The protocol is mild with wide substrate scope, and thus a range of 2-amino-1,3,4-oxadiazoles have been prepared.     

An efficient synthesis of conjugated 5-aryl-1,3,4-oxadiazoles from 3-heteroarylacrylohydrazides and acid chlorides

New derivatives of 5-aryl-2-[2-(2-furyl)ethenyl]-1,3,4-oxadiazoles and 5-aryl-2-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazoles are synthesized in a stepwise procedure through intermediate acyclic N′-arylcarbonyl-N-[2-(2-heteroaryl)acryloyl]hydrazines, starting from 3-(2-heteroaryl)acrylic acid hydrazides and acid chlorides. A facile one-pot methodology leading to the final 1,3,4-oxadiazoles is also described.     

[4 + 1] Cyclization of benzohydrazide and ClCF2COONa towards 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d5

A facile synthesis of 1,3,4-oxadiazoles and 1,3,4-oxadiazoles-d₅ via [4 + 1] cyclization of ClCF₂COONa with non-amine compounds containing amino groups is developed. Of note, this is the first time that halofluorinated compounds are used as C1 synthon to construct deuterated nitrogen-heterocyclic compounds. The current protocol features simple operation, readily accessible raw materials, wide substrate scope and valuable products     

AN EFFICIENT ONE POT SYNTHESIS OF 1,3,4-OXADIAZOLES

Various 1,3,4-oxadiazoles have been synthesized in excellent yields by BF₃?Et₂O promoted cyclodehydration of 1,2-diacyl and diaroyl hydrazines prepared in situ from corresponding acid chlorides and hydrazine.     

Novel syntheses of symmetrical 2,5-diaryl-1,3,4-oxadiazoles and 1,4-phenylenebis-1,3,4-oxadiazoles

The reactions of trichloromethylarenes with excess hydrazine hydrate in ethanol gives symmetrical 2,5-diaryl-1,3,4-oxadiazoles in 68–96% yields. The reaction of 1,4-bis(trichloromethyl)benzene with acylhydrazines in an ethanol-pyridine mixture gives the corresponding substituted or unsubstituted 1,4-phenylenebis-1,3,4-oxadiazoles in 35–51% yields. The mass spectra of 2,5-diaryl-1,3,4-oxadiazoles and 1,4-phenylenebis-1,3,4-oxadiazoles were studied. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2309–2316, November, 1998.     

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.     

Propylphosphonic anhydride (T3P): an efficient reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles

Propylphosphonic anhydride (T3P^®) has been demonstrated to be an efficient and mild reagent for the one-pot synthesis of 1,2,4-oxadiazoles, 1,3,4-oxadiazoles, and 1,3,4-thiadiazoles from carboxylic acids.     

Fluorinated heterocyclic compounds: an assay on the photochemistry of some fluorinated 1-oxa-2-azoles: an expedient route to fluorinated heterocycles

Photoinduced heterocyclic rearrangements of ON bond-containing azoles have been claimed in the synthesis of target fluorinated heterocyclic compounds. In this context, the photochemical behavior of some fluorinated 1,2,4-oxadiazoles has been investigated. Irradiations of 3-amino-5-perfluoroalkyl-1,2,4-oxadiazoles at λ=313 nm in methanol gave open-chain products arising from a reaction of the nucleophilic solvent with either the first formed ring-photolytic species or with a nitrilimine moiety generated from it. Differently, irradiations in methanol with the presence of triethylamine (TEA) followed competing phototransposition pathways leading to the ring-isomers 2-amino-5-perfluoroalkyl-1,3,4-oxadiazoles (major component) and the ring degenerate isomers 5-amino-3-perfluoroalkyl-1,2,4-oxadiazoles (minor component). On the other hand, 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles underwent ring-photoisomerization into 1,3,4-oxadiazoles when irradiations were carried out at λ=254 nm. In turn, the irradiation of the 3-phenyl-5-perfluoroheptyl-1,2,4-oxadiazole at λ=254 nm in methanol gave the solvolysis product, but no ring-isomerization was observed. Some mechanistic considerations are reported, and some applications in the synthesis of target fluorinated 1,3,4-oxadiazoles are claimed.     

Synthesis of 2,5-Dialkyl-1,3,4-oxadiazoles Bearing Carboxymethylamino Groups

A series of new symmetrical 2,5-dialkyl-1,3,4-oxadiazoles containing substituted alkyl groups at the terminal positions with substituents, such as bromine, isopropyloxycarbonylmethylamino, and carboxymethylamino, were successfully synthesized. The developed multistep method employed commercially available acid chlorides differing in alkyl chain length and terminal substituent, hydrazine hydrate, and phosphorus oxychloride. The intermediate bromine-containing 2,5-dialkyl-1,3,4-oxadiazoles were easily substituted with diisopropyl iminodiacetate, followed by hydrolysis in aqueous methanol solution giving the corresponding 1,3,4-oxadiazoles bearing carboxymethylamino substituents. The structure of all products was confirmed by conventional spectroscopic methods including ¹H NMR, ¹³C NMR, and HRMS.     

Synthesis of 2-amino-5-(5R-1,2,4-oxadiazolyl-3)-1,3,4-oxadiazoles

The interaction of 2-amino-1,3,4-oxadiazole-5-carboxamidoxime with nitriles in the presence of ZnCl₂ and HCl or with trichloroacetic anhydride affords 2-amino-5-(5R-1,2,4-oxadiazolyl-3)-1,3,4-oxadiazoles. Their reactions with N-nucleophiles have been studied.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2100–2103, December, 1993.