芳基肟胺菊酯类化合物和1，2，4－噁二唑衍生物的合成及其生物活性研究

芳基肟胺化合物与取代环丙烷羧酸酰氯在Ｅｔ_３Ｎ作用下室温反应得到芳基肟胺菊酯类化合物，在甲苯中回流反应则得到含取代环丙烷基的１，２，４－　二唑衍生物。前者在甲苯中回流，ＨＯＡｃ作催化剂时发生环化反应也生成１，２，４－　二唑衍生物．初步生物活性测试表明这些化合物具有的杀菌和除草活性．     

Synthesis,antibacterial and antifungal activities of new chiral 5-alkyl-3-(1′-benzenesulfonylpyrrolidin-2′-yl)-4,5-dihydro-1,2,4-oxadiazin-6-ones

Chiral α-bromoacid chlorides can be easily prepared from amino acids. Their condensation with new 1-benzenesulfonylpyrrolidin-2-carboxamidoxime derived from proline lead to the corresponding O-(bromoacyl) amidoximes. The latter afforded new chiral 5-alkyl-3-(1′-benzenesulfonylpyrrolidin-2′-yl)-4,5-dihydro-1,2,4oxadiazin-6-ones in good chemical yields via intramolecular cyclization in the presence of one equivalent of NaH. These new compounds were evaluated for their antibacterial and antifungal activities using micro-dilution tests against some strains of bacteria and fungi. Our compounds showed an excellent antibacterial activity, which is better than the drug levofloxacin.     

3,3-Dinitrobutyl-1,2,4-oxadiazoles

The syntheses of 3,5-bis(3,3-dinitrobutyl)-1,2,4-oxadiazole and a series of 3-aryl-5-(3,3-dinitrobutyl)-1,2,4-oxadiazoles were accomplished by treating 4,4-dinitropentanoyl chloride with the appropriate amidoximes to yield the intermediate O-(4,4-dinitropentanoyl)amidoximes, which were dehydrated to the 1,2,4-oxadiazoles.     

A novel synthesis of 1,2,4-oxadiazoles and isoxazoles

A novel synthesis of 1,2,4-oxadiazoles and isoxazoles is described by utilizing the reactions between amidoximes and α,β-alkynic aldehydes and/or ketones. Conjugate addition products, obtained from amidoximes and α,β-alkynic aldehydes and/or ketones, afford 1,2,4-oxadiazoles and isoxazoles when treated with bases and acids, respectively. 1,2,4-Oxadiazoles can also be synthesized directly from amidoximes and α,β-alkynic aldehydes in a one-pot manner under basic conditions. The reactions are general for a variety of starting compounds and tolerate the presence of aryl, heteroaryl and alkyl groups.     

Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety

An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.     

One-Pot Synthesis of New,Biologically Active 3,5-Disubstituted-1,2,4-oxadiazoles

New chiral 3,5-disubstituted-1,2,4-oxadiazoles have been prepared via an efficient one-pot procedure by the condensation of new chiral amidoximes derived from amino acids with aldehydes. This method is applicable to both aliphatic and aromatic aldehydes, leading easily to the corresponding pure oxadiazoles in excellent yields. These new compounds were tested for their antibacterial and antifungal activities using microdilution tests against some strains of bacteria and fungi, and they showed excellent antibacterial activity.     

A new approach to N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere via ionic liquid-phase technology

New N-3 functionalized 3,4-dihydropyrimidine-2(1H)-ones with 1,2,4-oxadiazole group as amide isostere were synthesized in six steps by ionic liquid-phase organic synthesis (IoLiPOS) methodology from ILP bound acetoacetate. The 3,4-dihydropyrimidine-2(1H)-one (3,4-DHPM) core was prepared in the first step by one-pot three-component Biginelli condensation followed by N-alkylation with chloroacetonitrile. Then the nitrile group appended on the 3,4-DHPM heterocycle was quantitatively transformed into amidoxime. Addition of aliphatic carboxylic anhydride or aromatic carboxylic acid to the amidoxime produced the expected 1,2,4-oxadiazole via the O-acylamidoxime intermediate grafted on the ILP bound 3,4-DHPM using two convergent methods. After cleavage by transesterification under mild conditions, the target compounds were obtained in good overall yields. The structures and the purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis.     

Unusual Formation of 1,2,4-Oxadiazine Core in Reaction of Amidoximes with Maleic or Fumaric Esters

We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. Different products can be synthesized selectively in good yields depending on the base used and the ratio of reactants: substituted (1,2,4-oxadiazin-6-yl)acetic acids, corresponding methyl esters, or hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4H-1,2,4-oxadiazin-5(6H)-ones. The reaction is tolerant to substituents’ electronic and steric effects in amidoximes. As a result, a series of 2-(5-oxo-3-(p-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazin-6-yl)acetic acids, their methyl esters, and 1,2,4-oxadiazoles based on them were prepared and characterized by HRMS, ¹H, and ¹³C NMR spectroscopy. The structures of three of them were elucidated with X-ray diffraction.     

Mass spectra of some perfluoroalkyl and perfluoroalkylether substituted 1,2,4-oxadiazoles

Electron impact fragmentation patterns were obtained for 1,4-bis[(5-perfluoro-n-heptyl)-1,2,4-oxadiazolyl]-benzene, its perfluoroalkylether substituted analogue, 3,5-bis(perfluoroalkyl)-, 3,5-bis(perfluoroalkylether)- and 3-perfluoroalkylether-5-perfluoroalkyl-1,2,4-oxadiazoles. In the compounds containing the phenylene group the molecular ion constituted the base peak; the main process was the breakdown of the oxadiazole ring with concurrent liberation of the perfluoroalkyl or perfluoroalkylether nitrile molecule; cleavage of the fluorinated chain α to the oxadiazole ring was found to take place to a considerable degree. In the perfluorinated 1,2,4-oxadiazoles cleavage β to the oxadiazole ring occurred preferentially; fragmentation of the ring itself took place to a limited degree only. The 3-perfluoroalkylether-5-perfluoroalkyl-1,2,4-oxadiazole appeared to undergo the primary β-cleavage exclusively at the perfluoroalkylether sidechain.     

Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives

Here, we represent preparative methods of synthesis of isomeric 3‐isoxadiazolylcoumarins and their derivatives. Two new synthetic methods have been developed for 3‐[1,2,4‐oxadiazol‐5‐yl]coumarins I . The first method is based on a three‐component condensation of coumarin‐;3‐carboxylic acids, 1,1′‐carbonyldiimidazole, and amidoximes. The second method essentially uses the interaction of 5‐cyanomethyl‐1,2,4‐oxadiazoles with salicylic aldehydes. General approach for preparation of 3‐[1,2,4‐oxadiazol‐3‐yl]coumarins II has been worked out. Moreover, aforementioned synthetic ways open the way for the synthesis of 2‐iminoderivatives III and IV not described before, those were diversified by reaction of nucleophilic substitution of 2‐imino group with a numerous amino compounds.     

A convenient synthesis of 3-substituted 5-guanidino-1,2,4-oxadiazoles

The reaction of amidoximes with cyanoguanidine in the presence of Lewis acids affords 3-substituted 5-guanidino-1,2,4-oxadiazoles. A study of the reaction of¹⁵N-labeled chloroacetamidoxime with cyanoguanidine showed that the formation of the oxadiazole ring occursvia the elimination of the amino group from the amidoxime fragment. 1,2,4-Oxadiazoles bearing the imidazole or pyrimidine moiety were synthesized.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 118–121, January, 1994.     

Synthesis of 3,5-disubstituted 1,2,4-oxadiazoles as peptidomimetic building blocks

Twelve new 1,2,4-oxadiazole based compounds have been synthesized. Their structures contain a protected amine and a carboxyl or an ester group, and thus serve as potential peptidomimetic building blocks. The synthetic route is simple and mild conditions are used so that the chirality of the starting amino acids is retained.     

Syntheses and degradations of fluorinated heterocyclics. IV. Imidoylamidoximes, 1,2,4-oxadiazole precursors

Perfluoroalkylether amidoximes free from amide-contamination were prepared from imidate esters. The amidoximes were stable at 110°C; at ～170°C partial decomposition to 1,2,4-oxadiazoles, admixed with other compounds, took place. Interactions between nitriles and amidoximes at 50°C resulted in the formation of imidoylamidoximes; these dissociated readily into their constituents when subjected to higher temperatures. At 70°C and above, in the presence of excess nitrile or other ammonia acceptors, the imidoylamidoximes afforded high yields of the corresponding 1,2,4- oxadiazoles.     

Synthesis of 5-substituted-3-[(2′S,3′S)-3′-hydroxy-2′-hydroxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazoles and their epimers

5-Phenyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10a and its epimer 11a, 5-methyl-3-[(2′R,3′S)-3′-hydroxy-2′-dimethoxymethyltetrahydrofuran-3′-yl]-1,2,4-oxadiazole 10b and its epimer 11b were synthesized from cyanohydrin benzoates 8a, 9a and cyanohydrin acetates 8b, 9b, respectively, by treatment with hydroxylamine in methanol via intramolecular transacylation and subsequent cyclization of the corresponding amidoximes. Hydrolysis and reduction of the dimethoxymethyl groups in the above compounds gave the desired compounds 12a, 13a, 12b and 13b.     

Mononuclear isoheterocyclic rearrangements. Note I. Interconversion of 3-benzoylamino-5-methyl-1,2,4-oxadiazole and 3-acetylamino-5-phenyl-1,2,4-oxadiazole

The first example of mononuclear isoheterocyclic rearrangement is reported. The 3-benzoylamino-5-methyl-1,2,4-oxadiazole ( 5 ) furnishes through a reversible process (slowly at room temperature in methanol, acetone or dioxane, fast in DMSO or in methanol in the presence of strong bases) a mixture of 5 and 3-acethylamino-5-phenyl-1,2,4-oxadiazole ( 6 ). The equilibrium process can be achieved also by heating 5 at 181° and the same reaction mixture can be obtained using 6 as the starting material. 3-Trichloroacetylamino-5-methyl-1,2,4-oxadiazole ( 7 ) was unaffected by similar treatment. The results obtained are discussed.     

Stereoselective preparation of 1,2,4-oxadiazole derivatives substituted by pentafluorophenyl by 1,3-dipolar cycloaddition reaction

1,3-Dipolar cycloaddition reactions of chiral imines obtained from optically active amino acids with nitrile oxides afforded 1,2,4-oxadiazole derivatives in moderate to good yields with good stereoselectivity. Investigation on the effect of bases suggested that triethylamine was prone to afford better stereoselectivity, while NaHCO₃ was prone to increase the reaction rates and yields.     

Absorption and luminescence spectra of 5-aryl-3-methyl-1,2,4-oxadiazoles and their chelate complexes with Zinc(II) and copper(II)

5-(2-Hydroxyphenyl)-3-methyl-1,2,4-oxadiazole and its O-methyl and O-acyl derivatives, as well as zinc(II) and copper(II) chelates, were synthesized. All these compounds showed luminescence with the emission maxima ranging from λ = 332 to 490 nm, but only 5-(2-methoxyphenyl)- and 5-(2-acetoxyphenyl)-3-methyl-1,2,4-oxadiazoles and zinc(II) complex of 5-(2-hydroxyphenyl)-3-methyl-1,2,4-oxadiazole were characterized by high luminescence quantum yield (φ = 0.308–0.452, 0.089–0.153, and 0.115–0.334, respectively). Stable conformers of 5-(2-hydroxyphenyl)-3-methyl-1,2,4-oxadiazole with different structures of the coordination entity were identified by DFT quantum chemical calculations.     

Structural modification studies of 3-piperonylsydnone. III. Some analogs of 3-piperonylsydnone and 2,4-diamino-5-piperonylpyrimidine

In a continued structural modification study of the antimalarial compounds 3-piperonylsydnone and 2,4-diamino-5-piperonylpyrimidine, the related piperonyl derivatives of ψ-1,2,3;4-oxatriazole, ψ-1,3,5-oxadiazole, pyrazole, tetrazole, 1,2,4-triazine, pyrrolidine, amino- and sulfamoyl-1,2,4-triazole, as well as some sydnones and diaminopyrimidines with side chains other than the piperonyl group have been synthesized. 3-(3,4-Ethylenedioxyphenyl)sydnone was found to double the survival time of Plasmodium berghei infected mice. The other compounds are not as active.     

A facile synthesis of 3‐Substituted 5‐Oxo‐1,2,4‐thiadiazoles from amidoximes

The reaction of amidoximes 1 with 1,1′‐thiocarbonyldiimidazole (TCDI) followed by treatment with silica gel or boron trifluoride diethyl etherate (BF₃·OEt₂) provided 3‐substituted 4,5‐dihydro‐5‐oxo‐1,2,4‐thiadiazoles 2 in moderate yields. The Lewis acids are considered to promote the rearrangement of the thioxocarbamate intermediates 5 to the thiol carbarn ate intermediates 7 , which cyclize to afford 4,5‐dihydro‐5‐oxo‐1,2,4‐thiadiazoles 2 .     

Mass spectrometry of heterocyclic compounds. V—Substituent effects on the fragmentation pathways of 3,5-diphenyl-1,2,4-oxadiazole derivatives

The 70 eV mass spectra of a number of derivatives of 3,5-diphenul-1,2,4-oxadiazole substituted either in the 5-phenyl (fifteen) or in the 3-phenyl (four) position, have been studied using exact mass measurements and metastable determinations by the defocusing technique. The substituent effects on the heterocyclic cleavage are not very important for electron-withdrawing and weak electron-donating groups. The main cleavage is the formal retro 1,3-dipolar cycloaddition with the positive charge retained by the C₇H₅NO (orYC₇H₄NO in the case of the 3-substituted derivatives) fragment specifically containing the 3-phenyl, as oreviously observed for 3,5-diphenyl-1,2,4-oxadiazole using labelling experiments. Two other minor primary processes leading to benzoyl and nitrile ions, both containing the 5-phenyl, become important in the case of the electron-donating substituted compounds. Correlation of the abundance of these fragmednts and of the molecular ions with σ⁺ (para) Brown constants is discussed. Proximity effets are shown by some ortho derivatives.